MEDU-05. THE ROLE OF GABA METABOLISM IN MEDULLOBLASTOMA

PubMed Central

Martirosian, Vahan; Deshpande, Krutika; Shackelford, Gregory; Julian, Alex; Lin, Michelle; Erdreich-Epstein, Anat; Chen, Thomas; Neman, Josh

2017-01-01

Abstract BACKGROUND: Brain tumors are the most common cause of childhood oncological death, and medulloblastoma (originating in the cerebellum) is the most common malignant pediatric brain tumor. In the microenvironment of the brain, especially the cerebellum, variables related to GABA, the major inhibitory neurotransmitter in the nervous system, are particularly prominent. Abnormal GABAergic Receptor activation has been described in in aggressive MYC-driven Group 3 medulloblastoma. However these studies did not look at the metabolic contribution of GABA for the development of medulloblastomas. In addition to its role in neurotransmission through GABA receptor, GABA can act as a trophic factor during nervous system development to influence cellular events including proliferation, migration, differentiation, synapse maturation, and cell death. Under conditions that inhibit the tricarboxylic acid cycle (TCA), impair respiration, and enhance the accumulation of reactive oxygen intermediates, GABA can be used as an NADH energy source for growth through the GABA-shunt pathway regulators (ABAT, SSADH, GAT-1, GAT-3). Therefore, we hypothesize that blocking GABA-metabolic-shunt will lead to growth suppression and invasiveness of medulloblastoma in the cerebellar GABA-rich microenvironment. RESULTS: Our results show RNA microarray from patient medulloblastoma tissue have high expression of GABA-shunt regulators with ~3-fold increase in the expression of ABAT in MYC amplified versus non-amplified MYC tumors. When medulloblastomas were supplemented with GABA, there was a significant fold change in expression of GABA-shunt mediators and induction of large and stable tumor spheres with Epithelial-Mesenchymal Transition gene expression signature. We next investigated whether a novel perrilyl alcohol-based small molecule NEO216 targeted the GABA-shunt metabolic pathway. NEO216 administration significantly reduced GABA-mediated NADH levels, reversed EMT-profiling, leading to loss of sphere formation. CONCLUSION: Thus, the expression of GABA-metabolic shunt in medulloblastoma could be a malignant microenvironmental adaptation for growth and metastasis that could potentially be exploited through targeted therapy for patients benefit.

Engineering the intracellular metabolism of Escherichia coli to produce gamma-aminobutyric acid by co-localization of GABA shunt enzymes.

PubMed

Pham, Van Dung; Somasundaram, Sivachandiran; Lee, Seung Hwan; Park, Si Jae; Hong, Soon Ho

2016-02-01

To direct the carbon flux from Krebs cycle into the gamma-aminobutyric acid (GABA) shunt pathway for the production of GABA by protein scaffold introduction in Escherichia coli. Escherichia coli was engineered to produce GABA from glucose by the co-localization of enzymes succinate semialdehyde dehydrogenase (GadD), GABA aminotransferase (PuuE) and GABA transporter (GadC) by protein scaffold. 0.7 g GABA l(-1) was produced from 10 g glucose l(-1) while no GABA was produced in wild type E. coli. pH 6 and 30 °C were optimum for GABA production, and GABA concentration increased to 1.12 g GABA l(-1) when 20 g glucose l(-1) was used. When competing metabolic networks were inactivated, GABA increased by 24 % (0.87 g GABA l(-1)). The novel GABA production system was constructed by co-localization of GABA shunt enzymes.

Exogenous γ-aminobutyric acid treatment affects citrate and amino acid accumulation to improve fruit quality and storage performance of postharvest citrus fruit.

PubMed

Sheng, Ling; Shen, Dandan; Luo, Yi; Sun, Xiaohua; Wang, Jinqiu; Luo, Tao; Zeng, Yunliu; Xu, Juan; Deng, Xiuxin; Cheng, Yunjiang

2017-02-01

The loss of organic acids during postharvest storage is one of the major factors that reduces the fruit quality and economic value of citrus. Citrate is the most important organic acid in citrus fruits. Molecular evidence has proved that γ-aminobutyric acid (GABA) shunt plays a key role in citrate metabolism. Here, we investigated the effects of exogenous GABA treatment on citrate metabolism and storage quality of postharvest citrus fruit. The content of citrate was significantly increased, which was primarily attributed to the inhibition of the expression of glutamate decarboxylase (GAD). Amino acids, including glutamate, alanine, serine, aspartate and proline, were also increased. Moreover, GABA treatment decreased the fruit rot rate. The activities of antioxidant enzymes and the content of energy source ATP were affected by the treatment. Our results indicate that GABA treatment is a very effective approach for postharvest quality maintenance and improvement of storage performance in citrus production. Copyright © 2016 Elsevier Ltd. All rights reserved.

Early life stress is a risk factor for excessive alcohol drinking and impulsivity in adults and is mediated via a CRF/GABA(A) mechanism.

PubMed

Gondré-Lewis, Marjorie C; Warnock, Kaitlin T; Wang, Hong; June, Harry L; Bell, Kimberly A; Rabe, Holger; Tiruveedhula, Veera Venkata Naga Phani Babu; Cook, James; Lüddens, Hartmut; Aurelian, Laure; June, Harry L

2016-01-01

Childhood stress and trauma are associated with substance use disorders in adulthood, but the neurological changes that confer increased vulnerability are largely unknown. In this study, maternal separation (MS) stress, restricted to the pre-weaning period, was used as a model to study mechanisms of protracted effects of childhood stress/traumatic experiences on binge drinking and impulsivity. Using an operant self-administration model of binge drinking and a delay discounting assay to measure impulsive-like behavior, we report that early life stress due to MS facilitated acquisition of binge drinking and impulsivity during adulthood in rats. Previous studies have shown heightened levels of corticotropin releasing factor (CRF) after MS, and here, we add that MS increased expression levels of GABA(A) α2 subunit in central stress circuits. To investigate the precise role of these circuits in regulating impulsivity and binge drinking, the CRF1 receptor antagonist antalarmin and the novel GABA(A) α2 subunit ligand 3-PBC were infused into the central amygdala (CeA) and medial prefrontal cortex (mPFC). Antalarmin and 3-PBC at each site markedly reduced impulsivity and produced profound reductions on binge-motivated alcohol drinking, without altering responding for sucrose. Furthermore, whole-cell patch-clamp studies showed that low concentrations of 3-PBC directly reversed the effect of relatively high concentrations of ethanol on α2β3γ2 GABA(A) receptors, by a benzodiazepine site-independent mechanism. Together, our data provide strong evidence that maternal separation, i.e. early life stress, is a risk factor for binge drinking, and is linked to impulsivity, another key risk factor for excessive alcohol drinking. We further show that pharmacological manipulation of CRF and GABA receptor signaling is effective to reverse binge drinking and impulsive-like behavior in MS rats. These results provide novel insights into the role of the brain stress systems in the development of impulsivity and excessive alcohol consumption.

[Dynamic changes of 'substantianigra-ventralislateralis-cortex' pathway neural activity coherence and neurotransmitters in rat during exhausting exercise].

PubMed

Hu, Yan-Ru; Liu, Xiao-Li; Qiao, De-Cai

2017-03-08

To reveal the possible mechanism of changes of 'substantianigra-ventralislateralis-cortex' pathway neural activity during one bout of exhausting exercise through observing the neural activity coherence between different nucleus and the concentration of extra-cellular glutamate (Glu) and gamma-aminobutyric acid (GABA). Male Wistar rats were randomly divided into neural activity real-time observation group, substantianigra (SNr) extracellular neurotransmitters observation group, ventralislateralis (VL) extracellular neuro-transmitters observation group and supplementary motor area (SMA) extracellular neurotransmitters observation group, 10 rats in each group. For rats of neural activity real-time observation group, by using LFPs and ECoG recording technique, and self-comparison, we simultaneously recorded the dynamic changes of neural activity of rat SNr, VL and SMA during one bout of exhausting exercise. The dynamic changes of ex-tracellular Glu and GABA in rat SNr, VL and SMA were also observed through microdialysis combined high performance liquid chromatography (HPLC) technique and self-comparison method. Based on the behavioral performance, the exhausting exercise process could be di-vided into 5 different stages, the rest condition, auto exercise period, early fatigue period, exhaustion condition and recovery period. The elec-trophysiological study results showed that, the coherence between neural activity in rat SNr, VL and SMA was significant between 0~30 Hz during all the procedure of exhausting exercise. Compared with the rest condition, the microdialysis study showed that the Glu concentrations and Glu/GABA ratio in SNr were decreased significantly during automatic exercise period ( P < 0.05, P < 0.01), the GABA concentrations were increased significantly ( P < 0.05, P < 0.01), while, in VL and cortex, the Glu concentrations and Glu/GABA ratio were increased significantly ( P < 0.05, P < 0.01), the GABA concentrations were decreased significantly ( P < 0.05, P < 0.01). Under early fatigue and ex-haustion conditions, compared with the rest condition,the Glu concentrations and Glu/GABA ratio in SNr were increased significantly ( P < 0.05, P < 0.01), the GABA concentrations were decreased significantly ( P < 0.05, P < 0.01), while the Glu concentrations and Glu/GABA ratio in VL and cortex were decreased significantly ( P < 0.05, P < 0.01), the GABA concentrations were increased significantly ( P < 0.05, P < 0.01). The neural net work communication between 'substantianigra-ventralislateralis-cortex' pathway exists, changes of Glu and GABA in the nucelus of the pathway are one of the factors resulting in the changes of neural activity.

Enhancement of GABA release through endogenous activation of axonal GABA(A) receptors in juvenile cerebellum.

PubMed

Trigo, Federico F; Chat, Mireille; Marty, Alain

2007-11-14

Recent evidence indicates the presence of presynaptic GABA(A) receptors (GABA(A)Rs) in the axon domain of several classes of central neurons, including cerebellar basket and stellate cells. Here, we investigate the possibility that these receptors could be activated in the absence of electrical or chemical stimulation. We find that low concentrations of GABA increase the frequency of miniature GABAergic synaptic currents. Submaximal concentrations of a GABA(A)R blocker, gabazine, decrease both the miniature current frequency and the probability of evoked GABA release. Zolpidem, an agonist of the benzodiazepine binding site, and NO-711 (1-[2-[[(diphenylmethylene)imino]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride), a blocker of GABA uptake, both increase the frequency of miniature currents. These effects occur up to postnatal day 14, but not later. Immunohistochemistry indicates the presence of alpha1-containing GABA(A)Rs in interneuron presynaptic terminals with a similar age dependence. We conclude that, under resting conditions, axonal GABA(A)Rs are significantly activated, that this activation results in enhanced GABA release, and that it can be augmented by increasing the affinity of GABA(A)Rs or reducing GABA uptake. Our findings suggest the existence of a positive-feedback mechanism involving presynaptic GABA(A)Rs that maintains a high release rate and a high local GABA concentration in the immature cerebellar network.

Impact of Precooling and Controlled-Atmosphere Storage on γ-Aminobutyric Acid (GABA) Accumulation in Longan (Dimocarpus longan Lour.) Fruit.

PubMed

Zhou, Molin; Ndeurumio, Kessy H; Zhao, Lei; Hu, Zhuoyan

2016-08-24

Longan (Dimocarpus longan Lour.) fruit cultivars 'Chuliang' and 'Shixia' were analyzed for γ-aminobutyric acid (GABA) accumulation after precooling and in controlled-atmosphere storage. Fruit were exposed to 5% O2 plus 3%, 5%, or 10% CO2 at 4 °C, and GABA and associated enzymes, aril firmness, and pericarp color were measured. Aril softening and pericarp browning were delayed by 5% CO2 + 5% O2. GABA concentrations and glutamate decarboxylase (GAD; EC 4.1.1.15) activities declined during storage at the higher-CO2 treatments. However, GABA aminotransferase (GABA-T; EC 2.6.1.19) activities in elevated CO2-treated fruit fluctuated during storage. GABA concentrations increased after precooling treatments. GAD activity and GABA-T activity were different between cultivars after precooling. GABA concentrations in fruit increased after 3 days of 10% CO2 + 5% O2 treatment and then declined as storage time increased. GABA accumulation was associated with stimulation of GAD activity rather than inhibition of GABA-T activity.

[The effect of multiple administrations of GABA and bicuculline into the rat neostriatum on the realization of a food-acquisition habit].

PubMed

Iakimovskiĭ, A F

1996-01-01

The effects of three-week daily intrastriatal GABA (45 mcg) and bicucullin (5 mcg) microinjections on operant performance in the Skinner's box were studied in rats. GABA was shown to facilitate the operant responses (the rate of lever pressings increased, spontaneous motor activity became optimized). Bicucullin produced the opposite effects, i.e., the operant skill practically disappeared at the second-third week of injections. The operant behaviour was substantially influences by such factors as neurosurgery trauma, narcosis, and injections as demonstrated in control experiments. The findings suggest the involvement of GABAergic neostriatal system in realization of conditioned motor alimentary behaviour.

High Gama-Aminobutyric Acid Contents Involved in Abamectin Resistance and Predation, an Interesting Phenomenon in Spider Mites

PubMed Central

Xu, Zhifeng; Liu, Yanchao; Wei, Peng; Feng, Kaiyang; Niu, Jinzhi; Shen, Guangmao; Lu, Wencai; Xiao, Wei; Wang, Jinjun; Smagghe, Guy J.; Xu, Qiang; He, Lin

2017-01-01

Abamectin has been widely used as an insecticide/acaricide for more than 30 years because of its superior bioactivity. Recently, an interesting phenomenon was identified in the carmine spider mite, Tetranychus cinnabarinus, an important pest in agriculture. The gamma aminobutyric acid (GABA) contents in a laboratory abamectin resistant strain of T. cinnabarinus (AbR) were significantly increased. Decreases in activity and mRNA expression of GABA transaminase (GABA-T) were responsible for GABA accumulation in AbR mites. To clarify the mechanism of GABA accumulation mediated abamectin resistance, three artificial approaches were conducted to increase GABA contents in susceptible mites, including feeding of vigabatrin (a specific inhibitor of GABA-T), feeding of exogenous GABA, and inhibition of GABA-T gene expression. The results showed that susceptible mites developed resistance to abamectin when the GABA contents were artificially increased. We also observed that the mites with higher GABA contents moved more slowly, which is consistent with the fact that GABA is an inhibitory neurotransmitter in arthropods. Subsequently, functional response assays revealed that predation rates of predatory mites on GABA accumulated abamectin-resistant mites were much higher than control groups. The tolerance to abamectin, slow crawling speed, and vulnerability to predators were all resulted from GABA accumulation. This relationship between GABA and predation was also confirmed in a field-collected population. Our finding indicates that predatory mites might be used as a tool for biological control to circumvent the development of abamectin resistance in mites. PMID:28443033

High Gama-Aminobutyric Acid Contents Involved in Abamectin Resistance and Predation, an Interesting Phenomenon in Spider Mites.

PubMed

Xu, Zhifeng; Liu, Yanchao; Wei, Peng; Feng, Kaiyang; Niu, Jinzhi; Shen, Guangmao; Lu, Wencai; Xiao, Wei; Wang, Jinjun; Smagghe, Guy J; Xu, Qiang; He, Lin

2017-01-01

Abamectin has been widely used as an insecticide/acaricide for more than 30 years because of its superior bioactivity. Recently, an interesting phenomenon was identified in the carmine spider mite, Tetranychus cinnabarinus , an important pest in agriculture. The gamma aminobutyric acid (GABA) contents in a laboratory abamectin resistant strain of T. cinnabarinus (AbR) were significantly increased. Decreases in activity and mRNA expression of GABA transaminase (GABA-T) were responsible for GABA accumulation in AbR mites. To clarify the mechanism of GABA accumulation mediated abamectin resistance, three artificial approaches were conducted to increase GABA contents in susceptible mites, including feeding of vigabatrin (a specific inhibitor of GABA-T), feeding of exogenous GABA, and inhibition of GABA-T gene expression. The results showed that susceptible mites developed resistance to abamectin when the GABA contents were artificially increased. We also observed that the mites with higher GABA contents moved more slowly, which is consistent with the fact that GABA is an inhibitory neurotransmitter in arthropods. Subsequently, functional response assays revealed that predation rates of predatory mites on GABA accumulated abamectin-resistant mites were much higher than control groups. The tolerance to abamectin, slow crawling speed, and vulnerability to predators were all resulted from GABA accumulation. This relationship between GABA and predation was also confirmed in a field-collected population. Our finding indicates that predatory mites might be used as a tool for biological control to circumvent the development of abamectin resistance in mites.

Imbalance between Glutamate and GABA in Fmr1 Knockout Astrocytes Influences Neuronal Development

PubMed Central

Wang, Lu; Wang, Yan; Zhou, Shimeng; Yang, Liukun; Shi, Qixin; Li, Yujiao; Zhang, Kun; Yang, Le; Zhao, Minggao; Yang, Qi

2016-01-01

Fragile X syndrome (FXS) is a form of inherited mental retardation that results from the absence of the fragile X mental retardation protein (FMRP), the product of the Fmr1 gene. Numerous studies have shown that FMRP expression in astrocytes is important in the development of FXS. Although astrocytes affect neuronal dendrite development in Fmr1 knockout (KO) mice, the factors released by astrocytes are still unclear. We cultured wild type (WT) cortical neurons in astrocyte-conditioned medium (ACM) from WT or Fmr1 KO mice. Immunocytochemistry and Western blotting were performed to detect the dendritic growth of both WT and KO neurons. We determined glutamate and γ-aminobutyric acid (GABA) levels using high-performance liquid chromatography (HPLC). The total neuronal dendritic length was reduced when cultured in the Fmr1 KO ACM. This neurotoxicity was triggered by an imbalanced release of glutamate and GABA from Fmr1 KO astrocytes. We found increased glutaminase and GABA transaminase (GABA-T) expression and decreased monoamine oxidase B expression in Fmr1 KO astrocytes. The elevated levels of glutamate contributed to oxidative stress in the cultured neurons. Vigabatrin (VGB), a GABA-T inhibitor, reversed the changes caused by glutamate and GABA release in Fmr1 KO astrocytes and the abnormal behaviors in Fmr1 KO mice. Our results indicate that the imbalance in the astrocytic glutamate and GABA release may be involved in the neuropathology and the underlying symptoms of FXS, and provides a therapeutic target for treatment. PMID:27517961

Exposure to repeated immobilization stress inhibits cocaine-induced increase in dopamine extracellular levels in the rat ventral tegmental area.

PubMed

Sotomayor-Zárate, Ramón; Abarca, Jorge; Araya, Katherine A; Renard, Georgina M; Andrés, María E; Gysling, Katia

2015-11-01

A higher vulnerability to drug abuse has been observed in human studies of individuals exposed to chronic or persistent stress, as well as in animal models of drug abuse. Here, we explored the effect of repeated immobilization stress on cocaine-induced increase in dopamine extracellular levels in VTA and its regulation by corticotropin-releasing factor (CRF) and GABA systems. Cocaine (10mg/Kg i.p.) induced an increase of VTA DA extracellular levels in control rats. However, this effect was not observed in repeated stress rats. Considering the evidence relating stress with CRF, we decided to perfuse CRF and CP-154526 (selective antagonist of CRF1 receptor) in the VTA of control and repeated stress rats, respectively. We observed that perfusion of 20μM CRF inhibited the increase of VTA DA extracellular levels induced by cocaine in control rats. Interestingly, we observed that in the presence of 10μM CP-154526, cocaine induced a significant increase of VTA DA extracellular levels in repeated stress rats. Regarding the role of VTA GABA neurotransmission, cocaine administration induced a significant increase in VTA GABA extracellular levels only in repeated stress rats. Consistently, cocaine was able to increase VTA DA extracellular levels in repeated stress rats when 100μM bicuculline, an antagonist of GABAA receptor, was perfused intra VTA. Thus, both CRF and GABA systems are involved in the lack of response to cocaine in the VTA of repeated stress rats. It is tempting to suggest that the loss of response in VTA dopaminergic neurons to cocaine, after repeated stress, is due to an interaction between CRF and GABA systems. Copyright © 2015 Elsevier Ltd. All rights reserved.

Ameliorative effect of synthetic γ-aminobutyric acid (GABA) on performance traits, antioxidant status and immune response in broiler exposed to cyclic heat stress.

PubMed

Chand, Naila; Muhammad, Sher; Khan, Rifat Ullah; Alhidary, Ibrahim Abdullah; Rehman, Zia Ur

2016-12-01

The aim of this study was to find the effect of synthetic γ-aminobutyric acid (GABA) on the performance, antioxidant status, and immune response in broiler exposed to summer stress. A total of 400-day-old male broiler chickens (Ross 308) was randomly distributed into five treatments (5 replicates). One group served as a control (basal diet only) while the others were supplemented with GABA at the rate of 25 (GABA-25), 50 (GABA 50), 75 (GABA-75), and 100 (GABA-100) mg/kg feed. The experiment was continued for 35 days. Feed intake during the third week was significantly higher (P < 0.05) in GABA-75 and GABA-100, however, it increased significantly (P < 0.05) in GABA-100 during the fourth and fifth week. Overall mean feed intake was significantly (P < 0.05) high in GABA-75 and GABA-100. From the results, we found that body weight improved significantly (P < 0.05) in GABA-50 in week-3. During the fourth, fifth, and overall, body weight increased significantly (P < 0.05) in GABA-100. Significantly, high (P < 0.05) feed conversion ratio (FCR) was found in GABA-100 during the third, fourth, fifth, and on an overall basis. Mean Malondialdehyde (MDA) decreased significantly (P < 0.05) in GABA-100 while Paraoxonase (PON1) and Newcastle disease (ND) titer increased significantly (P < 0.05) in the same group. We concluded that performance traits, antioxidant status, and immune response improved in broiler supplemented 100 mg/kg GABA, exposed to cyclic heat stress.

Development of tolerance to the effects of vigabatrin (gamma-vinyl-GABA) on GABA release from rat cerebral cortex, spinal cord and retina.

PubMed Central

Neal, M. J.; Shah, M. A.

1990-01-01

1. The effects of acute and chronic vigabatrin (gamma-vinyl-GABA) (GVG) administration on gamma-aminobutyric acid (GABA) levels and release in rat cortical slices, spinal cord slices and retinas were studied. 2. GVG (250 mgkg-1 i.p.) administered to rats 18 h before death (acute administration) produced an almost 3 fold increase in GABA levels of the cortex and spinal cord and a 6 fold increase in retinal GABA. The levels of glutamate, aspartate, glycine and taurine were unaffected. 3. When GVG (250 mgkg-1 i.p.) was administered daily for 17 days (chronic administration) a similar (almost 3 fold) increase in cortical GABA occurred but the increases in spinal and retinal GABA were reduced by approximately 40%. 4. Acute administration of GVG strikingly increased the potassium-evoked release (KCl 50 mM) of GABA from all three tissues. This enhanced evoked release was reduced by about 50% in tissues taken from rats that had been chronically treated with GVG. 5. Acute administration of GVG reduced GABA-transaminase (GABA-T) activity by approximately 80% in cortex and cord and by 98% in the retina. Following the chronic administration of GVG, there was a trend for GABA-T activities to recover (significant only in cortex). Acute administration of GVG had no effect on glutamic acid decarboxylase (GAD) activity in cortex or spinal cord. However, chronic treatment resulted in significant decreases in GAD activity in both the cortex and cord (35% and 50% reduction respectively).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2379037

Alleviation in the rat of a GABA-induced reduction in food intake and growth.

PubMed

Tews, J K; Repa, J J; Harper, A E

1984-07-01

Cold exposure and diet dilution which stimulate food intake of normal rats lessened depressions of food intake and growth induced by dietary GABA. During a 3-day adaptation to the cold, rats fed a diet containing 4.5% GABA lost weight; thereafter, food intake and growth rate differed little from those of cold control rats and were usually greater than those of normal rats fed GABA. Hepatic GABA-aminotransferase activity of cold-exposed rats fed the GABA diet increased to about twice that of normal control rats. Rats fed a control diet diluted by half with cellulose ate 50% more of this diet than of the undiluted diet but gained only 20% less weight. Rats ate twice as much of a diluted, 9% GABA diet as of an undiluted, 4.5% GABA diet (thus doubling their GABA intake) and gained three times as much weight. A novel food (condensed milk) barely lessened the adverse responses to GABA. These results show that conditions requiring rats to increase their food intake in order to maintain body weight can also increase their acceptance of a diet high in GABA.

Disruption of the GABA shunt affects mitochondrial respiration and virulence in the cereal pathogen Fusarium graminearum.

PubMed

Bönnighausen, Jakob; Gebhard, Daniel; Kröger, Cathrin; Hadeler, Birgit; Tumforde, Thomas; Lieberei, Reinhard; Bergemann, Jörg; Schäfer, Wilhelm; Bormann, Jörg

2015-12-01

The cereal pathogen Fusarium graminearum threatens food and feed production worldwide. It reduces the yield and poisons the remaining kernels with mycotoxins, notably deoxynivalenol (DON). We analyzed the importance of gamma-aminobutanoic acid (GABA) metabolism for the life cycle of this fungal pathogen. GABA metabolism in F. graminearum is partially regulated by the global nitrogen regulator AreA. Genetic disruption of the GABA shunt by deletion of two GABA transaminases renders the pathogen unable to utilize the plant stress metabolites GABA and putrescine. The mutants showed increased sensitivity against oxidative stress, GABA accumulation in the mycelium, downregulation of two key enzymes of the TCA cycle, disturbed potential gradient in the mitochondrial membrane and lower mitochondrial oxygen consumption. In contrast, addition of GABA to the wild type resulted in its rapid turnover and increased mitochondrial steady state oxygen consumption. GABA concentrations are highly upregulated in infected wheat tissues. We conclude that GABA is metabolized by the pathogen during infection increasing its energy production, whereas the mutants accumulate GABA intracellularly resulting in decreased energy production. Consequently, the GABA mutants are strongly reduced in virulence but, because of their DON production, are able to cross the rachis node. © 2015 John Wiley & Sons Ltd.

Oral administration of γ-aminobutyric acid and γ-oryzanol prevents stress-induced hypoadiponectinemia.

PubMed

Ohara, Kazuyuki; Kiyotani, Yuka; Uchida, Asako; Nagasaka, Reiko; Maehara, Hiroyuki; Kanemoto, Shigeharu; Hori, Masatoshi; Ushio, Hideki

2011-06-15

Metabolic syndrome is a cluster of risk factors including insulin resistance and type 2 diabetes and is found to associate partly with chronic stress at work in human. Adiponectin circulates in mammal blood mainly as a low molecular weight (LMW) trimer, hexamer, and a high molecular weight (HMW) multimers. Low circulating levels of adiponectin are related to metabolic syndrome. We have then investigated the influence of immobilization stress on plasma adiponectin concentrations in mice. Relative LMW and HMW adiponectin levels were markedly reduced by immobilization stress (0.66±0.07 and 0.59±0.06 after 102 h, respectively), significantly different from the control values (p<0.01 and 0.05, respectively). γ-Aminobutyric acid (GABA) and γ-oryzanol abundantly contained in germinated brown rice have some physiological functions. We further investigated the effect of GABA, γ-oryzanol, GABA plus γ-oryzanol on adiponectin levels in mice subjected to immobilization stress. GABA and γ-oryzanol significantly increased the relative LMW and HMW adiponectin levels under immobilization stress (1.10±0.11 and 0.99±0.19 after 102 h, respectively, for GABA; 1.08±0.17 and 1.15±0.17 after 102 h, respectively, for γ-oryzanol). Additionally, the co-administration of GABA and γ-oryzanol also increased both relative LMW and HMW adiponectin levels (1.02±0.07 and 0.99±0.10 after 102 h, respectively) and was effective in an earlier phase from 30 to 54 h. The results indicate that the co-administration of GABA and γ-oryzanol might be effective in preventing stress-induced hypoadiponectinemia in mice and be also a promising tool for improving metabolic syndrome aggravated by chronic stress. Copyright © 2011 Elsevier GmbH. All rights reserved.

Exogenous Application of GABA Improves PEG-Induced Drought Tolerance Positively Associated with GABA-Shunt, Polyamines, and Proline Metabolism in White Clover.

PubMed

Yong, Bin; Xie, Huan; Li, Zhou; Li, Ya-Ping; Zhang, Yan; Nie, Gang; Zhang, Xin-Quan; Ma, Xiao; Huang, Lin-Kai; Yan, Yan-Hong; Peng, Yan

2017-01-01

In order to investigate the physiological effects of exogenous γ-aminobutyric acid (GABA) on drought tolerance in white clover (Trifolium repens), GABA shunt, polyamines (PAs), and proline (Pro) metabolism were examined after plants pretreated with or without GABA (8 mM) and then exposed to water or 15% PEG-induced drought stress in growth chamber. In this study, exogenous application of GABA effectively alleviated drought-induced damage in leaves, as reflected by significantly higher relative water content, lower electrolyte leakage, lipid peroxidation, and leaf wilt. Exogenous GABA further promoted drought-induced increases in GABA transaminase and alpha ketone glutarate dehydrogenase activities, but inhibited glutamate decarboxylase activity under both control and drought conditions, resulting in an increase in endogenous glutamate (Glu) and GABA content. Besides, exogenous GABA could well accelerated PAs synthesis and suppressed PAs catabolism, which lead to the extremely enhanced different types of PAs content (free Put and Spd, insoluble bound Spd and Spm, soluble conjugated Spd and Spm, and total Put, Spd and Spm) under drought stress. In addition, exogenous GABA application further activated drought-induced Δ 1 -pyrroline-5-carboxylate synthetase and proline dehydrogenase activities, but suppressed drought-facilitated ornithine -δ-amino transferase activities, leading to a higher Pro accumulation and metabolism in GABA-pretreated plants in the middle and last period of drought. The results suggested that increased endogenous GABA by exogenous GABA treatment could improve drought tolerance of white clover associated with a positive regulation in the GABA-shunt, PAs and Pro metabolism.

Exogenous Application of GABA Improves PEG-Induced Drought Tolerance Positively Associated with GABA-Shunt, Polyamines, and Proline Metabolism in White Clover

PubMed Central

Yong, Bin; Xie, Huan; Li, Zhou; Li, Ya-Ping; Zhang, Yan; Nie, Gang; Zhang, Xin-Quan; Ma, Xiao; Huang, Lin-Kai; Yan, Yan-Hong; Peng, Yan

2017-01-01

In order to investigate the physiological effects of exogenous γ-aminobutyric acid (GABA) on drought tolerance in white clover (Trifolium repens), GABA shunt, polyamines (PAs), and proline (Pro) metabolism were examined after plants pretreated with or without GABA (8 mM) and then exposed to water or 15% PEG-induced drought stress in growth chamber. In this study, exogenous application of GABA effectively alleviated drought-induced damage in leaves, as reflected by significantly higher relative water content, lower electrolyte leakage, lipid peroxidation, and leaf wilt. Exogenous GABA further promoted drought-induced increases in GABA transaminase and alpha ketone glutarate dehydrogenase activities, but inhibited glutamate decarboxylase activity under both control and drought conditions, resulting in an increase in endogenous glutamate (Glu) and GABA content. Besides, exogenous GABA could well accelerated PAs synthesis and suppressed PAs catabolism, which lead to the extremely enhanced different types of PAs content (free Put and Spd, insoluble bound Spd and Spm, soluble conjugated Spd and Spm, and total Put, Spd and Spm) under drought stress. In addition, exogenous GABA application further activated drought-induced Δ1-pyrroline-5-carboxylate synthetase and proline dehydrogenase activities, but suppressed drought-facilitated ornithine -δ-amino transferase activities, leading to a higher Pro accumulation and metabolism in GABA-pretreated plants in the middle and last period of drought. The results suggested that increased endogenous GABA by exogenous GABA treatment could improve drought tolerance of white clover associated with a positive regulation in the GABA-shunt, PAs and Pro metabolism. PMID:29312009

Increased GAD67 mRNA levels are correlated with in vivo GABA synthesis in the MPTP-treated catecholamine-depleted goldfish brain.

PubMed

Hibbert, Benjamin; Fung, Irene; McAuley, Rebecca; Larivière, Katherine; MacNeil, Brian; Bafi-Yeboa, Nana; Livesey, John; Trudeau, Vance

2004-09-28

The role of catecholamine neuronal input on GABAergic activity in the hypothalamus, telencephalon, optic tectum, and cerebellum was investigated in early recrudescent female goldfish (Carassius auratus). A new quantitative technique was developed and validated, permitting concomitant quantification and correlational analysis of glutamic acid decarboxylase 65 (GAD65), GAD67, and GAD3 mRNA levels and in vivo GABA synthesis. Catecholamine depletion was achieved by the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 50 microg/g body weight) and dopamine (DA) depletion verified by HPLC. Endogenous GABA levels were increased by intraperitoneal administration of gamma-vinyl GABA (GVG; 300 microg/g body weight), an inhibitor of the GABA catabolic enzyme GABA transaminase. Treatment with MPTP resulted in a greater than twofold increase in GABA synthesis rate in the optic tectum and telencephalon. The increase in GABA synthesis rate was highly correlated with an increase in GAD67, but not GAD65 or GAD3 mRNA levels. These results suggest that catecholaminergic input exerts inhibitory effects on GABA synthesis rates through the modulation of GAD67 in the optic tectum and telencephalon. Together with previously published observations in rodents and primates, it is suggested that catecholaminergic control of GABA synthesis must have evolved more than 200 million years ago, before the emergence of the teleost fishes.

Effect of GABA on oxidative stress in the skeletal muscles and plasma free amino acids in mice fed high-fat diet.

PubMed

Xie, Z X; Xia, S F; Qiao, Y; Shi, Y H; Le, G W

2015-06-01

Increased levels of plasma free amino acids (pFAAs) can disturb the blood glucose levels in patients with obesity, diabetes mellitus and metabolic syndrome (MS) and are associated with enhanced protein oxidation. Oxidation of proteins, especially in the muscles, can promote protein degradation and elevate the levels of pFAAs. Gamma-aminobutyric acid (GABA), a food additive, can reduce high-fat diet (HFD)-induced hyperglycaemia; however, the mechanisms remain unclear. The aim of this study was to evaluate the effects of GABA on protein oxidation and pFAAs changes. One hundred male C57BL/6 mice were randomly divided into five groups that were fed with control diet, HFD and HFD supplied with 0.2%, 0.12% and 0.06% GABA in drinking water for 20 weeks respectively. HFD feeding led to muscular oxidative stress, protein oxidation, pFAA disorders, hyperglycaemia and augmented plasma GABA levels. Treatment with GABA restored normally fasting blood glucose level and dose-dependently inhibited body weight gains, muscular oxidation and protein degradation. While medium and low doses of GABA mitigated HFD-induced pFAA disorders, the high dose of GABA deteriorated the pFAA disorders. Medium dose of GABA increased the levels of GABA, but high dose of GABA reduced the levels of plasma GABA and increased the activity of succinic semialdehyde dehydrogenase in the liver. Therefore, treatment with GABA mitigated HFD-induced hyperglycaemia probably by repairing HFD-induced muscular oxidative stress and pFAA disorders in mice. Our data also suggest that an optimal dose of GABA is crucial for the prevention of excess GABA-related decrease in the levels of pFAA and GABA as well as obesity. Journal of Animal Physiology and Animal Nutrition © 2014 Blackwell Verlag GmbH.

GABA metabolism pathway genes, UGA1 and GAD1, regulate replicative lifespan in Saccharomycescerevisiae

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kamei, Yuka; Tamura, Takayuki; Yoshida, Ryo

2011-04-01

Highlights: {yields}We demonstrate that two genes in the yeast GABA metabolism pathway affect aging. {yields} Deletion of the UGA1 or GAD1 genes extends replicative lifespan. {yields} Addition of GABA to wild-type cultures has no effect on lifespan. {yields} Intracellular GABA levels do not differ in longevity mutants and wild-type cells. {yields} Levels of tricarboxylic acid cycle intermediates positively correlate with lifespan. -- Abstract: Many of the genes involved in aging have been identified in organisms ranging from yeast to human. Our previous study showed that deletion of the UGA3 gene-which encodes a zinc-finger transcription factor necessary for {gamma}-aminobutyric acid (GABA)-dependentmore » induction of the UGA1 (GABA aminotransferase), UGA2 (succinate semialdehyde dehydrogenase), and UGA4 (GABA permease) genes-extends replicative lifespan in the budding yeast Saccharomycescerevisiae. Here, we found that deletion of UGA1 lengthened the lifespan, as did deletion of UGA3; in contrast, strains with UGA2 or UGA4 deletions exhibited no lifespan extension. The {Delta}uga1 strain cannot deaminate GABA to succinate semialdehyde. Deletion of GAD1, which encodes the glutamate decarboxylase that converts glutamate into GABA, also increased lifespan. Therefore, two genes in the GABA metabolism pathway, UGA1 and GAD1, were identified as aging genes. Unexpectedly, intracellular GABA levels in mutant cells (except for {Delta}uga2 cells) did not differ from those in wild-type cells. Addition of GABA to culture media, which induces transcription of the UGA structural genes, had no effect on replicative lifespan of wild-type cells. Multivariate analysis of {sup 1}H nuclear magnetic resonance spectra for the whole-cell metabolite levels demonstrated a separation between long-lived and normal-lived strains. Gas chromatography-mass spectrometry analysis of identified metabolites showed that levels of tricarboxylic acid cycle intermediates positively correlated with lifespan extension. These results strongly suggest reduced activity of the GABA-metabolizing enzymes extends lifespan by shifting carbon metabolism toward respiration, as calorie restriction does.« less

In SilicoModel-driven Assessment of the Effects of Brain-derived Neurotrophic Factor Deficiency on Glutamate and Gamma-Aminobutyric Acid: Implications for Understanding Schizophrenia Pathophysiology.

PubMed

Agrawal, Rimjhim; Kalmady, Sunil Vasu; Venkatasubramanian, Ganesan

2017-05-31

Deficient brain-derived neurotrophic factor (BDNF) is one of the important mechanisms underlying the neuroplasticity abnormalities in schizophrenia. Aberration in BDNF signaling pathways directly or circuitously influences neurotransmitters like glutamate and gamma-aminobutyric acid (GABA). For the first time, this study attempts to construct and simulate the BDNF-neurotransmitter network in order to assess the effects of BDNF deficiency on glutamate and GABA. Using CellDesigner, we modeled BDNF interactions with calcium influx via N-methyl-D-aspartate receptor (NMDAR)- Calmodulin activation; synthesis of GABA via cell cycle regulators protein kinase B, glycogen synthase kinase and β-catenin; transportation of glutamate and GABA. Steady state stability, perturbation time-course simulation and sensitivity analysis were performed in COPASI after assigning the kinetic functions, optimizing the unknown parameters using random search and genetic algorithm. Study observations suggest that increased glutamate in hippocampus, similar to that seen in schizophrenia, could potentially be contributed by indirect pathway originated from BDNF. Deficient BDNF could suppress Glutamate decarboxylase 67-mediated GABA synthesis. Further, deficient BDNF corresponded to impaired transport via vesicular glutamate transporter, thereby further increasing the intracellular glutamate in GABAergic and glutamatergic cells. BDNF also altered calcium dependent neuroplasticity via NMDAR modulation. Sensitivity analysis showed that Calmodulin, cAMP response element-binding protein (CREB) and CREB regulated transcription coactivator-1 played significant role in this network. The study presents in silico quantitative model of biochemical network constituting the key signaling molecules implicated in schizophrenia pathogenesis. It provides mechanistic insights into putative contribution of deficient BNDF towards alterations in neurotransmitters and neuroplasticity that are consistent with current understanding of the disorder.

In Silico Model-driven Assessment of the Effects of Brain-derived Neurotrophic Factor Deficiency on Glutamate and Gamma-Aminobutyric Acid: Implications for Understanding Schizophrenia Pathophysiology

PubMed Central

Agrawal, Rimjhim; Kalmady, Sunil Vasu; Venkatasubramanian, Ganesan

2017-01-01

Objective Deficient brain-derived neurotrophic factor (BDNF) is one of the important mechanisms underlying the neuroplasticity abnormalities in schizophrenia. Aberration in BDNF signaling pathways directly or circuitously influences neurotransmitters like glutamate and gamma-aminobutyric acid (GABA). For the first time, this study attempts to construct and simulate the BDNF-neurotransmitter network in order to assess the effects of BDNF deficiency on glutamate and GABA. Methods Using CellDesigner, we modeled BDNF interactions with calcium influx via N-methyl-D-aspartate receptor (NMDAR)-Calmodulin activation; synthesis of GABA via cell cycle regulators protein kinase B, glycogen synthase kinase and β-catenin; transportation of glutamate and GABA. Steady state stability, perturbation time-course simulation and sensitivity analysis were performed in COPASI after assigning the kinetic functions, optimizing the unknown parameters using random search and genetic algorithm. Results Study observations suggest that increased glutamate in hippocampus, similar to that seen in schizophrenia, could potentially be contributed by indirect pathway originated from BDNF. Deficient BDNF could suppress Glutamate decarboxylase 67-mediated GABA synthesis. Further, deficient BDNF corresponded to impaired transport via vesicular glutamate transporter, thereby further increasing the intracellular glutamate in GABAergic and glutamatergic cells. BDNF also altered calcium dependent neuroplasticity via NMDAR modulation. Sensitivity analysis showed that Calmodulin, cAMP response element-binding protein (CREB) and CREB regulated transcription coactivator-1 played significant role in this network. Conclusion The study presents in silico quantitative model of biochemical network constituting the key signaling molecules implicated in schizophrenia pathogenesis. It provides mechanistic insights into putative contribution of deficient BNDF towards alterations in neurotransmitters and neuroplasticity that are consistent with current understanding of the disorder. PMID:28449558

Activating glutamate decarboxylase activity by removing the autoinhibitory domain leads to hyper γ-aminobutyric acid (GABA) accumulation in tomato fruit.

PubMed

Takayama, Mariko; Matsukura, Chiaki; Ariizumi, Tohru; Ezura, Hiroshi

2017-01-01

The C-terminal extension region of SlGAD3 is likely involved in autoinhibition, and removing this domain increases GABA levels in tomato fruits. γ-Aminobutyric acid (GABA) is a ubiquitous non-protein amino acid with several health-promoting benefits. In many plants including tomato, GABA is synthesized via decarboxylation of glutamate in a reaction catalyzed by glutamate decarboxylase (GAD), which generally contains a C-terminal autoinhibitory domain. We previously generated transgenic tomato plants in which tomato GAD3 (SlGAD3) was expressed using the 35S promoter/NOS terminator expression cassette (35S-SlGAD3-NOS), yielding a four- to fivefold increase in GABA levels in red-ripe fruits compared to the control. In this study, to further increase GABA accumulation in tomato fruits, we expressed SlGAD3 with (SlGAD3 OX ) or without (SlGAD3ΔC OX ) a putative autoinhibitory domain in tomato using the fruit ripening-specific E8 promoter and the Arabidopsis heat shock protein 18.2 (HSP) terminator. Although the GABA levels in SlGAD3 OX fruits were equivalent to those in 35S-SlGAD3-NOS fruits, GABA levels in SlGAD3ΔC OX fruits increased by 11- to 18-fold compared to control plants, indicating that removing the autoinhibitory domain increases GABA biosynthesis activity. Furthermore, the increased GABA levels were accompanied by a drastic reduction in glutamate and aspartate levels, indicating that enhanced GABA biosynthesis affects amino acid metabolism in ripe-fruits. Moreover, SlGAD3ΔC OX fruits exhibited an orange-ripe phenotype, which was associated with reduced levels of both carotenoid and mRNA transcripts of ethylene-responsive carotenogenic genes, suggesting that over activation of GAD influences ethylene sensitivity. Our strategy utilizing the E8 promoter and HSP terminator expression cassette, together with SlGAD3 C-terminal deletion, would facilitate the production of tomato fruits with increased GABA levels.

The effects of volatile anesthetics on the extracellular accumulation of [(3)H]GABA in rat brain cortical slices.

PubMed

Diniz, Paulo H C; Guatimosim, Cristina; Binda, Nancy S; Costa, Flávia L P; Gomez, Marcus V; Gomez, Renato S

2014-01-01

GABA is an inhibitory neurotransmitter that appears to be associated with the action of volatile anesthetics. These anesthetics potentiate GABA-induced postsynaptic currents by synaptic GABAA receptors, although recent evidence suggests that these agents also significantly affect extrasynaptic GABA receptors. However, the effect of volatile anesthetics on the extracellular concentration of GABA in the central nervous system has not been fully established. In the present study, rat brain cortical slices loaded with [(3)H]GABA were used to investigate the effect of halothane and sevoflurane on the extracellular accumulation of this neurotransmitter. The accumulation of [(3)H]GABA was significantly increased by sevoflurane (0.058, 0.11, 0.23, 0.46, and 0.93 mM) and halothane (0.006, 0.012, 0.024, 0.048, 0072, and 0.096 mM) with an EC50 of 0.26 mM and 35 μM, respectively. TTX (blocker of voltage-dependent Na(+) channels), EGTA (an extracellular Ca(2+) chelator) and BAPTA-AM (an intracellular Ca(2+) chelator) did not interfere with the accumulation of [(3)H]GABA induced by 0.23 mM sevoflurane and 0.048 mM halothane. SKF 89976A, a GABA transporter type 1 (GAT-1) inhibitor, reduced the sevoflurane- and halothane-induced increase in the accumulation of GABA by 57 and 63 %, respectively. Incubation of brain cortical slices at low temperature (17 °C), a condition that inhibits GAT function and reduces GABA release through reverse transport, reduced the sevoflurane- and halothane-induced increase in the accumulation of [(3)H]GABA by 82 and 75 %, respectively, relative to that at normal temperature (37 °C). Ouabain, a Na(+)/K(+) ATPase pump inhibitor, which is known to induce GABA release through reverse transport, abolished the sevoflurane and halothane effects on the accumulation of [(3)H]GABA. The effect of sevoflurane and halothane did not involve glial transporters because β-alanine, a blocker of GAT-2 and GAT-3, did not inhibit the effect of the anesthetics. In conclusion, the present study suggests that sevoflurane and halothane increase the accumulation of GABA by inducing the reverse transport of this neurotransmitter. Therefore, volatile anesthetics could interfere with neuronal excitability by increasing the action of GABA on synaptic and extrasynaptic GABA receptors.

Increased GABA-A receptor binding and reduced connectivity at the motor cortex in children with hemiplegic cerebral palsy: a multimodal investigation using 18F-fluoroflumazenil PET, immunohistochemistry, and MR imaging.

PubMed

Park, Hae-Jeong; Kim, Chul Hoon; Park, Eun Sook; Park, Bumhee; Oh, So Ra; Oh, Maeng-Keun; Park, Chang Il; Lee, Jong Doo

2013-08-01

γ-aminobutyric acid (GABA)-A receptor-mediated neural transmission is important to promote practice-dependent plasticity after brain injury. This study investigated alterations in GABA-A receptor binding and functional and anatomic connectivity within the motor cortex in children with cerebral palsy (CP). We conducted (18)F-fluoroflumazenil PET on children with hemiplegic CP to investigate whether in vivo GABA-A receptor binding is altered in the ipsilateral or contralateral hemisphere of the lesion site. To evaluate changes in the GABA-A receptor subunit after prenatal brain injury, we performed GABA-A receptor immunohistochemistry using rat pups with a diffuse hypoxic ischemic insult. We also performed diffusion tensor MR imaging and resting-state functional MR imaging on the same children with hemiplegic CP to investigate alterations in anatomic and functional connectivity at the motor cortex with increased GABA-A receptor binding. In children with hemiplegic CP, the (18)F-fluoroflumazenil binding potential was increased within the ipsilateral motor cortex. GABA-A receptors with the α1 subunit were highly expressed exclusively within cortical layers III, IV, and VI of the motor cortex in rat pups. The motor cortex with increased GABA-A receptor binding in children with hemiplegic CP had reduced thalamocortical and corticocortical connectivity, which might be linked to increased GABA-A receptor distribution in cortical layers in rats. Increased expression of the GABA-A receptor α1 subunit within the ipsilateral motor cortex may be an important adaptive mechanism after prenatal brain injury in children with CP but may be associated with improper functional connectivity after birth and have adverse effects on the development of motor plasticity.

Gad1 mRNA as a reliable indicator of altered GABA release from orexigenic neurons in the hypothalamus.

PubMed

Dicken, Matthew S; Hughes, Alexander R; Hentges, Shane T

2015-11-01

The strength of γ-aminobutyric acid (GABA)-mediated inhibitory synaptic input is a principle determinant of neuronal activity. However, because of differences in the number of GABA afferent inputs and the sites of synapses, it is difficult to directly assay for altered GABA transmission between specific cells. The present study tested the hypothesis that the level of mRNA for the GABA synthetic enzyme glutamate decarboxylase (GAD) can provide a reliable proxy for GABA release. This was tested in a mouse hypothalamic circuit important in the regulation of energy balance. Fluorescent in situ hybridization results show that the expression of Gad1 mRNA (encoding the GAD67 enzyme) was increased in hypothalamic neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons after an overnight fast, consistent with the ability of GABA from these neurons to stimulate food intake. Optogenetic studies confirmed that the observed increase in Gad1 mRNA correlated with an increase in the probability of GABA release from NPY/AgRP neurons onto downstream proopiomelanocortin neurons. Likewise, there was an increase in the readily releasable pool of GABA in NPY/AgRP neurons. Selective inhibition of GAD activity in NPY/AgRP neurons decreased GABA release, indicating that GAD67 activity, which is largely dictated by expression level, is a key determinant of GABA release. Altogether, it appears that Gad expression may be a reliable proxy of altered GABAergic transmission. Examining changes in Gad mRNA as a proxy for GABA release may be particularly helpful when the downstream targets are not known or when limited tools exist for detecting GABA release at a particular synapse. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Gad1 mRNA as a reliable indicator of altered GABA release from orexigenic neurons in the hypothalamus

PubMed Central

Dicken, Matthew S.; Hughes, Alexander R.; Hentges, Shane T.

2016-01-01

The strength of γ-aminobutyric acid (GABA)-mediated inhibitory synaptic input is a principle determinant of neuronal activity. However, because of differences in the number of GABA afferent inputs and the sites of synapses, it is difficult to directly assay for altered GABA transmission between specific cells. The present study tested the hypothesis that the level of mRNA for the GABA synthetic enzyme glutamate decarboxylase (GAD) can provide a reliable proxy for GABA release. This was tested in a mouse hypothalamic circuit important in the regulation of energy balance. Fluorescent in situ hybridization results show that the expression of Gad1 mRNA (encoding the GAD67 enzyme) was increased in hypothalamic neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons after an overnight fast, consistent with the ability of GABA from these neurons to stimulate food intake. Optogenetic studies confirmed that the observed increase in Gad1 mRNA correlated with an increase in the probability of GABA release from NPY/AgRP neurons onto downstream proopiomelanocortin neurons. Likewise, there was an increase in the readily releasable pool of GABA in NPY/AgRP neurons. Selective inhibition of GAD activity in NPY/AgRP neurons decreased GABA release, indicating that GAD67 activity, which is largely dictated by expression level, is a key determinant of GABA release. Altogether, it appears that Gad expression may be a reliable proxy of altered GABAergic transmission. Examining changes in Gad mRNA as a proxy for GABA release may be particularly helpful when the downstream targets are not known or when limited tools exist for detecting GABA release at a particular synapse. PMID:26370162

Gamma-vinyl GABA increases nonvesicular release of GABA and glutamate in the nucleus accumbens in rats via action on anion channels and GABA transporters

PubMed Central

Peng, Xiao-Qing; Gardner, Eliot L.

2013-01-01

Rationale γ-Amino butyric acid (GABA) is a well-characterized inhibitory neurotransmitter in the central nervous system, which may also stimulate nonvesicular release of other neurotransmitters under certain conditions. We have recently reported that γ-vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, elevates extracellular GABA but fails to alter dopamine release in the nucleus accumbens (NAc). Objectives Here, we investigated the mechanism(s) by which GVG elevates extracellular GABA levels and whether GVG also alters glutamate release in the NAc. Materials and methods In vivo microdialysis was used to simultaneously measure extracellular NAc GABA and glutamate before and after GVG administration in freely moving rats. Results Systemic administration of GVG or intra-NAc local perfusion of GVG significantly increased extracellular NAc GABA and glutamate. GVG-enhanced GABA was completely blocked by intra-NAc local perfusion of 5-nitro-2, 3-(phenylpropylamino)-benzoic acid (NPPB), a selective anion channel blocker and partially blocked by SKF89976A, a type 1 GABA transporter inhibitor. GVG-enhanced glutamate was completely blocked by NPPB or SKF89976A. Tetrodotoxin, a voltage-dependent Na+-channel blocker, failed to alter GVG-enhanced GABA and glutamate. Conclusions These data suggest that GVG-enhanced extracellular GABA and glutamate are mediated predominantly by the opening of anion channels and partially by the reversal of GABA transporters. Enhanced extracellular glutamate may functionally attenuate the pharmacological action of GABA and prevent enhanced GABA-induced excess inhibition. PMID:20033132

Acutely increasing δGABA(A) receptor activity impairs memory and inhibits synaptic plasticity in the hippocampus.

PubMed

Whissell, Paul D; Eng, Dave; Lecker, Irene; Martin, Loren J; Wang, Dian-Shi; Orser, Beverley A

2013-01-01

Extrasynaptic γ-aminobutyric acid type A (GABA(A)) receptors that contain the δ subunit (δGABA(A) receptors) are expressed in several brain regions including the dentate gyrus (DG) and CA1 subfields of the hippocampus. Drugs that increase δGABA(A) receptor activity have been proposed as treatments for a variety of disorders including insomnia, epilepsy and chronic pain. Also, long-term pretreatment with the δGABA(A) receptor-preferring agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) enhances discrimination memory and increases neurogenesis in the DG. Despite the potential therapeutic benefits of such treatments, the effects of acutely increasing δGABA(A) receptor activity on memory behaviors remain unknown. Here, we studied the effects of THIP (4 mg/kg, i.p.) on memory performance in wild-type (WT) and δGABA(A) receptor null mutant (Gabrd(-/-)) mice. Additionally, the effects of THIP on long-term potentiation (LTP), a molecular correlate of memory, were studied within the DG and CA1 subfields of the hippocampus using electrophysiological recordings of field potentials in hippocampal slices. The results showed that THIP impaired performance in the Morris water maze, contextual fear conditioning and object recognition tasks in WT mice but not Gabrd(-/-) mice. Furthermore, THIP inhibited LTP in hippocampal slices from WT but not Gabrd(-/-) mice, an effect that was blocked by GABA(A) receptor antagonist bicuculline. Thus, acutely increasing δGABA(A) receptor activity impairs memory behaviors and inhibits synaptic plasticity. These results have important implications for the development of therapies aimed at increasing δGABA(A) receptor activity.

Gamma-Aminobutyric acid and benzodiazepine receptors in the kindling model of epilepsy: a quantitative radiohistochemical study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shin, C.; Pedersen, H.B.; McNamara, J.O.

1985-10-01

Quantitative radiohistochemistry was utilized to study alterations of gamma-aminobutyric acid (GABA) and benzodiazepine receptors in the kindling model of epilepsy. The radioligands used for GABA and benzodiazepine receptors were (TH) muscimol and (TH)flunitrazepam, respectively. GABA receptor binding was increased by 22% in fascia dentata of the hippocampal formation but not in neocortex or substantia nigra of kindled rats. Within fascia dentata, GABA receptor binding was increased to an equivalent extent in stratum granulosum and throughout stratum moleculare; no increase was found in dentate hilus or stratum lacunosummoleculare or stratum radiatum of CA1. The increased binding was present at 24 hrmore » but not at 28 days after the last kindled seizure. The direction, anatomic distribution, and time course of the increased GABA receptor binding were paralleled by increased benzodiazepine receptor binding. The anatomic distribution of the increased GABA receptor binding is consistent with a localization to somata and dendritic trees of dentate granule cells. The authors suggest that increased GABA and benzodiazepine receptor binding may contribute to enhanced inhibition of dentate granule cells demonstrated electrophysiologically in kindled animals.« less

Functional neuroanatomy of the ventral striopallidal GABA pathway. New sites of intervention in the treatment of schizophrenia.

PubMed

O'Connor, W T

2001-08-15

Microdialysis was employed to investigate the dopamine, cholecystokinin (CCK) and neurotensin receptor regulation of ventral striopallidal GABA transmission by intra-accumbens perfusion with selective receptor ligands and monitoring local or ipsilateral ventral pallidal GABA release. In the dual probe studies intra-accumbens perfusion with the dopamine D1 and D2 receptor agonists SKF28293 and pergolide had no effect on ventral pallidal GABA, while both the D1 and D2 receptor antagonists SCH23390 and raclopride increased ventral pallidal GABA release. In contrast, intra-accumbens CCK decreased ventral pallidal GABA release and this was reversed by local perfusion with the CCK2 receptor antagonist PD134308 but not the CCK1 receptor antagonist L-364,718. In a single probe study intra-accumbens neurotensin increased local GABA release, which was strongly potentiated when the peptidase inhibitor phosphodiepryl 08 was perfused together with neurotensin. In addition, the neurotensin receptor antagonist SR48692 counteracted this phosphodiepryl 08 induced potentiated increased in GABA release. Taken together, these findings indicate that mesolimbic dopamine and CCK exert a respective tonic and phasic inhibition of ventral pallidal GABA release while the antipsychotic activity associated with D1 and D2 receptor antagonists may be explained by their ability to increase ventral striopallidal GABA transmission. Furthermore, the findings suggest that CCK2 receptor antagonists and neurotensin endopeptidase inhibitors may be useful antipsychotics.

Isolation and chemical characterization of agelaiatoxin8 (AvTx8) from Agelaia vicina wasp venom and its biological effects on GABA neurotransmission.

PubMed

Pizzo, Andrea B; Beleboni, Renê O; Gomes Carolino, Ruither O; de Oliveira, Luciana; Miranda, Antonio; Coutinho-Netto, Joaquim; Fontana, Andréia C K; Dos Santos, Wagner Ferreira

2017-10-01

Arthropod venoms are sources of molecules that may be useful tools to investigate molecular mechanisms of putative new medicines and laboratory drugs. Here we show the effects of the compound agelaiatoxin-8 (AVTx8), isolated from Agelaia vicina venom, on γ-aminobutyric acid (GABA) neurotransmission in rat brain synaptosomes. Analysis reveals that AvTx8 is composed by 14 amino acid residues with a molecular weight (MW) of 1567 Da. AvTx8 increased GABA release and inhibited GABA uptake in synaptosomes from rat cerebral cortex. AvTx8 inhibited GABA uptake and increased GABA release in the presence of Ca + , Na + , and K + channel blockers, suggesting that it acts directly on GABA transporters. In addition, AvTx8 significantly decreases GABA binding in synaptic membranes from rat brain cortex, suggesting that it also modulates the activity of GABA receptors. Moreover, AvTx8 decreased GAT-1- and GAT-3-mediated GABA uptake in transfected COS-7 cells. Accordingly, we suggest that AvTx8 modulates GABA neurotransmission and might provide a novel entry point for identifying a new class of GABA-modulating neuroprotective drugs. © 2017 Wiley Periodicals, Inc.

Dorsolateral Prefrontal Cortex GABA Concentration in Humans Predicts Working Memory Load Processing Capacity.

PubMed

Yoon, Jong H; Grandelis, Anthony; Maddock, Richard J

2016-11-16

The discovery of neural mechanisms of working memory (WM) would significantly enhance our understanding of complex human behaviors and guide treatment development for WM-related impairments found in neuropsychiatric conditions and aging. Although the dorsolateral prefrontal cortex (DLPFC) has long been considered critical for WM, we still know little about the neural elements and pathways within the DLPFC that support WM in humans. In this study, we tested whether an individual's DLPFC gamma-aminobutryic acid (GABA) content predicts individual differences in WM task performance using a novel behavioral approach. Twenty-three healthy adults completed a task that measured the unique contribution of major WM components (memory load, maintenance, and distraction resistance) to performance. This was done to address the possibility that components have differing GABA dependencies and the failure to parse WM into components would lead to missing true associations with GABA. The subjects then had their DLPFC GABA content measured by single-voxel proton magnetic spectroscopy. We found that individuals with lower DLPFC GABA showed greater performance degradation with higher load, accounting for 31% of variance, p (corrected) = 0.015. This relationship was component, neurochemical, and brain region specific. DLPFC GABA content did not predict performance sensitivity to other components tested; DLPFC glutamate + glutamine and visual cortical GABA content did not predict load sensitivity. These results confirm the involvement of DLPFC GABA in WM load processing in humans and implicate factors controlling DLPFC GABA content in the neural mechanisms of WM and its impairments. This study demonstrated for the first time that the amount of gamma-aminobutryic acid (GABA), the major inhibitory neurotransmitter of the brain, in an individual's prefrontal cortex predicts working memory (WM) task performance. Given that WM is required for many of the most characteristic cognitive and behavioral capabilities in humans, this finding could have a significant impact on our understanding of the neural basis of complex human behavior. Furthermore, this finding suggests that efforts to preserve or increase brain GABA levels could be fruitful in remediating WM-related deficits associated with neuropsychiatric conditions. Copyright © 2016 the authors 0270-6474/16/3611788-07$15.00/0.

Increased glutamate/GABA+ ratio in a shared autistic and schizotypal trait phenotype termed Social Disorganisation.

PubMed

Ford, Talitha C; Nibbs, Richard; Crewther, David P

2017-01-01

Autism and schizophrenia are multi-dimensional spectrum disorders that have substantial phenotypic overlap. This overlap is readily identified in the non-clinical population, and has been conceptualised as Social Disorganisation (SD). This study investigates the balance of excitatory glutamate and inhibitory γ -aminobutyric acid (GABA) concentrations in a non-clinical sample with high and low trait SD, as glutamate and GABA abnormalities are reported across the autism and schizophrenia spectrum disorders. Participants were 18 low (10 females) and 19 high (9 females) SD scorers aged 18 to 40 years who underwent 1 H-MRS for glutamate and GABA+macromolecule (GABA+) concentrations in right and left hemisphere superior temporal (ST) voxels. Reduced GABA+ concentration ( p  = 0.03) and increased glutamate/GABA+ ratio ( p  = 0.003) in the right ST voxel for the high SD group was found, and there was increased GABA+ concentration in the left compared to right ST voxel ( p  = 0.047). Bilateral glutamate concentration was increased for the high SD group ( p  = 0.006); there was no hemisphere by group interaction ( p  = 0.772). Results suggest that a higher expression of the SD phenotype may be associated with increased glutamate/GABA+ ratio in the right ST region, which may affect speech prosody processing, and lead behavioural characteristics that are shared within the autistic and schizotypal spectra.

Dual mechanisms regulating glutamate decarboxylases and accumulation of gamma-aminobutyric acid in tea (Camellia sinensis) leaves exposed to multiple stresses

PubMed Central

Mei, Xin; Chen, Yiyong; Zhang, Lingyun; Fu, Xiumin; Wei, Qing; Grierson, Don; Zhou, Ying; Huang, Yahui; Dong, Fang; Yang, Ziyin

2016-01-01

γ-Aminobutyric acid (GABA) is one of the major inhibitory neurotransmitters in the central nervous system. It has multiple positive effects on mammalian physiology and is an important bioactive component of tea (Camellia sinensis). GABA generally occurs at a very low level in plants but GABA content increases substantially after exposure to a range of stresses, especially oxygen-deficiency. During processing of tea leaves, a combination of anoxic stress and mechanical damage are essential for the high accumulation of GABA. This is believed to be initiated by a change in glutamate decarboxylase activity, but the underlying mechanisms are unclear. In the present study we characterized factors regulating the expression and activity of three tea glutamate decarboxylase genes (CsGAD1, 2, and 3), and their encoded enzymes. The results suggests that, unlike the model plant Arabidopsis thaliana, there are dual mechanisms regulating the accumulation of GABA in tea leaves exposed to multiple stresses, including activation of CsGAD1 enzymatic activity by calmodulin upon the onset of the stress and accumulation of high levels of CsGAD2 mRNA induced by a combination of anoxic stress and mechanical damage. PMID:27021285

Dual mechanisms regulating glutamate decarboxylases and accumulation of gamma-aminobutyric acid in tea (Camellia sinensis) leaves exposed to multiple stresses.

PubMed

Mei, Xin; Chen, Yiyong; Zhang, Lingyun; Fu, Xiumin; Wei, Qing; Grierson, Don; Zhou, Ying; Huang, Yahui; Dong, Fang; Yang, Ziyin

2016-03-29

γ-Aminobutyric acid (GABA) is one of the major inhibitory neurotransmitters in the central nervous system. It has multiple positive effects on mammalian physiology and is an important bioactive component of tea (Camellia sinensis). GABA generally occurs at a very low level in plants but GABA content increases substantially after exposure to a range of stresses, especially oxygen-deficiency. During processing of tea leaves, a combination of anoxic stress and mechanical damage are essential for the high accumulation of GABA. This is believed to be initiated by a change in glutamate decarboxylase activity, but the underlying mechanisms are unclear. In the present study we characterized factors regulating the expression and activity of three tea glutamate decarboxylase genes (CsGAD1, 2, and 3), and their encoded enzymes. The results suggests that, unlike the model plant Arabidopsis thaliana, there are dual mechanisms regulating the accumulation of GABA in tea leaves exposed to multiple stresses, including activation of CsGAD1 enzymatic activity by calmodulin upon the onset of the stress and accumulation of high levels of CsGAD2 mRNA induced by a combination of anoxic stress and mechanical damage.

Changes in plasma GABA concentration during vigabatrin treatment of epilepsy: a prospective study.

PubMed

Erdal, J; Gram, L; Alving, J; Löscher, W

1999-04-01

The aim of the present prospective study was to evaluate changes in plasma GABA concentration in relation to clinical response during vigabatrin treatment of epilepsy. We studied 29 patients with uncontrolled partial-onset seizures during open add-on vigabatrin treatment and measured plasma GABA and vigabatrin concentrations by a sensitive HPLC method. Following short-term treatment 17 out of 28 patients had a seizure reduction of > 50% (responders). After long-term treatment 16 out of 22 patients were responders. There was no difference between responders and nonresponders regarding pretreatment seizure frequency, treatment duration, vigabatrin dose, or plasma vigabatrin concentration. Responders had a significant (p < 0.001) increase in mean plasma GABA both after short-term (from 0.380 to 0.530 nmol/ml; mean increase: 48%) and after long-term (from 0.392 to 0.618 nmol/ml; mean increase: 71%) vigabatrin treatment, whilst nonresponders had no significant changes in GABA levels. However, since plasma GABA increased in a subgroup of nonresponders, mean plasma GABA levels did not differ between responders and nonresponders. Although plasma GABA increased significantly in the responder but not in the nonresponder group during vigabatrin treatment of patients with epilepsy, it does not seem to be a reliable marker of individual clinical response to vigabatrin treatment.

Prenatal Ontogeny as a Susceptibility Period for Cortical GABA Neuron Disturbances in Schizophrenia

PubMed Central

Volk, David W.; Lewis, David A.

2013-01-01

Cognitive deficits in schizophrenia have been linked to disturbances in GABA neurons in the prefrontal cortex. Furthermore, cognitive deficits in schizophrenia appear well before the onset of psychosis and have been reported to be present during early childhood and even during the first year of life. Taken together, these data raise the following question: Does the disease process that produces abnormalities in prefrontal GABA neurons in schizophrenia begin prenatally and disrupt the ontogeny of cortical GABA neurons? Here, we address this question through a consideration of evidence that genetic and/or environmental insults that occur during gestation initiate a pathogenetic process that alters cortical GABA neuron ontogeny and produces the pattern of GABA neuron abnormalities, and consequently cognitive difficulties, seen in schizophrenia. First, we review available evidence from postmortem human brain tissue studies characterizing alterations in certain subpopulations of prefrontal GABA neuron that provide clues to a prenatal origin in schizophrenia. Second, we review recent discoveries of transcription factors, cytokine receptors, and other developmental regulators that govern the birth, migration, specification, maturation, and survival of different subpopulations of prefrontal GABA neurons. Third, we discuss recent studies demonstrating altered expression of these ontogenetic factors in the prefrontal cortex in schizophrenia. Fourth, we discuss the potential role of disturbances in the maternal-fetal environment such as maternal immune activation in the development of GABA neuron dysfunction. Finally, we propose critical questions that need to be answered in future research to further investigate the role of altered GABA neuron ontogeny in the pathogenesis of schizophrenia. PMID:23769891

Gi-coupled γ-aminobutyric acid-B receptors cross-regulate phospholipase C and calcium in airway smooth muscle.

PubMed

Mizuta, Kentaro; Mizuta, Fumiko; Xu, Dingbang; Masaki, Eiji; Panettieri, Reynold A; Emala, Charles W

2011-12-01

γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system, and exerts its actions via both ionotropic (GABA(A)) and metabotropic (GABA(B)) receptors. Although the functional expression of GABA(B) receptors coupled to the G(i) protein was reported for airway smooth muscle, the role of GABA(B) receptors in airway responsiveness remains unclear. We investigated whether G(i)-coupled GABA(B) receptors cross-regulate phospholipase C (PLC), an enzyme classically regulated by G(q)-coupled receptors in human airway smooth muscle cells. Both the GABA(B)-selective agonist baclofen and the endogenous ligand GABA significantly increased the synthesis of inositol phosphate, whereas GABA(A) receptor agonists, muscimol, and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol exerted no effect. The baclofen-induced synthesis of inositol phosphate and transient increases in [Ca(2+)](i) were blocked by CGP35348 and CGP55845 (selective GABA(B) antagonists), pertussis toxin (PTX, which inactivates the G(i) protein), gallein (a G(βγ) signaling inhibitor), U73122 (an inhibitor of PLC-β), and xestospongin C, an inositol 1,4,5-triphosphate receptor blocker. Baclofen also potentiated the bradykinin-induced synthesis of inositol phosphate and transient increases in [Ca(2+)](i), which were blocked by CGP35348 or PTX. Moreover, baclofen potentiated the substance P-induced contraction of airway smooth muscle in isolated guinea pig tracheal rings. In conclusion, the stimulation of GABA(B) receptors in human airway smooth muscle cells rapidly mobilizes intracellular Ca(2+) stores by the synthesis of inositol phosphate via the activation of PLC-β, which is stimulated by G(βγ) protein liberated from G(i) proteins coupled to GABA(B) receptors. Furthermore, crosstalk between GABA(B) receptors and G(q)-coupled receptors potentiates the synthesis of inositol phosphate, transient increases in [Ca(2+)](i), and smooth muscle contraction through G(i) proteins.

Effects of rumen-protected γ-aminobutyric acid on performance and nutrient digestibility in heat-stressed dairy cows.

PubMed

Cheng, J B; Bu, D P; Wang, J Q; Sun, X Z; Pan, L; Zhou, L Y; Liu, W

2014-09-01

This experiment was conducted to investigate the effects of rumen-protected γ-aminobutyric acid (GABA) on performance and nutrient digestibility in heat-stressed dairy cows. Sixty Holstein dairy cows (141±15 d in milk, 35.9±4.3kg of milk/d, and parity 2.0±1.1) were randomly assigned to 1 of 4 treatments according to a completely randomized block design. Treatments consisted of 0 (control), 40, 80, or 120mg of true GABA/kg of dry matter (DM). The trial lasted 10wk. The average temperature-humidity indices at 0700, 1400, and 2200h were 78.4, 80.2, and 78.7, respectively. Rectal temperatures decreased linearly at 0700, 1400, and 2200h with increasing GABA concentration. Supplementation of GABA had no effect on respiration rates at any time point. Dry matter intake, energy-corrected milk, 4% fat-corrected milk, and milk fat yield tended to increase linearly with increasing GABA concentration. Supplementation of GABA affected, in a quadratic manner, milk protein and lactose concentrations, and milk protein yield, and the peak values were reached at a dose of 40mg of GABA/kg. Milk urea nitrogen concentration responded quadratically. Total solids content increased linearly with increasing GABA concentration. Supplementation of GABA had no effect on milk yield, lactose production, total solids, milk fat concentration, somatic cell score, or feed efficiency. Apparent total-tract digestibilities of DM, organic matter, crude protein, neutral detergent fiber, and acid detergent fiber were similar among treatments. These results indicate that rumen-protected GABA supplementation to dairy cows can alleviate heat stress by reducing rectal temperature, increase DM intake and milk production, and improve milk composition. The appropriate supplemental GABA level for heat-stressed dairy cows is 40mg/kg of DM. Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Functional role of ambient GABA in refining neuronal circuits early in postnatal development

PubMed Central

Cellot, Giada; Cherubini, Enrico

2013-01-01

Early in development, γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the mature brain, depolarizes and excites targeted neurons by an outwardly directed flux of chloride, resulting from the peculiar balance between the cation-chloride importer NKCC1 and the extruder KCC2. The low expression of KCC2 at birth leads to accumulation of chloride inside the cell and to the equilibrium potential for chloride positive respect to the resting membrane potential. GABA exerts its action via synaptic and extrasynaptic GABAA receptors mediating phasic and tonic inhibition, respectively. Here, recent data on the contribution of “ambient” GABA to the refinement of neuronal circuits in the immature brain have been reviewed. In particular, we focus on the hippocampus, where, prior to the formation of conventional synapses, GABA released from growth cones and astrocytes in a calcium- and SNARE (soluble N-ethylmaleimide-sensitive-factor attachment protein receptor)-independent way, diffuses away to activate in a paracrine fashion extrasynaptic receptors localized on distal neurons. The transient increase in intracellular calcium following the depolarizing action of GABA leads to inhibition of DNA synthesis and cell proliferation. Tonic GABA exerts also a chemotropic action on cell migration. Later on, when synapses are formed, GABA spilled out from neighboring synapses, acting mainly on extrasynaptic α5, β2, β3, and γ containing GABAA receptor subunits, provides the membrane depolarization necessary for principal cells to reach the window where intrinsic bursts are generated. These are instrumental in triggering calcium transients associated with network-driven giant depolarizing potentials which act as coincident detector signals to enhance synaptic efficacy at emerging GABAergic and glutamatergic synapses. PMID:23964205

Effects of NaCl Replacement with Gamma-Aminobutyric acid (GABA) on the Quality Characteristics and Sensorial Properties of Model Meat Products

PubMed Central

Chun, Ji-Yeon; Cho, Hyung-Yong; Min, Sang-Gi

2014-01-01

This study investigated the effects of γ-aminobutylic acid (GABA) on the quality and sensorial properties of both the GABA/NaCl complex and model meat products. GABA/NaCl complex was prepared by spray-drying, and the surface dimensions, morphology, rheology, and saltiness were characterized. For model meat products, pork patties were prepared by replacing NaCl with GABA. For characteristics of the complex, increasing GABA concentration increased the surface dimensions of the complex. However, GABA did not affect the rheological properties of solutions containing the complex. The addition of 2% GABA exhibited significantly higher saltiness than the control (no GABA treatment). In the case of pork patties, sensory testing indicated that the addition of GABA decreased the saltiness intensity. Both the intensity of juiciness and tenderness of patties containing GABA also scored lower than the control, based on the NaCl reduction. These results were consistent with the quality characteristics (cooking loss and texture profile analysis). Nevertheless, overall acceptability of the pork patties showed that up to 1.5%, patties containing GABA did not significantly differ from the control. Consequently, the results indicated that GABA has a potential application in meat products, but also manifested a deterioration of quality by the NaCl reduction, which warrants further exploration. PMID:26761294

GABAergic control of food intake in the meat-type chickens.

PubMed

Jonaidi, H; Babapour, V; Denbow, D M

2002-08-01

This study examined the effects of intracerebroventricular injections of gamma-aminobutyric acid (GABA) agonists on short-term food intake in meat-type cockerels. In Experiment 1, birds were injected with various doses of muscimol, a GABA(A) agonist. In Experiment 2, the birds received bicuculline, a GABA(A) antagonist, prior to injection of muscimol. In Experiment 3, the effect of varying doses of baclofen, a GABA(B) agonist, on food intake was determined. The intracerebroventricular injection of muscimol caused a dose-dependent increase in food intake. This effect was significantly attenuated by pretreatment with bicuculline. Food intake was not affected by the intracerebroventricular injection of baclofen. These results suggest that GABA acts within the brain of broilers at a GABA(A), but not GABA(B), receptor to increase voluntary food intake.

γ-Aminobutyric Acid Imparts Partial Protection from Salt Stress Injury to Maize Seedlings by Improving Photosynthesis and Upregulating Osmoprotectants and Antioxidants

PubMed Central

Wang, Yongchao; Gu, Wanrong; Meng, Yao; Xie, Tenglong; Li, Lijie; Li, Jing; Wei, Shi

2017-01-01

γ-Aminobutyric acid (GABA) has high physiological activity in plant stress physiology. This study showed that the application of exogenous GABA by root drenching to moderately (MS, 150 mM salt concentration) and severely salt-stressed (SS, 300 mM salt concentration) plants significantly increased endogenous GABA concentration and improved maize seedling growth but decreased glutamate decarboxylase (GAD) activity compared with non-treated ones. Exogenous GABA alleviated damage to membranes, increased in proline and soluble sugar content in leaves, and reduced water loss. After the application of GABA, maize seedling leaves suffered less oxidative damage in terms of superoxide anion (O2·−) and malondialdehyde (MDA) content. GABA-treated MS and SS maize seedlings showed increased enzymatic antioxidant activity compared with that of untreated controls, and GABA-treated MS maize seedlings had a greater increase in enzymatic antioxidant activity than SS maize seedlings. Salt stress severely damaged cell function and inhibited photosynthesis, especially in SS maize seedlings. Exogenous GABA application could reduce the accumulation of harmful substances, help maintain cell morphology, and improve the function of cells during salt stress. These effects could reduce the damage to the photosynthetic system from salt stress and improve photosynthesis and chlorophyll fluorescence parameters. GABA enhanced the salt tolerance of maize seedlings. PMID:28272438

Metabolic pathways regulated by γ-aminobutyric acid (GABA) contributing to heat tolerance in creeping bentgrass (Agrostis stolonifera)

PubMed Central

Li, Zhou; Yu, Jingjin; Peng, Yan; Huang, Bingru

2016-01-01

γ-Aminobutyric acid is a non-protein amino acid involved in various metabolic processes. The objectives of this study were to examine whether increased GABA could improve heat tolerance in cool-season creeping bentgrass through physiological analysis, and to determine major metabolic pathways regulated by GABA through metabolic profiling. Plants were pretreated with 0.5 mM GABA or water before exposed to non-stressed condition (21/19 °C) or heat stress (35/30 °C) in controlled growth chambers for 35 d. The growth and physiological analysis demonstrated that exogenous GABA application significantly improved heat tolerance of creeping bentgrass. Metabolic profiling found that exogenous application of GABA led to increases in accumulations of amino acids (glutamic acid, aspartic acid, alanine, threonine, serine, and valine), organic acids (aconitic acid, malic acid, succinic acid, oxalic acid, and threonic acid), sugars (sucrose, fructose, glucose, galactose, and maltose), and sugar alcohols (mannitol and myo-inositol). These findings suggest that GABA-induced heat tolerance in creeping bentgrass could involve the enhancement of photosynthesis and ascorbate-glutathione cycle, the maintenance of osmotic adjustment, and the increase in GABA shunt. The increased GABA shunt could be the supply of intermediates to feed the tricarboxylic acid cycle of respiration metabolism during a long-term heat stress, thereby maintaining metabolic homeostasis. PMID:27455877

A study on the involvement of GABA-transaminase in MCT induced pulmonary hypertension.

PubMed

Lingeshwar, Poorella; Kaur, Gurpreet; Singh, Neetu; Singh, Seema; Mishra, Akanksha; Shukla, Shubha; Ramakrishna, Rachumallu; Laxman, Tulsankar Sachin; Bhatta, Rabi Sankar; Siddiqui, Hefazat H; Hanif, Kashif

2016-02-01

Increased sympathetic nervous system (SNS) activity is associated with cardiovascular diseases but its role has not been completely explored in pulmonary hypertension (PH). Increased SNS activity is distinguished by elevated level of norepinephrine (NE) and activity of γ-Amino butyric acid Transminase (GABA-T) which degrades GABA, an inhibitory neurotransmitter within the central and peripheral nervous system. Therefore, we hypothesized that GABA-T may contribute in pathophysiology of PH by modulating level of GABA and NE. The effect of daily oral administration of GABA-T inhibitor, Vigabatrin (GVG, 50 and 75 mg/kg/day, 35 days) was studied following a single subcutaneous administration of monocrotaline (MCT, 60 mg/kg) in male SD rats. The pressure and hypertrophy of right ventricle (RV), oxidative stress, inflammation, pulmonary vascular remodelling were assessed after 35 days in MCT treated rats. The expression of GABA-T and HIF-1α was studied in lung tissue. The levels of plasma NE (by High performance liquid chromatography coupled with electrochemical detector; HPLC-ECD) and lung GABA (by liquid chromatography-mass spectrometry) were also estimated. GVG at both doses significantly attenuated increased in pressure (35.82 ± 4.80 mm Hg, p < 0.001; 28.37 ± 3.32 mm Hg, p < 0.001 respectively) and hypertrophy of RV, pulmonary vascular remodelling, oxidative stress and inflammation in lungs of MCT exposed rats. GVG also reduced the expression of GABA-T and HIF-1α in MCT treated rats. Increased NE level and decreased GABA level was also reversed by GVG in MCT exposed rats. GABA-T plays an important role in PH by modulating SNS activity and may be considered as a therapeutic target in PH. Copyright © 2015 Elsevier Ltd. All rights reserved.

Acute effects of sodium valproate and gamma-vinyl GABA on regional amino acid metabolism in the rat brain: incorporation of 2-[14C]glucose into amino acids.

PubMed

Chapman, A G; Riley, K; Evans, M C; Meldrum, B S

1982-09-01

Amino acid concentrations have been determined in rat brain regions (cortex, striatum, cerebellum, and hippocampus) by HPLC after administration of acute anticonvulsant doses of sodium valproate (400 mg/kg, i.p.) and gamma-vinyl-GABA (1 g/kg, i.p.). After valproate administration the GABA level increases only in the cortex; aspartic acid concentration decreases in the cortex and hippocampus, and glutamic acid decreases in the hippocampus and striatum and increases in the cortex and cerebellum. There are no changes in the concentrations of glutamine, taurine, glycine, serine, and alanine following valproate administration. Only the GABA level increases in all the regions after gamma-vinyl-GABA administration. Cortical analyses 2, 4 and 10 minutes after pulse labeling with 2-[14C]glucose, i.v., show no change in the rate of cortical glucose utilization in the valproate treated group. The rate of labeling of glutamic acid is also unchanged, but the rate of labeling of GABA is reduced following valproate administration. After gamma-vinyl-GABA administration there is no change in the rate of labeling of GABA. These biochemical findings can be interpreted in terms of a primary anticonvulsant action of valproate on membrane receptors with secondary effects on the metabolism of amino acid neurotransmitters. This contrasts with the primary action of gamma-vinyl-GABA on GABA-transaminase activity.

Determination of GABA and vigabatrin in human plasma by a rapid and simple HPLC method: correlation between clinical response to vigabatrin and increase in plasma GABA.

PubMed

Löscher, W; Fassbender, C P; Gram, L; Gramer, M; Hörstermann, D; Zahner, B; Stefan, H

1993-03-01

The novel antiepileptic drug vigabatrin (Sabril) acts by inhibiting degradation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), increasing the GABA concentrations in the brain. Because the GABA degrading enzyme GABA aminotransferase (GABA-T) is also present in peripheral tissues, including blood platelets, measurement of plasma GABA levels might be a useful indication of the pharmacological response to vigabatrin during therapeutic monitoring. However, because of the very low concentrations of GABA in plasma, the few methods available for plasma GABA analysis are time-consuming, difficult to perform and/or not selective enough because of potential interference with other plasma constituents. In the present study, a rapid, selective and sensitive amino acid analysis HPLC method has been developed for plasma GABA determination with fluorescence detection, using o-phthaldialdehyde as a precolumn derivatizing agent. By employing a 3 microns particle size reversed-phase column and a multi-step gradient system of two solvents, the very low endogenous concentration of GABA in human plasma could be reproducibly quantitated without interference of other endogenous compounds. Incubation of human plasma samples with GABA degrading enzyme(s) resulted in an almost total loss of the GABA peak, thus demonstrating the specificity of the method for GABA analysis. In addition to GABA and other endogenous amino acids, the HPLC method could be used to quantitate plasma levels of vigabatrin. Thus, this improved HPLC amino acid assay might be used to examine whether concomitant monitoring of plasma GABA and vigabatrin is useful for clinical purposes. This was examined in 20 epileptic patients undergoing chronic treatment with vigabatrin. The average plasma GABA level of these 20 patients did not differ significantly from non-epileptic controls. However, when epileptic patients were subdivided according to their clinical response to vigabatrin, vigabatrin responders had significantly higher GABA levels than nonresponders or controls. In contrast to the difference in plasma GABA, vigabatrin responders and nonresponders did not differ in dose or plasma level of vigabatrin. These data may indicate that determination of plasma GABA is a valuable non-invasive method for therapeutic monitoring in patients on medication with vigabatrin.

Enhancement of γ-aminobutyric acid production in recombinant Corynebacterium glutamicum by co-expressing two glutamate decarboxylase genes from Lactobacillus brevis.

PubMed

Shi, Feng; Jiang, Junjun; Li, Yongfu; Li, Youxin; Xie, Yilong

2013-11-01

γ-Aminobutyric acid (GABA), a non-protein amino acid, is a bioactive component in the food, feed and pharmaceutical fields. To establish an effective single-step production system for GABA, a recombinant Corynebacterium glutamicum strain co-expressing two glutamate decarboxylase (GAD) genes (gadB1 and gadB2) derived from Lactobacillus brevis Lb85 was constructed. Compared with the GABA production of the gadB1 or gadB2 single-expressing strains, GABA production by the gadB1-gadB2 co-expressing strain increased more than twofold. By optimising urea supplementation, the total production of L-glutamate and GABA increased from 22.57 ± 1.24 to 30.18 ± 1.33 g L⁻¹, and GABA production increased from 4.02 ± 0.95 to 18.66 ± 2.11 g L⁻¹ after 84-h cultivation. Under optimal urea supplementation, L-glutamate continued to be consumed, GABA continued to accumulate after 36 h of fermentation, and the pH level fluctuated. GABA production increased to a maximum level of 27.13 ± 0.54 g L⁻¹ after 120-h flask cultivation and 26.32 g L⁻¹ after 60-h fed-batch fermentation. The conversion ratio of L-glutamate to GABA reached 0.60-0.74 mol mol⁻¹. By co-expressing gadB1 and gadB2 and optimising the urea addition method, C. glutamicum was genetically improved for de novo biosynthesis of GABA from its own accumulated L-glutamate.

The PLC/IP3R/PKC Pathway is Required for Ethanol-enhanced GABA Release

PubMed Central

Kelm, M. Katherine; Weinberg, Richard J.; Criswell, Hugh E.; Breese, George R.

2010-01-01

Summary Research on the actions of ethanol at the GABAergic synapse has traditionally focused on postsynaptic mechanisms, but recent data demonstrate that ethanol also increases both evoked and spontaneous GABA release in many brain regions. Using whole-cell voltage-clamp recordings, we previously showed that ethanol increases spontaneous GABA release at the rat interneuron-Purkinje cell synapse. This presynaptic ethanol effect is dependent on calcium release from internal stores, possibly through activation of inositol 1,4,5-trisphosphate receptors (IP3Rs). After confirming that ethanol targets vesicular GABA release, in the present study we used electron microscopic immunohistochemistry to demonstrate that IP3Rs are located in presynaptic terminals of cerebellar interneurons. Activation of IP3Rs requires binding of IP3, generated through activation of phospholipase C (PLC). We find that the PLC antagonist edelfosine prevents ethanol from increasing spontaneous GABA release. Diacylglycerol generated by PLC and calcium released by activation of the IP3R activate protein kinase C (PKC). Ethanol-enhanced GABA release was blocked by two PKC antagonists, chelerythrine and calphostin C. When a membrane impermeable PKC antagonist, PKC (19-36), was delivered intracellularly to the postsynaptic neuron, ethanol continued to increase spontaneous GABA release. Overall, these results suggest that activation of the PLC/IP3R/PKC pathway is necessary for ethanol to increase spontaneous GABA release from presynaptic terminals onto Purkinje cells. PMID:20206640

Quantification of γ-aminobutyric acid (GABA) in 1 H MRS volumes composed heterogeneously of grey and white matter.

PubMed

Mikkelsen, Mark; Singh, Krish D; Brealy, Jennifer A; Linden, David E J; Evans, C John

2016-11-01

The quantification of γ-aminobutyric acid (GABA) concentration using localised MRS suffers from partial volume effects related to differences in the intrinsic concentration of GABA in grey (GM) and white (WM) matter. These differences can be represented as a ratio between intrinsic GABA in GM and WM: r M . Individual differences in GM tissue volume can therefore potentially drive apparent concentration differences. Here, a quantification method that corrects for these effects is formulated and empirically validated. Quantification using tissue water as an internal concentration reference has been described previously. Partial volume effects attributed to r M can be accounted for by incorporating into this established method an additional multiplicative correction factor based on measured or literature values of r M weighted by the proportion of GM and WM within tissue-segmented MRS volumes. Simulations were performed to test the sensitivity of this correction using different assumptions of r M taken from previous studies. The tissue correction method was then validated by applying it to an independent dataset of in vivo GABA measurements using an empirically measured value of r M . It was shown that incorrect assumptions of r M can lead to overcorrection and inflation of GABA concentration measurements quantified in volumes composed predominantly of WM. For the independent dataset, GABA concentration was linearly related to GM tissue volume when only the water signal was corrected for partial volume effects. Performing a full correction that additionally accounts for partial volume effects ascribed to r M successfully removed this dependence. With an appropriate assumption of the ratio of intrinsic GABA concentration in GM and WM, GABA measurements can be corrected for partial volume effects, potentially leading to a reduction in between-participant variance, increased power in statistical tests and better discriminability of true effects. Copyright © 2016 John Wiley & Sons, Ltd.

Quality components and antidepressant-like effects of GABA green tea.

PubMed

Teng, Jie; Zhou, Wen; Zeng, Zhen; Zhao, Wenfang; Huang, Yahui; Zhang, Xu

2017-09-20

Gamma (γ)-aminobutyric acid (GABA) green tea, with high GABA content, is a kind of special green tea. The goals of this study are to analyze the changes in quality components of green tea during anaerobic treatment, and to investigate whether or not the extract of GABA present in green tea can prevent depression or improve the depressive state of animals. Results showed that GABA content in green tea had increased significantly after anaerobic treatment. The contents of tea polysaccharides, total free amino acids, and water extracts were also increased whereas tea polyphenols were reduced. More importantly, the extract of GABA green tea could alleviate mouse depression and stress from desperate environments through the forced swim test (FST), tail suspension test (TST), mRNA and protein expression levels of GABA A receptors. Therefore, these results indicate that GABA green tea may have a health effect on prevention and alleviation of depression, and it works on the GABAergic neurotransmission of mouse cerebral cortex via up-regulating expression of the GABA A receptor α1 subunit, thus ameliorating depression.

GABAergic Neurotransmission in the Pontine Reticular Formation Modulates Hypnosis, Immobility, and Breathing during Isoflurane Anesthesia

PubMed Central

Vanini, Giancarlo; Watson, Christopher J.; Lydic, Ralph; Baghdoyan, Helen A.

2009-01-01

Background Many general anesthetics are thought to produce a loss of wakefulness, in part, by enhancing gamma-aminobutyric acid (GABA) neurotransmission. However, GABAergic neurotransmission in the pontine reticular formation promotes wakefulness. This study tested the hypotheses that: 1) relative to wakefulness, isoflurane decreases GABA levels in the pontine reticular formation; and 2) pontine reticular formation administration of drugs that increase or decrease GABA levels increases or decreases, respectively, isoflurane induction time. Methods To test hypothesis 1, cats (n = 5) received a craniotomy and permanent electrodes for recording the electroencephalogram and electromyogram. Dialysis samples were collected from the pontine reticular formation during isoflurane anesthesia and wakefulness. GABA levels were quantified using high performance liquid chromatography. For hypothesis 2, rats (n = 10) were implanted with a guide cannula aimed for the pontine reticular formation. Each rat received microinjections of Ringer’s (vehicle control), the GABA uptake inhibitor nipecotic acid, and the GABA synthesis inhibitor 3-mercaptopropionic acid. Rats were then anesthetized with isoflurane and induction time was quantified as loss of righting reflex. Breathing rate was also measured. Results Relative to wakefulness, GABA levels were significantly decreased by isoflurane. Increased power in the electroencephalogram and decreased activity in the electromyogram caused by isoflurane co-varied with pontine reticular formation GABA levels. Nipecotic acid and 3-mercaptopropionic acid significantly increased and decreased, respectively, isoflurane induction time. Nipecotic acid also increased breathing rate. Conclusion Decreasing pontine reticular formation GABA levels comprises one mechanism by which isoflurane causes loss of consciousness, altered cortical excitability, muscular hypotonia, and decreased respiratory rate. PMID:19034094

Gamma-aminobutyric acid-mediated neurotransmission in the pontine reticular formation modulates hypnosis, immobility, and breathing during isoflurane anesthesia.

PubMed

Vanini, Giancarlo; Watson, Christopher J; Lydic, Ralph; Baghdoyan, Helen A

2008-12-01

Many general anesthetics are thought to produce a loss of wakefulness, in part, by enhancing gamma-aminobutyric acid (GABA) neurotransmission. However, GABAergic neurotransmission in the pontine reticular formation promotes wakefulness. This study tested the hypotheses that (1) relative to wakefulness, isoflurane decreases GABA levels in the pontine reticular formation; and (2) pontine reticular formation administration of drugs that increase or decrease GABA levels increases or decreases, respectively, isoflurane induction time. To test hypothesis 1, cats (n = 5) received a craniotomy and permanent electrodes for recording the electroencephalogram and electromyogram. Dialysis samples were collected from the pontine reticular formation during isoflurane anesthesia and wakefulness. GABA levels were quantified using high-performance liquid chromatography. For hypothesis 2, rats (n = 10) were implanted with a guide cannula aimed for the pontine reticular formation. Each rat received microinjections of Ringer's (vehicle control), the GABA uptake inhibitor nipecotic acid, and the GABA synthesis inhibitor 3-mercaptopropionic acid. Rats were then anesthetized with isoflurane, and induction time was quantified as loss of righting reflex. Breathing rate was also measured. Relative to wakefulness, GABA levels were significantly decreased by isoflurane. Increased power in the electroencephalogram and decreased activity in the electromyogram caused by isoflurane covaried with pontine reticular formation GABA levels. Nipecotic acid and 3-mercaptopropionic acid significantly increased and decreased, respectively, isoflurane induction time. Nipecotic acid also increased breathing rate. Decreasing pontine reticular formation GABA levels comprises one mechanism by which isoflurane causes loss of consciousness, altered cortical excitability, muscular hypotonia, and decreased respiratory rate.

The Improvement of Sleep by Oral Intake of GABA and Apocynum venetum Leaf Extract.

PubMed

Yamatsu, Atsushi; Yamashita, Yusuke; Maru, Isafumi; Yang, Jinwei; Tatsuzaki, Jin; Kim, Mujo

2015-01-01

The effects of two food materials, γ-aminobutyric acid (GABA) produced by natural fermentation and Apocynum venetum leaf extract (AVLE), on the improvement of sleep were investigated in humans. The electroencephalogram (EEG) test revealed that oral administration of GABA (100 mg) and AVLE (50 mg) had beneficial effects on sleep. GABA shortened sleep latency by 5.3 min and AVLE increased non-rapid eye movement (REM) sleep time by 7.6%. Simultaneous intake of GABA and AVLE shortened sleep latency by 4.3 min and increased non-REM sleep time by 5.1%. The result of questionnaires showed that GABA and AVLE enabled subjects to realize the effects on sleep. These results mean that GABA can help people to fall asleep quickly, AVLE induces deep sleep, and they function complementarily with simultaneous intake. Since both GABA and AVLE are materials of foods and have been ingested for a long time, they can be regarded as safe and appropriate for daily intake in order to improve the quality of sleep.

Short-term dopaminergic regulation of GABA release in dopamine deafferented caudate-putamen is not directly associated with glutamic acid decarboxylase gene expression.

PubMed

O'Connor, W T; Lindefors, N; Brené, S; Herrera-Marschitz, M; Persson, H; Ungerstedt, U

1991-07-08

In vivo microdialysis and in situ hybridization were combined to study dopaminergic regulation of gamma-amino butyric acid (GABA) neurons in rat caudate-putamen (CPu). Potassium-stimulated GABA release in CPu was elevated following a dopamine deafferentation. Local perfusion with exogenous dopamine (50 microM) for 3 h via the microdialysis probe attenuated the potassium-stimulated increase in extracellular GABA in CPu. Expression of glutamic acid decarboxylase (GAD) mRNA was also increased in the dopamine deafferented CPu. However, local perfusion with dopamine had no significant attenuating effect on the increased GAD mRNA expression. These findings indicate that dopaminergic regulation of GABA neurons in the dopamine deafferented CPu includes both a short-term effect at the level of GABA release independent of changes in GAD mRNA expression and a long-term modulation at the level of GAD gene expression.

Anxiety in major depression and cerebrospinal fluid free gamma-aminobutyric acid.

PubMed

Mann, J John; Oquendo, Maria A; Watson, Kalycia Trishana; Boldrini, Maura; Malone, Kevin M; Ellis, Steven P; Sullivan, Gregory; Cooper, Thomas B; Xie, Shan; Currier, Dianne

2014-10-01

Low gamma-aminobutyric acid (GABA) is implicated in both anxiety and depression pathophysiology. They are often comorbid, but most clinical studies have not examined these relationships separately. We investigated the relationship of cerebrospinal fluid (CSF) free GABA to the anxiety and depression components of a major depressive episode (MDE) and to monoamine systems. Patients with a DSM-IV major depressive episode (N = 167: 130 major depressive disorder; 37 bipolar disorder) and healthy volunteers (N = 38) had CSF free GABA measured by gas chromatography mass spectroscopy. Monoamine metabolites were assayed by high performance liquid chromatography. Symptomatology was assessed by Hamilton depression rating scale. Psychic anxiety severity increased with age and correlated with lower CSF free GABA, controlling for age. CSF free GABA declined with age but was not related to depression severity. Other monoamine metabolites correlated positively with CSF GABA but not with psychic anxiety or depression severity. CSF free GABA was lower in MDD compared with bipolar disorder and healthy volunteers. GABA levels did not differ based on a suicide attempt history in mood disorders. Recent exposure to benzodiazepines, but not alcohol or past alcoholism, was associated with a statistical trend for more severe anxiety and lower CSF GABA. Lower CSF GABA may explain increasing severity of psychic anxiety in major depression with increasing age. This relationship is not seen with monoamine metabolites, suggesting treatments targeting the GABAergic system should be evaluated in treatment-resistant anxious major depression and in older patients. © 2014 Wiley Periodicals, Inc.

GABA Signaling Promotes Synapse Elimination and Axon Pruning in Developing Cortical Inhibitory Interneurons

PubMed Central

Wu, Xiaoyun; Fu, Yu; Knott, Graham; Lu, Jiangteng; Di Cristo, Graziella

2012-01-01

Accumulating evidence indicates that GABA acts beyond inhibitory synaptic transmission and regulates the development of inhibitory synapses in the vertebrate brain, but the underlying cellular mechanism is not well understood. We have combined live imaging of cortical GABAergic axons across time scales from minutes to days with single-cell genetic manipulation of GABA release to examine its role in distinct steps of inhibitory synapse formation in the mouse neocortex. We have shown previously, by genetic knockdown of GABA synthesis in developing interneurons, that GABA signaling promotes the maturation of inhibitory synapses and axons. Here we found that a complete blockade of GABA release in basket interneurons resulted in an opposite effect, a cell-autonomous increase in axon and bouton density with apparently normal synapse structures. These results not only demonstrate that GABA is unnecessary for synapse formation per se but also uncover a novel facet of GABA in regulating synapse elimination and axon pruning. Live imaging revealed that developing GABAergic axons form a large number of transient boutons, but only a subset was stabilized. Release blockade led to significantly increased bouton stability and filopodia density, increased axon branch extension, and decreased branch retraction. Our results suggest that a major component of GABA function in synapse development is transmission-mediated elimination of subsets of nascent contacts. Therefore, GABA may regulate activity-dependent inhibitory synapse formation by coordinately eliminating certain nascent contacts while promoting the maturation of other nascent synapses. PMID:22219294

Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target.

PubMed

Hiu, Takeshi; Farzampour, Zoya; Paz, Jeanne T; Wang, Eric Hou Jen; Badgely, Corrine; Olson, Andrew; Micheva, Kristina D; Wang, Gordon; Lemmens, Robin; Tran, Kevin V; Nishiyama, Yasuhiro; Liang, Xibin; Hamilton, Scott A; O'Rourke, Nancy; Smith, Stephen J; Huguenard, John R; Bliss, Tonya M; Steinberg, Gary K

2016-02-01

Ischaemic stroke is the leading cause of severe long-term disability yet lacks drug therapies that promote the repair phase of recovery. This repair phase of stroke occurs days to months after stroke onset and involves brain remapping and plasticity within the peri-infarct zone. Elucidating mechanisms that promote this plasticity is critical for the development of new therapeutics with a broad treatment window. Inhibiting tonic (extrasynaptic) GABA signalling during the repair phase was reported to enhance functional recovery in mice suggesting that GABA plays an important function in modulating brain repair. While tonic GABA appears to suppress brain repair after stroke, less is known about the role of phasic (synaptic) GABA during the repair phase. We observed an increase in postsynaptic phasic GABA signalling in mice within the peri-infarct cortex specific to layer 5; we found increased numbers of α1 receptor subunit-containing GABAergic synapses detected using array tomography, and an associated increased efficacy of spontaneous and miniature inhibitory postsynaptic currents in pyramidal neurons. Furthermore, we demonstrate that enhancing phasic GABA signalling using zolpidem, a Food and Drug Administration (FDA)-approved GABA-positive allosteric modulator, during the repair phase improved behavioural recovery. These data identify potentiation of phasic GABA signalling as a novel therapeutic strategy, indicate zolpidem's potential to improve recovery, and underscore the necessity to distinguish the role of tonic and phasic GABA signalling in stroke recovery. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.

Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target

PubMed Central

Paz, Jeanne T.; Wang, Eric Hou Jen; Badgely, Corrine; Olson, Andrew; Micheva, Kristina D.; Wang, Gordon; Lemmens, Robin; Tran, Kevin V.; Nishiyama, Yasuhiro; Liang, Xibin; Hamilton, Scott A.; O’Rourke, Nancy; Smith, Stephen J.; Huguenard, John R.; Bliss, Tonya M.

2016-01-01

Abstract Ischaemic stroke is the leading cause of severe long-term disability yet lacks drug therapies that promote the repair phase of recovery. This repair phase of stroke occurs days to months after stroke onset and involves brain remapping and plasticity within the peri-infarct zone. Elucidating mechanisms that promote this plasticity is critical for the development of new therapeutics with a broad treatment window. Inhibiting tonic (extrasynaptic) GABA signalling during the repair phase was reported to enhance functional recovery in mice suggesting that GABA plays an important function in modulating brain repair. While tonic GABA appears to suppress brain repair after stroke, less is known about the role of phasic (synaptic) GABA during the repair phase. We observed an increase in postsynaptic phasic GABA signalling in mice within the peri-infarct cortex specific to layer 5; we found increased numbers of α1 receptor subunit-containing GABAergic synapses detected using array tomography, and an associated increased efficacy of spontaneous and miniature inhibitory postsynaptic currents in pyramidal neurons. Furthermore, we demonstrate that enhancing phasic GABA signalling using zolpidem, a Food and Drug Administration (FDA)-approved GABA-positive allosteric modulator, during the repair phase improved behavioural recovery. These data identify potentiation of phasic GABA signalling as a novel therapeutic strategy, indicate zolpidem’s potential to improve recovery, and underscore the necessity to distinguish the role of tonic and phasic GABA signalling in stroke recovery. PMID:26685158

ANXIETY IN MAJOR DEPRESSION AND CEREBROSPINAL FLUID FREE GAMMA-AMINOBUTYRIC ACID

PubMed Central

Mann, J. John; Oquendo, Maria A.; Watson, Kalycia Trishana; Boldrini, Maura; Malone, Kevin M.; Ellis, Steven P.; Sullivan, Gregory; Cooper, Thomas B.; Xie, Shan; Currier, Dianne

2016-01-01

Background Low gamma-aminobutyric acid (GABA) is implicated in both anxiety and depression pathophysiology. They are often comorbid, but most clinical studies have not examined these relationships separately. We investigated the relationship of cerebrospinal fluid (CSF) free GABA to the anxiety and depression components of a major depressive episode (MDE) and to monoamine systems. Methods and Materials Patients with a DSM-IV major depressive episode (N = 167: 130 major depressive disorder; 37 bipolar disorder) and healthy volunteers (N = 38) had CSF free GABA measured by gas chromatography mass spectroscopy. Monoamine metabolites were assayed by high performance liquid chromatography. Symptomatology was assessed by Hamilton depression rating scale. Results Psychic anxiety severity increased with age and correlated with lower CSF free GABA, controlling for age. CSF free GABA declined with age but was not related to depression severity. Other monoamine metabolites correlated positively with CSF GABA but not with psychic anxiety or depression severity. CSF free GABA was lower in MDD compared with bipolar disorder and healthy volunteers. GABA levels did not differ based on a suicide attempt history in mood disorders. Recent exposure to benzodiazepines, but not alcohol or past alcoholism, was associated with a statistical trend for more severe anxiety and lower CSF GABA. Conclusions Lower CSF GABA may explain increasing severity of psychic anxiety in major depression with increasing age. This relationship is not seen with monoamine metabolites, suggesting treatments targeting the GABAergic system should be evaluated in treatment-resistant anxious major depression and in older patients. PMID:24865448

In vivo electroretinographic studies of the role of GABA C receptors in retinal signal processing

DOE PAGES

Wang, Jing; Mojumder, Deb Kumar; Yan, Jun; ...

2015-07-08

The retina expresses all three classes of receptors for the inhibitory neurotransmitter GABA (GABAR). Our study investigated roles of GABAR, especially GABA(C)R (GABA(A)-rho), in retinal signaling in vivo by studying effects on the mouse electroretinogram (ERG) of genetic deletion of GABA(C)R versus pharmacological blockade using receptor antagonists. Brief full-field flash ERGs were recorded from anesthetized GABA(C)R(-/-) mice, and WT C57BL/6 (B6) mice, before and after intravitreal injection of GABA(C)R antagonists, TPMPA, 3-APMPA, or the more recently developed 2-AEMP; GABA(A)R antagonist, SR95531; GABA(B)R antagonist, CGP, and agonist, baclofen. Intravitreal injections of TPMPA and SR95531 were also made in Brown Norway rats.more » The effect of 2-AEMP on GABA-induced current was tested directly in isolated rat rod bipolar cells, and 2-AEMP was found to preferentially block GABA(C)R in those cells. Maximum amplitudes of dark (DA) and light-adapted (LA) ERG b-waves were reduced in GABA(C)R(-/-) mice, compared to B6 mice, by 30-60%; a-waves were unaltered and oscillatory potential amplitudes were increased. In B6 mice, after injection of TPMPA (also in rats), 3-APMPA or 2-AEMP, ERGs became similar to ERGs of GABA(C)R(-/-) mice. Blockade of GABA(A)Rs and GABA(B)Rs, or agonism of GABA(B)Rs did not alter B6 DA b-wave amplitude. Furthermore, the negative scotopic threshold response (nSTR) was slightly less sensitive in GABA(C)R(-/-) than in B6 mice, and unaltered by 2-AEMP. However, amplitudes of nSTR and photopic negative response (PhNR), both of which originate from inner retina, were enhanced by TPMPA and 3-APMPA, each of which has GABA(B) agonist properties, and further increased by baclofen. The finding that genetic deletion of GABA(C)R, the GABA(C)R antagonist 2-AEMP, and other antagonists all reduced ERG b-wave amplitude, supports a role for CABA(C)R in determining the maximum response amplitude of bipolar cells contributing to the b-wave. GABA(C)R antagonists differed in their effects on nSTR and PhNR; antagonists with GABA(B) agonist properties enhanced light-driven responses whereas 2-AEMP did not.« less

2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABA A-ρ1 Receptors

DOE PAGES

Xie, A.; Yan, J.; Yue, L.; ...

2011-08-02

All three classes of receptors for the inhibitory neurotransmitter GABA (GABAR) are expressed in the retina. This study investigated roles of GABAR, especially GABA(C)R (GABA(A)-rho), in retinal signaling in vivo by studying effects on the mouse electroretinogram (ERG) of genetic deletion of GABA(C)R versus pharmacological blockade using receptor antagonists. Brief full-field flash ERGs were recorded from anesthetized GABA(C)R(-/-) mice, and WT C57BL/6 (B6) mice, before and after intravitreal injection of GABA(C)R antagonists, TPMPA, 3-APMPA, or the more recently developed 2-AEMP; GABA(A)R antagonist, SR95531; GABA(B)R antagonist, CGP, and agonist, baclofen. Intravitreal injections of TPMPA and SR95531 were also made in Brownmore » Norway rats. The effect of 2-AEMP on GABA-induced current was tested directly in isolated rat rod bipolar cells, and 2-AEMP was found to preferentially block GABA(C)R in those cells. Maximum amplitudes of dark (DA) and light-adapted (LA) ERG b-waves were reduced in GABA(C)R(-/-) mice, compared to B6 mice, by 30-60%; a-waves were unaltered and oscillatory potential amplitudes were increased. In B6 mice, after injection of TPMPA (also in rats), 3-APMPA or 2-AEMP, ERGs became similar to ERGs of GABA(C)R(-/-) mice. Blockade of GABA(A)Rs and GABA(B)Rs, or agonism of GABA(B)Rs did not alter B6 DA b-wave amplitude. The negative scotopic threshold response (nSTR) was slightly less sensitive in GABA(C)R(-/-) than in B6 mice, and unaltered by 2-AEMP. However, amplitudes of nSTR and photopic negative response (PhNR), both of which originate from inner retina, were enhanced by TPMPA and 3-APMPA, each of which has GABA(B) agonist properties, and further increased by baclofen. The finding that genetic deletion of GABA(C)R, the GABA(C)R antagonist 2-AEMP, and other antagonists all reduced ERG b-wave amplitude, supports a role for CABA(C)R in determining the maximum response amplitude of bipolar cells contributing to the b-wave. GABA(C)R antagonists differed in their effects on nSTR and PhNR; antagonists with GABA(B) agonist properties enhanced light-driven responses whereas 2-AEMP did not.« less

Enhanced productivity of gamma-amino butyric acid by cascade modifications of a whole-cell biocatalyst.

PubMed

Yang, Xinwei; Ke, Chongrong; Zhu, Jiangming; Wang, Yan; Zeng, Wenchao; Huang, Jianzhong

2018-04-01

We previously developed a gamma-amino butyric acid (GABA)-producing strain of Escherichia coli, leading to production of 614.15 g/L GABA at 45 °C from L-glutamic acid (L-Glu) with a productivity of 40.94 g/L/h by three successive whole-cell conversion cycles. However, the increase in pH caused by the accumulation of GABA resulted in inactivation of the biocatalyst and consequently led to relatively lower productivity. In this study, by overcoming the major problem associated with the increase in pH during the production process, a more efficient biocatalyst was obtained through cascade modifications of the previously reported E. coli strain. First, we introduced four amino acid mutations to the codon-optimized GadB protein from Lactococcus lactis to shift its decarboxylation activity toward a neutral pH, resulting in 306.65 g/L of GABA with 99.14 mol% conversion yield and 69.8% increase in GABA productivity. Second, we promoted transportation of L-Glu and GABA by removing the genomic region encoding the C-plug of GadC (a glutamate/GABA antiporter) to allow its transport path to remain open at a neutral pH, which improved the GABA productivity by 16.8% with 99.3 mol% conversion of 3 M L-Glu. Third, we enhanced the expression of soluble GadB by introducing the GroESL molecular chaperones, leading to 20.2% improvement in GABA productivity, with 307.40 g/L of GABA and a 61.48 g/L/h productivity obtained in one cycle. Finally, we inhibited the degradation of GABA by inactivation of gadA and gadB from the E. coli genome, which resulted in almost no GABA degradation after 40 h. After the cascade system modifications, the engineered recombinant E. coli strain achieved a 44.04 g/L/h productivity with a 99.6 mol% conversion of 3 M L-Glu in a 5-L bioreactor, about twofold increase in productivity compared to the starting strain. This increase represents the highest GABA productivity by whole-cell bioconversion using L-Glu as a substrate in one cycle observed to date, even better than the productivity obtained from the three successive conversion cycles.

Overexpression of CB2 cannabinoid receptors decreased vulnerability to anxiety and impaired anxiolytic action of alprazolam in mice.

PubMed

García-Gutiérrez, María S; Manzanares, Jorge

2011-01-01

Mice overexpressing CB2r (CB2xP) were exposed to open field (OF), light-dark box (LDB) and elevated plus maze (EPM) tests. Corticotropin-releasing factor (CRF) and pro-opiomelanocortin (POMC) mRNA were measured in paraventricular (PVN) and arcuate (ARC) nuclei of the hypothalamus after 30 minutes of restraint stress (RS). Anxiolytic effects of alprazolam (45 or 70 µg/kg, ip) were evaluated. GABA(A)α(2) and GABA(A)γ(2) mRNA were measured in the hippocampus (HIPP) and amygdala (AMY) of CB2xP and wild type (WT) mice. No differences were observed in the total distance travelled by CB2xP and WT mice in OF. Central and peripheral distances travelled significantly increased and decreased in CB2xP mice. Overexpression of CB2r reduced anxiety-like behaviours in LDB and EPM. In WT mice, RS increased CRF (82%) and POMC (42%) mRNA in the PVN and ARC nuclei, respectively. In CB2xP mice, RS also increased POMC (22%) mRNA in the ARC nucleus, but had no effect on CRF mRNA in the PVN nucleus. Administration of alprazolam was without effect in CB2xP mice. An increase of GABA(A)α(2) and GABA(A)γ(2) mRNA in the hippocampus and amygdala of CB2xP mice was observed. Our findings revealed that increased expression of CB2r significantly reduced anxiogenic-related behaviours, modified the response to stress and impaired the action of anxiolytic drugs.

Baclofen and phaclofen modulate GABA release from slices of rat cerebral cortex and spinal cord but not from retina.

PubMed Central

Neal, M. J.; Shah, M. A.

1989-01-01

1. The effects of (-)-baclofen, muscimol and phaclofen on endogenous gamma-aminobutyric acid (GABA) release from rat cortical slices, spinal cord slices and entire retinas were studied. 2. The spontaneous resting release of GABA from the three tissues was 3 to 6 pmol mg-1 wet wt 10 min-1. Depolarization of cortical slices with KCl (50 mM) (high-K) produced an 8 fold increase in GABA release but high-K did not evoke an increased release of GABA from spinal slices or retinas. 3. When rats were injected with gamma-vinyl-GABA (250 mg kg-1 i.p.) (GVG) 18 h before death, the tissue GABA stores were increased 3 to 6 fold and high-K then evoked striking Ca-dependent releases of GABA from all three tissues. Thus, in subsequent experiments, unless otherwise stated, the nervous tissues were taken from GVG-treated rats. 4. (-)-Baclofen (10 microM) significantly reduced the K-evoked release of GABA from cortical and spinal slices but retinal release was not affected, even at a concentration of (+/-)-baclofen of 1 mM. For cortical slices, the IC50 for baclofen was approximately 5.2 microM. The inhibitory effect of baclofen on GABA release from cortical slices also occurred in slices prepared from saline-injected rats, indicating that GVG treatment did not qualitatively affect the results. 5. The inhibitory effect of (-)-baclofen on the K-evoked release of GABA from cortical and spinal slices was antagonised by phaclofen (500 microM), confirming that baclofen was producing its effects by acting at the GABAB-receptor.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2804540

Inhibition of GABA synthesis in the prefrontal cortex increases locomotor activity but does not affect attention in the 5-choice serial reaction time task.

PubMed

Asinof, Samuel K; Paine, Tracie A

2013-02-01

Attention deficits are a core cognitive symptom of schizophrenia; the neuropathology underlying these deficits is not known. Attention is regulated, at least in part, by the prefrontal cortex (PFC), a brain area in which pathology of γ-aminobutyric acid (GABA) neurons has been consistently observed in post-mortem analysis of the brains of people with schizophrenia. Specifically, expression of the 67-kD isoform of the GABA synthesis enzyme glutamic acid decarboxylase (GAD67) is reduced in parvalbumin-containing fast-spiking GABA interneurons. Thus it is hypothesized that reduced cortical GABA synthesis and release may contribute to the attention deficits in schizophrenia. Here the effect of reducing cortical GABA synthesis with l-allylglycine (LAG) on attention was tested using three different versions of the 5-choice serial reaction time task (5CSRTT). Because 5CSRTT performance can be affected by locomotor activity, we also measured this behavior in an open field. Finally, the expression of Fos protein was used as an indirect measure of reduced GABA synthesis. Intra-cortical LAG (10 μg/0.5 μl/side) infusions increased Fos expression and resulted in hyperactivity in the open field. Intra-cortical LAG infusions did not affect attention in any version of the 5CSRTT. These results suggest that a general decrease in GABA synthesis is not sufficient to cause attention deficits. It remains to be tested whether a selective decrease in GABA synthesis in parvalbumin-containing GABA neurons could cause attention deficits. Decreased cortical GABA synthesis did increase locomotor activity; this may reflect the positive symptoms of schizophrenia. Copyright © 2012 Elsevier Ltd. All rights reserved.

Optimization of culture conditions for gamma-aminobutyric acid production in fermented adzuki bean milk.

PubMed

Song, Hung Yi; Yu, Roch Chui

2018-01-01

γ-Aminobutyric acid (GABA), a nonprotein amino acid, is widely distributed in nature and fulfills several physiological functions. In this study, various lactic acid strains commonly used to produce fermented milk products were inoculated into adzuki bean milk for producing GABA. The high GABA producing strain was selected in further experiment to improve the GABA production utilizing culture medium optimization. The results demonstrated that adzuki bean milk inoculated with Lactobacillus rhamnosus GG increased GABA content from 0.05 mg/mL to 0.44 mg/mL after 36 hours of fermentation, which showed the greatest elevation in this study. Furthermore, the optimal cultural condition to adzuki bean milk inoculated with L. rhamnosus GG to improve the GABA content was performed using response surface methodology. The results showed that GABA content was dependent on the addition of galactose, monosodium glutamate, and pyridoxine with which the increasing ratios of GABA were 23-38%, 24-68%, and 8-36%, respectively. The optimal culture condition for GABA production of adzuki bean milk was found at the content of 1.44% galactose, 2.27% monosodium glutamate, and 0.20% pyridoxine. Under the optimal cultural condition, the amount of GABA produced in the fermented adzuki bean milk was 1.12 mg/mL, which was 22.4-fold higher than that of the unfermented adzuki bean milk (0.05 mg/100 mL). The results suggested that the optimized cultural condition of adzuki bean milk inoculated with L. rhamnosus GG can increase GABA content for consumers as a daily supplement as suggested. Copyright © 2017. Published by Elsevier B.V.

Increased GABA(A) inhibition of the RVLM after hindlimb unloading in rats

NASA Technical Reports Server (NTRS)

Moffitt, Julia A.; Heesch, Cheryl M.; Hasser, Eileen M.

2002-01-01

Attenuated baroreflex-mediated increases in renal sympathetic nerve activity (RSNA) in hindlimb unloaded (HU) rats apparently are due to changes within the central nervous system. We hypothesized that GABA(A) receptor-mediated inhibition of the rostral ventrolateral medulla (RVLM) is increased after hindlimb unloading. Responses to bilateral microinjection of the GABA(A) antagonist (-)-bicuculline methiodide (BIC) into the RVLM were examined before and during caudal ventrolateral medulla (CVLM) inhibition in Inactin-anesthetized control and HU rats. Increases in mean arterial pressure (MAP), heart rate (HR), and RSNA in response to BIC in the RVLM were significantly enhanced in HU rats. Responses to bilateral CVLM blockade were not different. When remaining GABA(A) inhibition in the RVLM was blocked by BIC during CVLM inhibition, the additional increases in MAP and RSNA were significantly greater in HU rats. These data indicate that GABA(A) receptor-mediated inhibition of RVLM neurons is augmented after hindlimb unloading. Effects of input from the CVLM were unaltered. Thus, after cardiovascular deconditioning in rodents, the attenuated increase in sympathetic nerve activity in response to hypotension is associated with greater GABA(A) receptor-mediated inhibition of RVLM neurons originating at least in part from sources other than the CVLM.

Seizure-induced alterations in fast-spiking basket cell GABA currents modulate frequency and coherence of gamma oscillation in network simulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Proddutur, Archana; Yu, Jiandong; Elgammal, Fatima S.

2013-12-15

Gamma frequency oscillations have been proposed to contribute to memory formation and retrieval. Fast-spiking basket cells (FS-BCs) are known to underlie development of gamma oscillations. Fast, high amplitude GABA synapses and gap junctions have been suggested to contribute to gamma oscillations in FS-BC networks. Recently, we identified that, apart from GABAergic synapses, FS-BCs in the hippocampal dentate gyrus have GABAergic currents mediated by extrasynaptic receptors. Our experimental studies demonstrated two specific changes in FS-BC GABA currents following experimental seizures [Yu et al., J. Neurophysiol. 109, 1746 (2013)]: increase in the magnitude of extrasynaptic (tonic) GABA currents and a depolarizing shiftmore » in GABA reversal potential (E{sub GABA}). Here, we use homogeneous networks of a biophysically based model of FS-BCs to examine how the presence of extrasynaptic GABA conductance (g{sub GABA-extra}) and experimentally identified, seizure-induced changes in g{sub GABA-extra} and E{sub GABA} influence network activity. Networks of FS-BCs interconnected by fast GABAergic synapses developed synchronous firing in the dentate gamma frequency range (40–100 Hz). Systematic investigation revealed that the biologically realistic range of 30 to 40 connections between FS-BCs resulted in greater coherence in the gamma frequency range when networks were activated by Poisson-distributed dendritic synaptic inputs rather than by homogeneous somatic current injections, which were balanced for FS-BC firing frequency in unconnected networks. Distance-dependent conduction delay enhanced coherence in networks with 30–40 FS-BC interconnections while inclusion of gap junctional conductance had a modest effect on coherence. In networks activated by somatic current injections resulting in heterogeneous FS-BC firing, increasing g{sub GABA-extra} reduced the frequency and coherence of FS-BC firing when E{sub GABA} was shunting (−74 mV), but failed to alter average FS-BC frequency when E{sub GABA} was depolarizing (−54 mV). When FS-BCs were activated by biologically based dendritic synaptic inputs, enhancing g{sub GABA-extra} reduced the frequency and coherence of FS-BC firing when E{sub GABA} was shunting and increased average FS-BC firing when E{sub GABA} was depolarizing. Shifting E{sub GABA} from shunting to depolarizing potentials consistently increased network frequency to and above high gamma frequencies (>80 Hz). Since gamma oscillations may contribute to learning and memory processing [Fell et al., Nat. Neurosci. 4, 1259 (2001); Jutras et al., J. Neurosci. 29, 12521 (2009); Wang, Physiol. Rev. 90, 1195 (2010)], our demonstration that network oscillations are modulated by extrasynaptic inhibition in FS-BCs suggests that neuroactive compounds that act on extrasynaptic GABA receptors could impact memory formation by modulating hippocampal gamma oscillations. The simulation results indicate that the depolarized FS-BC GABA reversal, observed after experimental seizures, together with enhanced spillover extrasynaptic GABA currents are likely to promote generation of focal high frequency activity associated with epileptic networks.« less

Improvement in verbal memory following SSRI augmentation of antipsychotic treatment is associated with changes in the expression of mRNA encoding for the GABA-A receptor and BDNF in PMC of schizophrenic patients.

PubMed

Silver, Henry; Mandiuk, Nina; Einoch, Reef; Susser, Ehud; Danovich, Lena; Bilker, Warren; Youdim, Moussa; Weinreb, Orly

2015-05-01

Verbal memory impairment in schizophrenia is associated with abnormalities in gamma-aminobutyric acid (GABA)-ergic and brain-derived neurotrophic factor (BDNF) systems. Recent evidence from animal and clinical studies that adding fluvoxamine to antipsychotics alters the expression of transcripts encoding for the GABA-A receptor and BDNF led us to postulate that fluvoxamine augmentation may improve memory in schizophrenia. To test this, we examined the effect of add-on fluvoxamine on verbal memory and other cognitive functions and related it to the expression of mRNA coding for the GABA-A receptor and BDNF in peripheral mononuclear cells (PMC) of schizophrenic patients. Twenty-nine patients completed a 6-week study in which fluvoxamine (100 mg/day) was added to ongoing antipsychotic treatment. Verbal memory, abstraction working memory, object and face recognition, and psychomotor speed and clinical symptoms were assessed at baseline and after 3 and 6 weeks of treatment. Blood samples were taken at baseline and weeks 1, 3, and 6 and PMC was assayed for the GABA-A beta3 receptor and BDNF mRNA by quantitative real-time reverse transcription-PCR. Associative and logical verbal memory improved significantly and showed a significant correlation with changes in PMC BDNF and GABA-A beta3 receptor mRNA, which increased during treatment. Abstraction and object recognition improved, but this did not correlate with PMC measures. Negative and positive symptoms improved significantly; the latter showed significant correlations with changes in PMC measures. Addition of fluvoxamine to antipsychotics improves verbal memory. It is postulated that the mechanism involves enhanced GABA-A receptor/BDNF-dependent synaptic plasticity in the hippocampus.

Axonal GABAA receptors.

PubMed

Trigo, Federico F; Marty, Alain; Stell, Brandon M

2008-09-01

Type A GABA receptors (GABA(A)Rs) are well established as the main inhibitory receptors in the mature mammalian forebrain. In recent years, evidence has accumulated showing that GABA(A)Rs are prevalent not only in the somatodendritic compartment of CNS neurons, but also in their axonal compartment. Evidence for axonal GABA(A)Rs includes new immunohistochemical and immunogold data: direct recording from single axonal terminals; and effects of local applications of GABA(A)R modulators on action potential generation, on axonal calcium signalling, and on neurotransmitter release. Strikingly, whereas presynaptic GABA(A)Rs have long been considered inhibitory, the new studies in the mammalian brain mostly indicate an excitatory action. Depending on the neuron that is under study, axonal GABA(A)Rs can be activated by ambient GABA, by GABA spillover, or by an autocrine action, to increase either action potential firing and/or transmitter release. In certain neurons, the excitatory effects of axonal GABA(A)Rs persist into adulthood. Altogether, axonal GABA(A)Rs appear as potent neuronal modulators of the mammalian CNS.

A review of evidence for GABergic predominance/glutamatergic deficit as a common etiological factor in both schizophrenia and affective psychoses: more support for a continuum hypothesis of "functional" psychosis.

PubMed

Squires, R F; Saederup, E

1991-10-01

Virtually all antidepressant and antipsychotic drugs, including clozapine, rimcazole and lithium ion, are proconvulsants, and convulsive therapy, using metrazol, a known GABA-A antagonist, as well as electro-convulsive therapy, can be effective in treating both schizophrenia and affective psychoses. Many antidepressant and antipsychotic drugs, including clozapine, as well as some of their metabolites, reverse the inhibitory effect of GABA on 35S-TBPS binding, a reliable predictor of GABA-A receptor blockade. A review of relevant literature suggests that 1) "functional" psychoses constitute a continuum of disorders ranging from schizophrenia to affective psychoses with overlap of symptoms, heredity and treatments, 2) a weakening of GABergic inhibitory activity, or potentiation of counterbalancing glutamatergic neurotransmission, in the brain, may be involved in the therapeutic activities of both antidepressant and antipsychotic drugs, and 3) schizophrenia and the affective psychoses may be different expressions of the same underlying defect: GABergic preponderance/glutamatergic deficit. Schizophrenia and affective psychoses share the following: 1) several treatments are effective in both, 2) similar modes of inheritance, 3) congruent seasonal birth excesses, 4) enlarged cerebral ventricles and cerebellar vermian atrophy, 5) dexamethasone non-suppression. Both genetic and environmental factors are involved in both schizophrenia and affective psychoses, and several lines of evidence suggest that important environmental factors are neurotropic pathogens that selectively destroy glutamatergic neurons. One group of genes associated with psychoses may increase vulnerability to attack and destruction, by neurotropic pathogens, of excitatory glutamatergic neurons that counterbalance inhibitory GABergic neurons. A second group of genes may encode subunits of overactive GABA-A receptors, while a third group of genes may encode subunits of hypo-active glutamate receptors. Improved antipsychotic drugs may be found among selective blockers of GABA-A receptor subtypes and/or enhancers of glutamatergic neurotransmission. A mechanism similar to kindling, leading to long-lasting reduction of GABergic inhibition in the brain, may be involved in several treatments of psychoses.

Endogenous gamma-aminobutyric acid modulates tonic guinea pig airway tone and propofol-induced airway smooth muscle relaxation.

PubMed

Gallos, George; Gleason, Neil R; Virag, Laszlo; Zhang, Yi; Mizuta, Kentaro; Whittington, Robert A; Emala, Charles W

2009-04-01

Emerging evidence indicates that an endogenous autocrine/paracrine system involving gamma-aminobutyric acid (GABA) is present in airways. GABAA channels, GABAB receptors, and the enzyme that synthesizes GABA have been identified in airway epithelium and smooth muscle. However, the endogenous ligand itself, GABA, has not been measured in airway tissues. The authors sought to demonstrate that GABA is released in response to contractile agonists and tonically contributes a prorelaxant component to contracted airway smooth muscle. The amount and cellular localization of GABA in upper guinea pig airways under resting and contracted tone was determined by high pressure liquid chromatography and immunohistochemistry, respectively. The contribution that endogenous GABA imparts on the maintenance of airway smooth muscle acetylcholine-induced contraction was assessed in intact guinea pig airway tracheal rings using selective GABAA antagonism (gabazine) under resting or acetylcholine-contracted conditions. The ability of an allosteric agent (propofol) to relax a substance P-induced relaxation in an endogenous GABA-dependent manner was assessed. GABA levels increased and localized to airway smooth muscle after contractile stimuli in guinea pig upper airways. Acetylcholine-contracted guinea pig tracheal rings exhibited an increase in contracted force upon addition of the GABAA antagonist gabazine that was subsequently reversed by the addition of the GABAA agonist muscimol. Propofol dose-dependently relaxed a substance P contraction that was blocked by gabazine. These studies demonstrate that GABA is endogenously present and increases after contractile stimuli in guinea pig upper airways and that endogenous GABA contributes a tonic prorelaxant component in the maintenance of airway smooth muscle tone.

Enchancement of Gamma-Aminobutyric Acid Production by Co-Localization of Neurospora crassa OR74A Glutamate Decarboxylase with Escherichia coli GABA Transporter Via Synthetic Scaffold Complex.

PubMed

Somasundaram, Sivachandiran; Maruthamuthu, Murali Kannan; Ganesh, Irisappan; Eom, Gyeong Tae; Hong, Soon Ho

2017-09-28

Gamma-aminobutyric acid is a precursor of nylon-4, which is a promising heat-resistant biopolymer. GABA can be produced from the decarboxylation of glutamate by glutamate decarboxylase. In this study, a synthetic scaffold complex strategy was employed involving the Neurospora crassa glutamate decarboxylase (GadB) and Escherichia coli GABA antiporter (GadC) to improve GABA production. To construct the complex, the SH3 domain was attached to the N. crassa GadB, and the SH3 ligand was attached to the N-terminus, middle, and C-terminus of E. coli GadC. In the C-terminus model, 5.8 g/l of GABA concentration was obtained from 10 g/l glutamate. When a competing pathway engineered strain was used, the final GABA concentration was further increased to 5.94 g/l, which corresponds to 97.5% of GABA yield. With the introduction of the scaffold complex, the GABA productivity increased by 2.9 folds during the initial culture period.

Effects of exogenous gamma-aminobutyric acid on α-amylase activity in the aleurone of barley seeds.

PubMed

Sheng, Yidi; Xiao, Huiyuan; Guo, Chunli; Wu, Hong; Wang, Xiaojing

2018-03-03

Gamma-aminobutyric acid (GABA), a nonprotein amino acid, often accumulates in plants exposed to certain environmental stimuli. Previous studies indicated that a closed relationship existed between endogenous GABA and seed germination. However, there are few studies on the effect of exogenous GABA on seed germination. The objective of this study was to explore whether exogenous GABA affected α-amylase activity which the activation is an important stage in seed germination. The level of endogenous GABA in barley seeds rose gradually during germination, suggesting that endogenous GABA was involved in germination. We measured starch degradation under application of various concentration GABA and found that GABA promoted seed starch degradation with a dose-responsive effect. The relationship between GABA and α-amylase activity was investigated by treating barley aleurone with exogenous GABA. The result showed that α-amylase activity began to rise after about 24 h and reached a peak at 48 h. Molecular evidence suggested that GABA increased α-amylase gene expression. We explore the possible roles played by GABA in signal transduction. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Evaluation of improved γ-aminobutyric acid production in yogurt using Lactobacillus plantarum NDC75017.

PubMed

Shan, Y; Man, C X; Han, X; Li, L; Guo, Y; Deng, Y; Li, T; Zhang, L W; Jiang, Y J

2015-04-01

Most γ-aminobutyric acid (GABA)-producing microorganisms are lactic acid bacteria (LAB), but the yield of GABA is limited in most of these GABA-producing strains. In this study, the production of GABA was carried out by using Lactobacillus plantarum NDC75017, a strain screened from traditional fermented dairy products in China. Concentrations of substrate (l-monosodium glutamate, L-MSG) and coenzyme (pyridoxal-5-phosphate, PLP) of glutamate decarboxylase (GAD) and culture temperature were investigated to evaluate their effects on GABA yield of Lb. plantarum NDC75017. The results indicated that GABA production was related to GAD activity and biomass of Lb. plantarum NDC75017. Response surface methodology was used to optimize conditions of GABA production. The optimal factors for GABA production were L-MSG at 80 mM, PLP at 18 μM, and a culture temperature of 36 °C. Under these conditions, production of GABA was maximized at 314.56 mg/100 g. Addition of Lb. plantarum NDC75017 to a commercial starter culture led to higher GABA production in fermented yogurt. Flavor and texture of the prepared yogurt and the control yogurt did not differ significantly. Thus, Lb. plantarum NDC75017 has good potential for manufacture of GABA-enriched fermented milk products. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Field trial of GABA-fortified rice plants and oral administration of milled rice in spontaneously hypertensive rats.

PubMed

Kowaka, Emi; Shimajiri, Yasuka; Kawakami, Kouhei; Tongu, Miki; Akama, Kazuhito

2015-06-01

Hypertension is one of the most critical risk factors accompanying cardiovascular diseases. γ-Aminobutyric acid (GABA) is a non-protein amino acid that functions as a major neurotransmitter in mammals and also as a blood-pressure lowering agent. We previously produced GABA-fortified rice lines of a popular Japonica rice cultivar 'Koshihikari' by genetic manipulation of GABA shunt-related genes. In the study reported here, we grew these same novel rice lines in a field trial and administered the milled rice orally to rats. The yield parameters of the transgenic rice plants were almost unchanged compared to those of untransformed cv. 'Koshihikari' plants, while the rice grains of the transgenic plants contained a high GABA content (3.5 g GABA/kg brown rice; 0.75-0.85 GABA g/kg milled rice) in a greenhouse trial. Oral administration of a diet containing 2.5% GABA-fortified rice, with a daily intake for 8 weeks, had an approximately 20 mmHg anti-hypertensive effect in spontaneous hypertensive rats but not in normotensive Wistar-Kyoto rats. These results suggest that GABA-fortified rice may be applicable as a staple food to control or prevent hypertension.

Paracrine GABA and insulin regulate pancreatic alpha cell proliferation in a mouse model of type 1 diabetes.

PubMed

Feng, Allen L; Xiang, Yun-Yan; Gui, Le; Kaltsidis, Gesthika; Feng, Qingping; Lu, Wei-Yang

2017-06-01

This study aimed to elucidate the mechanism of increased proliferation of alpha cells in recent-onset type 1 diabetes. Pancreatic beta cells express GAD and produce γ-aminobutyric acid (GABA), which inhibits alpha cell secretion of glucagon. We explored the roles of GABA in alpha cell proliferation in conditions corresponding to type 1 diabetes in a mouse model and in vitro. Type 1 diabetes was induced by injecting the mice with streptozotocin (STZ). Some of the STZ-injected mice were treated with GABA (10 mg/kg daily) for 12 days. Isolated pancreatic islets were treated with STZ or STZ together with GABA for 2 days. The effects of GABA treatment on STZ-induced alpha cell proliferation in vivo and in vitro were assessed. The effect of muscimol, a GABA receptor agonist, on αTC1-6 cell proliferation was also examined. STZ injection substantially decreased levels of GAD, GABA and insulin in pancreatic beta cells 12 h after injection; this was followed by an upsurge of phosphorylated mechanistic target of rapamycin (p-mTOR) in the alpha cells at day 1, and a significant increase in alpha cell mass at day 3. Treating STZ-injected mice with GABA largely restored the immunodetectable levels of insulin and GAD in the beta cells and significantly decreased the number of aldehyde dehydrogenase 1 family, member A3 (ALDH1a3)-positive cells, alpha cell mass and hyperglucagonaemia. STZ treatment also increased alpha cell proliferation in isolated islets, which was reversed by co-treatment with GABA. Muscimol, together with insulin, significantly lowered the level of cytosolic Ca 2+ and p-mTOR, and decreased the proliferation rate of αTC1-6 cells. GABA signalling critically controls the alpha cell population in pancreatic islets. Low intraislet GABA may contribute to alpha cell hyperplasia in early type 1 diabetes.

Cocaine Dysregulates Opioid Gating of GABA Neurotransmission in the Ventral Pallidum

PubMed Central

Scofield, Michael D.; Rice, Kenner C.; Cheng, Kejun; Roques, Bernard P.

2014-01-01

The ventral pallidum (VP) is a target of dense nucleus accumbens projections. Many of these projections coexpress GABA and the neuropeptide enkephalin, a δ and μ opioid receptor (MOR) ligand. Of these two, the MOR in the VP is known to be involved in reward-related behaviors, such as hedonic responses to palatable food, alcohol intake, and reinstatement of cocaine seeking. Stimulating MORs in the VP decreases extracellular GABA, indicating that the effects of MORs in the VP on cocaine seeking are via modulating GABA neurotransmission. Here, we use whole-cell patch-clamp on a rat model of withdrawal from cocaine self-administration to test the hypothesis that MORs presynaptically regulate GABA transmission in the VP and that cocaine withdrawal changes the interaction between MORs and GABA. We found that in cocaine-extinguished rats pharmacological activation of MORs no longer presynaptically inhibited GABA release, whereas blocking the MORs disinhibited GABA release. Moreover, MOR-dependent long-term depression of GABA neurotransmission in the VP was lost in cocaine-extinguished rats. Last, GABA neurotransmission was found to be tonically suppressed in cocaine-extinguished rats. These substantial synaptic changes indicated that cocaine was increasing tone on MOR receptors. Accordingly, increasing endogenous tone by blocking the enzymatic degradation of enkephalin inhibited GABA neurotransmission in yoked saline rats but not in cocaine-extinguished rats. In conclusion, our results indicate that following withdrawal from cocaine self-administration enkephalin levels in the VP are elevated and the opioid modulation of GABA neurotransmission is impaired. This may contribute to the difficulties withdrawn addicts experience when trying to resist relapse. PMID:24431463

GABA predicts visual intelligence.

PubMed

Cook, Emily; Hammett, Stephen T; Larsson, Jonas

2016-10-06

Early psychological researchers proposed a link between intelligence and low-level perceptual performance. It was recently suggested that this link is driven by individual variations in the ability to suppress irrelevant information, evidenced by the observation of strong correlations between perceptual surround suppression and cognitive performance. However, the neural mechanisms underlying such a link remain unclear. A candidate mechanism is neural inhibition by gamma-aminobutyric acid (GABA), but direct experimental support for GABA-mediated inhibition underlying suppression is inconsistent. Here we report evidence consistent with a global suppressive mechanism involving GABA underlying the link between sensory performance and intelligence. We measured visual cortical GABA concentration, visuo-spatial intelligence and visual surround suppression in a group of healthy adults. Levels of GABA were strongly predictive of both intelligence and surround suppression, with higher levels of intelligence associated with higher levels of GABA and stronger surround suppression. These results indicate that GABA-mediated neural inhibition may be a key factor determining cognitive performance and suggests a physiological mechanism linking surround suppression and intelligence. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Linking γ-aminobutyric acid A receptor to epidermal growth factor receptor pathways activation in human prostate cancer.

PubMed

Wu, Weijuan; Yang, Qing; Fung, Kar-Ming; Humphreys, Mitchell R; Brame, Lacy S; Cao, Amy; Fang, Yu-Ting; Shih, Pin-Tsen; Kropp, Bradley P; Lin, Hsueh-Kung

2014-03-05

Neuroendocrine (NE) differentiation has been attributed to the progression of castration-resistant prostate cancer (CRPC). Growth factor pathways including the epidermal growth factor receptor (EGFR) signaling have been implicated in the development of NE features and progression to a castration-resistant phenotype. However, upstream molecules that regulate the growth factor pathway remain largely unknown. Using androgen-insensitive bone metastasis PC-3 cells and androgen-sensitive lymph node metastasis LNCaP cells derived from human prostate cancer (PCa) patients, we demonstrated that γ-aminobutyric acid A receptor (GABA(A)R) ligand (GABA) and agonist (isoguvacine) stimulate cell proliferation, enhance EGF family members expression, and activate EGFR and a downstream signaling molecule, Src, in both PC-3 and LNCaP cells. Inclusion of a GABA(A)R antagonist, picrotoxin, or an EGFR tyrosine kinase inhibitor, Gefitinib (ZD1839 or Iressa), blocked isoguvacine and GABA-stimulated cell growth, trans-phospohorylation of EGFR, and tyrosyl phosphorylation of Src in both PCa cell lines. Spatial distributions of GABAAR α₁ and phosphorylated Src (Tyr416) were studied in human prostate tissues by immunohistochemistry. In contrast to extremely low or absence of GABA(A)R α₁-positive immunoreactivity in normal prostate epithelium, elevated GABA(A)R α₁ immunoreactivity was detected in prostate carcinomatous glands. Similarly, immunoreactivity of phospho-Src (Tyr416) was specifically localized and limited to the nucleoli of all invasive prostate carcinoma cells, but negative in normal tissues. Strong GABAAR α₁ immunoreactivity was spatially adjacent to the neoplastic glands where strong phospho-Src (Tyr416)-positive immunoreactivity was demonstrated, but not in adjacent to normal glands. These results suggest that the GABA signaling is linked to the EGFR pathway and may work through autocrine or paracine mechanism to promote CRPC progression. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Complete spinal cord injury (SCI) transforms how brain derived neurotrophic factor (BDNF) affects nociceptive sensitization.

PubMed

Huang, Yung-Jen; Lee, Kuan H; Grau, James W

2017-02-01

Noxious stimulation can induce a lasting increase in neural excitability within the spinal cord (central sensitization) that can promote pain and disrupt adaptive function (maladaptive plasticity). Brain-derived neurotrophic factor (BDNF) is known to regulate the development of plasticity and has been shown to impact the development of spinally-mediated central sensitization. The latter effect has been linked to an alteration in GABA-dependent inhibition. Prior studies have shown that, in spinally transected rats, exposure to regular (fixed spaced) stimulation can counter the development of maladaptive plasticity and have linked this effect to an up-regulation of BDNF. Here it is shown that application of the irritant capsaicin to one hind paw induces enhanced mechanical reactivity (EMR) after spinal cord injury (SCI) and that the induction of this effect is blocked by pretreatment with fixed spaced shock. This protective effect was eliminated if rats were pretreated with the BDNF sequestering antibody TrkB-IgG. Intrathecal (i.t.) application of BDNF prevented, but did not reverse, capsaicin-induced EMR. BDNF also attenuated cellular indices (ERK and pERK expression) of central sensitization after SCI. In uninjured rats, i.t. BDNF enhanced, rather than attenuated, capsaicin-induced EMR and ERK/pERK expression. These opposing effects were related to a transformation in GABA function. In uninjured rats, BDNF reduced membrane-bound KCC2 and the inhibitory effect of the GABA A agonist muscimol. After SCI, BDNF increased KCC2 expression, which would help restore GABAergic inhibition. The results suggest that SCI transforms how BDNF affects GABA function and imply that the clinical usefulness of BDNF will depend upon the extent of fiber sparing. Copyright © 2016 Elsevier Inc. All rights reserved.

Enhancing Contents of γ-Aminobutyric Acid (GABA) and Other Micronutrients in Dehulled Rice during Germination under Normoxic and Hypoxic Conditions.

PubMed

Ding, Junzhou; Yang, Tewu; Feng, Hao; Dong, Mengyi; Slavin, Margaret; Xiong, Shanbai; Zhao, Siming

2016-02-10

Biofortification of staple grains with high contents of essential micronutrients is an important strategy to overcome micronutrient malnutrition. However, few attempts have targeted at γ-aminobutyric acid (GABA), a functional nutrient for aging populations. In this study, two rice cultivars, Heinuo and Xianhui 207, were used to investigate changes in GABA and other nutritional compounds of dehulled rice after germination under normoxic and hypoxic conditions. Forty-one metabolites were identified in both cultivars treated by normoxic germination, whereas the germinated dehulled rice of Heinuo and Xianhui 207 under hypoxic treatment had 43 and 41 metabolites identified, respectively. GABA increased in dehulled rice after germination, especially under hypoxia. Meanwhile, a number of other health-beneficial and/or flavor-related compounds such as lysine and d-mannose increased after the hypoxic treatment. The accumulation of GABA exhibited genotype-specific modes in both normoxic and hypoxic treatments. With regard to GABA production, Xianhui 207 was more responsive to the germination process than Heinuo, whereas Heinuo was more responsive to hypoxia than Xianhui 207. This study provides a promising approach to biofortify dehulled rice with increased GABA and other nutrients through metabolomic-based regulation.

Endogenous γ-aminobutyric Acid Modulates Tonic Guinea Pig Airway Tone and Propofol-induced Airway Smooth Muscle Relaxation

PubMed Central

Gallos, George; Gleason, Neil R.; Virag, Laszlo; Zhang, Yi; Mizuta, Kentauro; Whittington, Robert A.; Emala, Charles W.

2009-01-01

Background Emerging evidence indicates that an endogenous autocrine/paracrine system involving γ-aminobutyric acid (GABA) is present in airways. GABAA channels, GABAB receptors and the enzyme that synthesizes GABA have been identified in airway epithelium and smooth muscle. However, the endogenous ligand itself, GABA, has not been measured in airway tissues. We sought to demonstrate that GABA is released in response to contractile agonists and tonically contributes a pro-relaxant component to contracted airway smooth muscle. Methods The amount and cellular localization of GABA in upper guinea pig airways under resting and contracted tone was determined by high pressure liquid chromatography and immunohistochemistry, respectively. The contribution that endogenous GABA imparts on the maintenance of airway smooth muscle acetylcholine-induced contraction was assessed in intact guinea pig airway tracheal rings using selective GABAA antagonism (gabazine) under resting or acetylcholine-contracted conditions. The ability of an allosteric agent (propofol) to relax a substance P-induced relaxation in an endogenous GABA-dependent manner was assessed. Results GABA levels increased and localized to airway smooth muscle following contractile stimuli in guinea pig upper airways. Acetylcholine-contracted guinea pig tracheal rings exhibited an increase in contracted force upon addition of the GABAA antagonist gabazine which was subsequently reversed by the addition of the GABAA agonist muscimol. Propofol dose-dependently relaxed a substance P contraction that was blocked by gabazine. Conclusion These studies demonstrate that GABA is endogenously present and increases following contractile stimuli in guinea pig upper airways and that endogenous GABA contributes a tonic pro-relaxant component in the maintenance of airway smooth muscle tone. PMID:19322939

Invasive ability of human renal cell carcinoma cell line Caki-2 is accelerated by gamma-aminobutyric acid, via sustained activation of ERK1/2 inducible matrix metalloproteinases.

PubMed

Inamoto, Teruo; Azuma, Haruhito; Sakamoto, Takeshi; Kiyama, Satoshi; Ubai, Takanobu; Kotake, Yatsugu; Watanabe, Masahito; Katsuoka, Yoji

2007-10-01

Gamma-aminobutyric acid (GABA) was first discovered as an inhibitory neurotransmitter in the central nervous system (CNS) and has been reported to have a variety of functions, including regulation of cell division, cell differentiation and maturation, and to be involved in the development of certain cancers outside the CNS. In the present study, using the human renal cell carcinoma cell line Caki-2, we demonstrated that GABA stimulation significantly increased the expression of MMP-2 and -9 and subsequently increased the invasive activity of the cancer cells. Because MAPK signaling is one of the key regulators of MMP expression, we further evaluated MAPK signaling after stimulation with GABA. It was found that GABA stimulation promoted the phosphorylation of MAPKs, including ERK1/2, JNK, and p38. ERK1/2 phosphorylation was sustained for up to 12 h, while phosphorylation of JNK and p38 returned to the endogenous level by 30 min. It was noteworthy that the ras/raf/MEK/ERK pathway inhibitor PD98059 attenuated GABA-induced MMP-9 expression and that both PD98059 and MMP inhibitors attenuated the GABA-induced invasive activity of Caki-2 cells. Moreover, data obtained by depletion of the MEK/ERK pathway using interfering RNA transfection of Caki-2 cells clearly corroborated the above results, as both MMP-9 expression and GABA-induced invasive ability were decreased significantly. We also demonstrated that the GABA-induced increase in invasive ability via ERK1/2 up-regulation was mediated mainly through the GABA-B receptor. These results indicate that GABA stimulation promotes cancer cell invasion and that the effect is partly due to ERK1/2-dependent up-regulation of MMPs.

Effects of yoga versus walking on mood, anxiety, and brain GABA levels: a randomized controlled MRS study.

PubMed

Streeter, Chris C; Whitfield, Theodore H; Owen, Liz; Rein, Tasha; Karri, Surya K; Yakhkind, Aleksandra; Perlmutter, Ruth; Prescot, Andrew; Renshaw, Perry F; Ciraulo, Domenic A; Jensen, J Eric

2010-11-01

Yoga and exercise have beneficial effects on mood and anxiety. γ-Aminobutyric acid (GABA)-ergic activity is reduced in mood and anxiety disorders. The practice of yoga postures is associated with increased brain GABA levels. This study addresses the question of whether changes in mood, anxiety, and GABA levels are specific to yoga or related to physical activity. Healthy subjects with no significant medical/psychiatric disorders were randomized to yoga or a metabolically matched walking intervention for 60 minutes 3 times a week for 12 weeks. Mood and anxiety scales were taken at weeks 0, 4, 8, 12, and before each magnetic resonance spectroscopy scan. Scan 1 was at baseline. Scan 2, obtained after the 12-week intervention, was followed by a 60-minute yoga or walking intervention, which was immediately followed by Scan 3. The yoga subjects (n = 19) reported greater improvement in mood and greater decreases in anxiety than the walking group (n = 15). There were positive correlations between improved mood and decreased anxiety and thalamic GABA levels. The yoga group had positive correlations between changes in mood scales and changes in GABA levels. The 12-week yoga intervention was associated with greater improvements in mood and anxiety than a metabolically matched walking exercise. This is the first study to demonstrate that increased thalamic GABA levels are associated with improved mood and decreased anxiety. It is also the first time that a behavioral intervention (i.e., yoga postures) has been associated with a positive correlation between acute increases in thalamic GABA levels and improvements in mood and anxiety scales. Given that pharmacologic agents that increase the activity of the GABA system are prescribed to improve mood and decrease anxiety, the reported correlations are in the expected direction. The possible role of GABA in mediating the beneficial effects of yoga on mood and anxiety warrants further study.

Increased GABA Levels in Medial Prefrontal Cortex of Young Adults with Narcolepsy

PubMed Central

Kim, Seog Ju; Lyoo, In Kyoon; Lee, Yujin S.; Sung, Young Hoon; Kim, Hengjun J.; Kim, Jihyun H.; Kim, Kye Hyun; Jeong, Do-Un

2008-01-01

Study Objectives: To explore absolute concentrations of brain metabolites including gamma amino-butyric acid (GABA) in the medial prefrontal cortex and basal ganglia of young adults with narcolepsy. Design: Proton magnetic resonance (MR) spectroscopy centered on the medial prefrontal cortex and the basal ganglia was acquired. The absolute concentrations of brain metabolites including GABA and glutamate were assessed and compared between narcoleptic patients and healthy comparison subjects. Setting: Sleep and Chronobiology Center at Seoul National University Hospital; A high strength 3.0 Tesla MR scanner in the Department of Radiology at Seoul National University Hospital. Patients or Participants: Seventeen young adults with a sole diagnosis of HLA DQB1 0602 positive narcolepsy with cataplexy (25.1 ± 4.6 years old) and 17 healthy comparison subjects (26.8 ± 4.8 years old). Interventions: N/A. Measurements and Results: Relative to comparison subjects, narcoleptic patients had higher GABA concentration in the medial prefrontal cortex (t = 4.10, P <0.001). Narcoleptic patients with nocturnal sleep disturbance had higher GABA concentration in the medial prefrontal cortex than those without nocturnal sleep disturbance (t = 2.45, P= 0.03), but had lower GABA concentration than comparison subjects (t = 2.30, P = 0.03). Conclusions: The current study reports that young adults with narcolepsy had a higher GABA concentration in the medial prefrontal cortex, which was more prominent in patients without nocturnal sleep disturbance. Our findings suggest that the medial prefrontal GABA level may be increased in narcolepsy, and the increased medial prefrontal GABA might be a compensatory mechanism to reduce nocturnal sleep disturbances in narcolepsy. Citation: Kim SJ; Lyoo IK; Lee YS; Sung YH; Kim HJ; Kim JH; Kim KH; Jeong DU. Increased GABA levels in medial prefrontal cortex of young adults with narcolepsy. SLEEP 2008;31(3):342-347. PMID:18363310

Is plasma GABA level a biomarker of Post-Traumatic Stress Disorder (PTSD) severity? A preliminary study.

PubMed

Trousselard, Marion; Lefebvre, Bertrand; Caillet, Lionel; Andruetan, Yann; de Montleau, Franck; Denis, Josiane; Canini, Frédéric

2016-07-30

An increased reactivity to the environment is observed in Post-Traumatic Stress Disorder (PTSD). It would be related to impairment of the Gamma Amino Butyric Acid (GABA) neurotransmission. The study aimed to evaluate plasma GABA concentration as a candidate for PTSD severity biomarker. This hypothesis was studied in 17 PTSD patients and 17 healthy Controls using classic and emotional Stroop paradigms. Plasma GABA concentrations were assessed before and after both Stroop tests to evaluate GABA basal tone and GABA reactivity (change in GABAp), respectively. During baseline, PTSD had lower plasma GABA concentrations than the Controls. After the Stroop conflicts GABA reactivity was also lower in PTSD than in the Controls. The GABA baseline tone was negatively correlated with the severity of the PTSD symptoms. This relation was only marginally observed for GABA reactivity. The results produced a trend due to the small size of the sample compared to the number of statistical results given. Altogether, the reduced GABA concentration observed in PTSD could be considered as a possible biomarker for PTSD severity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Olfactory bulb short axon cell release of GABA and dopamine produces a temporally biphasic inhibition-excitation response in external tufted cells.

PubMed

Liu, Shaolin; Plachez, Celine; Shao, Zuoyi; Puche, Adam; Shipley, Michael T

2013-02-13

Evidence for coexpression of two or more classic neurotransmitters in neurons has increased, but less is known about cotransmission. Ventral tegmental area (VTA) neurons corelease dopamine (DA), the excitatory transmitter glutamate, and the inhibitory transmitter GABA onto target cells in the striatum. Olfactory bulb (OB) short axon cells (SACs) form interglomerular connections and coexpress markers for DA and GABA. Using an optogenetic approach, we provide evidence that mouse OB SACs release both GABA and DA onto external tufted cells (ETCs) in other glomeruli. Optical activation of channelrhodopsin specifically expressed in DAergic SACs produced a GABA(A) receptor-mediated monosynaptic inhibitory response, followed by DA-D(1)-like receptor-mediated excitatory response in ETCs. The GABA(A) receptor-mediated hyperpolarization activates I(h) current in ETCs; synaptically released DA increases I(h), which enhances postinhibitory rebound spiking. Thus, the opposing actions of synaptically released GABA and DA are functionally integrated by I(h) to generate an inhibition-to-excitation "switch" in ETCs. Consistent with the established role of I(h) in ETC burst firing, we show that endogenous DA release increases ETC spontaneous bursting frequency. ETCs transmit sensory signals to mitral/tufted output neurons and drive intraglomerular inhibition to shape glomerulus output to downstream olfactory networks. GABA and DA cotransmission from SACs to ETCs may play a key role in regulating output coding across the glomerular array.

Gamma-aminobutyric acid depletion affects stomata closure and drought tolerance of Arabidopsis thaliana.

PubMed

Mekonnen, Dereje Worku; Flügge, Ulf-Ingo; Ludewig, Frank

2016-04-01

A rapid accumulation of γ-aminobutyric acid (GABA) during biotic and abiotic stresses is well documented. However, the specificity of the response and the primary role of GABA under such stress conditions are hardly understood. To address these questions, we investigated the response of the GABA-depleted gad1/2 mutant to drought stress. GABA is primarily synthesized from the decarboxylation of glutamate by glutamate decarboxylase (GAD) which exists in five copies in the genome of Arabidopsis thaliana. However, only GAD1 and GAD2 are abundantly expressed, and knockout of these two copies dramatically reduced the GABA content. Phenotypic analysis revealed a reduced shoot growth of the gad1/2 mutant. Furthermore, the gad1/2 mutant was wilted earlier than the wild type following a prolonged drought stress treatment. The early-wilting phenotype was due to an increase in stomata aperture and a defect in stomata closure. The increase in stomata aperture contributed to higher stomatal conductance. The drought oversensitive phenotype of the gad1/2 mutant was reversed by functional complementation that increases GABA level in leaves. The functionally complemented gad1/2 x pop2 triple mutant contained more GABA than the wild type. Our findings suggest that GABA accumulation during drought is a stress-specific response and its accumulation induces the regulation of stomatal opening thereby prevents loss of water. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

High gamma-aminobutyric acid level in cortical tubers in epileptic infants with tuberous sclerosis complex measured with the MEGA-editing J-difference method and a three-Tesla clinical MRI Instrument.

PubMed

Taki, Masako Minato; Harada, Masafumi; Mori, Kenji; Kubo, Hitoshi; Nose, Ayumi; Matsuda, Tsuyoshi; Nishitani, Hiromu

2009-10-01

The purpose of this study was to estimate the gamma-aminobutyric acid (GABA) and glutamate plus glutamine (Glx) concentrations in the cortical tubers of patients with tuberous sclerosis complex (TSC) using the MEGA-editing J-difference method and a stimulated echo-acquisition mode with a short echo time, and to determine which abnormality was more dominant between GABA and Glx in patients with TSC with epilepsy. This study included six patients with TSC (mean age, 4.3 years) and seven control subjects (mean age, 4.8 years). Measurements were obtained with a three-Tesla apparatus and postprocessing was conducted with an LCModel. The GABA level in the cortical gray matter (cgGABA) was calculated as a result of segmentation in voxels and from the literature values for gray and white matter ratios for GABA. Increased GABA and myo-inositol (mI) concentrations and a decreased N-acetyl aspartate (NAA) concentration were observed in the cortical tubers. The cgGABA level, and cgGABA/NAA and cgGABA/Glx ratios were also higher in patients with TSC than in control subjects. No significant difference was found in Glx concentration between patients with TSC and control subjects. Although the number of patients with TSC in this study was small, the increase in GABA and no significant change in Glx were consistent with previous neurochemical studies and support the hypothesis that brain GABA plays a key role in the pathophysiology of epilepsy during the process of neuronal development.

Effects of intraperitoneal administration of the GABAB receptor positive allosteric modulator 2,6-di tert-butyl-4-(2-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) on food intake in non-deprived rats.

PubMed

Ebenezer, Ivor S

2012-09-05

γ-Aminobutyric acid-(B) (GABA(B)) receptor positive allosteric modulators (PAMs) act on an allosteric site on the GABA(B) receptor to potentiate the effects of GABA and GABA(B) receptor agonists. It has previously been demonstrated that the GABA(B) receptor agonist baclofen increases food intake in non-deprived rats. The aim of this study was to investigate whether the GABA(B) receptor PAM 2,6-di tert-butyl-4-(2-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) would (i) increase food intake, and (ii) potentiate the hyperphagic effects of baclofen in rats. In Experiment 1, the effects of intraperitoneal (i.p.) administration of CGP7930 (1, 6 and 12 mg/kg) was investigated on food intake in non-deprived male Wistar rats. The 12 mg/kg dose of CGP7930 significantly increased cumulative food intake 30, 60 and 120 min (P<0.05, in each case) after administration. The 1 and 6 mg/kg doses were without effect. In Experiment 2, the effects of pretreatment with CGP7930 (6 mg/kg; i.p.) 5 min prior to administration of baclofen (2mg/kg, i.p.) was investigated on 30min cumulative food intake in non-deprived male Wistar rats. Baclofen (2mg/kg) significantly increased food intake compared with vehicle treatment (P<0.01). CGP7930 (6 mg/kg) had no effect on feeding. However, pretreatment with CGP7930 (6 mg/kg) significantly potentiated the hyperphagic effects of baclofen (2mg/kg) (P<0.01). These findings show that CGP7930 increases food intake and enhances the hyperphagic effects of baclofen, and are consistent with in vitro studies that suggest that it potentiates the effects of endogenous GABA and GABA(B) receptor agonists by allosteric modulation of the GABA(B) receptor. Copyright © 2012 Elsevier B.V. All rights reserved.

Plasticity of rat central inhibitory synapses through GABA metabolism

PubMed Central

Engel, Dominique; Pahner, Ingrid; Schulze, Katrin; Frahm, Christiane; Jarry, Hubertus; Ahnert-Hilger, Gudrun; Draguhn, Andreas

2001-01-01

The production of the central inhibitory transmitter GABA (γ-aminobutyric acid) varies in response to different patterns of activity. It therefore seems possible that GABA metabolism can determine inhibitory synaptic strength and that presynaptic GABA content is a regulated parameter for synaptic plasticity. We altered presynaptic GABA metabolism in cultured rat hippocampal slices using pharmacological tools. Degradation of GABA by GABA-transaminase (GABA-T) was blocked by γ-vinyl-GABA (GVG) and synthesis of GABA through glutamate decarboxylase (GAD) was suppressed with 3-mercaptopropionic acid (MPA). We measured miniature GABAergic postsynaptic currents (mIPSCs) in CA3 pyramidal cells using the whole-cell patch clamp technique. Elevated intra-synaptic GABA levels after block of GABA-T resulted in increased mIPSC amplitude and frequency. In addition, tonic GABAergic background noise was enhanced by GVG. Electron micrographs from inhibitory synapses identified by immunogold staining for GABA confirmed the enhanced GABA content but revealed no further morphological alterations. The suppression of GABA synthesis by MPA had opposite functional consequences: mIPSC amplitude and frequency decreased and current noise was reduced compared with control. However, we were unable to demonstrate the decreased GABA content in biochemical analyses of whole slices or in electron micrographs. We conclude that the transmitter content of GABAergic vesicles is variable and that postsynaptic receptors are usually not saturated, leaving room for up-regulation of inhibitory synaptic strength. Our data reveal a new mechanism of plasticity at central inhibitory synapses and provide a rationale for the activity-dependent regulation of GABA synthesis in mammals. PMID:11533137

Craving for alcohol and food during treatment for alcohol dependence: modulation by T allele of 1519T>C GABAAalpha6.

PubMed

Han, Doug Hyun; Bolo, Nicholas; Daniels, Melissa A; Lyoo, In Kyoon; Min, Kyung Joon; Kim, Chang Hyun; Renshaw, Perry F

2008-09-01

Craving for alcohol and food has been studied in association with alcohol dependence and eating disorders, respectively. One subclass of the gamma-aminobutyric acid (GABA) receptor, 1519T>C GABA(A)alpha6 has been reported to be associated with both alcohol dependence and weight gain. In this study, we hypothesized that patients being treated for alcohol dependence would report decreased craving for alcohol, but an increased craving for food during a 4-week treatment period. We further hypothesized that the T allele of the 1519T>C GABA(A)alpha6 gene would modulate the extent of changes in craving for alcohol and food. This study included 98 male inpatients being treated for alcohol dependence. A 7-point visual analog scale was applied to evaluate relative levels of alcohol and food craving at baseline and again 4 weeks later. Body weight was also checked at the same periods. Genotyping of the 1519T>C SNP in GABA(A)alpha6 was carried out by restriction fragment length polymorphism. There were significant changes in craving for alcohol and food in all patients with alcohol dependence. During the treatment period, body weight increased in all patients with alcohol dependence. Changes in alcohol and food craving in T-allele carriers (CT + TT) of 1519T>C GABA(A)alpha6 were greater than those observed in CC homozygotes. In T-allele carriers, body weight significantly increased and the changes in weight showed a negative correlation with the change in the craving for alcohol and a positive correlation with the changes in craving for food. The current results suggest that in T-allele carriers the change in craving for alcohol during treatment for alcohol dependence is negatively associated with changes in craving for food. The T allele of the 1519T>C GABA(A)alpha6 gene may be one of the modulating factors associated with changes in craving for alcohol and food during treatment of patients with alcohol dependence.

Zinc ion enhances GABA tea-mediated oxidative DNA damage.

PubMed

Chuang, Show-Mei; Wang, Hsueh-Fang; Hsiao, Ching-Chuan; Cherng, Shur-Hueih

2012-02-15

GABA tea is a tea product that contains a high level of γ-aminobutyric acid (GABA). Previous study has demonstrated a synergistic effect of GABA tea and copper ions on DNA breakage. This study further explored whether zinc (Zn), a nonredox metal, modulated DNA cleavage induced by GABA tea extract. In a cell-free system, Zn(2+) significantly enhanced GABA tea extract and (-)-epigallocatechin-3-gallate (EGCG)- or H(2)O(2)-induced DNA damage at 24 h of incubation. Additionally, low dosages of GABA tea extract (1-10 μg/mL) possessed pro-oxidant activity to increase H(2)O(2)/Zn(2+)-induced DNA cleavage in a dose-dependent profile. By use of various reactive oxygen scavengers, it was observed that glutathione, catalase, and potassium iodide effectively inhibited DNA degradation caused by the GABA tea extract/H(2)O(2)/Zn(2+) system. Moreover, the data showed that the GABA tea extract itself (0.5-5 mg/mL) could induce DNA cleavage in a long-term exposure (48 h). EGCG, but not the GABA tea extract, enhanced H(2)O(2)-induced DNA cleavage. In contrast, GABA decreased H(2)O(2)- and EGCG-induced DNA cleavage, suggesting that GABA might contribute the major effect on the antioxidant activity of GABA tea extract. Furthermore, a comet assay revealed that GABA tea extract (0.25 mg/mL) and GABA had antioxidant activity on H(2)O(2)-induced DNA breakage in human peripheral lymphocytes. Taken together, these findings indicate that GABA tea has the potential of both pro-oxidant and antioxidant. It is proposed that a balance between EGCG-induced pro-oxidation and GABA-mediated antioxidation may occur in a complex mixture of GABA tea extract.

Relationship of executive functioning deficits to N-acetyl aspartate (NAA) and gamma-aminobutyric acid (GABA) in youth with bipolar disorder.

PubMed

Huber, Rebekah S; Kondo, Douglas G; Shi, Xian-Feng; Prescot, Andrew P; Clark, Elaine; Renshaw, Perry F; Yurgelun-Todd, Deborah A

2018-01-01

Although cognitive deficits in bipolar disorder (BD) have been repeatedly observed, our understanding of these impairments at a mechanistic level remains limited. Few studies that investigated cognitive impairments in bipolar illness have examined the association with brain biochemistry. This pilot study utilized proton magnetic resonance spectroscopy ( 1 H-MRS) to evaluate the relationship between neurocognitive performance and brain metabolites in youth with BD. Thirty participants, twenty depressed BD participants and ten healthy comparison participants, ages 13-21, completed mood and executive function measures. 1 H-MRS data were also acquired from the anterior cingulate cortex (ACC) using two-dimensional (2D) J-resolved 1 H-MRS sequence. Proton metabolites including N-acetyl aspartate (NAA) and gamma-aminobutyric acid (GABA) were quantified for both groups. Participants with BD performed significantly lower on executive functioning measures than comparison participants. There were significant positive correlations between Wisconsin Card Sorting Test (WCST) performance and NAA (p < .001) and GABA (p < .01) in the ACC in bipolar youth, such that as WCST performance increased, both NAA and GABA levels increased. Small sample size and lack of control for medications. These findings build on previous observations of biochemical alterations associated with BD and indicate that executive functioning deficits in bipolar youth are correlated with NAA and GABA. These results suggest that cognitive deficits occur early in the course of illness and may reflect risk factors associated with altered neurochemistry. Further investigation of the relationship between brain metabolites and cognition in BD may lead to important information for developing novel, targeted interventions. Copyright © 2017 Elsevier B.V. All rights reserved.

In vivo evaluation of the hippocampal glutamate, GABA and the BDNF levels associated with spatial memory performance in a rodent model of neuropathic pain.

PubMed

Saffarpour, S; Shaabani, M; Naghdi, N; Farahmandfar, M; Janzadeh, A; Nasirinezhad, F

2017-06-01

Patients with chronic pain usually suffer from learning and memory impairment which may significantly decrease their quality of life. Despite laboratory and clinical studies, the mechanism underlying this memory impairment remains elusive. We evaluated the effect of chronic pain on the glutamate and GABA levels and BDNF expression in the CA1 region of hippocampus as a possible explanation for memory impairment related to neuropathic pain. In this respect, 30 male rats were randomly allocated to 3 groups as control, sham and neuropathic. Neuropathic pain was induced by a chronic constriction injury of the sciatic nerve (CCI) and mechanical allodynia and the spatial memory was assessed using the Von Frey filaments and Morris water maze respectively. To determine the potential mechanisms, the in vivo extracellular levels of glutamate and γ-aminobutyric acid (GABA) were measured by microdialysis and the brain-derived neurotrophic factor (BDNF) expression was determined by using western blots technique in the hippocampus on days 14 and 21 post-CCI. We showed that CCI impaired spatial learning and memory in Morris water maze (MWM) task. BDNF expression level and glutamate concentration significantly decreased in rats with chronic constriction injury of the sciatic nerve (P<0.001, F=7.3, F=23.23). In addition, GABA increased in hippocampal CA1 region (P<0.001, F=39.2) when the pain threshold was minimum. Nevertheless, these changes reversed while pain was relieved spontaneously. Chronic pain induced by constriction of the sciatic nerve impairs the spatial learning and memory function in rats. This effect exerts through the increase in GABA concentration and decrease in the glutamate and BDNF levels in the CA1 region of the hippocampus. Copyright © 2017 Elsevier Inc. All rights reserved.

Oxytocin modulates GABAAR subunits to confer neuroprotection in stroke in vitro.

PubMed

Kaneko, Yuji; Pappas, Colleen; Tajiri, Naoki; Borlongan, Cesar V

2016-10-21

Oxytocin protects against ischemia-induced inflammation and oxidative stress, and is associated with GABA (γ-aminobutyric acid, an inhibitory neurotransmitter) signaling transduction in neurons. However, the molecular mechanism by which oxytocin affords neuroprotection, especially the interaction between oxytocin receptor and GABA A receptor (GABA A R), remains to be elucidated. Primary rat neural cells were exposed to oxytocin before induction of experimental acute stroke model via oxygen-glucose deprivation-reperfusion (OGD/R) injury. Pretreatment with oxytocin increased cell viability, decreased the cell damage against oxidative stress, and prevented the release of high mobility group box1 during OGD/R. However, introduction of oxytocin during OGD/R did not induce neuroprotection. Although oxytocin did not affect the glutathione-related cellular metabolism before OGD, oxytocin modulated the expression levels of GABA A R subunits, which function to remove excessive neuronal excitability via chloride ion influx. Oxytocin-pretreated cells significantly increased the chloride ion influx in response to GABA and THIP (δ-GABA A R specific agonist). This study provides evidence that oxytocin regulated GABA A R subunits in affording neuroprotection against OGD/R injury.

Regulated lysosomal trafficking as a mechanism for regulating GABAA receptor abundance at synapses in Caenorhabditis elegans.

PubMed

Davis, Kathleen M; Sturt, Brianne L; Friedmann, Andrew J; Richmond, Janet E; Bessereau, Jean-Louis; Grant, Barth D; Bamber, Bruce A

2010-08-01

GABA(A) receptor plasticity is important for both normal brain function and disease progression. We are studying GABA(A) receptor plasticity in Caenorhabditis elegans using a genetic approach. Acute exposure of worms to the GABA(A) agonist muscimol hyperpolarizes postsynaptic cells, causing paralysis. Worms adapt after several hours, but show uncoordinated locomotion consistent with decreased GABA signaling. Using patch-clamp and immunofluorescence approaches, we show that GABA(A) receptors are selectively removed from synapses during adaptation. Subunit mRNA levels were unchanged, suggesting a post-transcriptional mechanism. Mutants with defective lysosome function (cup-5) show elevated GABA(A) receptor levels at synapses prior to muscimol exposure. During adaptation, these receptors are removed more slowly, and accumulate in intracellular organelles positive for the late endosome marker GFP-RAB-7. These findings suggest that chronic agonist exposure increases endocytosis and lysosomal trafficking of GABA(A) receptors, leading to reduced levels of synaptic GABA(A) receptors and reduced postsynaptic GABA sensitivity.

Optimization of γ-aminobutyric acid production by Lactobacillus plantarum Taj-Apis362 from honeybees.

PubMed

Tajabadi, Naser; Ebrahimpour, Afshin; Baradaran, Ali; Rahim, Raha Abdul; Mahyudin, Nor Ainy; Manap, Mohd Yazid Abdul; Bakar, Fatimah Abu; Saari, Nazamid

2015-04-15

Dominant strains of lactic acid bacteria (LAB) isolated from honey bees were evaluated for their γ-aminobutyric acid (GABA)-producing ability. Out of 24 strains, strain Taj-Apis362 showed the highest GABA-producing ability (1.76 mM) in MRS broth containing 50 mM initial glutamic acid cultured for 60 h. Effects of fermentation parameters, including initial glutamic acid level, culture temperature, initial pH and incubation time on GABA production were investigated via a single parameter optimization strategy. The optimal fermentation condition for GABA production was modeled using response surface methodology (RSM). The results showed that the culture temperature was the most significant factor for GABA production. The optimum conditions for maximum GABA production by Lactobacillus plantarum Taj-Apis362 were an initial glutamic acid concentration of 497.97 mM, culture temperature of 36 °C, initial pH of 5.31 and incubation time of 60 h, which produced 7.15 mM of GABA. The value is comparable with the predicted value of 7.21 mM.

Interactive effects of glutamine and gamma-aminobutyric acid on growth performance and skeletal muscle amino acid metabolism of 22-42-day-old broilers exposed to hot environment.

PubMed

Hu, Hong; Bai, Xi; Shah, Assar Ali; Dai, Sifa; Wang, Like; Hua, Jinling; Che, Chuanyan; He, Shaojun; Wen, Aiyou; Jiang, Jinpeng

2016-06-01

The present experiment was conducted to investigate the interactive effects between dietary glutamine (Gln, 0 and 5 g/kg) and gamma-aminobutyric acid (GABA, 0 and 100 mg/kg) on growth performance and amino acid (AA) metabolism of broilers under hot environment. A total of 360 22-day-old Arbor Acres male chickens were randomly assigned to five treatment groups under thermoneutral chamber (PC, 23 °C) and cyclic heat stress (HS, 30-34 °C cycling) conditions. Compared with the PC group, cyclic HS decreased (P < 0.05) daily weight gain (DWG), daily feed consumption (DFC), the concentrations of Gln, glutamate (Glu), and GABA, and the activities of glutaminase and glutamic acid decarboxylase (GAD) in breast muscle at 28, 35, and 42 days, while it increased (P < 0.05) the activities of glutamine synthetase (GS) and gamma-aminobutyric acid transaminase (GABA-T) at 28, 35, and 42 days. Dietary Gln and GABA improved (P < 0.05) DWG and DFC of broilers under cyclic HS during 28-42 days. In breast muscle, the Gln supplementation increased (P < 0.05) the concentrations of Gln (28, 35, and 42 days), Glu (28, 35, and 42 days), and GABA (42 days) and the activities of glutaminase (28, 35, and 42 days) and GAD (28, 35, and 42 days) but decreased (P < 0.05) GS activities at 28, 35, and 42 days and GABA-T activities at 28 days. The addition of GABA increased (P < 0.05) the concentrations of Gln and Glu and activities of glutaminase and GAD, while it decreased (P < 0.05) GABA-T activities at 28, 35, and 42 days. Significant interactions (P < 0.05) between Gln and GABA were found on breast skeletal muscle Gln concentrations, glutaminase activities, GS activities at 28 and 35 days, and DWG, GABA concentrations, and GABA-T activities at 28, 35, and 42 days in broilers under cyclic HS. In conclusion, the present results indicated that the interactions of exogenous Gln and GABA could offer a potential nutritional strategy to prevent HS-related depression in skeletal muscle Gln and GABA metabolism of broilers.

Interactive effects of glutamine and gamma-aminobutyric acid on growth performance and skeletal muscle amino acid metabolism of 22-42-day-old broilers exposed to hot environment

NASA Astrophysics Data System (ADS)

Hu, Hong; Bai, Xi; Shah, Assar Ali; Dai, Sifa; Wang, Like; Hua, Jinling; Che, Chuanyan; He, Shaojun; Wen, Aiyou; Jiang, Jinpeng

2016-06-01

The present experiment was conducted to investigate the interactive effects between dietary glutamine (Gln, 0 and 5 g/kg) and gamma-aminobutyric acid (GABA, 0 and 100 mg/kg) on growth performance and amino acid (AA) metabolism of broilers under hot environment. A total of 360 22-day-old Arbor Acres male chickens were randomly assigned to five treatment groups under thermoneutral chamber (PC, 23 °C) and cyclic heat stress (HS, 30-34 °C cycling) conditions. Compared with the PC group, cyclic HS decreased ( P < 0.05) daily weight gain (DWG), daily feed consumption (DFC), the concentrations of Gln, glutamate (Glu), and GABA, and the activities of glutaminase and glutamic acid decarboxylase (GAD) in breast muscle at 28, 35, and 42 days, while it increased ( P < 0.05) the activities of glutamine synthetase (GS) and gamma-aminobutyric acid transaminase (GABA-T) at 28, 35, and 42 days. Dietary Gln and GABA improved ( P < 0.05) DWG and DFC of broilers under cyclic HS during 28-42 days. In breast muscle, the Gln supplementation increased ( P < 0.05) the concentrations of Gln (28, 35, and 42 days), Glu (28, 35, and 42 days), and GABA (42 days) and the activities of glutaminase (28, 35, and 42 days) and GAD (28, 35, and 42 days) but decreased ( P < 0.05) GS activities at 28, 35, and 42 days and GABA-T activities at 28 days. The addition of GABA increased ( P < 0.05) the concentrations of Gln and Glu and activities of glutaminase and GAD, while it decreased ( P < 0.05) GABA-T activities at 28, 35, and 42 days. Significant interactions ( P < 0.05) between Gln and GABA were found on breast skeletal muscle Gln concentrations, glutaminase activities, GS activities at 28 and 35 days, and DWG, GABA concentrations, and GABA-T activities at 28, 35, and 42 days in broilers under cyclic HS. In conclusion, the present results indicated that the interactions of exogenous Gln and GABA could offer a potential nutritional strategy to prevent HS-related depression in skeletal muscle Gln and GABA metabolism of broilers.

Muscimol increases acetylcholine release by directly stimulating adult striatal cholinergic interneurons.

PubMed

Login, I S; Pal, S N; Adams, D T; Gold, P E

1998-01-01

Because GabaA ligands increase acetylcholine (ACh) release from adult striatal slices, we hypothesized that activation of GabaA receptors on striatal cholinergic interneurons directly stimulates ACh secretion. Fractional [3H]ACh release was recorded during perifusion of acutely dissociated, [3H]choline-labeled, adult male rat striata. The GabaA agonist, muscimol, immediately stimulated release maximally approximately 300% with EC50 = approximately 1 microM. This action was enhanced by the allosteric GabaA receptor modulators, diazepam and secobarbital, and inhibited by the GabaA antagonist, bicuculline, by ligands for D2 or muscarinic cholinergic receptors or by low calcium buffer, tetrodotoxin or vesamicol. Membrane depolarization inversely regulated muscimol-stimulated secretion. Release of endogenous and newly synthesized ACh was stimulated in parallel by muscimol without changing choline release. Muscimol pretreatment inhibited release evoked by K+ depolarization or by receptor-mediated stimulation with glutamate. Thus, GabaA receptors on adult striatal cholinergic interneurons directly stimulate voltage- and calcium-dependent exocytosis of ACh stored in vesamicol-sensitive synaptic vesicles. The action depends on the state of membrane polarization and apparently depolarizes the membrane in turn. This functional assay demonstrates that excitatory GabaA actions are not limited to neonatal tissues. GabaA-stimulated ACh release may be prevented in situ by normal tonic dopaminergic and muscarinic input to cholinergic neurons.

The effects of agonists of ionotropic GABA(A) and metabotropic GABA(B) receptors on learning.

PubMed

Zyablitseva, Evgeniya A; Kositsyn, Nikolay S; Shul'gina, Galina I

2009-05-01

The research described here investigates the role played by inhibitory processes in the discriminations made by the nervous system of humans and animals between familiar and unfamiliar and significant and nonsignificant events. This research compared the effects of two inhibitory mediators of gamma-aminobutyric acid (GABA): 1) phenibut, a nonselective agonist of ionotropic GABA(A) and metabotropic GABA(B) receptors and 2) gaboxadol a selective agonist of ionotropic GABA(A) receptors on the process of developing active defensive and inhibitory conditioned reflexes in alert non-immobilized rabbits. It was found that phenibut, but not gaboxadol, accelerates the development of defensive reflexes at an early stage of conditioning. Both phenibut and gaboxadol facilitate the development of conditioned inhibition, but the effect of gaboxadol occurs at later stages of conditioning and is less stable than that of phenibut. The earlier and more stable effects of phenibut, as compared to gaboxadol, on storage in memory of the inhibitory significance of a stimulus may occur because GABA(B) receptors play the dominant role in the development of internal inhibition during an early stage of conditioning. On the other hand this may occur because the participation of both GABA(A) and GABA(B) receptors are essential to the process. We discuss the polyfunctionality of GABA receptors as a function of their structure and the positions of the relevant neurons in the brain as this factor can affect regulation of various types of psychological processes.

Nicotine induces self-renewal of pancreatic cancer stem cells via neurotransmitter-driven activation of sonic hedgehog signalling.

PubMed

Al-Wadei, Mohammed H; Banerjee, Jheelam; Al-Wadei, Hussein A N; Schuller, Hildegard M

2016-01-01

A small subpopulation of pancreatic cancer cells with characteristics of stem cells drive tumour initiation, progression and metastasis. A better understanding of the regulation of cancer stem cells may lead to more effective cancer prevention and therapy. We have shown that the proliferation and migration of pancreatic cancer cell lines is activated by the nicotinic receptor-mediated release of stress neurotransmitters, responses reversed by γ-aminobutyric acid (GABA). However, the observed cancer inhibiting effects of GABA will only succeed clinically if GABA inhibits pancreatic cancer stem cells (PCSCs) in addition to the more differentiated cancer cells that comprise the majority of cancer tissues and cell lines. Using PCSCs isolated from two pancreatic cancer patients by cell sorting and by spheroid formation assay from pancreatic cancer cell line Panc-1, we tested the hypothesis that nicotine induces the self-renewal of PCSCs. Nicotinic acetylcholine receptors (nAChRs) α3, α4, α5 and α7 were expressed and chronic exposure to nicotine increased the protein expression of these receptors. Immunoassays showed that PCSCs produced the stress neurotransmitters epinephrine and norepinephrine and the inhibitory neurotransmitter GABA. Chronic nicotine significantly increased the production of stress neurotransmitters and sonic hedgehog (SHH) while inducing Gli1 protein and decreasing GABA. GABA treatment inhibited the induction of SHH and Gli1. Spheroid formation and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide assays showed significant nicotine-induced increases in self renewal and cell proliferation, responses blocked by GABA. Our data suggest that nicotine increases the SHH-mediated malignant potential of PCSCs and that GABA prevents these effects. Copyright © 2015 Elsevier Ltd. All rights reserved.

Glutamate/GABA+ ratio is associated with the psychosocial domain of autistic and schizotypal traits.

PubMed

Ford, Talitha C; Nibbs, Richard; Crewther, David P

2017-01-01

The autism and schizophrenia spectra overlap to a large degree in the social and interpersonal domains. Similarly, abnormal excitatory glutamate and inhibitory γ-aminobutyric acid (GABA) neurotransmitter concentrations have been reported for both spectra, with the interplay of these neurotransmitters important for cortical excitation to inhibition regulation. This study investigates whether these neurotransmitter abnormalities are specific to the shared symptomatology, and whether the degree of abnormality increases with increasing symptom severity. Hence, the relationship between the glutamate/GABA ratio and autism and schizophrenia spectrum traits in an unmedicated, subclinical population was investigated. A total of 37 adults (19 female, 18 male) aged 18-38 years completed the Autism Spectrum Quotient (AQ) and Schizotypal Personality Questionnaire (SPQ), and participated in the resting state proton magnetic resonance spectroscopy study in which sequences specific for quantification of glutamate and GABA+ concentration were applied to a right and left superior temporal voxel. There were significant, moderate, positive relationships between right superior temporal glutamate/GABA+ ratio and AQ, SPQ and AQ+SPQ total scores (p<0.05), SPQ subscales Social Anxiety, No Close Friend, Constricted Affect, Odd Behaviour, Odd Speech, Ideas of Reference and Suspiciousness, and AQ subscales Social Skills, Communication and Attention Switching (p<0.05); increased glutamate/GABA+ coinciding with higher scores on these subscales. Only the relationships between glutamate/GABA+ ratio and Social Anxiety, Constricted Affect, Social Skills and Communication survived multiple comparison correction (p< 0.004). Left superior temporal glutamate/GABA+ ratio reduced with increasing restricted imagination (p<0.05). These findings demonstrate evidence for an association between excitatory/inhibitory neurotransmitter concentrations and symptoms that are shared between the autism and schizophrenia spectra.

Drug-induced GABA transporter currents enhance GABA release to induce opioid withdrawal behaviors.

PubMed

Bagley, Elena E; Hacker, Jennifer; Chefer, Vladimir I; Mallet, Christophe; McNally, Gavan P; Chieng, Billy C H; Perroud, Julie; Shippenberg, Toni S; Christie, MacDonald J

2011-10-30

Neurotransmitter transporters can affect neuronal excitability indirectly via modulation of neurotransmitter concentrations or directly via transporter currents. A physiological or pathophysiological role for transporter currents has not been described. We found that GABA transporter 1 (GAT-1) cation currents directly increased GABAergic neuronal excitability and synaptic GABA release in the periaqueductal gray (PAG) during opioid withdrawal in rodents. In contrast, GAT-1 did not indirectly alter GABA receptor responses via modulation of extracellular GABA concentrations. Notably, we found that GAT-1-induced increases in GABAergic activity contributed to many PAG-mediated signs of opioid withdrawal. Together, these data support the hypothesis that GAT-1 activity directly produces opioid withdrawal signs through direct hyperexcitation of GABAergic PAG neurons and nerve terminals, which presumably enhances GABAergic inhibition of PAG output neurons. These data provide, to the best of our knowledge, the first evidence that dysregulation of a neurotransmitter transporter current is important for the maladaptive plasticity that underlies opiate withdrawal.

Manganese exposure alters extracellular GABA, GABA receptor and transporter protein and mRNA levels in the developing rat brain

PubMed Central

Anderson, Joel G.; Fordahl, Steve C.; Cooney, Paula T.; Weaver, Tara L.; Colyer, Christa L.; Erikson, Keith M.

2011-01-01

Unlike other essential trace elements (e.g., zinc and iron) it is the toxicity of manganese (Mn) that is more common in human populations than its deficiency. Data suggest alterations in dopamine biology may drive the effects associated with Mn neurotoxicity, though recently γ-aminobutyric acid (GABA) has been implicated. In addition, iron deficiency (ID), a common nutritional problem, may cause disturbances in neurochemistry by facilitating accumulation of Mn in the brain. Previous data from our lab have shown decreased brain tissue levels of GABA as well as decreased 3H-GABA uptake in synaptosomes as a result of Mn exposure and ID. These results indicate a possible increase in the concentration of extracellular GABA due to alterations in expression of GABA transport and receptor proteins. In this study weanling-male Sprague-Dawley rats were randomly placed into one of four dietary treatment groups: control (CN; 35 mg Fe/kg diet), iron-deficient (ID; 6 mg Fe/kg diet), CN with Mn supplementation (via the drinking water; 1 g Mn/L) (CNMn), and ID with Mn supplementation (IDMn). Using in vivo microdialysis, an increase in extracellular GABA concentrations in the striatum was observed in response to Mn exposure and ID although correlational analysis reveals that extracellular GABA is related more to extracellular iron levels and not Mn. A diverse effect of Mn exposure and ID was observed in the regions examined via Western blot and RT-PCR analysis, with effects on mRNA and protein expression of GAT-1, GABAA, and GABAB differing between and within the regions examined. For example, Mn exposure reduced GAT-1 protein expression by approximately 50% in the substantia nigra, while increasing mRNA expression approximately four-fold, while in the caudate putamen mRNA expression was decreased with no effect on protein expression. These data suggest that Mn exposure results in an increase in extracellular GABA concentrations via altered expression of transport and receptor proteins, which may be the basis of the neurological characteristics of manganism. PMID:18771689

Influence of GABA and GABA-producing Lactobacillus brevis DPC 6108 on the development of diabetes in a streptozotocin rat model.

PubMed

Marques, T M; Patterson, E; Wall, R; O'Sullivan, O; Fitzgerald, G F; Cotter, P D; Dinan, T G; Cryan, J F; Ross, R P; Stanton, C

2016-06-01

The aim of this study was to investigate if dietary administration of γ-aminobutyric acid (GABA)-producing Lactobacillus brevis DPC 6108 and pure GABA exert protective effects against the development of diabetes in streptozotocin (STZ)-induced diabetic Sprague Dawley rats. In a first experiment, healthy rats were divided in 3 groups (n=10/group) receiving placebo, 2.6 mg/kg body weight (bw) pure GABA or L. brevis DPC 6108 (~10(9)microorganisms). In a second experiment, rats (n=15/group) were randomised to five groups and four of these received an injection of STZ to induce type 1 diabetes. Diabetic and non-diabetic controls received placebo [4% (w/v) yeast extract in dH2O], while the other three diabetic groups received one of the following dietary supplements: 2.6 mg/kg bw GABA (low GABA), 200 mg/kg bw GABA (high GABA) or ~10(9) L. brevis DPC 6108. L. brevis DPC 6108 supplementation was associated with increased serum insulin levels (P<0.05), but did not alter other metabolic markers in healthy rats. Diabetes induced by STZ injection decreased body weight (P<0.05), increased intestinal length (P<0.05) and stimulated water and food intake. Insulin was decreased (P<0.05), whereas glucose was increased (P<0.001) in all diabetic groups, compared with non-diabetic controls. A decrease (P<0.01) in glucose levels was observed in diabetic rats receiving L. brevis DPC 6108, compared with diabetic-controls. Both the composition and diversity of the intestinal microbiota were affected by diabetes. Microbial diversity in diabetic rats supplemented with low GABA was not reduced (P>0.05), compared with non-diabetic controls while all other diabetic groups displayed reduced diversity (P<0.05). L. brevis DPC 6108 attenuated hyperglycaemia induced by diabetes but additional studies are needed to understand the mechanisms involved in this reduction.

[ERK activation effects on GABA secretion inhibition induced by SDF-1 in hippocampal neurons of rats].

PubMed

Zhang, Zi-juan; Guo, Mei-xia; Xing, Ying

2015-09-01

To investigate the effect of extracellular regulating kinase (ERK) signaling pathway on the secretion of gamma-aminobutyric acid (GABA) in cultured rat hippocampal neurons induced by stromal cell derived factor-1 (SDF-1). The hippocampal neurons of newborn SD rats were cultured and identified in vitro; the phosphorylation level of ERK1/2 was examined by Western blot; ELISA was used to detect the effect of PD98059, a ERK1/2 specific blocker on GABA secretion of cultured hippocampal neurons and Western blot were adopted to measure the protein expression levels of glutamate decarboxylase (GAD65/67) and gamma aminobutyric acid transporter (GAT); after blocking ERK1/2 signaling pathway with PD98059; RT-PCR was used to detect the mRNA expression levels of GAT-1 and GAD65 after treated with PD98059. The levels of ERKl/2 phosphorylation were increased significantly by SDF1 acting on hippocampal neurons, and CX-CR4 receptor blocker AMD3100, could inhibit SDF-1 induced ERK1/2 activation; SDF-1 could inhibit the secretion of GABA in cultured hippocampal neurons, and ERK1/2 specific inhibitor PD98059, could partly reverse the inhibition of GABA secretion by SDF-1. The effects of SDF-1 on cultured hippocampal neurons was to decrease the mRNA genesis of glutamic acid decarboxylase GAD65 and GABA transporter GAT-1, besides, ERK inhibitor PD98059 could effectively flip the effect of SDF-1. The results of Western blot showed that SDF-1 could inhibit the protein expression of GAT-1 and GAD65/67 in hippocampal neurons and the inhibition of GAT-1 and GAD65/67 protein expression could be partially restored by ERK1/2 blocker. SDF-1 acts on the CXCR4 of hippocampal neurons in vitro, and inhibits the expression of GAD by activating the ERK1/2 signaling pathway, and this may represent one possible pathway of GABA secretion inhibition.

Stellate and pyramidal neurons in goldfish telencephalon respond differently to anoxia and GABA receptor inhibition.

PubMed

Hossein-Javaheri, Nariman; Wilkie, Michael P; Lado, Wudu E; Buck, Leslie T

2017-02-15

With oxygen deprivation, the mammalian brain undergoes hyper-activity and neuronal death while this does not occur in the anoxia-tolerant goldfish ( Carassius auratus ). Anoxic survival of the goldfish may rely on neuromodulatory mechanisms to suppress neuronal hyper-excitability. As γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, we decided to investigate its potential role in suppressing the electrical activity of goldfish telencephalic neurons. Utilizing whole-cell patch-clamp recording, we recorded the electrical activities of both excitatory (pyramidal) and inhibitory (stellate) neurons. With anoxia, membrane potential ( V m ) depolarized in both cell types from -72.2 mV to -57.7 mV and from -64.5 mV to -46.8 mV in pyramidal and stellate neurons, respectively. While pyramidal cells remained mostly quiescent, action potential frequency (AP f ) of the stellate neurons increased 68-fold. Furthermore, the GABA A receptor reversal potential ( E - GABA ) was determined using the gramicidin perforated-patch-clamp method and found to be depolarizing in pyramidal (-53.8 mV) and stellate neurons (-42.1 mV). Although GABA was depolarizing, pyramidal neurons remained quiescent as E GABA was below the action potential threshold (-36 mV pyramidal and -38 mV stellate neurons). Inhibition of GABA A receptors with gabazine reversed the anoxia-mediated response. While GABA B receptor inhibition alone did not affect the anoxic response, co-antagonism of GABA A and GABA B receptors (gabazine and CGP-55848) led to the generation of seizure-like activities in both neuron types. We conclude that with anoxia, V m depolarizes towards E GABA which increases AP f in stellate neurons and decreases AP f in pyramidal neurons, and that GABA plays an important role in the anoxia tolerance of goldfish brain. © 2017. Published by The Company of Biologists Ltd.

Synchronization by Food Access Modifies the Daily Variations in Expression and Activity of Liver GABA Transaminase

PubMed Central

De Ita-Pérez, Dalia; Vázquez-Martínez, Olivia; Villalobos-Leal, Mónica

2014-01-01

Daytime restricted feeding (DRF) is an experimental protocol that influences the circadian timing system and underlies the expression of a biological clock known as the food entrained oscillator (FEO). Liver is the organ that reacts most rapidly to food restriction by adjusting the functional relationship between the molecular circadian clock and the metabolic networks. γ-Aminobutyric acid (GABA) is a signaling molecule in the liver, and able to modulate the cell cycle and apoptosis. This study was aimed at characterizing the expression and activity of the mostly mitochondrial enzyme GABA transaminase (GABA-T) during DRF/FEO expression. We found that DRF promotes a sustained increase of GABA-T in the liver homogenate and mitochondrial fraction throughout the entire day-night cycle. The higher amount of GABA-T promoted by DRF was not associated to changes in GABA-T mRNA or GABA-T activity. The GABA-T activity in the mitochondrial fraction even tended to decrease during the light period. We concluded that DRF influences the daily variations of GABA-T mRNA levels, stability, and catalytic activity of GABA-T. These data suggest that the liver GABAergic system responds to a metabolic challenge such as DRF and the concomitant appearance of the FEO. PMID:24809054

Synchronization by food access modifies the daily variations in expression and activity of liver GABA transaminase.

PubMed

De Ita-Pérez, Dalia; Méndez, Isabel; Vázquez-Martínez, Olivia; Villalobos-Leal, Mónica; Díaz-Muñoz, Mauricio

2014-01-01

Daytime restricted feeding (DRF) is an experimental protocol that influences the circadian timing system and underlies the expression of a biological clock known as the food entrained oscillator (FEO). Liver is the organ that reacts most rapidly to food restriction by adjusting the functional relationship between the molecular circadian clock and the metabolic networks. γ-Aminobutyric acid (GABA) is a signaling molecule in the liver, and able to modulate the cell cycle and apoptosis. This study was aimed at characterizing the expression and activity of the mostly mitochondrial enzyme GABA transaminase (GABA-T) during DRF/FEO expression. We found that DRF promotes a sustained increase of GABA-T in the liver homogenate and mitochondrial fraction throughout the entire day-night cycle. The higher amount of GABA-T promoted by DRF was not associated to changes in GABA-T mRNA or GABA-T activity. The GABA-T activity in the mitochondrial fraction even tended to decrease during the light period. We concluded that DRF influences the daily variations of GABA-T mRNA levels, stability, and catalytic activity of GABA-T. These data suggest that the liver GABAergic system responds to a metabolic challenge such as DRF and the concomitant appearance of the FEO.

EFFECTS OF DEVELOPMENTAL EXPOSURE TO HEPTACHLOR ON THE CHOLINERGIC SYSTEM IN RATS.

EPA Science Inventory

Heptachlor is an environmentally persistent cyclodiene pesticide which is a known antagonist of the -aminobutyric acid (GABA)A receptor. Since GABA is a trophic factor for the development of other neurotransmitter systems (Lauder et al., Perspectives in Developmental Neurobiolog...

Exogenous γ-aminobutyric acid (GABA) affects pollen tube growth via modulating putative Ca2+-permeable membrane channels and is coupled to negative regulation on glutamate decarboxylase

PubMed Central

Yu, Guang-Hui; Zou, Jie; Feng, Jing; Peng, Xiong-Bo; Wu, Ju-You; Wu, Ying-Liang; Palanivelu, Ravishankar; Sun, Meng-Xiang

2014-01-01

γ-Aminobutyric acid (GABA) is implicated in pollen tube growth, but the molecular and cellular mechanisms that it mediates are largely unknown. Here, it is shown that exogenous GABA modulates putative Ca2+-permeable channels on the plasma membranes of tobacco pollen grains and pollen tubes. Whole-cell voltage-clamp experiments and non-invasive micromeasurement technology (NMT) revealed that the influx of Ca2+ increases in pollen tubes in response to exogenous GABA. It is also demonstrated that glutamate decarboxylase (GAD), the rate-limiting enzyme of GABA biosynthesis, is involved in feedback controls of Ca2+-permeable channels to fluctuate intracellular GABA levels and thus modulate pollen tube growth. The findings suggest that GAD activity linked with Ca2+-permeable channels relays an extracellular GABA signal and integrates multiple signal pathways to modulate tobacco pollen tube growth. Thus, the data explain how GABA mediates the communication between the style and the growing pollen tubes. PMID:24799560

Role of Vasopressin in Rat Models of Salt-Dependent Hypertension.

PubMed

Prager-Khoutorsky, Masha; Choe, Katrina Y; Levi, David I; Bourque, Charles W

2017-05-01

Dietary salt intake increases both plasma sodium and osmolality and therefore increases vasopressin (VP) release from the neurohypophysis. Although this effect could increase blood pressure by inducing fluid reabsorption and vasoconstriction, acute activation of arterial baroreceptors inhibits VP neurons via GABA A receptors to oppose high blood pressure. Here we review recent findings demonstrating that this protective mechanism fails during chronic high salt intake in rats. Two recent studies showed that chronic high sodium intake causes an increase in intracellular chloride concentration in VP neurons. This effect causes GABA A receptors to become excitatory and leads to the emergence of VP-dependent hypertension. One study showed that the increase in intracellular chloride was provoked by a decrease in the expression of the chloride exporter KCC2 mediated by local secretion of brain-derived neurotrophic factor and activation of TrkB receptors. Prolonged high dietary salt intake can cause pathological plasticity in a central homeostatic circuit that controls VP secretion and thereby contribute to peripheral vasoconstriction and hypertension.

Metaplasticity within the spinal cord: Evidence brain-derived neurotrophic factor (BDNF), tumor necrosis factor (TNF), and alterations in GABA function (ionic plasticity) modulate pain and the capacity to learn.

PubMed

Grau, James W; Huang, Yung-Jen

2018-04-07

Evidence is reviewed that behavioral training and neural injury can engage metaplastic processes that regulate adaptive potential. This issue is explored within a model system that examines how training affects the capacity to learn within the lower (lumbosacral) spinal cord. Response-contingent (controllable) stimulation applied caudal to a spinal transection induces a behavioral modification indicative of learning. This behavioral change is not observed in animals that receive stimulation in an uncontrollable manner. Exposure to uncontrollable stimulation also engages a process that disables spinal learning for 24-48 h. Controllable stimulation has the opposite effect; it engages a process that enables learning and prevents/reverses the learning deficit induced by uncontrollable stimulation. These observations suggest that a learning episode can impact the capacity to learn in future situations, providing an example of behavioral metaplasticity. The protective/restorative effect of controllable stimulation has been linked to an up-regulation of brain-derived neurotrophic factor (BDNF). The disruption of learning has been linked to the sensitization of pain (nociceptive) circuits, which is enabled by a reduction in GABA-dependent inhibition. After spinal cord injury (SCI), the co-transporter (KCC2) that regulates the outward flow of Cl - is down-regulated. This causes the intracellular concentration of Cl - to increase, reducing (and potentially reversing) the inward flow of Cl - through the GABA-A receptor. The shift in GABA function (ionic plasticity) increases neural excitability caudal to injury and sets the stage for nociceptive sensitization. The injury-induced shift in KCC2 is related to the loss of descending serotonergic (5HT) fibers that regulate plasticity within the spinal cord dorsal horn through the 5HT-1A receptor. Evidence is presented that these alterations in spinal plasticity impact pain in a brain-dependent task (place conditioning). The findings suggest that ionic plasticity can affect learning potential, shifting a neural circuit from dampened/hard-wired to excitable/plastic. Copyright © 2018 Elsevier Inc. All rights reserved.

Galanin-Expressing GABA Neurons in the Lateral Hypothalamus Modulate Food Reward and Noncompulsive Locomotion.

PubMed

Qualls-Creekmore, Emily; Yu, Sangho; Francois, Marie; Hoang, John; Huesing, Clara; Bruce-Keller, Annadora; Burk, David; Berthoud, Hans-Rudolf; Morrison, Christopher D; Münzberg, Heike

2017-06-21

The lateral hypothalamus (LHA) integrates reward and appetitive behavior and is composed of many overlapping neuronal populations. Recent studies associated LHA GABAergic neurons (LHA GABA ), which densely innervate the ventral tegmental area (VTA), with modulation of food reward and consumption; yet, LHA GABA projections to the VTA exclusively modulated food consumption, not reward. We identified a subpopulation of LHA GABA neurons that coexpress the neuropeptide galanin (LHA Gal ). These LHA Gal neurons also modulate food reward, but lack direct VTA innervation. We hypothesized that LHA Gal neurons may represent a subpopulation of LHA GABA neurons that mediates food reward independent of direct VTA innervation. We used chemogenetic activation of LHA Gal or LHA GABA neurons in mice to compare their role in feeding behavior. We further analyzed locomotor behavior to understand how differential VTA connectivity and transmitter release in these LHA neurons influences this behavior. LHA Gal or LHA GABA neuronal activation both increased operant food-seeking behavior, but only activation of LHA GABA neurons increased overall chow consumption. Additionally, LHA Gal or LHA GABA neuronal activation similarly induced locomotor activity, but with striking differences in modality. Activation of LHA GABA neurons induced compulsive-like locomotor behavior; while LHA Gal neurons induced locomotor activity without compulsivity. Thus, LHA Gal neurons define a subpopulation of LHA GABA neurons without direct VTA innervation that mediate noncompulsive food-seeking behavior. We speculate that the striking difference in compulsive-like locomotor behavior is also based on differential VTA innervation. The downstream neural network responsible for this behavior and a potential role for galanin as neuromodulator remains to be identified. SIGNIFICANCE STATEMENT The lateral hypothalamus (LHA) regulates motivated feeding behavior via GABAergic LHA neurons. The molecular identity of LHA GABA neurons is heterogeneous and largely undefined. Here we introduce LHA Gal neurons as a subset of LHA GABA neurons that lack direct innervation of the ventral tegmental area (VTA). LHA Gal neurons are sufficient to drive motivated feeding and locomotor activity similar to LHA GABA neurons, but without inducing compulsive-like behaviors, which we propose to require direct VTA innervation. Our study integrates galanin-expressing LHA neurons into our current understanding of the neuronal circuits and molecular mechanisms of the LHA that contribute to motivated feeding behaviors. Copyright © 2017 the authors 0270-6474/17/376053-13$15.00/0.

The GABA uptake inhibitor beta-alanine reduces pilocarpine-induced tremor and increases extracellular GABA in substantia nigra pars reticulata as measured by microdialysis.

PubMed

Ishiwari, Keita; Mingote, Susana; Correa, Merce; Trevitt, Jennifer T; Carlson, Brian B; Salamone, John D

2004-12-30

Substantia nigra pars reticulata (SNr) is a major output nucleus of the basal ganglia that receives GABAergic projections from neostriatum and globus pallidus. Previous research has shown that local pharmacological manipulations of GABA in SNr can influence tremulous jaw movements in rats. Tremulous jaw movements are defined as rapid vertical deflections of the lower jaw that resemble chewing but are not directed at a particular stimulus, and evidence indicates that these movements share many characteristics with parkinsonian tremor in humans. In order to investigate the role of GABA in motor functions related to tremor, the present study tested the GABA uptake blocker beta-alanine for its ability to reduce pilocarpine-induced tremulous jaw movements. In a parallel experiment, the effect of an active dose of beta-alanine on dialysate levels of GABA in SNr was assessed using microdialysis methods. GABA levels in dialysis samples were measured using high performance liquid chromatography with electrochemical detection. beta-Alanine (250-500 mg/kg) significantly reduced tremulous jaw movements induced by pilocarpine (4.0 mg/kg). Moreover, systemic administration of beta-alanine at a dose that reduced tremulous jaw movements (500 mg/kg) resulted in a substantial increase in extracellular levels of GABA in SNr compared to the pre-injection baseline. Thus, the present results are consistent with the hypothesis that GABAergic tone in SNr plays a role in the regulation of tremulous jaw movements. This research may lead to a better understanding of how parkinsonian symptoms are modulated by SNr GABA mechanisms.

Contribution of synchronized GABAergic neurons to dopaminergic neuron firing and bursting.

PubMed

Morozova, Ekaterina O; Myroshnychenko, Maxym; Zakharov, Denis; di Volo, Matteo; Gutkin, Boris; Lapish, Christopher C; Kuznetsov, Alexey

2016-10-01

In the ventral tegmental area (VTA), interactions between dopamine (DA) and γ-aminobutyric acid (GABA) neurons are critical for regulating DA neuron activity and thus DA efflux. To provide a mechanistic explanation of how GABA neurons influence DA neuron firing, we developed a circuit model of the VTA. The model is based on feed-forward inhibition and recreates canonical features of the VTA neurons. Simulations revealed that γ-aminobutyric acid (GABA) receptor (GABAR) stimulation can differentially influence the firing pattern of the DA neuron, depending on the level of synchronization among GABA neurons. Asynchronous activity of GABA neurons provides a constant level of inhibition to the DA neuron and, when removed, produces a classical disinhibition burst. In contrast, when GABA neurons are synchronized by common synaptic input, their influence evokes additional spikes in the DA neuron, resulting in increased measures of firing and bursting. Distinct from previous mechanisms, the increases were not based on lowered firing rate of the GABA neurons or weaker hyperpolarization by the GABAR synaptic current. This phenomenon was induced by GABA-mediated hyperpolarization of the DA neuron that leads to decreases in intracellular calcium (Ca 2+ ) concentration, thus reducing the Ca 2+ -dependent potassium (K + ) current. In this way, the GABA-mediated hyperpolarization replaces Ca 2+ -dependent K + current; however, this inhibition is pulsatile, which allows the DA neuron to fire during the rhythmic pauses in inhibition. Our results emphasize the importance of inhibition in the VTA, which has been discussed in many studies, and suggest a novel mechanism whereby computations can occur locally. Copyright © 2016 the American Physiological Society.

Contribution of synchronized GABAergic neurons to dopaminergic neuron firing and bursting

PubMed Central

Myroshnychenko, Maxym; Zakharov, Denis; di Volo, Matteo; Gutkin, Boris; Lapish, Christopher C.; Kuznetsov, Alexey

2016-01-01

In the ventral tegmental area (VTA), interactions between dopamine (DA) and γ-aminobutyric acid (GABA) neurons are critical for regulating DA neuron activity and thus DA efflux. To provide a mechanistic explanation of how GABA neurons influence DA neuron firing, we developed a circuit model of the VTA. The model is based on feed-forward inhibition and recreates canonical features of the VTA neurons. Simulations revealed that γ-aminobutyric acid (GABA) receptor (GABAR) stimulation can differentially influence the firing pattern of the DA neuron, depending on the level of synchronization among GABA neurons. Asynchronous activity of GABA neurons provides a constant level of inhibition to the DA neuron and, when removed, produces a classical disinhibition burst. In contrast, when GABA neurons are synchronized by common synaptic input, their influence evokes additional spikes in the DA neuron, resulting in increased measures of firing and bursting. Distinct from previous mechanisms, the increases were not based on lowered firing rate of the GABA neurons or weaker hyperpolarization by the GABAR synaptic current. This phenomenon was induced by GABA-mediated hyperpolarization of the DA neuron that leads to decreases in intracellular calcium (Ca2+) concentration, thus reducing the Ca2+-dependent potassium (K+) current. In this way, the GABA-mediated hyperpolarization replaces Ca2+-dependent K+ current; however, this inhibition is pulsatile, which allows the DA neuron to fire during the rhythmic pauses in inhibition. Our results emphasize the importance of inhibition in the VTA, which has been discussed in many studies, and suggest a novel mechanism whereby computations can occur locally. PMID:27440240

Fast detection of extrasynaptic GABA with a whole-cell sniffer.

PubMed

Christensen, Rasmus K; Petersen, Anders V; Schmitt, Nicole; Perrier, Jean-François

2014-01-01

Gamma-amino-butyric acid (GABA) is the main inhibitory transmitter of the brain. It operates by binding to specific receptors located both inside and outside synapses. The extrasynaptic receptors are activated by spillover from GABAergic synapses and by ambient GABA in the extracellular space. Ambient GABA is essential for adjusting the excitability of neurons. However, due to the lack of suitable methods, little is known about its dynamics. Here we describe a new technique that allows detection of GABA transients and measurement of the steady state GABA concentration with high spatial and temporal resolution. We used a human embryonic kidney (HEK) cell line that stably expresses GABAA receptors composed of α1, β2, and γ2 subunits. We recorded from such a HEK cell with the whole-cell patch-clamp technique. The presence of GABA near the HEK cell generated a measurable electric current whose magnitude increased with concentration. A fraction of the current did not inactivate during prolonged exposition to GABA. This technique, which we refer to as a "sniffer" allows the measurement of ambient GABA concentration inside nervous tissue with a resolution of few tens of nanomolars. In addition, the sniffer detects variations in the extrasynaptic GABA concentration with millisecond time resolution. Pilot experiments demonstrate that the sniffer is able to report spillover of GABA induced by synaptic activation in real time. This is the first report on a GABA sensor that combines the ability to detect fast transients and to measure steady concentrations.

Fast detection of extrasynaptic GABA with a whole-cell sniffer

PubMed Central

Christensen, Rasmus K.; Petersen, Anders V.; Schmitt, Nicole; Perrier, Jean-François

2014-01-01

Gamma-amino-butyric acid (GABA) is the main inhibitory transmitter of the brain. It operates by binding to specific receptors located both inside and outside synapses. The extrasynaptic receptors are activated by spillover from GABAergic synapses and by ambient GABA in the extracellular space. Ambient GABA is essential for adjusting the excitability of neurons. However, due to the lack of suitable methods, little is known about its dynamics. Here we describe a new technique that allows detection of GABA transients and measurement of the steady state GABA concentration with high spatial and temporal resolution. We used a human embryonic kidney (HEK) cell line that stably expresses GABAA receptors composed of α1, β2, and γ2 subunits. We recorded from such a HEK cell with the whole-cell patch-clamp technique. The presence of GABA near the HEK cell generated a measurable electric current whose magnitude increased with concentration. A fraction of the current did not inactivate during prolonged exposition to GABA. This technique, which we refer to as a “sniffer” allows the measurement of ambient GABA concentration inside nervous tissue with a resolution of few tens of nanomolars. In addition, the sniffer detects variations in the extrasynaptic GABA concentration with millisecond time resolution. Pilot experiments demonstrate that the sniffer is able to report spillover of GABA induced by synaptic activation in real time. This is the first report on a GABA sensor that combines the ability to detect fast transients and to measure steady concentrations. PMID:24860433

Modulation of GABA receptors expressed in Xenopus oocytes by 13-L-hydroxylinoleic acid and food additives.

PubMed

Aoshima, H; Tenpaku, Y

1997-12-01

To study the effects of 13-L-hydroxylinoleic acid (LOH) and food additives on gamma-aminobutyric acid (GABA) receptors, ionotropic GABA receptors were expressed in Xenopus oocytes by injecting mRNAs prepared from rat whole brain. LOH, which was prepared by reduction of 13-L-hydroperoxylinoleic acid (LOOH), inhibited the response of GABA receptors in the presence of high concentrations of GABA. LOH also inhibited nicotinic acetylcholine, glycine, and kainate receptors, while it had little effect on NMDA receptors expressed in Xenopus oocytes. However, LOH potentiated the response of GABA receptors as well as LOOH in the presence of low concentrations of GABA, possibly increasing the affinity of GABA for the receptors, while linoleic acid did not. Since some modification of the compounds seemed to change their effects on GABA receptors, the responses of GABA receptors elicited by 10 microM GABA were measured in the presence of compounds with various kinds of functional groups or the structural isomers of pentanol. Potentiation of GABA receptors depended strongly on the species of functional groups and also depended on the structure of the isomers. Then effects of various kinds of food additives on GABA receptors were also examined; perfumes such as alcohols or esters potentiated the responses strongly, while hexylamine, nicotinamide, or caffeine inhibited the responses, mainly in a competitive manner, and vanillin inhibited the responses noncompetitively. These results suggest the possibility that production of LOOH and LOH, or intake of much of some food additives, modulates the neural transmission in the brain, especially through ionotropic GABA receptors and changes the frame of the human mind, as alcohol or tobacco does.

Glutamate modulation of GABA transport in retinal horizontal cells of the skate

PubMed Central

Kreitzer, Matthew A; Andersen, Kristen A; Malchow, Robert Paul

2003-01-01

Transport of the amino acid GABA into neurons and glia plays a key role in regulating the effects of GABA in the vertebrate retina. We have examined the modulation of GABA-elicited transport currents of retinal horizontal cells by glutamate, the likely neurotransmitter of vertebrate photoreceptors. Enzymatically isolated external horizontal cells of skate were examined using whole-cell voltage-clamp techniques. GABA (1 mm) elicited an inward current that was completely suppressed by the GABA transport inhibitors tiagabine (10 μm) and SKF89976-A (100 μm), but was unaffected by 100 μm picrotoxin. Prior application of 100 μm glutamate significantly reduced the GABA-elicited current. Glutamate depressed the GABA dose-response curve without shifting the curve laterally or altering the voltage dependence of the current. The ionotropic glutamate receptor agonists kainate and AMPA also reduced the GABA-elicited current, and the effects of glutamate and kainate were abolished by the ionotropic glutamate receptor antagonist 6-cyano-7-nitroquinoxaline. NMDA neither elicited a current nor modified the GABA-induced current, and metabotropic glutamate analogues were also without effect. Inhibition of the GABA-elicited current by glutamate and kainate was reduced when extracellular calcium was removed and when recording pipettes contained high concentrations of the calcium chelator BAPTA. Caffeine (5 mm) and thapsigargin (2 nm), agents known to alter intracellular calcium levels, also reduced the GABA-elicited current, but increases in calcium induced by depolarization alone did not. Our data suggest that glutamate regulates GABA transport in retinal horizontal cells through a calcium-dependent process, and imply a close physical relationship between calcium-permeable glutamate receptors and GABA transporters in these cells. PMID:12562999

The GABA Hypothesis in Essential Tremor: Lights and Shadows.

PubMed

Gironell, Alexandre

2014-01-01

The gamma-aminobutyric acid (GABA) hypothesis in essential tremor (ET) implies a disturbance of the GABAergic system, especially involving the cerebellum. This review examines the evidence of the GABA hypothesis. The review is based on published data about GABA dysfunction in ET, taking into account studies on cerebrospinal fluid, pathology, electrophysiology, genetics, neuroimaging, experimental animal models, and human drug therapies. Findings from several studies support the GABA hypothesis in ET. The hypothesis follows four steps: 1) cerebellar neurodegeneration with Purkinje cell loss; 2) a decrease in GABA system activity in deep cerebellar neurons; 3) disinhibition in output deep cerebellar neurons with pacemaker activity; and 4) an increase in rhythmic activity of the thalamus and thalamo-cortical circuit, contributing to the generation of tremor. Doubts have been cast on this hypothesis, however, by the fact that it is based on relatively few works, controversial post-mortem findings, and negative genetic studies on the GABA system. Furthermore, GABAergic drug efficacy is low and some GABAergic drugs do not have antitremoric efficacy. The GABA hypothesis continues to be the most robust pathophysiological hypothesis to explain ET. There is light in all GABA hypothesis steps, but a number of shadows cannot be overlooked. We need more studies to clarify the neurodegenerative nature of the disease, to confirm the decrease of GABA activity in the cerebellum, and to test more therapies that enhance the GABA transmission specifically in the cerebellum area.

γ-Aminobutyric acid transaminase deficiency impairs central carbon metabolism and leads to cell wall defects during salt stress in Arabidopsis roots.

PubMed

Renault, Hugues; El Amrani, Abdelhak; Berger, Adeline; Mouille, Grégory; Soubigou-Taconnat, Ludivine; Bouchereau, Alain; Deleu, Carole

2013-05-01

Environmental constraints challenge cell homeostasis and thus require a tight regulation of metabolic activity. We have previously reported that the γ-aminobutyric acid (GABA) metabolism is crucial for Arabidopsis salt tolerance as revealed by the NaCl hypersensitivity of the GABA transaminase (GABA-T, At3g22200) gaba-t/pop2-1 mutant. In this study, we demonstrate that GABA-T deficiency during salt stress causes root and hypocotyl developmental defects and alterations of cell wall composition. A comparative genome-wide transcriptional analysis revealed that expression levels of genes involved in carbon metabolism, particularly sucrose and starch catabolism, were found to increase upon the loss of GABA-T function under salt stress conditions. Consistent with the altered mutant cell wall composition, a number of cell wall-related genes were also found differentially expressed. A targeted quantitative analysis of primary metabolites revealed that glutamate (GABA precursor) accumulated while succinate (the final product of GABA metabolism) significantly decreased in mutant roots after 1 d of NaCl treatment. Furthermore, sugar concentration was twofold reduced in gaba-t/pop2-1 mutant roots compared with wild type. Together, our results provide strong evidence that GABA metabolism is a major route for succinate production in roots and identify GABA as a major player of central carbon adjustment during salt stress. © 2012 Blackwell Publishing Ltd.

Effect of dietary protein and GABA on food intake, growth and tissue amino acids in cats.

PubMed

Tews, J K; Rogers, Q R; Morris, J G; Harper, A E

1984-02-01

GABA at 5%, but not 3%, of a low protein diet depressed food intake and growth of kittens. Adaptation to high protein prevented these effects. When cats adapted to low or high protein were fed a meal containing GABA, plasma GABA concentration after 2 hr was 8-fold higher in the low than in the high protein group; clearance was almost complete within 6 hr. Concentrations of proline, branched-chain, other large neutral and basic (especially ornithine) amino acids increased more when cats were fed a high rather than a low protein meal; glycine decreased. At 6 hr, concentrations had consistently returned to initial levels only in the low protein group. Feeding the high protein diet ad lib increased tissue concentrations of threonine, proline and the branched-chain amino acids. Hepatic or renal GABA-aminotransferase activity was not altered in kittens fed the high protein diet. Kidney activity was 10-fold that of liver, which may contribute to the better tolerance of GABA by cats than by rats.

Accumulation of GABAergic neurons, causing a focal ambient GABA gradient, and downregulation of KCC2 are induced during microgyrus formation in a mouse model of polymicrogyria.

PubMed

Wang, Tianying; Kumada, Tatsuro; Morishima, Toshitaka; Iwata, Satomi; Kaneko, Takeshi; Yanagawa, Yuchio; Yoshida, Sachiko; Fukuda, Atsuo

2014-04-01

Although focal cortical malformations are considered neuronal migration disorders, their formation mechanisms remain unknown. We addressed how the γ-aminobutyric acid (GABA)ergic system affects the GABAergic and glutamatergic neuronal migration underlying such malformations. A focal freeze-lesion (FFL) of the postnatal day zero (P0) glutamic acid decarboxylase-green fluorescent protein knock-in mouse neocortex produced a 3- or 4-layered microgyrus at P7. GABAergic interneurons accumulated around the necrosis including the superficial region during microgyrus formation at P4, whereas E17.5-born, Cux1-positive pyramidal neurons outlined the GABAergic neurons and were absent from the superficial layer, forming cell-dense areas in layer 2 of the P7 microgyrus. GABA imaging showed that an extracellular GABA level temporally increased in the GABAergic neuron-positive area, including the necrotic center, at P4. The expression of the Cl(-) transporter KCC2 was downregulated in the microgyrus-forming GABAergic and E17.5-born glutamatergic neurons at P4; these cells may need a high intracellular Cl(-) concentration to induce depolarizing GABA effects. Bicuculline decreased the frequency of spontaneous Ca(2+) oscillations in these microgyrus-forming cells. Thus, neonatal FFL causes specific neuronal accumulation, preceded by an increase in ambient GABA during microgyrus formation. This GABA increase induces GABAA receptor-mediated Ca(2+) oscillation in KCC2-downregulated microgyrus-forming cells, as seen in migrating cells during early neocortical development.

Elevating Endogenous GABA Levels with GAT-1 Blockade Modulates Evoked but Not Induced Responses in Human Visual Cortex

PubMed Central

Muthukumaraswamy, Suresh D; Myers, Jim F M; Wilson, Sue J; Nutt, David J; Hamandi, Khalid; Lingford-Hughes, Anne; Singh, Krish D

2013-01-01

The electroencephalographic/magnetoencephalographic (EEG/MEG) signal is generated primarily by the summation of the postsynaptic currents of cortical principal cells. At a microcircuit level, these glutamatergic principal cells are reciprocally connected to GABAergic interneurons. Here we investigated the relative sensitivity of visual evoked and induced responses to altered levels of endogenous GABAergic inhibition. To do this, we pharmacologically manipulated the GABA system using tiagabine, which blocks the synaptic GABA transporter 1, and so increases endogenous GABA levels. In a single-blinded and placebo-controlled crossover study of 15 healthy participants, we administered either 15 mg of tiagabine or a placebo. We recorded whole-head MEG, while participants viewed a visual grating stimulus, before, 1, 3 and 5 h post tiagabine ingestion. Using beamformer source localization, we reconstructed responses from early visual cortices. Our results showed no change in either stimulus-induced gamma-band amplitude increases or stimulus-induced alpha amplitude decreases. However, the same data showed a 45% reduction in the evoked response component at ∼80 ms. These data demonstrate that, in early visual cortex the evoked response shows a greater sensitivity compared with induced oscillations to pharmacologically increased endogenous GABA levels. We suggest that previous studies correlating GABA concentrations as measured by magnetic resonance spectroscopy to gamma oscillation frequency may reflect underlying variations such as interneuron/inhibitory synapse density rather than functional synaptic GABA concentrations. PMID:23361120

In Vivo Measurement of GABA Transmission in Healthy Subjects and Schizophrenia Patients

PubMed Central

Frankle, W. Gordon; Cho, Raymond Y.; Prasad, Konasale M.; Mason, N. Scott; Paris, Jennifer; Himes, Michael L.; Walker, Christopher; Lewis, David A.; Narendran, Rajesh

2016-01-01

Objective Postmortem studies in schizophrenia reveal alterations in gene products that regulate the release and extracellular persistence of GABA. However, results of in vivo studies of schizophrenia measuring total tissue GABA with magnetic resonance spectroscopy (MRS) have been inconsistent. Neither the postmortem nor the MRS studies directly address the physiological properties of GABA neurotransmission. The present study addresses this question through an innovative positron emission tomography (PET) paradigm. Method The binding of [11C]flumazenil, a benzodiazepine-specific PET radiotracer, was measured before and after administration of tiagabine (0.2 mg/kg of body weight), a GABA membrane transporter (GAT1) blocker, in 17 off-medication patients with schizophrenia and 22 healthy comparison subjects. Increased extracellular GABA, through GAT1 blockade, enhances the affinity of GABAA receptors for benzodiazepine ligands, detected as an increase in [11C]flumazenil tissue distribution volume (VT). Results [11C]Flumazenil VT was significantly increased across all cortical brain regions in the healthy comparison group but not in the schizophrenia group. This lack of effect was most prominent in the antipsychotic-naive schizophrenia group. In this subgroup, [11C]flumazenil ΔVT in the medial temporal lobe was correlated with positive symptoms, and baseline [11C] flumazenil VT in the medial temporal lobe was negatively correlated with visual learning. In the healthy comparison group but not the schizophrenia group, [11C]flumazenil ΔVT was positively associated with gamma-band oscillation power. Conclusions This study demonstrates, for the first time, an in vivo impairment in GABA transmission in schizophrenia, most prominent in antipsychotic-naive individuals. The impairment in GABA transmission appears to be linked to clinical symptoms, disturbances in cortical oscillations, and cognition. PMID:26133962

In vivo measurement of GABA transmission in healthy subjects and schizophrenia patients.

PubMed

Frankle, W Gordon; Cho, Raymond Y; Prasad, Konasale M; Mason, N Scott; Paris, Jennifer; Himes, Michael L; Walker, Christopher; Lewis, David A; Narendran, Rajesh

2015-11-01

Postmortem studies in schizophrenia reveal alterations in gene products that regulate the release and extracellular persistence of GABA. However, results of in vivo studies of schizophrenia measuring total tissue GABA with magnetic resonance spectroscopy (MRS) have been inconsistent. Neither the postmortem nor the MRS studies directly address the physiological properties of GABA neurotransmission. The present study addresses this question through an innovative positron emission tomography (PET) paradigm. The binding of [(11)C]flumazenil, a benzodiazepine-specific PET radiotracer, was measured before and after administration of tiagabine (0.2 mg/kg of body weight), a GABA membrane transporter (GAT1) blocker, in 17 off-medication patients with schizophrenia and 22 healthy comparison subjects. Increased extracellular GABA, through GAT1 blockade, enhances the affinity of GABAA receptors for benzodiazepine ligands, detected as an increase in [(11)C]flumazenil tissue distribution volume (VT). [(11)C]Flumazenil VT was significantly increased across all cortical brain regions in the healthy comparison group but not in the schizophrenia group. This lack of effect was most prominent in the antipsychotic-naive schizophrenia group. In this subgroup, [(11)C]flumazenil ΔVT in the medial temporal lobe was correlated with positive symptoms, and baseline [(11)C]flumazenil VT in the medial temporal lobe was negatively correlated with visual learning. In the healthy comparison group but not the schizophrenia group, [(11)C]flumazenil ΔVT was positively associated with gamma-band oscillation power. This study demonstrates, for the first time, an in vivo impairment in GABA transmission in schizophrenia, most prominent in antipsychotic-naive individuals. The impairment in GABA transmission appears to be linked to clinical symptoms, disturbances in cortical oscillations, and cognition.

GABAergic Transmission in Rat Pontine Reticular Formation Regulates the Induction Phase of Anesthesia and Modulates Hyperalgesia Caused by Sleep Deprivation

PubMed Central

Vanini, Giancarlo; Nemanis, Kriste; Baghdoyan, Helen A.; Lydic, Ralph

2014-01-01

The oral part of the pontine reticular formation (PnO) contributes to the regulation of sleep, anesthesia, and pain. The role of PnO GABA in modulating these states remains incompletely understood. The present study used time to Loss and time to Resumption of Righting Response (LoRR and RoRR) as surrogate measures of loss and resumption of consciousness. This study tested three hypotheses: (1) pharmacologically manipulating GABA levels in rat PnO alters LoRR, RoRR, and nociception; (2) propofol decreases GABA levels in the PnO; and (3) inhibiting GABA synthesis in the PnO blocks hyperalgesia caused by sleep deprivation. Administering a GABA synthesis inhibitor (3-MPA) or a GABA uptake inhibitor (NPA) into rat PnO significantly altered LoRR caused by propofol. 3-MPA significantly decreased LoRR for propofol (−18%). NPA significantly increased LoRR during administration of propofol (36%). Neither 3-MPA nor NPA altered RoRR following cessation of propofol or isoflurane delivery. The finding that LoRR was decreased by 3-MPA and increased by NPA is consistent with measures showing that extracellular GABA levels in the PnO were decreased (41%) by propofol. Thermal nociception was significantly decreased by 3-MPA and increased by NPA, and 3-MPA blocked the hyperalgesia caused by sleep deprivation. The results demonstrate that GABA levels in the PnO regulate the time for loss of consciousness caused by propofol, extend the concept that anesthetic induction and emergence are not inverse processes, and suggest that GABAergic transmission in the PnO mediates hyperalgesia caused by sleep loss. PMID:24674578

GABAergic transmission in rat pontine reticular formation regulates the induction phase of anesthesia and modulates hyperalgesia caused by sleep deprivation.

PubMed

Vanini, Giancarlo; Nemanis, Kriste; Baghdoyan, Helen A; Lydic, Ralph

2014-07-01

The oral part of the pontine reticular formation (PnO) contributes to the regulation of sleep, anesthesia and pain. The role of PnO γ-aminobutyric acid (GABA) in modulating these states remains incompletely understood. The present study used time to loss and time to resumption of righting response (LoRR and RoRR) as surrogate measures of loss and resumption of consciousness. This study tested three hypotheses: (i) pharmacologically manipulating GABA levels in rat PnO alters LoRR, RoRR and nociception; (ii) propofol decreases GABA levels in the PnO; and (iii) inhibiting GABA synthesis in the PnO blocks hyperalgesia caused by sleep deprivation. Administering a GABA synthesis inhibitor [3-mercaptopropionic acid (3-MPA)] or a GABA uptake inhibitor [nipecotic acid (NPA)] into rat PnO significantly altered LoRR caused by propofol. 3-MPA significantly decreased LoRR for propofol (-18%). NPA significantly increased LoRR during administration of propofol (36%). Neither 3-MPA nor NPA altered RoRR following cessation of propofol or isoflurane delivery. The finding that LoRR was decreased by 3-MPA and increased by NPA is consistent with measures showing that extracellular GABA levels in the PnO were decreased (41%) by propofol. Thermal nociception was significantly decreased by 3-MPA and increased by NPA, and 3-MPA blocked the hyperalgesia caused by sleep deprivation. The results demonstrate that GABA levels in the PnO regulate the time for loss of consciousness caused by propofol, extend the concept that anesthetic induction and emergence are not inverse processes, and suggest that GABAergic transmission in the PnO mediates hyperalgesia caused by sleep loss. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

GABA(B) receptors, schizophrenia and sleep dysfunction: a review of the relationship and its potential clinical and therapeutic implications.

PubMed

Kantrowitz, Joshua; Citrome, Leslie; Javitt, Daniel

2009-08-01

Evidence for an intrinsic relationship between sleep, cognition and the symptomatic manifestations of schizophrenia is accumulating. This review presents evidence for the possible utility of GABA(B) receptor agonists for the treatment of subjective and objective sleep abnormalities related to schizophrenia. At the phenotypic level, sleep disturbance occurs in 16-30% of patients with schizophrenia and is related to reduced quality of life and poor coping skills. On the neurophysiological level, studies suggest that sleep deficits reflect a core component of schizophrenia. Specifically, slow-wave sleep deficits, which are inversely correlated with cognition scores, are seen. Moreover, sleep plays an increasingly well documented role in memory consolidation in schizophrenia. Correlations of slow-wave sleep deficits with impaired reaction time and declarative memory have also been reported. Thus, both behavioural insomnia and sleep architecture are critical therapeutic targets in patients with schizophrenia. However, long-term treatment with antipsychotics often results in residual sleep dysfunction and does not improve slow-wave sleep, and adjunctive GABA(A) receptor modulators, such as benzodiazepines and zolpidem, can impair sleep architecture and cognition in schizophrenia. GABA(B) receptor agonists have therapeutic potential in schizophrenia. These agents have minimal effect on rapid eye movement sleep while increasing slow-wave sleep. Preclinical associations with increased expression of genes related to slow-wave sleep production and circadian rhythm function have also been reported. GABA(B) receptor deficits result in a sustained hyperdopaminergic state and can be reversed by a GABA(B) receptor agonist. Genetic, postmortem and electrophysiological studies also associate GABA(B) receptors with schizophrenia. While studies thus far have not shown significant effects, prior focus on the use of GABA(B) receptor agonists has been on the positive symptoms of schizophrenia, with minimal investigation of GABA(B) receptor agonists such as baclofen or gamma-hydroxybutyric acid and their effects on sleep architecture, cognition and negative symptoms in patients with schizophrenia. Further study is needed.

Zolpidem modulation of phasic and tonic GABA currents in the rat dorsal motor nucleus of the vagus

PubMed Central

Gao, Hong; Smith, Bret N.

2010-01-01

Zolpidem is a widely prescribed sleep aid with relative selectivity for GABAA receptors containing α1–3 subunits. We examined the effects of zolpidem on the inhibitory currents mediated by GABAA receptors using whole-cell patch-clamp recordings from DMV neurons in transverse brainstem slices from rat. Zolpidem prolonged the decay time of mIPSCs and of muscimol-evoked whole-cell GABAergic currents, and it occasionally enhanced the amplitude of mIPSCs. The effects were blocked by flumazenil, a benzodiazepine antagonist. Zolpidem also hyperpolarized the resting membrane potential, with a concomitant decrease in input resistance and action potential firing activity in a subset of cells. Zolpidem did not clearly alter the GABAA receptor-mediated tonic current (Itonic) under baseline conditions, but after elevating extracellular GABA concentration with nipecotic acid, a non-selective GABA transporter blocker, zolpidem consistently and significantly increased the tonic GABA current. This increase was suppressed by flumazenil and gabazine. These results suggest that α1–3 subunits are expressed in synaptic GABAA receptors on DMV neurons. The baseline tonic GABA current is likely not mediated by these same low affinity, zolpidem-sensitive GABAA receptors. However, when the extracellular GABA concentration is increased, zolpidem-sensitive extrasynaptic GABAA receptors containing α1–3 subunits contribute to the Itonic. PMID:20226798

Effect of γ-Aminobutyric Acid-producing Lactobacillus Strain on Laying Performance, Egg Quality and Serum Enzyme Activity in Hy-Line Brown Hens under Heat Stress.

PubMed

Zhu, Y Z; Cheng, J L; Ren, M; Yin, L; Piao, X S

2015-07-01

Heat-stress remains a costly issue for animal production, especially for poultry as they lack sweat glands, and alleviating heat-stress is necessary for ensuring animal production in hot environment. A high γ-aminobutyric acid (GABA)-producer Lactobacillus strain was used to investigate the effect of dietary GABA-producer on laying performance and egg quality in heat-stressed Hy-line brown hens. Hy-Line brown hens (n = 1,164) at 280 days of age were randomly divided into 4 groups based on the amount of freeze-dried GABA-producer added to the basal diet as follows: i) 0 mg/kg, ii) 25 mg/kg, iii) 50 mg/kg, and iv) 100 mg/kg. All hens were subjected to heat-stress treatment through maintaining the temperature and the relative humidity at 28.83±3.85°C and 37% to 53.9%, respectively. During the experiment, laying rate, egg weight and feed intake of hens were recorded daily. At the 30th and 60th day after the start of the experiment, biochemical parameters, enzyme activity and immune activity in serum were measured. Egg production, average egg weight, average daily feed intake, feed conversion ratio and percentage of speckled egg, soft shell egg and misshaped egg were significantly improved (p<0.05) by the increasing supplementation of the dietary GABA-producer. Shape index, eggshell thickness, strength and weight were increased linearly with increasing GABA-producer supplementation. The level of calcium, phosphorus, glucose, total protein and albumin in serum of the hens fed GABA-producing strain supplemented diet was significantly higher (p<0.05) than that of the hens fed the basal diet, whereas cholesterol level was decreased. Compared with the basal diet, GABA-producer strain supplementation increased serum level of glutathione peroxidase (p = 0.009) and superoxide dismutase. In conclusion, GABA-producer played an important role in alleviating heat-stress, the isolated GABA-producer strain might be a potential natural and safe probiotic to use to improve laying performance and egg quality in heat-stressed hens.

Early Developmental Disturbances of Cortical Inhibitory Neurons: Contribution to Cognitive Deficits in Schizophrenia

PubMed Central

Volk, David W.; Lewis, David A.

2014-01-01

Cognitive dysfunction is a disabling and core feature of schizophrenia. Cognitive impairments have been linked to disturbances in inhibitory (gamma-aminobutyric acid [GABA]) neurons in the prefrontal cortex. Cognitive deficits are present well before the onset of psychotic symptoms and have been detected in early childhood with developmental delays reported during the first year of life. These data suggest that the pathogenetic process that produces dysfunction of prefrontal GABA neurons in schizophrenia may be related to altered prenatal development. Interestingly, adult postmortem schizophrenia brain tissue studies have provided evidence consistent with a disease process that affects different stages of prenatal development of specific subpopulations of prefrontal GABA neurons. Prenatal ontogeny (ie, birth, proliferation, migration, and phenotypic specification) of distinct subpopulations of cortical GABA neurons is differentially regulated by a host of transcription factors, chemokine receptors, and other molecular markers. In this review article, we propose a strategy to investigate how alterations in the expression of these developmental regulators of subpopulations of cortical GABA neurons may contribute to the pathogenesis of cortical GABA neuron dysfunction and consequently cognitive impairments in schizophrenia. PMID:25053651

Trans-synaptic (GABA-dopamine) modulation of cocaine induced dopamine release: A potential therapeutic strategy for cocaine abuse

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dewey, S.L.; Straughter-Moore, R.; Chen, R.

We recently developed a new experimental strategy for measuring interactions between functionally-linked neurotransmitter systems in the primate and human brain with PET. As part of this research, we demonstrated that increases in endogenous GABA concentrations significantly reduced striatal dopamine concentrations in the primate brain. We report here the application of the neurotransmitter interaction paradigm with PET and with microdialysis to the investigation of a novel therapeutic strategy for treating cocaine abuse based on the ability of GABA to inhibit cocaine induced increases in striatal dopamine. Using gamma-vinyl GABA (GVG, a suicide inhibitor of GABA transaminase), we performed a series ofmore » PET studies where animals received a baseline PET scan with labeled raclopride injection, animals received cocaine (2.0 mg/kg). Normally, a cocaine challenge significantly reduces the striatal binding of {sup 11}C-raclopride. However, in animals pretreated with GVG, {sup 11}C-raclopride binding was less affected by a cocaine challenge compared to control studies. Furthermore, microdialysis studies in freely moving rats demonstrate that GVG (300 mg/kg) significantly inhibited cocaine-induced increases in extracellular dopamine release. GVG also attenuated cocaine-induced increases in locomotor activity. However, at a dose of 100 mg/kg, GVG had no effect. Similar findings were obtained with alcohol. Alcohol pretreatment dose dependantly (1-4 g/kg) inhibited cocaine-induced increases in extracellular dopamine concentrations in freely moving rats. Taken together, these studies suggest that therapeutic strategies targeted at increasing central GABA concentrations may be beneficial for the treatment of cocaine abuse.« less

GAD65 Promoter Polymorphism rs2236418 Modulates Harm Avoidance in Women via Inhibition/Excitation Balance in the Rostral ACC.

PubMed

Colic, Lejla; Li, Meng; Demenescu, Liliana Ramona; Li, Shija; Müller, Iris; Richter, Anni; Behnisch, Gusalija; Seidenbecher, Constanze I; Speck, Oliver; Schott, Björn H; Stork, Oliver; Walter, Martin

2018-05-30

Anxiety disorders are common and debilitating conditions with higher prevalence in women. However, factors that predispose women to anxiety phenotypes are not clarified. Here we investigated potential contribution of the single nucleotide polymorphism rs2236418 in GAD2 gene to changes in regional inhibition/excitation balance, anxiety-like traits, and related neural activity in both sexes. One hundred and five healthy individuals were examined with high-field (7T) multimodal magnetic resonance imaging (MRI); including resting-state functional MRI in combination with assessment of GABA and glutamate (Glu) levels via MR spectroscopy. Regional GABA/Glu levels in anterior cingulate cortex (ACC) subregions were assessed as mediators of gene-personality interaction for the trait harm avoidance and moderation by sex was tested. In AA homozygotes, with putatively lower GAD2 promoter activity, we observed increased intrinsic neuronal activity and higher inhibition/excitation balance in pregenual ACC (pgACC) compared with G carriers. The pgACC drove a significant interaction of genotype, region, and sex, where inhibition/excitation balance was significantly reduced only in female AA carriers. This finding was specific for rs2236418 as other investigated single nucleotide polymorphisms of the GABA synthesis related enzymes ( GAD1 , GAD2 , and GLS ) were not significant. Furthermore, only in women there was a negative association of pgACC GABA/Glu ratios with harm avoidance. A moderated-mediation model revealed that pgACC GABA/Glu also mediated the association between the genotype variant and level of harm avoidance, dependent on sex. Our data thus provide new insights into the neurochemical mechanisms that control emotional endophenotypes in humans and constitute predisposing factors for the development of anxiety disorders in women. SIGNIFICANCE STATEMENT Anxiety disorders are among the most common and burdensome psychiatric disorders, with higher prevalence rates in women. The causal mechanisms are, however, poorly understood. In this study we propose a neurobiological basis that could help to explain female bias of anxiety endophenotypes. Using magnetic resonance brain imaging and personality questionnaires we show an interaction of the genetic variation rs2236418 in the GAD2 gene and sex on GABA/glutamate (Glu) balance in the pregenual anterior cingulate cortex (pgACC), a region previously connected to affect regulation and anxiety disorders. The GAD2 gene polymorphism further influenced baseline neuronal activity in the pgACC. Importantly, GABA/Glu was shown to mediate the relationship between the genetic variant and harm avoidance, however, only in women. Copyright © 2018 the authors 0270-6474/18/385068-11$15.00/0.

Seizure-induced alterations in fast-spiking basket cell GABA currents modulate frequency and coherence of gamma oscillation in network simulations

NASA Astrophysics Data System (ADS)

Proddutur, Archana; Yu, Jiandong; Elgammal, Fatima S.; Santhakumar, Vijayalakshmi

2013-12-01

Gamma frequency oscillations have been proposed to contribute to memory formation and retrieval. Fast-spiking basket cells (FS-BCs) are known to underlie development of gamma oscillations. Fast, high amplitude GABA synapses and gap junctions have been suggested to contribute to gamma oscillations in FS-BC networks. Recently, we identified that, apart from GABAergic synapses, FS-BCs in the hippocampal dentate gyrus have GABAergic currents mediated by extrasynaptic receptors. Our experimental studies demonstrated two specific changes in FS-BC GABA currents following experimental seizures [Yu et al., J. Neurophysiol. 109, 1746 (2013)]: increase in the magnitude of extrasynaptic (tonic) GABA currents and a depolarizing shift in GABA reversal potential (EGABA). Here, we use homogeneous networks of a biophysically based model of FS-BCs to examine how the presence of extrasynaptic GABA conductance (gGABA-extra) and experimentally identified, seizure-induced changes in gGABA-extra and EGABA influence network activity. Networks of FS-BCs interconnected by fast GABAergic synapses developed synchronous firing in the dentate gamma frequency range (40-100 Hz). Systematic investigation revealed that the biologically realistic range of 30 to 40 connections between FS-BCs resulted in greater coherence in the gamma frequency range when networks were activated by Poisson-distributed dendritic synaptic inputs rather than by homogeneous somatic current injections, which were balanced for FS-BC firing frequency in unconnected networks. Distance-dependent conduction delay enhanced coherence in networks with 30-40 FS-BC interconnections while inclusion of gap junctional conductance had a modest effect on coherence. In networks activated by somatic current injections resulting in heterogeneous FS-BC firing, increasing gGABA-extra reduced the frequency and coherence of FS-BC firing when EGABA was shunting (-74 mV), but failed to alter average FS-BC frequency when EGABA was depolarizing (-54 mV). When FS-BCs were activated by biologically based dendritic synaptic inputs, enhancing gGABA-extra reduced the frequency and coherence of FS-BC firing when EGABA was shunting and increased average FS-BC firing when EGABA was depolarizing. Shifting EGABA from shunting to depolarizing potentials consistently increased network frequency to and above high gamma frequencies (>80 Hz). Since gamma oscillations may contribute to learning and memory processing [Fell et al., Nat. Neurosci. 4, 1259 (2001); Jutras et al., J. Neurosci. 29, 12521 (2009); Wang, Physiol. Rev. 90, 1195 (2010)], our demonstration that network oscillations are modulated by extrasynaptic inhibition in FS-BCs suggests that neuroactive compounds that act on extrasynaptic GABA receptors could impact memory formation by modulating hippocampal gamma oscillations. The simulation results indicate that the depolarized FS-BC GABA reversal, observed after experimental seizures, together with enhanced spillover extrasynaptic GABA currents are likely to promote generation of focal high frequency activity associated with epileptic networks.

The central GABAergic system and control of food intake under different experimental conditions.

PubMed

Olgiati, V R; Netti, C; Guidobono, F; Pecile, A

1980-01-01

Intracerebroventricular injections of gamma-aminobutyric acid (GABA) and of the GABA-transaminase inhibitor, ethanolamine-O-sulphate (EOS), decreased the food intake of freely-fed (GABA and EOS) and food-deprived rats (EOS). The effect, still evident 24 h after treatment, was not decreased by the GABA receptor-blocker bicuculline. In contrast, intracerebroventricular injections of the GABA receptor-agonist, muscimol, caused an increase in food intake of freely-fed rats that was antagonized by bicuculline. The eating of animals receiving only bicuculline was stimulated in free-feeding and depressed in food-deprived conditions. These opposite results suggest that muscimol binds preferentially to some GABA receptors, probably those within the satiety-controlling areas (i.e. ventromedial hypothalamus), and that bicuculline influences mainly those postsynaptic neurons where GABAergic inputs prevail. These observations and the data from EOS- and GABA-treated rats provide evidence for involvement of GABA neurons in the regulation of feeding behaviour. The balance of the different effects produced in each of these areas by this modulation appears to be a decrease in feeding behaviour.

Cytosolic Accumulation of L-Proline Disrupts GABA-Ergic Transmission through GAD Blockade.

PubMed

Crabtree, Gregg W; Park, Alan J; Gordon, Joshua A; Gogos, Joseph A

2016-10-04

Proline dehydrogenase (PRODH), which degrades L-proline, resides within the schizophrenia-linked 22q11.2 deletion suggesting a role in disease. Supporting this, elevated L-proline levels have been shown to increase risk for psychotic disorders. Despite the strength of data linking PRODH and L-proline to neuropsychiatric diseases, targets of disease-relevant concentrations of L-proline have not been convincingly described. Here, we show that Prodh-deficient mice with elevated CNS L-proline display specific deficits in high-frequency GABA-ergic transmission and gamma-band oscillations. We find that L-proline is a GABA-mimetic and can act at multiple GABA-ergic targets. However, at disease-relevant concentrations, GABA-mimesis is limited to competitive blockade of glutamate decarboxylase leading to reduced GABA production. Significantly, deficits in GABA-ergic transmission are reversed by enhancing net GABA production with the clinically relevant compound vigabatrin. These findings indicate that accumulation of a neuroactive metabolite can lead to molecular and synaptic dysfunction and help to understand mechanisms underlying neuropsychiatric disease. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Amino acids acting as transmitters in amyotrophic lateral sclerosis (ALS).

PubMed

Niebroj-Dobosz, I; Janik, P

1999-07-01

In amyotrophic lateral sclerosis (ALS), a neurodegenerative disease of unknown origin, excitotoxic mechanisms are supposed to be involved. Divergent results are, however, presented either because of the heterogeneity of this disease, and/or different methodologies used to evaluate the excitotoxic amino acids content. The results of the most sensitive high performance liquid chromatography (HPLC) techniques with precolumn derivatization of fasting serum and CSF glutamate, aspartate, glycine and gamma-aminobutyric acid (GABA) in mild and severely progressing ALS cases are presented here. We studied 25 ALS patients with different course of the disease and controls, which consisted of 10 cases with other motor neuron diseases and 20 healthy, age-matched subjects. In the ALS patients with a mild course of the disease serum glutamate and aspartate content was either normal or slightly decreased, in all of these cases a rise in GABA and glycine was present. In the severely progressing ALS cases serum glutamate and aspartate was increased. The GABA content was either normal or increased, the glycine level appeared to be either normal or decreased. In CSF the amino acids changes in ALS were less pronounced as compared to serum. The most frequent finding was the increase in GABA concentration both in the mild and the severely progressing group. CSF glutamate in ALS patients with mild course of the disease was decreased, in the severely progressing cases the glutamate level appeared in a broad range from decreased to increased values. CSF aspartate was either normal or elevated, glycine values were present in a broad range from decreased to increased values. In the other tested motor neuron diseases no consistent changes in serum and CSF amino acids concentration was observed. The data from serum and CSF indicate that in ALS an imbalance between excitatory and inhibitory amino acids might be present in the brain, which may be induced in different ways in particular ALS patients. It may be an important factor for the mediation of neurons death.

The effect of fermented buckwheat on producing l-carnitine- and γ-aminobutyric acid (GABA)-enriched designer eggs.

PubMed

Park, Namhyeon; Lee, Tae-Kyung; Nguyen, Thi Thanh Hanh; An, Eun-Bae; Kim, Nahyun M; You, Young-Hyun; Park, Tae-Sub; Kim, Doman

2017-07-01

The potential of fermented buckwheat as a feed additive was studied to increase l-carnitine and γ-aminobutyric acid (GABA) in designer eggs. Buckwheat contains high levels of lysine, methionine and glutamate, which are precursors for the synthesis of l-carnitine and GABA. Rhizopus oligosporus was used for the fermentation of buckwheat to produce l-carnitine and GABA that exert positive effects such as enhanced metabolism, antioxidant activities, immunity and blood pressure control. A novel analytical method for simultaneously detecting l-carnitine and GABA was developed using liquid chromatography/mass spectrometry (LC/MS) and LC/MS/MS. The fermented buckwheat extract contained 4 and 34 times more l-carnitine and GABA respectively compared with normal buckwheat. Compared with the control, the fermented buckwheat extract-fed group showed enriched l-carnitine (13.6%) and GABA (8.4%) in the yolk, though only l-carnitine was significantly different (P < 0.05). Egg production (9.4%), albumen weight (2.1%) and shell weight (5.8%) were significantly increased (P < 0.05). There was no significant difference in yolk weight, and total cholesterol (1.9%) and triglyceride (4.9%) in the yolk were lowered (P < 0.05). Fermented buckwheat as a feed additive has the potential to produce l-carnitine- and GABA-enriched designer eggs with enhanced nutrition and homeostasis. These designer eggs pose significant potential to be utilized in superfood production and supplement industries. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

A Residue in Loop 9 of the β2-Subunit Stabilizes the Closed State of the GABAA Receptor*

PubMed Central

Williams, Carrie A.; Bell, Shannon V.; Jenkins, Andrew

2010-01-01

In γ-aminobutyric acid type A (GABAA) receptors, the structural elements that couple ligand binding to channel opening remain poorly defined. Here, site-directed mutagenesis was used to determine if Loop 9 on the non-GABA binding site interface of the β2-subunit may be involved in GABAA receptor activation. Specifically, residues Gly170-Gln185 of the β2-subunit were mutated to alanine, co-expressed with wild-type α1- and γ2S-subunits in human embryonic kidney (HEK) 293 cells and assayed for their activation by GABA, the intravenous anesthetic propofol and the endogenous neurosteroid pregnanolone using whole cell macroscopic recordings. Three mutants, G170A, V175A, and G177A, produced 2.5-, 6.7-, and 5.6-fold increases in GABA EC50 whereas one mutant, Q185A, produced a 5.2-fold decrease in GABA EC50. None of the mutations affected the ability of propofol or pregnanolone to potentiate a submaximal GABA response, but the Q185A mutant exhibited 8.3- and 3.5-fold increases in the percent direct activation by propofol and pregnanolone, respectively. Mutant Q185A receptors also had an increased leak current that was sensitive to picrotoxin, indicating an increased gating efficiency. Further Q185E, Q185L, and Q185W substitutions revealed a strong correlation between the hydropathy of the amino acid at this position and the GABA EC50. Taken together, these results indicate that β2 Loop 9 is involved in receptor activation by GABA, propofol, and pregnanolone and that β2(Q185) participates in hydrophilic interactions that are important for stabilizing the closed state of the GABAA receptor. PMID:20007704

[Local GABA-ergic modulation of serotonergic neuron activity in the nucleus raphe magnus].

PubMed

Iniushkin, A N; Merkulova, N A; Orlova, A O; Iniushkina, E M

2009-07-01

In voltage-clamp experimental on slices of the rat brainstem the effects of 5-HT and GABA on serotonergic neurons of nucleus raphe magnus were investigated. Local applications of 5-HT induced an increase in IPCSs frequency and amplitude in 45% of serotonergic cells. The effect suppressed by the blocker of fast sodium channels tetradotoxin. Antagonist of GABA receptor gabazine blocked IPSCs in neurons both sensitive and non-sensitive to 5-HT action. Applications of GABA induced a membrane current (I(GABA)), which was completely blocked by gabazine. The data suggest self-control of the activity of serotonergic neurons in nucleus raphe magnus by negative feedback loop via local GABAergic interneurons.

Gama-aminobutyric acid accumulation in Elsholtzia splendens in response to copper toxicity*

PubMed Central

Yang, Xiao-e; Peng, Hong-yun; Tian, Sheng-ke

2005-01-01

A solution with different Cu supply levels was cultured to investigate gama-aminobutyric acid (GABA) accumulation in Elsholtzia splendens, a native Chinese Cu-tolerant and accumulating plant species. Increasing Cu from 0.25 to 500 μmol/L significantly enhanced levels of GABA and histidine (His), but considerably decreased levels of aspartate (Asp) and glutamate (Glu) in the leaves. The leaf Asp level negatively correlated with leaf Cu level, while leaf GABA level positively correlated with leaf Cu level. The leaf Glu level negatively correlated with leaf GABA level in Elsholtzia splendens. The depletion of leaf Glu may be related to the enhanced synthesis of leaf GABA under Cu stress. PMID:15633244

Changes of body temperature and thermoregulatory responses of freely moving rats during GABAergic pharmacological stimulation to the preoptic area and anterior hypothalamus in several ambient temperatures.

PubMed

Ishiwata, Takayuki; Saito, Takehito; Hasegawa, Hiroshi; Yazawa, Toru; Kotani, Yasunori; Otokawa, Minoru; Aihara, Yasutsugu

2005-06-28

Action of gamma-aminobutyric acid (GABA) in the preoptic area and anterior hypothalamus (PO/AH) has been implicated to regulate body temperature (T(b)). However, its precise role in thermoregulation remains unclear. Moreover, little is known about its release pattern in the PO/AH during active thermoregulation. Using microdialysis and telemetry techniques, we measured several parameters related to thermoregulation of freely moving rats during pharmacological stimulation of GABA in normal (23 degrees C), cold (5 degrees C), and hot (35 degrees C) ambient temperatures. We also measured extracellular GABA levels in the PO/AH during cold (5 degrees C) and heat (35 degrees C) exposure combined with microdialysis and high performance liquid chromatography (HPLC). Perfusion of GABA(A) agonist muscimol into the PO/AH increased T(b), which is associated with increased heart rate (HR), as an index of heat production in all ambient temperatures. Although tail skin temperature (T(tail)) as an index of heat loss increased only under normal ambient temperatures, its response was relatively delayed in comparison with HR and T(b), suggesting that the increase in T(tail) was a secondary response to increased HR and T(b). Locomotor activity also increased in all ambient temperatures, but its response was not extraordinary. Interestingly, thermoregulatory responses were different after perfusion of GABA(A) antagonist bicuculline at each ambient temperature. In normal ambient temperature conditions, perfusion of bicuculline had no effect on any parameter. However, under cold ambient temperature, the procedure induced significant hypothermia concomitant with a decrease in HR in spite of hyperactivity and increase of T(tail). It induced hyperthermia with the increase of HR but no additional change of T(tail) in hot ambient temperature conditions. Furthermore, the extracellular GABA level increased significantly during cold exposure. Its release was lower during heat exposure than in a normal environment. These results indicate that GABA in the PO/AH is an important neurotransmitter for disinhibition of heat production and inhibition of heat loss under cold ambient temperature. It is a neurotransmitter for inhibition of heat production under hot ambient temperature.

Homocysteine alters cerebral microvascular integrity and causes remodeling by antagonizing GABA-A receptor*

PubMed Central

Lominadze, David; Tyagi, Neetu; Sen, Utpal; Ovechkin, Alexander; Tyagi, Suresh C.

2012-01-01

High levels of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy), are associated with cerebrovascular diseases, such as vascualr dementia, stroke, and Alzheimer's disease. The -amino butyric acid (GABA) is a inhibitory neurotransmitter and a ligand of GABA-A receptor. By inhibiting excitatory response it may decrease complications associated with vascular dementia and stroke. Hcy specifically competes with the GABA-A receptors and acts as an excitotoxic neurotransmitter. Previously we have shown that Hcy increases levels of NADPH oxidase and reactive oxygen species (ROS), and decreases levels of thioredoxin and peroxiredoxin by antagonizing the GABA-A receptor. Hcy treatment leads to activation of matrix metalloproteinases (MMPs) in cerebral circualtion by inducing redox stress and ROS. The hypothesis is that Hcy induces MMPs and suppresses tissue inhibitors of metalloproteinase (TIMPs), in part, by inhibiting the GABA-A receptor. This leads to degradation of the matrix and disruption of the blood brain barrier. The brain cortex of transgenic mouse model of HHcy (cystathionine -synthase, CBS −/+) and GABA-A receptor null mice treated with and without muscimol (GABA-A receptor agonist) was analysed. The mRNA levels were measured by Q-RT-PCR. Levels of MMP-2, -9, -13, and TIMP-1, -2, -3, and -4 were evaluated by in situ labeling and PCR-gene arrays. Pial venular permeability to fluorescence-labeled albumin was assessed with intravital fluorescence microscopy. We found that Hcy increases metalloproteinase activity and decreases TIMP-4 by antagonizing the GABA-A receptor. The results demonstrate a novel mechanism in which brain microvascular permeability changes during HHcy and vascular dementias, and have therapeutic ramifications for microvascular disease in Alzheimer's patients. PMID:22886392

Embryonic GABA(B) receptor blockade alters cell migration, adult hypothalamic structure, and anxiety- and depression-like behaviors sex specifically in mice.

PubMed

Stratton, Matthew S; Staros, Michelle; Budefeld, Tomaz; Searcy, Brian T; Nash, Connor; Eitel, Chad; Carbone, David; Handa, Robert J; Majdic, Gregor; Tobet, Stuart A

2014-01-01

Neurons of the paraventricular nucleus of the hypothalamus (PVN) regulate the hypothalamic- pituitary-adrenal (HPA) axis and the autonomic nervous system. Females lacking functional GABA(B) receptors because of a genetic disruption of the R1 subunit have altered cellular characteristics in and around the PVN at birth. The genetic disruption precluded appropriate assessments of physiology or behavior in adulthood. The current study was conducted to test the long term impact of a temporally restricting pharmacological blockade of the GABA(B) receptor to a 7-day critical period (E11-E17) during embryonic development. Experiments tested the role of GABA(B) receptor signaling in fetal development of the PVN and later adult capacities for adult stress related behaviors and physiology. In organotypic slices containing fetal PVN, there was a female specific, 52% increase in cell movement speeds with GABA(B) receptor antagonist treatment that was consistent with a sex-dependent lateral displacement of cells in vivo following 7 days of fetal exposure to GABA(B) receptor antagonist. Anxiety-like and depression-like behaviors, open-field activity, and HPA mediated responses to restraint stress were measured in adult offspring of mothers treated with GABA(B) receptor antagonist. Embryonic exposure to GABA(B) receptor antagonist resulted in reduced HPA axis activation following restraint stress and reduced depression-like behaviors. There was also increased anxiety-like behavior selectively in females and hyperactivity in males. A sex dependent response to disruptions of GABA(B) receptor signaling was identified for PVN formation and key aspects of physiology and behavior. These changes correspond to sex specific prevalence in similar human disorders, namely anxiety disorders and hyperactivity.

Effect of progesterone on the expression of GABA(A) receptor subunits in the prefrontal cortex of rats: implications of sex differences and brain hemisphere.

PubMed

Andrade, Susie; Arbo, Bruno D; Batista, Bruna A M; Neves, Alice M; Branchini, Gisele; Brum, Ilma S; Barros, Helena M T; Gomez, Rosane; Ribeiro, Maria Flavia M

2012-12-01

Progesterone is a neuroactive hormone with non-genomic effects on GABA(A) receptors (GABA(A)R). Changes in the expression of GABA(A)R subunits are related to depressive-like behaviors in rats. Moreover, sex differences and depressive behaviors have been associated with prefrontal brain asymmetry in rodents and humans. Thus, our objective was to investigate the effect of progesterone on the GABA(A)R α1 and γ2 subunits mRNA expression in the right and left prefrontal cortex of diestrus female and male rats exposed to the forced swimming test (FST). Male and female rats (n = 8/group) were randomly selected to receive a daily dose of progesterone (0·4 mg·kg⁻¹) or vehicle, during two complete female estrous cycles (8-10 days). On the experiment day, male rats or diestrus female rats were euthanized 30 min after the FST. Our results showed that progesterone significantly increased the α1 subunit mRNA in both hemispheres of male and female rats. Moreover, there was an inverse correlation between depressive-like behaviors and GABA(A)R α1 subunit mRNA expression in the right hemisphere in female rats. Progesterone decreased the GABA(A)R γ2 mRNA expression only in the left hemisphere of male rats. Therefore, we conclude that the GABA(A) system displays an asymmetric distribution according to sex and that progesterone, at lower doses, presents an antidepressant effect after increasing the GABA(A) R α1 subunit expression in the right prefrontal cortex of female rats. Copyright © 2012 John Wiley & Sons, Ltd.

In vivo gamma-aminobutyric acid and glutamate levels in people with first-episode schizophrenia: A proton magnetic resonance spectroscopy study.

PubMed

Chiu, P W; Lui, Simon S Y; Hung, Karen S Y; Chan, Raymond C K; Chan, Queenie; Sham, P C; Cheung, Eric F C; Mak, Henry K F

2018-03-01

Gamma-aminobutyric acid (GABA) dysfunction and its consequent imbalance are implicated in the pathophysiology of schizophrenia. Reduced GABA production would lead to a disinhibition of glutamatergic neurons and subsequently cause a disruption of the modulation between GABAergic interneurons and glutamatergic neurons. In this study, levels of GABA, Glx (summation of glutamate and glutamine), and other metabolites in the anterior cingulate cortex were measured and compared between first-episode schizophrenia subjects and healthy controls (HC). Diagnostic potential of GABA and Glx as upstream biomarkers for schizophrenia was explored. Nineteen first-episode schizophrenia subjects and fourteen HC participated in this study. Severity of clinical symptoms of patients was measured with Positive and Negative Syndrome Scale (PANSS). Metabolites were measured using proton magnetic resonance spectroscopy, and quantified using internal water as reference. First-episode schizophrenia subjects revealed reduced GABA and myo-inositol (mI), and increased Glx and choline (Cho), compared to HC. No significant correlation was found between metabolite levels and PANSS scores. Receiver operator characteristics analyses showed Glx had higher sensitivity and specificity (84.2%, 92.9%) compared to GABA (73.7%, 64.3%) for differentiating schizophrenia patients from HC. Combined model of both GABA and Glx revealed the best sensitivity and specificity (89.5%, 100%). This study simultaneously showed reduction in GABA and elevation in Glx in first-episode schizophrenia subjects, and this might provide insights on explaining the disruption of modulation between GABAergic interneurons and glutamatergic neurons. Elevated Cho might indicate increased membrane turnover; whereas reduced mI might reflect dysfunction of the signal transduction pathway. In vivo Glx and GABA revealed their diagnostic potential for schizophrenia. Copyright © 2017 Elsevier B.V. All rights reserved.

Is GABA neurotransmission enhanced in auditory thalamus relative to inferior colliculus?

PubMed Central

Cai, Rui; Kalappa, Bopanna I.; Brozoski, Thomas J.; Ling, Lynne L.

2013-01-01

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central auditory system. Sensory thalamic structures show high levels of non-desensitizing extrasynaptic GABAA receptors (GABAARs) and a reduction in the redundancy of coded information. The present study compared the inhibitory potency of GABA acting at GABAARs between the inferior colliculus (IC) and the medial geniculate body (MGB) using quantitative in vivo, in vitro, and ex vivo experimental approaches. In vivo single unit studies compared the ability of half maximal inhibitory concentrations of GABA to inhibit sound-evoked temporal responses, and found that GABA was two to three times (P < 0.01) more potent at suppressing MGB single unit responses than IC unit responses. In vitro whole cell patch-clamp slice recordings were used to demonstrate that gaboxadol, a δ-subunit selective GABAAR agonist, was significantly more potent at evoking tonic inhibitory currents from MGB neurons than IC neurons (P < 0.01). These electrophysiological findings were supported by an in vitro receptor binding assay which used the picrotoxin analog [3H]TBOB to assess binding in the GABAAR chloride channel. MGB GABAARs had significantly greater total open chloride channel capacity relative to GABAARs in IC (P < 0.05) as shown by increased total [3H]TBOB binding. Finally, a comparative ex vivo measurement compared endogenous GABA levels and suggested a trend towards higher GABA concentrations in MGB than in IC. Collectively, these studies suggest that, per unit GABA, high affinity extrasynaptic and synaptic GABAARs confer a significant inhibitory GABAAR advantage to MGB neurons relative to IC neurons. This increased GABA sensitivity likely underpins the vital filtering role of auditory thalamus. PMID:24155003

Hippocampal low-frequency stimulation inhibits afterdischarge and increases GABA (A) receptor expression in amygdala-kindled pharmacoresistant epileptic rats.

PubMed

Wu, Guofeng; Wang, Likun; Hong, Zhen; Ren, Siying; Zhou, Feng

2017-08-01

The purpose of the present study was to observe the effects of hippocampal low-frequency stimulation (Hip-LFS) on amygdala afterdischarge and GABA (A) receptor expression in pharmacoresistant epileptic (PRE) rats. A total of 110 healthy adult male Wistar rats were used to generate a model of epilepsy by chronic stimulation of the amygdala. Sixteen PRE rats were selected from 70 amygdala-kindled rats by testing their response to Phenytoin and Phenobarbital, and they were randomly assigned to a pharmacoresistant stimulation group (PRS group, 8 rats) or a pharmacoresistant control group (PRC group, 8 rats). A stimulation electrode was implanted into the hippocampus of all of the rats. Hip-LFS was administered twice per day in the PRS group for two weeks. Simultaneously, amygdala stimulus-induced seizures and afterdischarge were recorded. After the hippocampal stimulation was terminated, the brain tissues were obtained to determine the GABA (A) receptors by a method of immumohistochemistry and a real-time polymerase chain reaction. The stages and duration of the amygdala stimulus-induced epileptic seizures were decreased in the PRS group. The afterdischarge threshold was increased and the duration as well as the afterdischarge frequency was decreased. Simultaneously, the GABA (A) expression was significantly increased in the PRS group. Hip-LFS may inhibit amygdala stimulus-induced epileptic seizures and up-regulate GABA (A) receptor expression in PRE rats. The antiepileptic effects of hippocampal stimulation may be partly achieved by increasing the GABA (A) receptor.

Epigenetic regulation of dorsal raphe GABA(B1a) associated with isolation-induced abnormal responses to social stimulation in mice.

PubMed

Araki, Ryota; Hiraki, Yosuke; Nishida, Shoji; Kuramoto, Nobuyuki; Matsumoto, Kinzo; Yabe, Takeshi

2016-02-01

In isolation-reared mice, social encounter stimulation induces locomotor hyperactivity and activation of the dorsal raphe nucleus (DRN), suggesting that dysregulation of dorsal raphe function may be involved in abnormal behaviors. In this study, we examined the involvement of dorsal raphe GABAergic dysregulation in the abnormal behaviors of isolation-reared mice. We also studied an epigenetic mechanism underlying abnormalities of the dorsal raphe GABAergic system. Both mRNA and protein levels of GABA(B1a), a GABA(B) receptor subunit, were increased in the DRN of isolation-reared mice, compared with these levels in group-reared mice. In contrast, mRNA levels for other GABAergic system-related genes (GABA(A) receptor α1, β2 and γ2 subunits, GABA(B) receptor 1b and 2 subunits, and glutamate decarboxylase 67 and 65) were unchanged. Intra-DRN microinjection of 0.06 nmol baclofen (a GABA(B) receptor agonist) exacerbated encounter-induced hyperactivity and aggressive behavior, while microinjection of 0.3 nmol phaclofen (a GABA(B) receptor antagonist) attenuated encounter-induced hyperactivity and aggressive behavior in isolation-reared mice. Furthermore, microinjection of 0.06 nmol baclofen elicited encounter-induced hyperactivity in group-reared mice. Neither baclofen nor phaclofen affected immobility time in the forced swim test and hyperactivity in a novel environment of isolation reared mice. Bisulfite sequence analyses revealed that the DNA methylation level of the CpG island around the transcription start site (TSS) of GABA(B1a) was decreased in the DRN of isolation-reared mice. Chromatin immunoprecipitation analysis showed that histone H3 was hyperacetylated around the TSS of GABA(B1a) in the DRN of isolation-reared mice. These findings indicate that an increase in dorsal raphe GABA(B1a) expression via epigenetic regulation is associated with abnormal responses to social stimulation such as encounter-induced hyperactivity and aggressive behavior in isolation-reared mice. Copyright © 2015 Elsevier Ltd. All rights reserved.

Insulin Regulates GABAA Receptor-Mediated Tonic Currents in the Prefrontal Cortex.

PubMed

Trujeque-Ramos, Saraí; Castillo-Rolón, Diego; Galarraga, Elvira; Tapia, Dagoberto; Arenas-López, Gabina; Mihailescu, Stefan; Hernández-López, Salvador

2018-01-01

Recent studies, have shown that insulin increases extrasynaptic GABA A receptor-mediated currents in the hippocampus, causing alterations of neuronal excitability. The prefrontal cortex (PFC) is another brain area which is involved in cognition functions and expresses insulin receptors. Here, we used electrophysiological, molecular, and immunocytochemical techniques to examine the effect of insulin on the extrasynaptic GABA A receptor-mediated tonic currents in brain slices. We found that insulin (20-500 nM) increases GABA A -mediated tonic currents. Our results suggest that insulin promotes the trafficking of extrasynaptic GABA A receptors from the cytoplasm to the cell membrane. Western blot analysis and immunocytochemistry showed that PFC extrasynaptic GABA A receptors contain α-5 and δ subunits. Insulin effect on tonic currents decreased the firing rate and neuronal excitability in layer 5-6 PFC cells. These effects of insulin were dependent on the activation of the PI3K enzyme, a key mediator of the insulin response within the brain. Taken together, these results suggest that insulin modulation of the GABA A -mediated tonic currents can modify the activity of neural circuits within the PFC. These actions could help to explain the alterations of cognitive processes associated with changes in insulin signaling.

Low single dose gabapentin does not affect prefrontal and occipital gamma-aminobutyric acid concentrations.

PubMed

Preuss, Nora; van der Veen, Jan Willem; Carlson, Paul J; Shen, Jun; Hasler, Gregor

2013-12-01

The γ-aminobutyric acid (GABA) system has been proposed as a target for novel antidepressant and anxiolytic treatments. Emerging evidence suggests that gabapentin (GBP), an anticonvulsant drug that significantly increases brain GABA levels, is effective in the treatment of anxiety disorders. The current study was designed to measure prefrontal and occipital GABA levels in medication-free healthy subjects after taking 0mg, 150mg and 300mg GBP. Subjects were scanned on a 3T scanner using a transmit-receive head coil that provided a relatively homogenous radiofrequency field to obtain spectroscopy measurement in the medial prefrontal (MPFC) and occipital cortex (OCC). There was no dose-dependent effect of GBP on GABA levels in the OCC or MPFC. There was also no effect on Glx, choline or N-acetyl-aspartate concentrations. The previously reported finding of increased GABA levels after GBP treatment is not evident for healthy subjects at the dose of 150 and 300mg. As a result, if subjects are scanned on a 3T scanner, low dose GPB is not useful as an experimental challenge agent on the GABA system. © 2013 Elsevier B.V. All rights reserved.

Association study of GABA system genes polymorphisms with amphetamine-induced psychotic disorder in a Han Chinese population.

PubMed

Zhang, Kai; Zhao, Yan; Wang, Qingzhong; Jiang, Haifeng; Du, Jiang; Yu, Shunying; Zhao, Min

2016-05-27

GABA system genes have been implicated in neurotrophy and neurogenesis, which play pivotal roles in an individual's variation in vulnerability to amphetamine addiction or amphetamine-induced psychosis (AIP). We hypothesized that common genetic variants in the GABA system genes may be associated with amphetamine-induced psychotic disorder. In our study, thirty-six single nucleotide polymorphisms (SNPs) within the GABA system genes were genotyped in 400 amphetamine-induced psychotic disorder patients and 400 amphetamine use disorders patients (AUP) (not including those categorized as psychosis) in the Han Chinese population. In this study, 51.88% of the Han Chinese amphetamine-type substance use disorder patients met the criteria of amphetamine-induced psychotic disorder, and 79.5% amphetamine-induced psychotic disorder patients had auditory hallucinations, while 46.5% had delusions of reference. The allele frequency of rs1129647 showed nominal association with AIP in the Han Chinese population (P=0.03). Compared with AUP group patients, T allele frequency of AIP group patients was significantly increased. The adjustment for age and gender factors in the AIP and AUP patients was executed using unconditional logistic regression under five inheritance models. The genotype frequency of rs1129647 showed nominal association with AIP in the log-additive model (P=0.04). The genotype frequency of rs2290733 showed nominal association with AIP in the recessive model (P=0.04). Compared with female AIP patients, male patients were more likely to have the CC genotype of rs17545383 (P=0.04). Moreover, we determined that more male patients carried the T allele of rs2290733 in the AIP group (P=0.004). Unfortunately, the significant differences did not survive Benjamini-Hochberg false discovery rate correction (adjusted P>0.05). No association between the SNPs of the GABA system genes and amphetamine-induced psychotic disorder risk was identified. No haplotype of the GABA system genes affected amphetamine-induced psychotic disorder risk. This report describes the first association study between the GABA system genes and amphetamine-induced psychotic disorder in the Han Chinese population. Our data may provide a reference for future research. Copyright © 2016. Published by Elsevier Ireland Ltd.

Effects of new fluorinated analogues of GABA, pregabalin bioisosters, on the ambient level and exocytotic release of [3H]GABA from rat brain nerve terminals.

PubMed

Borisova, T; Pozdnyakova, N; Shaitanova, E; Gerus, I; Dudarenko, M; Haufe, G; Kukhar, V

2017-01-15

Recently, we have shown that new fluorinated analogues of γ-aminobutyric acid (GABA), bioisosters of pregabalin (β-i-Bu-GABA), i.e. β-polyfluoroalkyl-GABAs (FGABAs), with substituents: β-CF 3 -β-OH (1), β-CF 3 (2); β-CF 2 CF 2 H (3), are able to increase the initial rate of [ 3 H]GABA uptake by isolated rat brain nerve terminals (synaptosomes), and this effect is higher than that of pregabalin. So, synthesized FGABAs are structural but not functional analogues of GABA. Herein, we assessed the effects of synthesized FGABAs (100μM) on the ambient level and exocytotic release of [ 3 H]GABA in nerve terminals and compared with those of pregabalin (100μM). It was shown that FGABAs 1-3 did not influence the ambient level of [ 3 H]GABA in the synaptosomal preparations, and this parameter was also not altered by pregabalin. During blockage of GABA transporters GAT1 by specific inhibitor NO-711, FGABAs and pregabalin also did not change ambient [ 3 H]GABA in synaptosomal preparations. Exocytotic release of [ 3 H]GABA from synaptosomes decreased in the presence of FGABAs 1-3 and pregabalin, and the effects of FGABAs 1 &3 were more significant than those of FGABAs 2 and pregabalin. FGABAs 1-3/pregabalin-induced decrease in exocytotic release of [ 3 H]GABA from synaptosomes was not a result of changes in the potential of the plasma membrane. Therefore, new synthesized FGABAs 1 &3 were able to decrease exocytotic release of [ 3 H]GABA from nerve terminals more effectively in comparison to pregabalin. Absence of unspecific side effects of FGABAs 1 &3 on the membrane potential makes these compounds perspective for medical application. Copyright © 2016 Elsevier Ltd. All rights reserved.

GABA(A) receptors in the pontine reticular formation of C57BL/6J mouse modulate neurochemical, electrographic, and behavioral phenotypes of wakefulness.

PubMed

Flint, RaShonda R; Chang, Theresa; Lydic, Ralph; Baghdoyan, Helen A

2010-09-15

Drugs that potentiate transmission at GABA(A) receptors are widely used to enhance sleep and to cause general anesthesia. The mechanisms underlying these effects are unknown. This study tested the hypothesis that GABA(A) receptors in the pontine reticular nucleus, oral part (PnO) of mouse modulate five phenotypes of arousal: sleep and wakefulness, cortical electroencephalogram (EEG) activity, acetylcholine (ACh) release in the PnO, breathing, and recovery time from general anesthesia. Microinjections into the PnO of saline (vehicle control), the GABA(A) receptor agonist muscimol, muscimol with the GABA(A) receptor antagonist bicuculline, and bicuculline alone were performed in male C57BL/6J mice (n = 33) implanted with EEG recording electrodes. Muscimol caused a significant increase in wakefulness and decrease in rapid eye movement (REM) and non-REM (NREM) sleep. These effects were reversed by coadministration of bicuculline. Bicuculline administered alone caused a significant decrease in wakefulness and increase in NREM sleep and REM sleep. Muscimol significantly increased EEG power in the delta range (0.5-4 Hz) during wakefulness and in the theta range (4-9 Hz) during REM sleep. Dialysis delivery of bicuculline to the PnO of male mice (n = 18) anesthetized with isoflurane significantly increased ACh release in the PnO, decreased breathing rate, and increased anesthesia recovery time. All drug effects were concentration dependent. The effects on phenotypes of arousal support the conclusion that GABA(A) receptors in the PnO promote wakefulness and suggest that increasing GABAergic transmission in the PnO may be one mechanism underlying the phenomenon of paradoxical behavioral activation by some benzodiazepines.

CSF GABA is reduced in first-episode psychosis and associates to symptom severity

PubMed Central

Orhan, F; Fatouros-Bergman, H; Goiny, M; Malmqvist, A; Piehl, F; Engberg, Göran; Erhardt, Sophie; Schwieler, Lilly; Orhan, Funda; Malmqvist, Anna; Hedberg, Mikael; Farde, Lars; Cervenka, Simon; Flyckt, Lena; Collste, Karin; Ikonen, Pauliina; Piehl, Fredrik; Agartz, Ingrid; Cervenka, S; Collste, K; Victorsson, P; Sellgren, C M; Flyckt, L; Erhardt, S; Engberg, G

2018-01-01

Schizophrenia is characterized by a multiplicity of symptoms arising from almost all domains of mental function. γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain and is increasingly recognized to have a significant role in the pathophysiology of the disorder. In the present study, cerebrospinal fluid (CSF) concentrations of GABA were analyzed in 41 first-episode psychosis (FEP) patients and 21 age- and sex-matched healthy volunteers by high-performance liquid chromatography. We found lower CSF GABA concentration in FEP patients compared with that in the healthy volunteers, a condition that was unrelated to antipsychotic and/or anxiolytic medication. Moreover, lower CSF GABA levels were associated with total and general score of Positive and Negative Syndrome Scale, illness severity and probably with a poor performance in a test of attention. This study offers clinical in vivo evidence for a potential role of GABA in early-stage schizophrenia. PMID:28289277

A high-fat diet decreases GABA concentration in the frontal cortex and hippocampus of rats.

PubMed

Sandoval-Salazar, Cuauhtemoc; Ramírez-Emiliano, Joel; Trejo-Bahena, Aurora; Oviedo-Solís, Cecilia I; Solís-Ortiz, Martha Silvia

2016-02-29

It has been proposed that the γ-aminobutyric acid (GABA) plays a key role in the regulation of food intake and body weight by controlling the excitability, plasticity and the synchronization of neuronal activity in the frontal cortex (FC). It has been also proposed that the high-fat diet (HFD) could disturb the metabolism of glutamate and consequently the GABA levels, but the mechanism is not yet clearly understood. Therefore, the aim of this study was to investigate the effect of a HFD on the GABA levels in the FC and hippocampus of rats. The HFD significantly increased weight gain and blood glucose levels, whereas decreased the GABA levels in the FC and hippocampus compared with standard diet-fed rats. HFD decreases GABA levels in the FC and hippocampus of rat, which likely disrupts the GABAergic inhibitory processes, underlying feeding behavior.

Nonvesicular inhibitory neurotransmission via reversal of the GABA transporter GAT-1

PubMed Central

Wu, Yuanming; Wang, Wengang; Díez-Sampedro, Ana; Richerson, George B.

2007-01-01

SUMMARY GABA transporters play an important but poorly understood role in neuronal inhibition. They can reverse, but this is widely thought to occur only under pathological conditions. Here we use a heterologous expression system to show that the reversal potential of GAT-1 under physiologically relevant conditions is near the normal resting potential of neurons, and that reversal can occur rapidly enough to release GABA during simulated action potentials. We then use paired recordings from cultured hippocampal neurons, and show that GABAergic transmission is not prevented by four methods widely used to block vesicular release. This nonvesicular neurotransmission was potently blocked by GAT-1 antagonists, and was enhanced as predicted by agents that increase cytosolic [GABA] or [Na+]. The results indicate that GAT-1 regulates tonic inhibition by clamping ambient [GABA] at a level high enough to activate high affinity GABAA receptors, and that transporter-mediated GABA release can contribute to phasic inhibition. PMID:18054861

Altered cortical GABA neurotransmission in schizophrenia: insights into novel therapeutic strategies.

PubMed

Stan, Ana D; Lewis, David A

2012-06-01

Altered markers of cortical GABA neurotransmission are among the most consistently observed abnormalities in postmortem studies of schizophrenia. The altered markers are particularly evident between the chandelier class of GABA neurons and their synaptic targets, the axon initial segment (AIS) of pyramidal neurons. For example, in the dorsolateral prefrontal cortex of subjects with schizophrenia immunoreactivity for the GABA membrane transporter is decreased in presynaptic chandelier neuron axon terminals, whereas immunoreactivity for the GABAA receptor α2 subunit is increased in postsynaptic AIS. Both of these molecular changes appear to be compensatory responses to a presynaptic deficit in GABA synthesis, and thus could represent targets for novel therapeutic strategies intended to augment the brain's own compensatory mechanisms. Recent findings that GABA inputs from neocortical chandelier neurons can be powerfully excitatory provide new ideas about the role of these neurons in the pathophysiology of cortical dysfunction in schizophrenia, and consequently in the design of pharmacological interventions.

S-(N, N-diethylcarbamoyl)glutathione (carbamathione), a disulfiram metabolite and its effect on nucleus accumbens and prefrontal cortex dopamine, GABA, and glutamate: A microdialysis study

PubMed Central

Faiman, Morris D.; Kaul, Swetha; Latif, Shaheen A.; Williams, Todd D.; Lunte, Craig E.

2015-01-01

Disulfiram (DSF), used for the treatment of alcohol use disorders (AUDs) for over six decades, most recently has shown promise for treating cocaine dependence. Although DSF’s mechanism of action in alcohol abuse is due to the inhibition of liver mitochondrial aldehyde dehydrogenase (ALDH2), its mechanism of action in the treatment of cocaine dependence is unknown. DSF is a pro-drug, forming a number of metabolites each with discrete pharmacological actions. One metabolite formed during DSF bioactivation is S-(N, N-diethylcarbamoyl) glutathione (carbamathione) (carb). We previously showed that carb affects glutamate binding. In the present studies, we employed microdialysis techniques to investigate the effect of carb administration on dopamine (DA), GABA, and glutamate (Glu) in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), two brain regions implicated in substance abuse dependence. The effect of DSF on DA, GABA, and Glu in the NAc also was determined. Both studies were carried out in male rats. Carb (20, 50, 200 mg/kg i v) in a dose-dependent manner increased DA, decreased GABA, and had a biphasic effect on Glu, first increasing and then decreasing Glu in both the NAc and mPFC. These changes all occurred concurrently. After carb administration, NAc and mPFC carb, as well as carb in plasma, were rapidly eliminated with a half-life for each approximately 4 min, while the changes in DA, GABA, and GLu in the NAc and mPFC persisted for approximately two hours. The maximal increase in carb (Cmax) in the NAc and mPFC after carb administration was dose-dependent, as was the area under the curve (AUC). DSF (200 mg/kg i p) also increased DA, decreased GABA, and had a biphasic effect on Glu in the NAc similar to that observed in the NAc after carb administration. When the cytochrome P450 inhibitor N-benzylimidazole (NBI) (20 mg/kg i p) was administered before DSF dosing, no carb could be detected in the NAc and plasma and also no changes in NAc DA, GABA, and GLu occurred. Changes in these neurotransmitters occurred only if carb was formed from DSF. When NBI was administered prior to dosing with carb, the increase in DA, decrease in GABA, and biphasic effect on GLu was similar to that seen after dosing with carb only. The i p or i v administration of carb showed similar changes in DA, GABA, and GLu, except the time to reach Cmax for DA as well as the changes in GABA, and GLu after i p administration occurred later. The elimination half-life of carb and the area under the curve (AUC) were similar after both routes of administration. It is concluded that carb must be formed from DSF before any changes in DA, GABA, and GLu in the NAc and mPFC are observed. DSF and carb, when administered to rats, co-release DA, GABA, and GLu. Carb, once formed can cross the blood brain barrier and enter the brain. Although inhibition of liver ALDH2 is the accepted mechanism for DSF’s action in treating AUDs, the concurrent changes in DA, GABA, and GLu in the NAc and mPFC after DSF administration suggest that changes in these neurotransmitters as a potential mechanism of action not only for AUDs, but also for cocaine dependence cannot be excluded. PMID:23891816

γ-Aminobutyric acid (GABA) oral rinse reduces capsaicin-induced burning mouth pain sensation: An experimental quantitative sensory testing study in healthy subjects.

PubMed

Zhang, Y; Wang, K; Arendt-Nielsen, L; Cairns, B E

2018-02-01

In burning mouth patients, analgesia after oral administration of clonazepam may result from modulation of peripheral γ-aminobutyric acid (GABA) receptors. The effect of oral administration of test solutions (water, 0.5 mol/L or 0.05 mol/L GABA, 1% lidocaine) was investigated for the amelioration of pain and sensitivity induced by application of capsaicin (1%, 2 min) to the tongue of thirty healthy male and female subjects in this four-session, randomized, placebo-controlled, double-blinded, cross-over study. Intra-oral quantitative sensory testing was used to assess cold (CDT), warm (WDT) and mechanical (MDT) detection thresholds as well as mechanical (MPT) and heat (HPT) pain thresholds. Capsaicin-induced pain intensity was continuously rated on a 0-10 electronic visual analogue scale (VAS). The area under the VAS curve (VASAUC) after rinsing was calculated for each solution. Capsaicin application on the tongue evoked burning pain with a peak of 4.8/10, and significantly increased CDT and MDT while significantly decreasing WDT, HPT, and MPT. The VASAUC was significantly smaller after oral rinse with 0.05 mol/L GABA, 0.5 mol/L GABA, and 1% lidocaine than after oral rinse with water. Rinse with 0.5 mol/L or 0.05 mol/L GABA were similarly effective in decreasing VASAUC. Rinsing with either 1% lidocaine, 0.5 mol/L or 0.05 mol/L GABA also significantly attenuated the effects of capsaicin on WDT and HPT in a treatment independent manner. There were no sex-related differences in these effects of GABA. Capsaicin-induced burning tongue pain and decreases in WDT and HPT can be ameliorated by rinsing the mouth with lidocaine and GABA solutions. Rinsing the mouth with an oral GABA containing solution ameliorated burning pain and increased heat sensitivity produced by application of capsaicin to the tongue. This finding suggests that GABA can act as a local analgesic agent in the oral cavity. © 2017 European Pain Federation - EFIC®.

Evidence that GABA ρ subunits contribute to functional ionotropic GABA receptors in mouse cerebellar Purkinje cells

PubMed Central

Harvey, Victoria L; Duguid, Ian C; Krasel, Cornelius; Stephens, Gary J

2006-01-01

Ionotropic γ-amino butyric acid (GABA) receptors composed of heterogeneous molecular subunits are major mediators of inhibitory responses in the adult CNS. Here, we describe a novel ionotropic GABA receptor in mouse cerebellar Purkinje cells (PCs) using agents reported to have increased affinity for ρ subunit-containing GABAC over other GABA receptors. Exogenous application of the GABAC-preferring agonist cis-4-aminocrotonic acid (CACA) evoked whole-cell currents in PCs, whilst equimolar concentrations of GABA evoked larger currents. CACA-evoked currents had a greater sensitivity to the selective GABAC antagonist (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) than GABA-evoked currents. Focal application of agonists produced a differential response profile; CACA-evoked currents displayed a much more pronounced attenuation with increasing distance from the PC soma, displayed a slower time-to-peak and exhibited less desensitization than GABA-evoked currents. However, CACA-evoked currents were also completely blocked by bicuculline, a selective agent for GABAA receptors. Thus, we describe a population of ionotropic GABA receptors with a mixed GABAA/GABAC pharmacology. TPMPA reduced inhibitory synaptic transmission at interneurone–Purkinje cell (IN–PC) synapses, causing clear reductions in miniature inhibitory postsynaptic current (mIPSC) amplitude and frequency. Combined application of NO-711 (a selective GABA transporter subtype 1 (GAT-1) antagonist) and SNAP-5114 (a GAT-(2)/3/4 antagonist) induced a tonic GABA conductance in PCs; however, TPMPA had no effect on this current. Immunohistochemical studies suggest that ρ subunits are expressed predominantly in PC soma and proximal dendritic compartments with a lower level of expression in more distal dendrites; this selective immunoreactivity contrasted with a more uniform distribution of GABAA α1 subunits in PCs. Finally, co-immunoprecipitation studies suggest that ρ subunits can form complexes with GABAA receptor α1 subunits in the cerebellar cortex. Overall, these data suggest that ρ subunits contribute to functional ionotropic receptors that mediate a component of phasic inhibitory GABAergic transmission at IN–PC synapses in the cerebellum. PMID:16945976

GABA dramatically improves glucose tolerance in streptozotocin-induced diabetic rats fed with high-fat diet.

PubMed

Sohrabipour, Shahla; Sharifi, Mohammad Reza; Talebi, Ardeshir; Sharifi, Mohammadreza; Soltani, Nepton

2018-05-05

Skeletal muscle, hepatic insulin resistance, and beta cell dysfunction are the characteristic pathophysiological features of type 2 diabetes mellitus. GABA has an important role in pancreatic islet cells. The present study attempted to clarify the possible mechanism of GABA to improve glucose tolerance in a model of type 2 diabetes mellitus in rats. Fifty Wistar rats were divided into five groups: NDC that was fed the normal diet, CD which received a high-fat diet with streptozotocin, CD-GABA animals that received GABA via intraperitoneal injection, plus CD-Ins1 and CD-Ins2 groups which were treated with low and high doses of insulin, respectively. Body weight and blood glucose were measured weekly. Intraperitoneal glucose tolerance test (IPGTT), insulin tolerance test (ITT), urine volume, amount of water drinking, and food intake assessments were performed monthly. The hyperinsulinemic euglycemic clamp was done for assessing insulin resistance. Plasma insulin and glucagon were measured. Abdominal fat was measured. Glucagon receptor, Glucose 6 phosphatase, Phosphoenolpyruvate carboxykinase genes expression were evaluated in liver and Glucose transporter 4 (GLUT4) genes expression and protein translocation were evaluated in the muscle. GABA or insulin therapy improved blood glucose, insulin level, IPGTT, ITT, gluconeogenesis pathway, Glucagon receptor, body weight and body fat in diabetic rats. GLUT4 gene and protein expression increased. GABA whose beneficial effect was comparable to that of insulin, also increased glucose infusion rate during an euglycemic clamp. GABA could improve insulin resistance via rising GLUT4 and also decreasing the gluconeogenesis pathway and Glucagon receptor gene expression. Copyright © 2018. Published by Elsevier B.V.

[Influence of exogenous gamma-aminobutyric acid (GABA) on GABA metabolism and amino acid contents in roots of melon seedling under hypoxia stress].

PubMed

Wang, Chun-Yan; Li, Jing-Rui; Xia, Qing-Ping; Wu, Xiao-Lei; Gao, Hong-Bo

2014-07-01

This paper investigated the influence of gamma-aminobutyric acid (GABA) on GABA metabolism and amino acid content under hypoxia stress by accurately controlling the level of dissolved oxygen in hydroponics, using the roots of melon 'Xiyu 1' seedlings as the test material. The results showed that compared with the control, the growth of roots was inhibited seriously under hypoxia stress. Meanwhile, the hypoxia-treated roots had significantly higher activities of glutamate decarboxylase (GAD), glutamate dehydrogenase (GDH), glutamate synthase (GOGAT), glutamine synthetase (GS), alanine aminotransferase (ALT), aspartate aminotransferase (AST) as well as the contents of GABA, pyruvic acid, alanine (Ala) and aspartic acid (Asp). But the contents of glutamic acid (Glu) and alpha-keto glutaric acid in roots under hypoxia stress was obviously lower than those of the control. Exogenous treatment with GABA alleviated the inhibition effect of hypoxia stress on root growth, which was accompanied by an increase in the contents of endogenous GABA, Glu, alpha-keto glutaric acid and Asp. Furthermore, under hypoxia stress, the activities of GAD, GDH, GOGAT, GS, ALT, AST as well as the contents of pyruvic acid and Ala significantly decreased in roots treated with GABA. However, adding GABA and viny-gamma-aminobutyric acid (VGB) reduced the alleviation effect of GABA on melon seedlings under hypoxia stress. The results suggested that absorption of GABA by roots could alleviate the injury of hypoxia stress to melon seedlings. This meant that GABA treatment allows the normal physiological metabolism under hypoxia by inhibiting the GAD activity through feedback and maintaining higher Glu content as well as the bal- ance of carbon and nitrogen.

Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder.

PubMed

Tripp, Adam; Oh, Hyunjung; Guilloux, Jean-Philippe; Martinowich, Keri; Lewis, David A; Sibille, Etienne

2012-11-01

The subgenual anterior cingulate cortex is implicated in the pathology and treatment response of major depressive disorder. Low levels of brain-derived neurotrophic factor (BDNF) and reduced markers for GABA function, including in the amygdala, are reported in major depression, but their contribution to subgenual anterior cingulate cortex dysfunction is not known. Using polymerase chain reaction, we first assessed the degree to which BDNF controls mRNA expression (defined as BDNF dependency) of 15 genes relating to GABA and neuropeptide functions in the cingulate cortex of mice with reduced BDNF function (BDNF-heterozygous [Bdnf(+/-)] mice and BDNF exon-IV knockout [Bdnf(KIV)] mice). Gene expression was then quantified in the subgenual anterior cingulate cortex of 51 postmortem subjects with major depressive disorder and comparison subjects (total subjects, N=102; 49% were women) and compared with previous amygdala results. Based on the results in Bdnf(+/-) and Bdnf(KIV) mice, genes were sorted into high, intermediate, and no BDNF dependency sets. In postmortem human subjects with major depression, BDNF receptor (TRKB) expression, but not BDNF, was reduced. Postmortem depressed subjects exhibited down-regulation in genes with high and intermediate BDNF dependency, including markers of dendritic targeting interneurons (SST, NPY, and CORT) and a GABA synthesizing enzyme (GAD2). Changes extended to BDNF-independent genes (PVALB and GAD1). Changes were greater in men (potentially because of low baseline expression in women), displayed notable differences from prior amygdala results, and were not explained by demographic or clinical factors other than sex. These parallel human/mouse analyses provide direct (low TRKB) and indirect (low expression of BDNF-dependent genes) evidence in support of decreased BDNF signaling in the subgenual anterior cingulate cortex in individuals with major depressive disorder, implicate dendritic targeting GABA neurons and GABA synthesis, and, together, suggest a common BDNF-/GABA-related pathology in major depression with sex- and brain region-specific features.

Glial Control of Endocannabinoid Heterosynaptic Modulation in Hypothalamic Magnocellular Neuroendocrine Cells

PubMed Central

Popescu, Ion R.

2013-01-01

Cannabinoid receptors are functionally operant at both glutamate and GABA synapses on hypothalamic magnocellular neuroendocrine cells; however, retrograde endocannabinoid actions are evoked at only glutamate synapses. We tested whether the functional targeting of evoked retrograde endocannabinoid actions to glutamate, and not GABA, synapses on magnocellular neurons is the result of the spatial restriction of extracellular endocannabinoids by astrocytes. Whole-cell GABA synaptic currents were recorded in magnocellular neurons in rat hypothalamic slices following manipulations to reduce glial buffering of extracellular signals. Depolarization- and glucocorticoid-evoked retrograde endocannabinoid suppression of synaptic GABA release was not detected under normal conditions, but occurred in both oxytocin and vasopressin neurons under conditions of attenuated glial coverage and depressed glial metabolic function, suggesting an emergent endocannabinoid modulation of GABA synapses with the loss of astrocyte function. Tonic endocannabinoid suppression of GABA release was insensitive to glial manipulation. Blocking cannabinoid transport mimicked, and increasing the extracellular viscosity reversed, the effect of suppressed glial buffering on the endocannabinoid modulation of GABA release. Evoked, but not tonic, endocannabinoid modulation of GABA synapses was mediated by 2-arachidonoylglycerol. Therefore, depolarization- and glucocorticoid-evoked 2-arachidonoylglycerol release from magnocellular neurons is spatially restricted to glutamate synapses by astrocytes, but spills over onto GABA synapses under conditions of reduced astrocyte buffering; tonic endocannabinoid modulation of GABA release, in contrast, is likely mediated by anandamide and is insensitive to astrocytic buffering. Astrocytes, therefore, provide dynamic control of stimulus-evoked 2-arachidonoylglycerol, but not tonic anandamide, regulation of GABA synaptic inputs to magnocellular neuroendocrine cells under different physiological conditions. PMID:24227742

Medial frontal GABA is lower in older schizophrenia: a MEGA-PRESS with macromolecule suppression study.

PubMed

Rowland, L M; Krause, B W; Wijtenburg, S A; McMahon, R P; Chiappelli, J; Nugent, K L; Nisonger, S J; Korenic, S A; Kochunov, P; Hong, L E

2016-02-01

Gamma-butyric acid (GABA) dysfunction has been implicated in the pathophysiology of schizophrenia and its cognitive deficits. Proton magnetic resonance spectroscopy (MRS) was used to test the hypothesis that older participants with schizophrenia have lower anterior cingulate GABA levels compared with older control participants. One-hundred forty-five participants completed this study. For detection of GABA, spectra were acquired from the medial frontal/anterior cingulate cortex using a macromolecule-suppressed MEGA-PRESS sequence. Patients were evaluated for psychopathology and all participants completed neuropsychological tests of working memory, processing speed and functional capacity. GABA levels were significantly lower in the older participants with schizophrenia (n=31) compared with the older control (n=37) group (P=0.003) but not between the younger control (n=40) and schizophrenia (n=29) groups (P=0.994). Age strongly predicted GABA levels in the schizophrenia group accounting for 42% of the variance, but the effect of age was less in the control group accounting for 5.7% of the variance. GABA levels were specifically related to working memory but not processing speed performance, functional capacity, or positive or negative symptom severity. This is the largest MRS study of GABA in schizophrenia and the first to examine GABA without macromolecule contamination, a potentially significant issue in previous studies. GABA levels more rapidly declined with advancing age in the schizophrenia compared with the control group. Interventions targeted at halting the decline or increasing GABA levels may improve functional outcomes and quality of life as patients with schizophrenia age.

Medial Frontal GABA is Lower in Older Schizophrenia: A MEGA-PRESS with Macromolecule Suppression Study

PubMed Central

Rowland, Laura M; Krause, Benjamin W.; Wijtenburg, S. Andrea; McMahon, Robert P.; Chiappelli, Joshua; Nugent, Katie L.; Nisonger, Sarah J.; Korenic, Stephanie A.; Kochunov, Peter; Hong, L. Elliot

2015-01-01

Gamma-butyric acid (GABA) dysfunction has been implicated in the pathophysiology of schizophrenia and its cognitive deficits. Proton magnetic resonance spectroscopy (MRS) was used to test the hypothesis that older participants with schizophrenia have lower anterior cingulate GABA levels compared to older control participants. One-hundred and forty-five participants completed this study. For detection of GABA, spectra were acquired from the medial frontal/anterior cingulate cortex using a macromolecule-suppressed MEGA-PRESS sequence. Patients were evaluated for psychopathology and all participants completed neuropsychological tests of working memory, processing speed, and functional capacity. GABA levels were significantly lower in the older participants with schizophrenia(n=31) compared to the older control(n=37) group (p=0.003) but not between the younger control(n=40) and schizophrenia (n=29) groups (p=0.994). Age strongly predicted GABA levels in the schizophrenia group accounting for 42% of the variance, but the effect of age was less in the control group accounting for 5.7% of the variance. GABA levels were specifically related to working memory but not processing speed performance, functional capacity, or positive or negative symptom severity. This is the largest MRS study of GABA in schizophrenia and the first to examine GABA without macromolecule contamination, a potentially significant issue in previous studies. GABA levels more rapidly declined with advancing age in the schizophrenia compared to the control group. Interventions targeted at halting the decline or increasing GABA levels may improve functional outcomes and quality of life as patients with schizophrenia age. PMID:25824298

Gamma-aminobutyric acid (GABA) stimulates pancreatic cancer growth through overexpressing GABAA receptor pi subunit.

PubMed

Takehara, Akio; Hosokawa, Masayo; Eguchi, Hidetoshi; Ohigashi, Hiroaki; Ishikawa, Osamu; Nakamura, Yusuke; Nakagawa, Hidewaki

2007-10-15

Gamma-aminobutyric acid (GABA) functions primarily as an inhibitory neurotransmitter in the mature central nervous system, and GABA/GABA receptors are also present in nonneural tissues, including cancer, but their precise function in nonneuronal or cancerous cells has thus far been poorly defined. Through the genome-wide cDNA microarray analysis of pancreatic ductal adenocarcinoma (PDAC) cells as well as subsequent reverse transcription-PCR and Northern blot analyses, we identified the overexpression of GABA receptor pi subunit (GABRP) in PDAC cells. We also found the expression of this peripheral type GABAA receptor subunit in few adult human organs. Knockdown of endogenous GABRP expression in PDAC cells by small interfering RNA attenuated PDAC cell growth, suggesting its essential role in PDAC cell viability. Notably, the addition of GABA into the cell culture medium promoted the proliferation of GABRP-expressing PDAC cells, but not GABRP-negative cells, and GABAA receptor antagonists inhibited this growth-promoting effect by GABA. The HEK293 cells constitutively expressing exogenous GABRP revealed the growth-promoting effect of GABA treatment. Furthermore, GABA treatment in GABRP-positive cells increased intracellular Ca2+ levels and activated the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/Erk) cascade. Clinical PDAC tissues contained a higher level of GABA than normal pancreas tissues due to the up-regulation of glutamate decarboxylase 1 expression, suggesting their autocrine/paracrine growth-promoting effect in PDACs. These findings imply that GABA and GABRP could play important roles in PDAC development and progression, and that this pathway can be a promising molecular target for the development of new therapeutic strategies for PDAC.

Endogenous GABA levels in the pontine reticular formation are greater during wakefulness than during rapid eye movement sleep.

PubMed

Vanini, Giancarlo; Wathen, Bradley L; Lydic, Ralph; Baghdoyan, Helen A

2011-02-16

Studies using drugs that increase or decrease GABAergic transmission suggest that GABA in the pontine reticular formation (PRF) promotes wakefulness and inhibits rapid eye movement (REM) sleep. Cholinergic transmission in the PRF promotes REM sleep, and levels of endogenous acetylcholine (ACh) in the PRF are significantly greater during REM sleep than during wakefulness or non-REM (NREM) sleep. No previous studies have determined whether levels of endogenous GABA in the PRF vary as a function of sleep and wakefulness. This study tested the hypothesis that GABA levels in cat PRF are greatest during wakefulness and lowest during REM sleep. Extracellular GABA levels were measured during wakefulness, NREM sleep, REM sleep, and the REM sleep-like state (REM(Neo)) caused by microinjecting neostigmine into the PRF. GABA levels varied significantly as a function of sleep and wakefulness, and decreased significantly below waking levels during REM sleep (-42%) and REM(Neo) (-63%). The decrease in GABA levels during NREM sleep (22% below waking levels) was not statistically significant. Compared with NREM sleep, GABA levels decreased significantly during REM sleep (-27%) and REM(Neo) (-52%). Comparisons of REM sleep and REM(Neo) revealed no differences in GABA levels or cortical EEG power. GABA levels did not vary significantly as a function of dialysis site within the PRF. The inverse relationship between changes in PRF levels of GABA and ACh during REM sleep indicates that low GABAergic tone combined with high cholinergic tone in the PRF contributes to the generation of REM sleep.

Endogenous GABA levels in the pontine reticular formation are greater during wakefulness than during REM sleep

PubMed Central

Vanini, Giancarlo; Wathen, Bradley L.; Lydic, Ralph; Baghdoyan, Helen A.

2011-01-01

Studies using drugs that increase or decrease GABAergic transmission suggest that GABA in the pontine reticular formation (PRF) promotes wakefulness and inhibits rapid eye movement (REM) sleep. Cholinergic transmission in the PRF promotes REM sleep, and levels of endogenous acetylcholine (ACh) in the PRF are significantly greater during REM sleep than during wakefulness or non-REM (NREM) sleep. No previous studies have determined whether levels of endogenous GABA in the PRF vary as a function of sleep and wakefulness. This study tested the hypothesis that GABA levels in cat PRF are greatest during wakefulness and lowest during REM sleep. Extracellular GABA levels were measured during wakefulness, NREM sleep, REM sleep, and the REM sleep-like state (REMNeo) caused by microinjecting neostigmine into the PRF. GABA levels varied significantly as a function of sleep and wakefulness, and decreased significantly below waking levels during REM sleep (−42%) and REMNeo (−63%). The decrease in GABA levels during NREM sleep (22% below waking levels) was not statistically significant. Compared to NREM sleep, GABA levels decreased significantly during REM sleep (−27%) and REMNeo (−52%). Comparisons of REM sleep and REMNeo revealed no differences in GABA levels or cortical EEG power. GABA levels did not vary significantly as a function of dialysis site within the PRF. The inverse relationship between changes in PRF levels of GABA and ACh during REM sleep indicates that low GABAergic tone combined with high cholinergic tone in the PRF contributes to the generation of REM sleep. PMID:21325533

[Schizophrenia and cortical GABA neurotransmission].

PubMed

Hashimoto, Takanori; Matsubara, Takuro; Lewis, David A

2010-01-01

Individuals with schizophrenia show disturbances in a number of brain functions that regulate cognitive, affective, motor, and sensory processing. The cognitive deficits associated with dysfunction of the dorsolateral prefrontal cortex result, at least in part, from abnormalities in GABA neurotransmission, as reflected in a specific pattern of altered expression of GABA-related molecules. First, mRNA levels for the 67-kilodalton isoform of glutamic acid decarboxylase (GAD67), an enzyme principally responsible for GABA synthesis, and the GABA membrane transporter GAT1, which regulates the reuptake of synaptically released GABA, are decreased in a subset of GABA neurons. Second, affected GABA neurons include those that express the calcium-binding protein parvalbumin (PV), because PV mRNA levels are decreased in the prefrontal cortex of subjects with schizophrenia and GAD67 mRNA is undetectable in almost half of PV-containing neurons. These changes are accompanied by decreased GAT1 expression in the presynaptic terminals of PV-containing neurons and by increased postsynaptic GABA-A receptor alpha2 subunit expression at the axon initial segments of pyramidal neurons. These findings indicate decreased GABA synthesis/release by PV-containing GABA neurons and compensatory changes at synapses formed by these neurons. Third, another subset of GABA neurons that express the neuropeptide somatostatin (SST) also appear to be affected because their specific markers, SST and neuropeptide Y mRNAs, are decreased in a manner highly correlated with the decreases in GAD67 mRNA. Finally, mRNA levels for GABA-A receptor subunits for synaptic (alpha1 and gamma2) and extra-synaptic (delta) receptors are decreased, indicating alterations in both synaptic and extra-synaptic GABA neurotransmission. Together, this pattern of changes indicates that the altered GABA neurotransmission is specific to PV-containing and SST-containing GABA neuron subsets and involves both synaptic and extra-synaptic GABA-A receptors. Our recent analyses demonstrated that this pattern exists across diverse cortical areas including the prefrontal, anterior cingulate, primary motor, and primary visual cortices. GABA neurotransmission by PV-containing and SST-containing neurons is important for the generation of cortical oscillatory activities in the gamma (30-100 Hz) and theta (4-7 Hz) bands, respectively. These oscillatory activities have been proposed to play critical roles in regulating the efficiency of information transfer between neurons and neuronal networks in the cortex. Altered cortical GABA neurotransmission appears to contribute to disturbances in diverse functions through affecting the generation of cortical oscillations in schizophrenia.

Contrast adaptation in cat visual cortex is not mediated by GABA.

PubMed

DeBruyn, E J; Bonds, A B

1986-09-24

The possible involvement of gamma-aminobutyric acid (GABA) in contrast adaptation in single cells in area 17 of the cat was investigated. Iontophoretic application of N-methyl bicuculline increased cell responses, but had no effect on the magnitude of adaptation. These results suggest that contrast adaptation is the result of inhibition through a parallel pathway, but that GABA does not mediate this process.

Role of external and internal calcium on heterocarrier-mediated transmitter release.

PubMed

Fassio, A; Bonanno, G; Fontana, G; Usai, C; Marchi, M; Raiteri, M

1996-04-01

Release-regulating heterocarriers exist on brain nerve endings. We have investigated in this study the mechanisms involved in the neurotransmitter release evoked by GABA heterocarrier activation. GABA increased the basal release of [3H]acetylcholine and [3H]noradrenaline from rat hippocampal synaptosomes and of [3H]dopamine from striatal synaptosomes. These GABA effects, insensitive to GABA receptor antagonists, were prevented by inhibiting GABA uptake but not by blocking noradrenaline, choline, or dopamine transport. Lack of extracellular Ca2+ or addition of tetrodotoxin selectively abolished the GABA-evoked release of [3H]noradrenaline, leaving unaffected that of [3H]acetylcholine or [3H]dopamine. 1,2-Bis(2-aminophenoxyl)-ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM) or vesamicol attenuated the release of [3H]acetylcholine elicited by GABA. Reserpine, but not BAPTA-AM, prevented the effect of GABA on [3H] dopamine release. Autoreceptor activation inhibited the GABA-evoked release of [3H]noradrenaline but not that of [3H]acetylcholine or [3H]dopamine. It is concluded that (a) the release of [3H]noradrenaline consequent to activation of GABA heterocarriers sited on noradrenergic terminals meets the criteria of a conventional exocytotic process, (b) the extracellular [Ca2+]-independent releases of [3H]acetylcholine and [3H]dopamine appear to occur from vesicles possibly through involvement of intraterminal Ca2+, and (c) autoreceptor activation only affects heterocarrier-mediated vesicular release linked to entry of extracellular Ca2+.

Activation induced changes in GABA: Functional MRS at 7T with MEGA-sLASER.

PubMed

Chen, Chen; Sigurdsson, Hilmar P; Pépés, Sophia E; Auer, Dorothee P; Morris, Peter G; Morgan, Paul S; Gowland, Penny A; Jackson, Stephen R

2017-08-01

Functional magnetic resonance spectroscopy (fMRS) has been used to assess the dynamic metabolic responses of the brain to a physiological stimulus non-invasively. However, only limited information on the dynamic functional response of γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain, is available. We aimed to measure the activation-induced changes in GABA unambiguously using a spectral editing method, instead of the conventional direct detection techniques used in previous fMRS studies. The Mescher-Garwood-semi-localised by adiabatic selective refocusing (MEGA-sLASER) sequence was developed at 7T to obtain the time course of GABA concentration without macromolecular contamination. A significant decrease (-12±5%) in the GABA to total creatine ratio (GABA/tCr) was observed in the motor cortex during a period of 10min of hand-clenching, compared to an initial baseline level (GABA/tCr =0.11±0.02) at rest. An increase in the Glx (glutamate and glutamine) to tCr ratio was also found, which is in agreement with previous findings. In contrast, no significant changes in NAA/tCr and tCr were detected. With consistent and highly efficient editing performance for GABA detection and the advantage of visually identifying GABA resonances in the spectra, MEGA-sLASER is demonstrated to be an effective method for studying of dynamic changes in GABA at 7T. Copyright © 2017 Elsevier Inc. All rights reserved.

Low dietary protein is associated with an increase in food intake and a decrease in the in vitro release of radiolabeled glutamate and GABA from the lateral hypothalamus.

PubMed

White, B D; Du, F; Higginbotham, D A

2003-12-01

Moderately low-protein diets lead to a rapid increase in food intake and body fat. The increase in feeding is associated with a decrease in the concentration of serum urea nitrogen, suggesting that the low-protein-induced increase in food intake may be related to the decreased metabolism of nitrogen from amino acids. We hypothesized that low dietary protein would be associated with a decrease in the synaptic release of two nitrogen-containing neurotransmitters, GABA and glutamate, whose nitrogen can be derived from amino acids. In this study, we examined the effects of a low-protein diet (10% casein) in Sprague-Dawley rats on the in vitro release of 3H-GABA and 14C-glutamate from the lateral and medial hypothalamus. The low-protein diet increased food intake by about 25% after one day. After four days, the in vitro release of radiolabeled GABA and glutamate was assessed. The calcium-dependent, potassium-stimulated release of radiolabeled GABA and glutamate from the lateral hypothalamus was decreased in rats fed the low-protein diet. The magnitude of neurotransmitter release from the lateral hypothalamus inversely correlated with food intake. No dietary differences in the release of neurotransmitters from the medial hypothalamus were observed. These results support the contention that alterations in nitrogen metabolism are associated with low-protein-induced feeding.

Treatment of GABA from Fermented Rice Germ Ameliorates Caffeine-Induced Sleep Disturbance in Mice

PubMed Central

Mabunga, Darine Froy N.; Gonzales, Edson Luck T.; Kim, Hee Jin; Choung, Se Young

2015-01-01

γ-Aminobutyric acid (GABA), a major inhibitory neurotransmitter in the mammalian central nervous system, is involved in sleep physiology. Caffeine is widely used psychoactive substance known to induce wakefulness and insomnia to its consumers. This study was performed to examine whether GABA extracts from fermented rice germ ameliorates caffeine-induced sleep disturbance in mice, without affecting spontaneous locomotor activity and motor coordination. Indeed, caffeine (10 mg/kg, i.p.) delayed sleep onset and reduced sleep duration of mice. Conversely, rice germ ferment extracts-GABA treatment (10, 30, or 100 mg/kg, p.o.), especially at 100 mg/kg, normalized the sleep disturbance induced by caffeine. In locomotor tests, rice germ ferment extracts-GABA slightly but not significantly reduced the caffeine-induced increase in locomotor activity without affecting motor coordination. Additionally, rice germ ferment extracts-GABA per se did not affect the spontaneous locomotor activity and motor coordination of mice. In conclusion, rice germ ferment extracts-GABA supplementation can counter the sleep disturbance induced by caffeine, without affecting the general locomotor activities of mice. PMID:25995826

Intra-accumbens baclofen, but not muscimol, mimics the effects of food withdrawal on feeding behaviour.

PubMed

Pulman, K G T; Somerville, E M; Clifton, P G

2010-11-01

Intra-accumbens stimulation of GABA receptors results in a robust increase in food intake. However the differential consequences of stimulating GABA(A) and GABA(B) receptors in the nucleus accumbens have not been extensively explored with respect to feeding behaviour. Here we compare the effects of the GABA(B) receptor agonist baclofen and GABA(A) receptor agonist muscimol, infused into the nucleus accumbens shell, on food intake and related behavior patterns. Baclofen (110-440 ρmol) dose dependently enhanced intake and delayed the onset of satiety within the test period as did the effects of 4-8h food withdrawal. Muscimol (220-660 ρmol) enhanced intake but also disrupted the sequence of associated behaviours at every dose tested. We conclude that GABA(B) receptors in the nucleus accumbens shell may play a role in relation to feeding motivation whereas GABA(A) receptors may, as previously suggested, have a more restricted role in relation to the motor components of approach to food and ingestion. Copyright © 2010 Elsevier Inc. All rights reserved.

Substance P provoked gamma-aminobutyric acid release from the myenteric plexus of the guinea-pig small intestine.

PubMed Central

Tanaka, C; Taniyama, K

1985-01-01

The release of [3H]gamma-aminobutyric acid (GABA) from the isolated small intestine of the guinea-pig pre-loaded with [3H]GABA was measured in the presence of substance P and vasoactive intestinal polypeptide (VIP). Substance P (10(-10)-10(-7) M) produced a dose-dependent increase in the fractional rate of [3H]GABA release. VIP, even at 10(-7) M, did not affect the spontaneous [3H]GABA release nor the release of [3H]GABA evoked by electrical transmural stimulation (0.5 ms, 15 V, 10 Hz for 30 s). The release of endogenous GABA from the isolated small intestine was measured in the presence of substance P (10(-9) M). After 60 min superfusion, the spontaneous release of GABA was 4.61 +/- 0.14 pmol min-1 g-1 wet wt. (n = 20). Substance P (10(-9) M) produced an approximate 2-fold spontaneous release of endogeneous GABA (8.74 +/- 0.21 pmol min-1 g-1 wet wt. (n = 10)). Perfusion with Ca-free medium containing 1 mM-EGTA and tetrodotoxin (3 X 10(-7) M) inhibited the release of endogenous GABA evoked by substance P (10(-9) M). (D-Pro2, D-Trp7,9) substance P (10(-6) M) antagonized the release of endogenous GABA evoked by substance P (10(-9) M). These results indicate that substance P induces a neuronal release of GABA through its receptor located in the guinea-pig small intestine. Substance P (10(-11)-10(-7) M) produced a dose-dependent increase in the fractional rate of [3H]acetylcholine (ACh) release from the isolated small intestine pre-loaded with [3H]choline. The release of [3H]ACh evoked by substance P (10(-9) M) was inhibited by perfusion with Ca-free medium containing 1 mM-EGTA, tetrodotoxin (3 X 10(-7) M) and (D-Pro2, D-Trp7,9)substance P (10(-6) M). Bicuculline (10(-6) M) inhibited the release of [3H]ACh evoked by substance P (10(-9) M) by 68.1 +/- 4.6% (n = 5), thereby suggesting that the substance P-evoked ACh release is partly mediated through the endogenous GABA released by substance P. These results provide evidence for the neurotransmitter role of GABA and a possible excitatory role of substance P on the GABAergic neurones in the myenteric plexus of the guinea-pig small intestine. PMID:2410602

Verification of γ-Amino-Butyric Acid (GABA) Signaling System Components in Periodontal Ligament Cells In Vivo and In Vitro.

PubMed

Konermann, Anna; Kantarci, Alpdogan; Wilbert, Steven; Van Dyke, Thomas; Jäger, Andreas

2016-11-01

CNS key neurotransmitter γ-amino-butyric acid (GABA) and its signaling components are likewise detectable in non-neuronal tissues displaying inter alia immunomodulatory functions. This study aimed at identifying potential glutamate decarboxylase (GAD)65 and GABA receptor expression in periodontal ligament (PDL) cells in vivo and in vitro, with particular regard to inflammation and mechanical loading. Gene expression was analyzed in human PDL cells at rest or in response to IL-1ß (5 ng/ml) or TNFα (5 ng/ml) challenge via qRT-PCR. Western blot determined constitutive receptor expression, and confocal laser scanning fluorescence microscopy visualized expression changes induced by inflammation. ELISA quantified GAD65 release. Immunocytochemistry was performed for GABA component detection in vitro on mechanically loaded PDL cells, and in vivo on rat upper jaw biopsies with mechanically induced root resorptions. Statistical significance was set at p < 0.05. GABA B1 , GABA B2 , GABA A1 , and GABA A3 were ubiquitously expressed both on gene and protein level. GABA A2 and GAD65 were undetectable in resting cells, but induced by inflammation. GABA B1 exhibited the highest basal gene expression (6.97 % ± 0.16). IL-1ß markedly increased GABA B2 on a transcriptional (57.28-fold ± 12.40) and protein level seen via fluorescence microscopy. TNFα-stimulated PDL cells released GAD65 (3.68 pg/ml ± 0.17 after 24 h, 5.77 pg/ml ± 0.65 after 48 h). Immunocytochemistry revealed GAD65 expression in mechanically loaded PDL cells. In vivo, GABA components were varyingly expressed in an inflammatory periodontal environment. PDL cells differentially express GABA signaling components and secrete GAD65. Inflammation and mechanical loading regulate these neurotransmitter molecules, which are also detectable in vivo and are potentially involved in periodontal pathophysiology.

Activation of GABA-A receptors during postnatal brain development increases anxiety- and depression-related behaviors in a time- and dose-dependent manner in adult mice.

PubMed

Salari, Ali-Akbar; Bakhtiari, Amir; Homberg, Judith R

2015-08-01

Disturbances of the gamma-amino butyric acid-ergic (GABAergic) system during postnatal development can have long-lasting consequences for later life behavior, like the individual's response to stress. However, it is unclear which postnatal windows of sensitivity to GABA-ergic modulations are associated with what later-life behavioral outcomes. Therefore, we sought to determine whether neonatal activation of the GABA-A receptor during two postnatal periods, an early window (postnatal day 3-5) and a late window (postnatal day 14-16), can affect anxiety- and depression-related behaviors in male mice in later life. To this end, mice were treated with either saline or muscimol (50, 100, 200, 300 and 500μg/kg) during the early and late postnatal periods. An additional group of mice was treated with the GABA-A receptor antagonist bicuculline+muscimol. When grown to adulthood male mice were exposed to behavioral tests to measure anxiety- and depression-related behaviors. Baseline and stress-induced corticosterone (CORT) levels were also measured. The results indicate that early postnatal and to a lesser extent later postnatal exposure to the GABA-A receptor agonist muscimol increased anxiety-like behavior and stress-induced CORT levels in adults. Moreover, the early postnatal treatment with muscimol increased depression-like behavior with increasing baseline CORT levels. The anxiogenic and depression-like later-life consequences could be antagonized by bicuculline. Our findings suggest that GABA-A receptor signaling during early-life can influence anxiety- and depression-related behaviors in a time- and dose-dependent manner in later life. Our findings help to increase insight in the developmental mechanisms contributing to stress-related disorders. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Temperature dependence and GABA modulation of (TH)triazolam binding in the rat brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Earle, M.E.; Concas, A.; Wamsley, J.K.

1987-07-27

The hypnotic triazolam (TZ), a triazolobenzodiazepine displays a short physiological half life and has been used for the treatment of insomnia related to anxiety states. The authors major objectives were the direct measurement of the temperature dependence and the gamma-aminobutyric acid (GABA) effect of (TH)TZ binding in the rat brain. Saturation studies showed a shift to lower affinity with increasing temperatures (K/sub d/ = 0.27 +/- 08 nM at 0C; K/sub d/ = 1.96 +/- 0.85 nM at 37C) while the B/sub max/ values remained unchanged (1220 +/- 176 fmoles/mg protein at 0C and 1160 +/- 383 fmoles/mg protein atmore » 37C). Saturation studies of (TH)TZ binding in the presence or absence of GABA (100 M) showed a GABA-shift. At 0C the K/sub d/ values were (K/sub d/ = 0.24 +/- 0.03 nM/-GABA; K/sub d/ = 0.16 +/- 0.04/+GABA) and at 37C the K/sub d/ values were (K/sub d/ = 1.84 +/- 0.44 nM/-GABA; K/sub d/ = 0.95 +/- 0.29 nM/+GABA). In contrast to reported literature, the authors findings show that TZ interacts with benzodiazepine receptors with a temperature dependence and GABA-shift consistent with predicted behavior for benzodiazepine agonists. 20 references, 3 tables.« less

gamma-Aminobutyric acid production in small and large intestine of normal and germ-free Wistar rats. Influence of food intake and intestinal flora.

PubMed

van Berlo, C L; de Jonge, H R; van den Bogaard, A E; van Eijk, H M; Janssen, M A; Soeters, P B

1987-09-01

In recent hypotheses concerning the pathogenesis of hepatic encephalopathy, gamma-aminobutyric acid (GABA) is claimed to be produced by the colonic flora, although enzymes necessary to generate GABA have been reported to be present in intestinal mucosa. In this study, using normal and germ-free Wistar rats, we determined GABA levels and amino-grams of arterial blood and of venous effluent from small and large bowel. The data indicate that large and small intestinal mucosa significantly contribute to GABA production. In the fasted state GABA concentrations are greater in the venous effluent of the small bowel than in the venous effluent of the large bowel. Feeding increases the arterioportal differences, and uptake in the small bowel is still significantly higher than in the large bowel. This process is not, or can only be to a minor degree, bacterially mediated, because GABA production in the gut both in the fed and fasted state is of similar magnitude in germ-free and normal animals. gamma-Aminobutyric acid release correlates significantly with glutamine uptake in the small bowel of fasted rats. Only a small fraction of the glutamine taken up is needed to account for GABA release, so that conclusions concerning which amino acids may serve as precursors of GABA cannot be drawn. Further studies are needed to delineate the metabolic pathways leading to GABA synthesis.

Gamma-aminobutyric acid, a potential tumor suppressor for small airway-derived lung adenocarcinoma.

PubMed

Schuller, Hildegard M; Al-Wadei, Hussein A N; Majidi, Mourad

2008-10-01

Pulmonary adenocarcinoma (PAC) is the leading type of lung cancer in smokers and non-smokers that arises in most cases from small airway epithelial cells. PAC has a high mortality due to its aggressive behavior and resistance to cancer therapeutics. We have shown previously that the proliferation of human PAC cells NCI-H322 and immortalized human small airway epithelial cells HPL1D is stimulated by cyclic adenosine monophosphate (cAMP)/protein kinase A-dependent phosphorylation of cyclic adenosine monophosphate response element-binding (CREB) protein and transactivation of the epidermal growth factor receptor and that this pathway is activated by beta-1-adrenoreceptors (beta(1)-ARs) and the non-genomic estrogen receptor beta. Our current in vitro studies with HPL1D and NCI-H322 cells showed that signaling via the gamma-amino butyric acid receptor (GABA(B)R) strongly inhibited base level and isoproterenol-induced cAMP, p-CREB, cyclic adenosine monophosphate response element-luciferase activity and p-extracellular regulated kinase-1 (ERK1)/2 and effectively blocked DNA synthesis and cell migration. The inhibitory effects of gamma-amino butyric acid (GABA) were disinhibited by the GABA(B)R antagonist CGP-35348 or GABA(B)R knockdown. Immunohistochemical investigation of hamster lungs showed significant underexpression of GABA in animals with small airway-derived PACs induced by the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These findings suggest that GABA may have tumor suppressor function in small airway epithelia and the PACs derived from them and that downregulation of GABA by NNK may contribute to the development of this cancer in smokers. Our findings suggest that marker-guided treatment with GABA or a GABA(B)R agonist of individuals with downregulated pulmonary GABA may provide a novel targeted approach for the prevention of PAC in smokers.

GABA receptors, alcohol dependence and criminal behavior.

PubMed

Terranova, Claudio; Tucci, Marianna; Sartore, Daniela; Cavarzeran, Fabiano; Di Pietra, Laura; Barzon, Luisa; Palù, Giorgio; Ferrara, Santo D

2013-09-01

The aim of this study was to analyze the connection between alcohol dependence and criminal behavior by an integrated genetic-environmental approach. The research, structured as a case-control study, examined 186 alcohol-dependent males; group 1 (N = 47 convicted subjects) was compared with group 2 (N = 139 no previous criminal records). Genetic results were innovative, highlighting differences in genotype distribution (p = 0.0067) in group 1 for single-nucleotide polymorphism rs 3780428, located in the intronic region of subunit 2 of the GABA B receptor gene (GABBR2). Some environmental factors (e.g., grade repetition) were associated with criminal behavior; others (e.g., attendance at Alcoholics Anonymous) were inversely related to convictions. The concomitant presence of the genetic and environmental factors found to be associated with the condition of alcohol-dependent inmate showed a 4-fold increase in the risk of antisocial behavior. The results need to be replicated on a larger population to develop new preventive and therapeutic proposals. © 2013 American Academy of Forensic Sciences.

Antagonism of GABA-B but not GABA-A receptors in the VTA prevents stress- and intra-VTA CRF-induced reinstatement of extinguished cocaine seeking in rats

PubMed Central

Blacktop, Jordan M.; Vranjkovic, Oliver; Mayer, Matthieu; Van Hoof, Matthew; Baker, David A.; Mantsch, John R.

2015-01-01

Stress-induced reinstatement of cocaine seeking requires corticotropin releasing factor (CRF) actions in the ventral tegmental area (VTA). However the mechanisms through which CRF regulates VTA function to promote cocaine use are not fully understood. Here we examined the role of GABAergic neurotransmission in the VTA mediated by GABA-A or GABA-B receptors in the reinstatement of extinguished cocaine seeking by a stressor, uncontrollable intermittent footshock, or bilateral intra-VTA administration of CRF. Rats underwent repeated daily cocaine self-administration (1.0 mg/kg/ing; 14 × 6 hrs/day) and extinction and were tested for reinstatement in response to footshock (0.5 mA, 0.5” duration, average every 40 sec; range 10–70 sec) or intra-VTA CRF delivery (500 ng/side) following intra-VTA pretreatment with the GABA-A antagonist, bicuculline, the GABA-B antagonist, 2-hydroxysaclofen or vehicle. Intra-VTA bicuculline (1, 10 or 20 ng/side) failed to block footshock- or CRF-induced cocaine seeking at either dose tested. By contrast, 2-hydroxysaclofen (0.2 or 2 µg/side) prevented reinstatement by both footshock and intra-VTA CRF at a concentration that failed to attenuate food-reinforced lever pressing (45 mg sucrose-sweetened pellets; FR4 schedule) in a separate group of rats. These data suggest that GABA-B receptor-dependent CRF actions in the VTA mediate stress-induced cocaine seeking and that GABA-B receptor antagonists may have utility for the management of stress-induced relapse in cocaine addicts. PMID:26596556

Optogenetic and pharmacological evidence that somatostatin‐GABA neurons are important regulators of parasympathetic outflow to the stomach

PubMed Central

Lewin, Amanda E.; Vicini, Stefano; Richardson, Janell; Dretchen, Kenneth L.; Gillis, Richard A.

2016-01-01

Key points The dorsal motor nucleus of the vagus (DMV) in the brainstem consists primarily of vagal preganglionic neurons that innervate postganglionic neurons of the upper gastrointestinal tract.The activity of the vagal preganglionic neurons is predominantly regulated by GABAergic transmission in the DMV.The present findings indicate that the overwhelming GABAergic drive present at the DMV is primarily from somatostatin positive GABA (Sst‐GABA) DMV neurons.Activation of both melanocortin and μ‐opioid receptors at the DMV inhibits Sst‐GABA DMV neurons.Sst‐GABA DMV neurons may serve as integrative targets for modulating vagal output activity to the stomach. Abstract We have previously shown that local GABA signalling in the brainstem is an important determinant of vagally‐mediated gastric activity. However, the neural identity of this GABA source is currently unknown. To determine this, we focused on the somatostatin positive GABA (Sst‐GABA) interneuron in the dorsal motor nucleus of the vagus (DMV), a nucleus that is intimately involved in regulating gastric activity. Also of particular interest was the effect of melanocortin and μ‐opioid agonists on neural activity of Sst‐GABA DMV neurons because their in vivo administration in the DMV mimics GABA blockade in the nucleus. Experiments were conducted in brain slice preparation of transgenic adult Sst‐IRES‐Cre mice expressing tdTomato fluorescence, channelrhodopsin‐2, archaerhodopsin or GCaMP3. Electrophysiological recordings were obtained from Sst‐GABA DMV neurons or DiI labelled gastric‐antrum projecting DMV neurons. Our results show that optogenetic stimulation of Sst‐GABA neurons results in a robust inhibition of action potentials of labelled premotor DMV neurons to the gastric‐antrum through an increase in inhibitory post‐synaptic currents. The activity of the Sst‐GABA neurons in the DMV is inhibited by both melanocortin and μ‐opioid agonists. These agonists counteract the pronounced inhibitory effect of Sst‐GABA neurons on vagal pre‐motor neurons in the DMV that control gastric motility. These observations demonstrate that Sst‐GABA neurons in the brainstem are crucial for regulating the activity of gastric output neurons in the DMV. Additionally, they suggest that these neurons serve as targets for converging CNS signals to regulate parasympathetic gastric function. PMID:26959279

Optogenetic and pharmacological evidence that somatostatin-GABA neurons are important regulators of parasympathetic outflow to the stomach.

PubMed

Lewin, Amanda E; Vicini, Stefano; Richardson, Janell; Dretchen, Kenneth L; Gillis, Richard A; Sahibzada, Niaz

2016-05-15

The dorsal motor nucleus of the vagus (DMV) in the brainstem consists primarily of vagal preganglionic neurons that innervate postganglionic neurons of the upper gastrointestinal tract. The activity of the vagal preganglionic neurons is predominantly regulated by GABAergic transmission in the DMV. The present findings indicate that the overwhelming GABAergic drive present at the DMV is primarily from somatostatin positive GABA (Sst-GABA) DMV neurons. Activation of both melanocortin and μ-opioid receptors at the DMV inhibits Sst-GABA DMV neurons. Sst-GABA DMV neurons may serve as integrative targets for modulating vagal output activity to the stomach. We have previously shown that local GABA signalling in the brainstem is an important determinant of vagally-mediated gastric activity. However, the neural identity of this GABA source is currently unknown. To determine this, we focused on the somatostatin positive GABA (Sst-GABA) interneuron in the dorsal motor nucleus of the vagus (DMV), a nucleus that is intimately involved in regulating gastric activity. Also of particular interest was the effect of melanocortin and μ-opioid agonists on neural activity of Sst-GABA DMV neurons because their in vivo administration in the DMV mimics GABA blockade in the nucleus. Experiments were conducted in brain slice preparation of transgenic adult Sst-IRES-Cre mice expressing tdTomato fluorescence, channelrhodopsin-2, archaerhodopsin or GCaMP3. Electrophysiological recordings were obtained from Sst-GABA DMV neurons or DiI labelled gastric-antrum projecting DMV neurons. Our results show that optogenetic stimulation of Sst-GABA neurons results in a robust inhibition of action potentials of labelled premotor DMV neurons to the gastric-antrum through an increase in inhibitory post-synaptic currents. The activity of the Sst-GABA neurons in the DMV is inhibited by both melanocortin and μ-opioid agonists. These agonists counteract the pronounced inhibitory effect of Sst-GABA neurons on vagal pre-motor neurons in the DMV that control gastric motility. These observations demonstrate that Sst-GABA neurons in the brainstem are crucial for regulating the activity of gastric output neurons in the DMV. Additionally, they suggest that these neurons serve as targets for converging CNS signals to regulate parasympathetic gastric function. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Activation of inactivation process initiates rapid eye movement sleep.

PubMed

Mallick, Birendra Nath; Singh, Abhishek; Khanday, Mudasir Ahmad

2012-06-01

Interactions among REM-ON and REM-OFF neurons form the basic scaffold for rapid eye movement sleep (REMS) regulation; however, precise mechanism of their activation and cessation, respectively, was unclear. Locus coeruleus (LC) noradrenalin (NA)-ergic neurons are REM-OFF type and receive GABA-ergic inputs among others. GABA acts postsynaptically on the NA-ergic REM-OFF neurons in the LC and presynaptically on the latter's projection terminals and modulates NA-release on the REM-ON neurons. Normally during wakefulness and non-REMS continuous release of NA from the REM-OFF neurons, which however, is reduced during the latter phase, inhibits the REM-ON neurons and prevents REMS. At this stage GABA from substantia nigra pars reticulate acting presynaptically on NA-ergic terminals on REM-ON neurons withdraws NA-release causing the REM-ON neurons to escape inhibition and being active, may be even momentarily. A working-model showing neurochemical-map explaining activation of inactivation process, showing contribution of GABA-ergic presynaptic inhibition in withdrawing NA-release and dis-inhibition induced activation of REM-ON neurons, which in turn activates other GABA-ergic neurons and shutting-off REM-OFF neurons for the initiation of REMS-generation has been explained. Our model satisfactorily explains yet unexplained puzzles (i) why normally REMS does not appear during waking, rather, appears following non-REMS; (ii) why cessation of LC-NA-ergic-REM-OFF neurons is essential for REMS-generation; (iii) factor(s) which does not allow cessation of REM-OFF neurons causes REMS-loss; (iv) the association of changes in levels of GABA and NA in the brain during REMS and its deprivation and associated symptoms; v) why often dreams are associated with REMS. Copyright © 2012 Elsevier Ltd. All rights reserved.

Role of the Sensorimotor Cortex in Tourette Syndrome using Multimodal Imaging

PubMed Central

Tinaz, Sule; Belluscio, Beth A.; Malone, Patrick; van der Veen, Jan Willem; Hallett, Mark; Horovitz, Silvina G.

2016-01-01

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by motor and vocal tics. Most patients describe uncomfortable premonitory sensations preceding the tics and a subjective experience of increased sensitivity to tactile stimuli. These reports indicate that a sensory processing disturbance is an important component of TS together with motor phenomena. Thus, we focused our investigation on the role of the sensorimotor cortex (SMC) in TS using multimodal neuroimaging techniques. We measured the gamma-aminobutyric acid (GABA)+/Creatine (Cre) ratio in the SMC using GABA 1H magnetic resonance spectroscopy. We recorded the baseline beta activity in the SMC using magnetoencephalography and correlated GABA+/Cre ratio with baseline beta band power. Finally, we examined the resting state functional connectivity (FC) pattern of the SMC using functional magnetic resonance imaging (fMRI). GABA+/Cre ratio in the SMC did not differ between patients and controls. Correlation between the baseline beta band power and GABA+/Cre ratio was abnormal in patients. The anterior insula showed increased FC with the SMC in patients. These findings suggest that altered limbic input to the SMC and abnormal GABA-mediated beta oscillations in the SMC may underpin some of the sensorimotor processing disturbances in TS and contribute to tic generation. PMID:25044024

Ketone bodies and brain glutamate and GABA metabolism.

PubMed

Daikhin, Y; Yudkoff, M

1998-01-01

The effects of ketone bodies on brain metabolism of glutamate and GABA were studied in three different systems: synaptosomes, cultured astrocytes and the whole animal. In synaptosomes the addition of either acetoacetate or 3-OH-butyrate was associated with diminished consumption of glutamate via transamination to aspartate and increased formation of labelled GABA from either L-[2H5-2,3,3,4, 4]glutamine or L-[15N]glutamine. There was no effect of ketone bodies on synaptosomal GABA transamination. An increase of total forebrain GABA and a diminution of aspartate was noted when mice were injected intraperitoneally with 3-OH-butyrate. In cultured astrocytes the addition of acetoacetate to the medium was associated with a significantly enhanced rate of citrate production and with a diminution in the rate of conversion of [15N]glutamate to [15N]aspartate. These data are consistent with the hypothesis that the metabolism of ketone bodies to acetyl-CoA results in a diminution of the pool of brain oxaloacetate, which is consumed in the citrate synthetase reaction (oxaloacetate + acetyl-CoA --> citrate). As less oxaloacetate is available to the aspartate aminotransferase reaction, thereby lowering the rate of glutamate transamination, more glutamate becomes accessible to the glutamate decarboxylase pathway, thereby favoring the synthesis of GABA.

Ribosomal binding site sequences and promoters for expressing glutamate decarboxylase and producing γ-aminobutyrate in Corynebacterium glutamicum.

PubMed

Shi, Feng; Luan, Mingyue; Li, Yongfu

2018-04-18

Glutamate decarboxylase (GAD) converts L-glutamate (Glu) into γ-aminobutyric acid (GABA). Corynebacterium glutamicum that expresses exogenous GAD gene, gadB2 or gadB1, can synthesize GABA from its own produced Glu. To enhance GABA production in C. glutamicum, ribosomal binding site (RBS) sequence and promoter were searched and optimized for increasing the expression efficiency of gadB2. R4 exhibited the highest strength among RBS sequences tested, with 6 nt the optimal aligned spacing (AS) between RBS and start codon. This combination of RBS sequence and AS contributed to gadB2 expression, increased GAD activity by 156% and GABA production by 82% compared to normal strong RBS and AS combination. Then, a series of native promoters were selected for transcribing gadB2 under optimal RBS and AS combination. P dnaK , P dtsR , P odhI and P clgR expressed gadB2 and produced GABA as effectively as widely applied P tuf and P cspB promoters and more effectively than P sod promoter. However, each native promoter did not work as well as the synthetic strong promoter P tacM , which produced 20.2 ± 0.3 g/L GABA. Even with prolonged length and bicistronic architecture, the strength of P dnaK did not enhance. Finally, gadB2 and mutant gadB1 were co-expressed under the optimal promoter and RBS combination, thus converted Glu into GABA completely and improved GABA production to more than 25 g/L. This study provides useful promoters and RBS sequences for gene expression in C. glutamicum.

Mechanisms of carbacholine and GABA action on resting membrane potential and Na+/K+-ATPase of Lumbricus terrestris body wall muscles.

PubMed

Volkov, Eugeny M; Nurullin, Leniz F; Volkov, Michael E; Nikolsky, Eugeny E; Vyskočil, Frantisek

2011-04-01

This work was aimed to identify the action of several ion channel and pump inhibitors as well as nicotinic, GABAergic, purinergic and serotoninergic drugs on the resting membrane potential (RMP) and assess the role of cholinergic and GABAergic sensitivity in earthworm muscle electrogenesis. The nicotinic agonists acetylcholine (ACh), carbacholine (CCh) and nicotine depolarize the RMP at concentrations of 5 μM and higher. The nicotinic antagonists (+)tubocurarine, α-bungarotoxin, muscarinic antagonists atropine and hexamethonium do not remove or prevent the CCh-induced depolarization. Verapamil, tetrodotoxin, removal of Cl(-) and Ca(2+) from the solution also cannot prevent the depolarization by CCh. In a Na(+)-free medium, however, CCh lost this depolarization ability and this indicates that the drug opens the sodium permeable pathway. Serotonin, glutamate, glycine, adenosine triphosphate (ATP) and cis-4-aminocrotonic acid (GABA(C) receptor antagonist) had no effect on the RMP. On the other hand, isoguvacin, γ-aminobutyric acid (GABA) and baclofen (GABA(B) receptor agonist) hyperpolarized the RMP. Ouabain, bicucullin (GABA(A) antagonist) and phaclofen (GABA(B) antagonist), as well as the removal of Cl(-), suppressed the effect of GABA and baclofen. CCh did not enhance the depolarization generated by ouabain but, on the other hand, hindered the hyperpolarizing activity of baclofen both in the absence and presence of atropine and (+)tubocurarine. The long-term application of CCh depolarizes the RMP primarily by inhibiting the Na(+)/K(+)-ATPase. The muscle membrane also contains A and B type GABA binding sites, the activation of which increases the RMP at the expense of increasing the action of ouabain- and Cl(-) -sensitive electrogenic pumps. Copyright © 2010 Elsevier Inc. All rights reserved.

Sleep-promoting effects of a GABA/5-HTP mixture: Behavioral changes and neuromodulation in an invertebrate model.

PubMed

Hong, Ki-Bae; Park, Yooheon; Suh, Hyung Joo

2016-04-01

This study was to investigate the sleep promoting effects of combined γ-aminobutyric acid (GABA) and 5-hydroxytryptophan (5-HTP), by examining neuronal processes governing mRNA level alterations, as well as assessing neuromodulator concentrations, in a fruit fly model. Behavioral assays were applied to investigate subjective nighttime activity, sleep episodes, and total duration of subjective nighttime sleep of two amino acids and GABA/5-HTP mixture with caffeine treated flies. Also, real-time PCR and HPLC analysis were applied to analyze the signaling pathway. Subjective nighttime activity and sleep patterns of individual flies significantly decreased with 1% GABA treatment in conjunction with 0.1% 5-HTP treatment (p<0.001). Furthermore, GABA/5-HTP mixture resulted in significant differences between groups related to sleep patterns (40%, p<0.017) and significantly induced subjective nighttime sleep in the awake model (p<0.003). These results related to transcript levels of the GABAB receptor (GABAB-R1) and serotonin receptor (5-HT1A), compared to the control group. In addition, GABA/5-HTP mixture significantly increased GABA levels 1h and 12h following treatment (2.1 fold and 1.2 fold higher than the control, respectively) and also increased 5-HTP levels (0 h: 1.01 μg/protein, 12h: 3.45 μg/protein). In this regard, we successfully demonstrated that using a GABA/5-HTP mixture modulates subjective nighttime activity, sleep episodes, and total duration of subjective nighttime sleep to a greater extent than single administration of each amino acid, and that this modulation occurs via GABAergic and serotonergic signaling. Copyright © 2016 Elsevier Inc. All rights reserved.

The Association Between Clinical Characteristics of Migraine and Brain GABA Levels: An Exploratory Study.

PubMed

Aguila, Maria-Eliza R; Rebbeck, Trudy; Leaver, Andrew M; Lagopoulos, Jim; Brennan, Patrick C; Hübscher, Markus; Refshauge, Kathryn M

2016-10-01

Migraine is prevalent and disabling yet is poorly understood. One way to better understand migraine is to examine its clinical characteristics and potential biomarkers such as gamma-aminobutyric acid (GABA). The primary objective of this study was to explore whether relevant disease characteristics of migraine are associated with brain GABA levels. Twenty adults fulfilling the established diagnostic criteria for migraine and 20 age- and gender-matched controls completed this cross-sectional study. Pain, central sensitization, negative emotional state, and perceived disability were measured using Short-form McGill Pain Questionnaire-2, Central Sensitization Inventory, Depression Anxiety Stress Scales-21, and Headache Impact Test-6, respectively. Secondary analysis of brain GABA levels of the same cohort measured using proton magnetic resonance spectroscopy was conducted. The migraine group had significantly higher scores than the control group on pain, central sensitization, and disability. Correlation analyses showed fair positive association between GABA levels and pain and central sensitization scores. No association was found between GABA levels and emotional state and disability. These findings are preliminary evidence supporting the use of questionnaires and GABA levels in characterizing migraine better and broadening the diagnostic process. These findings also strengthen the rationale for the role of GABA in migraine pathophysiology and corroborate the potential of GABA as a migraine biomarker. Higher pain and central sensitization scores were associated with increased brain GABA levels in individuals with migraine. These findings offer preliminary evidence for the usefulness of measuring pain and central sensitization in migraine and provide some support for the possible role of GABA in migraine pathophysiology and its potential as a diagnostic marker. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

Alterations in food intake elicited by GABA and opioid agonists and antagonists administered into the ventral tegmental area region of rats.

PubMed

Echo, Joyce A; Lamonte, Nicole; Ackerman, Tsippa F; Bodnar, Richard J

2002-05-01

Food intake is significantly increased following administration of mu-selective opioid agonists into the ventral tegmental area (VTA) region acting through multiple local opioid receptor subtypes. Since GABA receptor agonists in the VTA region are capable of eliciting feeding, the present study investigated whether feeding elicited by the mu-selective opioid agonist [D-Ala(2), NMe(4), Gly-ol(5)]-enkephalin (DAMGO) in the VTA region was altered by pretreatment into the same site with equimolar doses of either GABA(A) (bicuculline) or GABA(B) (saclofen) antagonists, and further, whether pretreatment with either general opioid or selective GABA receptor antagonists decreased feeding elicited by GABA(A) (muscimol) or GABA(B) (baclofen) agonists in the VTA region. DAMGO-induced feeding in the VTA region was dose-dependently decreased following pretreatment with either GABA(A) or GABA(B) antagonists in the absence of significant alterations in food intake by the antagonists per se. However, the presence of short-lived seizures following bicuculline in the VTA region suggests that this ingestive effect was caused by nonspecific actions. In contrast, GABA(B) receptors are involved in the full expression of mu-opioid agonist-induced feeding in this region since saclofen failed to elicit either seizure activity or a conditioned taste aversion. Pretreatment with naltrexone in the VTA region reduced intake elicited by baclofen, but not muscimol. Finally, baclofen-induced feeding was significantly reduced by saclofen, but not bicuculline, pretreatment in the VTA region. Therefore, possible coregulation between GABA(B) and opioid receptors in the VTA region, as suggested by immunocytochemical evidence, is supported by these behavioral effects upon ingestion.

Betaine attenuates memory impairment after water-immersion restraint stress and is regulated by the GABAergic neuronal system in the hippocampus.

PubMed

Kunisawa, Kazuo; Kido, Kiwamu; Nakashima, Natsuki; Matsukura, Takuya; Nabeshima, Toshitaka; Hiramatsu, Masayuki

2017-02-05

GABA mediated neuronal system regulates hippocampus-dependent memory and stress responses by controlling plasticity and neuronal excitability. Here, we demonstrate that betaine ameliorates water-immersion restraint stress (WIRS)-induced memory impairments. This improvement was inhibited by a betaine/GABA transporter-1 (GABA transporter-2: GAT2) inhibitor, NNC 05-2090. In this study, we investigated whether memory amelioration by betaine was mediated by the GABAergic neuronal system. Adult male mice were co-administered betaine and GABA receptor antagonists after WIRS. We also examined whether memory impairment after WIRS was attenuated by GABA receptor agonists. The memory functions were evaluated using a novel object recognition test 3-6 days after WIRS and/or the step-down type passive avoidance test at 7-8 days. The co-administration of the GABA A receptor antagonist bicuculline (1mg/kg) or the GABA B receptor antagonist phaclofen (10mg/kg) 1h after WIRS suppressed the memory-improving effects induced by betaine. Additionally, the administration of the GABA A receptor agonist muscimol (1mg/kg) or the GABA B receptor agonist baclofen (10mg/kg) 1h after WIRS attenuated memory impairments. These results were similar to the data observed with betaine. The treatment with betaine after WIRS significantly decreased the expression of GABA transaminase, and this effect was partially blocked by NNC 05-2090 in the hippocampus. WIRS caused a transient increase in hippocampal GABA levels and the changes after WIRS were not affected by betaine treatment in an in vivo microdialysis study. These results suggest that the beneficial effects of betaine may be mediated in part by changing the GABAergic neuronal system. Copyright © 2016 Elsevier B.V. All rights reserved.

Olfactory bulb short axon cell release of GABA and dopamine produces a temporally biphasic inhibition-excitation response in external tufted cells

PubMed Central

Liu, Shaolin; Plachez, Celine; Shao, Zuoyi; Puche, Adam; Shipley, Michael T.

2013-01-01

Evidence for co-expression of two or more classic neurotransmitters in neurons has increased but less is known about co-transmission. Ventral tegmental area (VTA) neurons, co-release dopamine (DA), the excitatory transmitter glutamate and the inhibitory transmitter GABA onto target cells in the striatum. Olfactory bulb (OB) short axon cells (SACs) form interglomerular connections and co-express markers for dopamine (DA) and GABA. Using an optogenetic approach we provide evidence that mouse OB SACs release both GABA and DA onto external tufted cells (ETCs) in other glomeruli. Optical activation of channelrhodopsin specifically expressed in DAergic SACs produced a GABAA receptor-mediated monosynaptic inhibitory response followed by DA-D1-like receptor-mediated excitatory response in ETCs. The GABAA receptor-mediated hyperpolarization activates Ih current in ETCs; synaptically released DA increases Ih, which enhances post-inhibitory rebound spiking. Thus, the opposing actions of synaptically released GABA and DA are functionally integrated by Ih to generate an inhibition-to-excitation “switch” in ETCs. Consistent with the established role of Ih in ETC burst firing, we show that endogenous DA release increases ETC spontaneous bursting frequency. ETCs transmit sensory signals to mitral/tufted output neurons and drive intraglomerular inhibition to shape glomerulus output to downstream olfactory networks. GABA and DA co-transmission from SACs to ETCs may play a key role in regulating output coding across the glomerular array. PMID:23407950

Clarified Açaí (Euterpe oleracea) Juice as an Anticonvulsant Agent: In Vitro Mechanistic Study of GABAergic Targets.

PubMed

Arrifano, Gabriela P F; Lichtenstein, Mathieu P; Souza-Monteiro, José Rogério; Farina, Marcelo; Rogez, Hervé; Carvalho, José Carlos Tavares; Suñol, Cristina; Crespo-López, Maria Elena

2018-01-01

Seizures affect about 50 million people around the world. Approximately 30% of seizures are refractory to the current pharmacological arsenal, so, the pursuit of new therapeutic alternatives is essential. Clarified Euterpe oleracea (EO) juice showed anticonvulsant properties similar to diazepam in an in vivo model with pentylenetetrazol, a GABA A receptor blocker. This study investigated the effects of EO on the main GABAergic targets for anticonvulsant drugs, analyzing the effect on the GABA receptor's benzodiazepine and picrotoxinin binding sites and the GABA uptake. Primary cultures of cortical neurons and astrocytes were treated with EO (0-25%) for up to 90 min. [ 3 H]Flunitrazepam and [ 3 H]TBOB binding, [ 3 H]GABA uptake, cell viability, and morphology were assayed. Nonlethal concentrations of EO increased agonist binding and decreased antagonist binding in cortical neurons. Low concentrations significantly inhibited GABA uptake, especially in astrocytes, suggesting an accumulation of endogenous GABA in the synaptic cleft. The results demonstrate, for the first time, that EO can improve GABAergic neurotransmission via interactions with GABA A receptor and modulation of GABA uptake. Understanding these molecular mechanisms will help in the treatment of seizures and epilepsy, especially in developing countries where geographic isolation and low purchasing power are the main barriers to access to adequate treatment.

GABA (γ-Aminobutyric Acid) Uptake Via the GABA Permease GabP Represses Virulence Gene Expression in Pseudomonas syringae pv. tomato DC3000.

PubMed

McCraw, S L; Park, D H; Jones, R; Bentley, M A; Rico, A; Ratcliffe, R G; Kruger, N J; Collmer, A; Preston, G M

2016-12-01

The nonprotein amino acid γ-aminobutyric acid (GABA) is the most abundant amino acid in the tomato (Solanum lycopersicum) leaf apoplast and is synthesized by Arabidopsis thaliana in response to infection by the bacterial pathogen Pseudomonas syringae pv. tomato DC3000 (hereafter called DC3000). High levels of exogenous GABA have previously been shown to repress the expression of the type III secretion system (T3SS) in DC3000, resulting in reduced elicitation of the hypersensitive response (HR) in the nonhost plant tobacco (Nicotiana tabacum). This study demonstrates that the GABA permease GabP provides the primary mechanism for GABA uptake by DC3000 and that the gabP deletion mutant ΔgabP is insensitive to GABA-mediated repression of T3SS expression. ΔgabP displayed an enhanced ability to elicit the HR in young tobacco leaves and in tobacco plants engineered to produce increased levels of GABA, which supports the hypothesis that GABA uptake via GabP acts to regulate T3SS expression in planta. The observation that P. syringae can be rendered insensitive to GABA through loss of gabP but that gabP is retained by this bacterium suggests that GabP is important for DC3000 in a natural setting, either for nutrition or as a mechanism for regulating gene expression. [Formula: see text] Copyright © 2016 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .

Respiratory response to microinjections of GABA and penicillin into various parts of the ventral respiratory group.

PubMed

Vedyasova, O A; Kovalyov, A M

2012-06-01

Experiments on rats showed that local injection of GABA (10(-4) M) into the rostral and caudal compartments of the ventral respiratory groups decreased the respiratory rhythm, but increased lung ventilation (especially injection into the rostral part). Penicillin (10(-7) M) injected into the rostral division increased the tidal volume and practically did not change the respiratory rate, but its injection into the caudal part reduced the tidal volume and increased respiratory rate. These results indicate that GABAergic mechanisms including GABA(A) sites play an ambiguous role in the regulation of respiration at the level of the rostral and caudal parts of the ventral respiratory group.

Interplay between DISC1 and GABA signaling regulates neurogenesis in mice and risk for schizophrenia.

PubMed

Kim, Ju Young; Liu, Cindy Y; Zhang, Fengyu; Duan, Xin; Wen, Zhexing; Song, Juan; Feighery, Emer; Lu, Bai; Rujescu, Dan; St Clair, David; Christian, Kimberly; Callicott, Joseph H; Weinberger, Daniel R; Song, Hongjun; Ming, Guo-li

2012-03-02

How extrinsic stimuli and intrinsic factors interact to regulate continuous neurogenesis in the postnatal mammalian brain is unknown. Here we show that regulation of dendritic development of newborn neurons by Disrupted-in-Schizophrenia 1 (DISC1) during adult hippocampal neurogenesis requires neurotransmitter GABA-induced, NKCC1-dependent depolarization through a convergence onto the AKT-mTOR pathway. In contrast, DISC1 fails to modulate early-postnatal hippocampal neurogenesis when conversion of GABA-induced depolarization to hyperpolarization is accelerated. Extending the period of GABA-induced depolarization or maternal deprivation stress restores DISC1-dependent dendritic regulation through mTOR pathway during early-postnatal hippocampal neurogenesis. Furthermore, DISC1 and NKCC1 interact epistatically to affect risk for schizophrenia in two independent case control studies. Our study uncovers an interplay between intrinsic DISC1 and extrinsic GABA signaling, two schizophrenia susceptibility pathways, in controlling neurogenesis and suggests critical roles of developmental tempo and experience in manifesting the impact of susceptibility genes on neuronal development and risk for mental disorders. Copyright © 2012 Elsevier Inc. All rights reserved.

Kindling alters entorhinal cortex-hippocampal interaction by increased efficacy of presynaptic GABA(B) autoreceptors in layer III of the entorhinal cortex.

PubMed

Gloveli, Tengis; Behr, Joachim; Dugladze, Tamar; Kokaia, Zaal; Kokaia, Merab; Heinemann, Uwe

2003-08-01

We studied the effect of kindling, a model of temporal lobe epilepsy, on the frequency-dependent information transfer from the entorhinal cortex to the hippocampus in vitro. In control rats repetitive synaptic activation of layer III projection cells resulted in a frequency dependent depression of the synaptic transfer of action potentials to the hippocampus. One-to-two-days after kindling this effect was strongly reduced. Although no substantial change in synaptic inhibition upon single electrical stimulation was detected in kindled rats, there was a significant depression in the prolonged inhibition following high frequency stimulation. In kindled animals, paired-pulse depression (PPD) of stimulus-evoked IPSCs in layer III neurons was significantly stronger than in control rats. The increase of PPD is most likely caused by an increased presynaptic GABA(B) receptor-mediated autoinhibition. In kindled animals activation of presynaptic GABA(B) receptors by baclofen (10 microM) suppressed monosynaptic IPSCs significantly more than in control rats. In contrast, activation of postsynaptic GABA(B) receptors by baclofen was accompanied by comparable changes of the membrane conductance in both animal groups. Thus, in kindled animals activation of the layer III-CA1 pathway is facilitated by an increased GABA(B) receptor-mediated autoinhibition leading to an enhanced activation of the monosynaptic EC-CA1 pathway.

α5GABAA Receptors Mediate Tonic Inhibition in the Spinal Cord Dorsal Horn and Contribute to the Resolution Of Hyperalgesia.

PubMed

Perez-Sanchez, Jimena; Lorenzo, Louis-Etienne; Lecker, Irene; Zurek, Agnieszka A; Labrakakis, Charalampos; Bridgwater, Erica M; Orser, Beverley A; De Koninck, Yves; Bonin, Robert P

2017-06-01

Neuronal inhibition mediated by GABA A receptors constrains nociceptive processing in the spinal cord, and loss of GABAergic inhibition can produce allodynia and hyperalgesia. Extrasynaptic α5 subunit-containing GABA A receptors (α5GABA A Rs) generate a tonic conductance that inhibits neuronal activity and constrains learning and memory; however, it is unclear whether α5GABA A Rs similarly generate a tonic conductance in the spinal cord dorsal horn to constrain nociception. We assessed the distribution of α5GABA A Rs in the spinal cord dorsal horn by immunohistochemical analysis, and the activity and function of α5GABA A Rs in neurons of the superficial dorsal horn using electrophysiological and behavioral approaches in male, null-mutant mice lacking the GABA A R α5 subunit (Gabra5-/-) and wild-type mice (WT). The expression of α5GABA A Rs in the superficial dorsal horn followed a laminar pattern of distribution, with a higher expression in lamina II than lamina I. Similarly, the tonic GABA A current in lamina II neurons had a larger contribution from α5GABA A Rs than in lamina I, with no significant contribution of these receptors to synaptic GABA A current. In behavioural tests, WT and Gabra5-/- mice exhibited similar acute thermal and mechanical nociception, and similar mechanical sensitization immediately following intraplantar capsaicin or Complete Freund's Adjuvant (CFA). However, Gabra5-/- mice showed prolonged recovery from sensitization in these models, and increased responses in the late phase of the formalin test. Overall, our data suggest that tonically-active α5GABA A Rs in the spinal cord dorsal horn accelerate the resolution of hyperalgesia and may therefore serve as a novel therapeutic target to promote recovery from pathological pain. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Differential association of GABAB receptors with their effector ion channels in Purkinje cells.

PubMed

Luján, Rafael; Aguado, Carolina; Ciruela, Francisco; Cózar, Javier; Kleindienst, David; de la Ossa, Luis; Bettler, Bernhard; Wickman, Kevin; Watanabe, Masahiko; Shigemoto, Ryuichi; Fukazawa, Yugo

2018-04-01

Metabotropic GABA B receptors mediate slow inhibitory effects presynaptically and postsynaptically through the modulation of different effector signalling pathways. Here, we analysed the distribution of GABA B receptors using highly sensitive SDS-digested freeze-fracture replica labelling in mouse cerebellar Purkinje cells. Immunoreactivity for GABA B1 was observed on presynaptic and, more abundantly, on postsynaptic compartments, showing both scattered and clustered distribution patterns. Quantitative analysis of immunoparticles revealed a somato-dendritic gradient, with the density of immunoparticles increasing 26-fold from somata to dendritic spines. To understand the spatial relationship of GABA B receptors with two key effector ion channels, the G protein-gated inwardly rectifying K + (GIRK/Kir3) channel and the voltage-dependent Ca 2+ channel, biochemical and immunohistochemical approaches were performed. Co-immunoprecipitation analysis demonstrated that GABA B receptors co-assembled with GIRK and Ca V 2.1 channels in the cerebellum. Using double-labelling immunoelectron microscopic techniques, co-clustering between GABA B1 and GIRK2 was detected in dendritic spines, whereas they were mainly segregated in the dendritic shafts. In contrast, co-clustering of GABA B1 and Ca V 2.1 was detected in dendritic shafts but not spines. Presynaptically, although no significant co-clustering of GABA B1 and GIRK2 or Ca V 2.1 channels was detected, inter-cluster distance for GABA B1 and GIRK2 was significantly smaller in the active zone than in the dendritic shafts, and that for GABA B1 and Ca V 2.1 was significantly smaller in the active zone than in the dendritic shafts and spines. Thus, GABA B receptors are associated with GIRK and Ca V 2.1 channels in different subcellular compartments. These data provide a better framework for understanding the different roles played by GABA B receptors and their effector ion channels in the cerebellar network.

Neurochemistry of major depression: a study using magnetic resonance spectroscopy.

PubMed

Godlewska, Beata R; Near, Jamie; Cowen, Philip J

2015-02-01

Magnetic resonance spectroscopy (MRS) is an acceptable non-invasive means of studying brain neurochemistry in depression. Previous studies in depressed patients have focused on measurement of the amino acid neurotransmitters, γ-aminobutyric acid (GABA) and glutamate. The aim of this study is to use MRS in conjunction with the ultrashort echo time 'SPECIAL' technique to measure cortical levels of GABA, glutamate and glutathione (GSH) levels in unmedicated patients with major depression. We also examined the effect of 6-week treatment with the selective serotonin re-uptake inhibitor, escitalopram. We studied patients with DSM-IV major depression and healthy age-matched controls using proton MRS. GABA, glutamate and GSH were measured relative to creatine in a voxel placed in occipital cortex. There was no difference in GABA or glutamate levels between depressed participants and controls; however, depressed patients had lower GSH levels. Six-week escitalopram treatment, which resulted in significant clinical responses in some patients, did not alter concentrations of GABA, glutamate or GSH. The sources of variability of GABA and glutamate measures in different studies of depressed patients require further study. Our results suggest that concomitant treatment with selective serotonin re-uptake inhibitors (SSRIs) is unlikely to be an important confounding factor. If lowered GSH levels can be confirmed, they may represent the presence of oxidative stress in some depressed patients.

[Effect of acupuncture at different acupoints on expression of hypothalamic GABA and GABA(A) receptor proteins in insomnia rats].

PubMed

Zhou, Yan-Li; Gao, Xi-Yan; Wang, Pei-Yu; Ren, Shan

2012-08-01

To observe the effect of acupuncture of "Shenmai" (BL 62) and "Zhaohai" (KI 6), "Shenmen" (HT 7), etc. on the expression of hypothalamic gamma-aminobutyric acid (GABA) and GABA(A) receptor (GABA(A)R) proteins in experimental insomnia rats so as to explore its mechanism underlying improving sleeping. Seventy Wistar rats were randomly divided into normal control, model, "Sanyinjiao" (SP6), "Neiguan" (PC 6), "Zusanli" (ST 36), "Shenmen" (HT7), and "Shenmai" (BL 62)-Zhaohai (KI 6, BL 62-KI 6) groups, with 10 rats in each group. Insomnia model was established by intraperitoneal injection of chlorophenylalanine solution (PCPA, 1 mL/100 g). An acupuncture needle was inserted into each of the bilateral HT 7, PC 6, SP 6, ST 36 and BL 62-KI 6 respectively and manipulated for about 1 min, once daily for 7 days. Hypothamic GABA and GABA(A)R protein expressions were detected by immunohistochemistry. The animals' physical ability was evaluated by using pole-climbing test in a water tank. In comparison with the normal control group, the numbers of hypothalamic GABA immunoreaction (IR)- and GABA(A)R IR-positive neurons and the pole-climbing time were reduced significantly in the model group (P < 0.05). While in comparison with the model group, the numbers of hypothalamic GABA IR-positive neurons and those of hypothalamic GABA(A)R IR-positive neurons in the HT 7, PC 6, SP 6, ST 36 and BL 62-KI 6 groups, as well as the pole-climbing duration in the SP 6, ST 36 and BL 62-KI 6 groups were increased considerably (P < 0.05, P < 0.01). The effects of HT 7 and BL 62-KI 6 groups were significantly superior to those of PC 6, ST 36 and SP 6 groups in up-regulating GABA and GABA(A)R expression, and the effect of BL 62-KI 6 group was remarkably better than those of HT 7, PC 6, SP 6 and ST 36 groups in lengthening the pole-climbing time (P < 0.05). Acupuncture can effectively suppress insomnia induced down-regulation of hypothalamic GABA and GABA(A)R in rats and lengthen pole-climbing time, which may contribute to its effect in relieving insomnia.

Gamma-amino butyric acid (GABA) release in the ciliated protozoon Paramecium occurs by neuronal-like exocytosis.

PubMed

Ramoino, P; Milanese, M; Candiani, S; Diaspro, A; Fato, M; Usai, C; Bonanno, G

2010-04-01

Paramecium primaurelia expresses a significant amount of gamma-amino butyric acid (GABA). Paramecia possess both glutamate decarboxylase (GAD)-like and vesicular GABA transporter (vGAT)-like proteins, indicating the ability to synthesize GABA from glutamate and to transport GABA into vesicles. Using antibodies raised against mammalian GAD and vGAT, bands with an apparent molecular weight of about 67 kDa and 57 kDa were detected. The presence of these bands indicated a similarity between the proteins in Paramecium and in mammals. VAMP, syntaxin and SNAP, putative proteins of the release machinery that form the so-called SNARE complex, are present in Paramecium. Most VAMP, syntaxin and SNAP fluorescence is localized in spots that vary in size and density and are primarily distributed near the plasma membrane. Antibodies raised against mammal VAMP-3, sintaxin-1 or SNAP-25 revealed protein immunoblot bands having molecular weights consistent with those observed in mammals. Moreover, P. primaurelia spontaneously releases GABA into the environment, and this neurotransmitter release significantly increases after membrane depolarization. The depolarization-induced GABA release was strongly reduced not only in the absence of extracellular Ca(2+) but also by pre-incubation with bafilomycin A1 or with botulinum toxin C1 serotype. It can be concluded that GABA occurs in Paramecium, where it is probably stored in vesicles capable of fusion with the cell membrane; accordingly, GABA can be released from Paramecium by stimulus-induced, neuronal-like exocytotic mechanisms.

Cell type specificity of GABA(A) receptor mediated signaling in the hippocampus.

PubMed

Semyanov, A

2003-08-01

Inhibitory signaling mediated by ionotropic GABA(1) receptors generally acts as a major brake against excessive excitability in the brain. This is especially relevant in epilepsy-prone structures such as the hippocampus, in which GABA(A) receptor mediated inhibition is critical in suppressing epileptiform activity. Indeed, potentiating GABA(A) receptor mediated signaling is an important target for antiepileptic drug therapy. GABA(A) receptor mediated inhibition has different roles in the network dependent on the target neuron. Inhibiting principal cells will thus reduce network excitability, whilst inhibiting interneurons will increase network excitability; GABAergic therapeutic agents do not distinguish between these two alternatives, which may explain why, on occasion, GABAergic antiepileptic drugs can be proconvulsant. The importance of the target-cell for the effect of neuroactive drugs has emerged from a number of recent studies. Immunocytochemical data have suggested non-uniform distribution of GABA(A) receptor subunits among hippocampal interneurons and pyramidal cells. This has been confirmed by subsequent electropharmacological data. These have demonstrated that compounds which act on GABA(A) receptors or the extracellular GABA concentration can have distinct effects in different neuronal populations. Recently, it has also been discovered that presynaptic glutamate heteroreceptors can modulate GABA release in the hippocampus in a postsynaptic cell-specific manner. Since systemically administrated drugs may act on different neuronal subtypes, they can exhibit paradoxical effects. Distinguishing compounds that have target specific effects on GABAergic signaling may lead to novel and more effective treatments against epilepsy.

Impact of oral supplementation of Glutamate and GABA on memory performance and neurochemical profile in hippocampus of rats.

PubMed

Tabassum, Saiqa; Ahmad, Saara; Madiha, Syeda; Khaliq, Saima; Shahzad, Sidrah; Batool, Zehra; Haider, Saida

2017-05-01

Glutamate (GLU) and gamma-amino butyric acid (GABA) are essential amino acids (AA) for brain function serving as excitatory and inhibitory neurotransmitter respectively. Their tablets are available in market for improving gut function and muscle performance. Despite of having a major role during memory formation and processing, effects of these tablets on brain functioning like learning and memory have not been investigated. Therefore, present study is aimed to investigate the effects of orally supplemented GLU and GABA on learning and memory performance and further to monitor related effects of these orally supplemented GLU and GABA on brain levels of these AA. Three groups of rats were supplemented orally with drinking water (control group) or suspension of tablets of GABA and Glutamate, respectively for four weeks. Cognitive performance was determined using behavioral tests (Novel object recognition test, Morris water maze, Passive avoidance test) measuring recognition, spatial reference and aversive memory. Levels of GLU, GABA and acetylcholine (ACh) were estimated in rat hippocampus. Results showed that chronic oral administration of GLU and GABA tablets has a significant impact on brain function and can alter GLU and GABA content in rat hippocampus. Compared to GABA, GLU supplementation specifically enhances memory performance via increasing ACh. Thus, GLU can be suggested as a useful supplement for improving learning and memory performance and neurochemical status of brain and in future could be effective in the treatment of neurological disorders affecting learning and memory performance.

Effect of Γ-aminobutyric acid on kidney injury induced by renal ischemia-reperfusion in male and female rats: Gender-related difference.

PubMed

Vafapour, Marzieh; Nematbakhsh, Mehdi; Monajemi, Ramesh; Mazaheri, Safoora; Talebi, Ardeshir; Talebi, Nahid; Shirdavani, Soheyla

2015-01-01

The most important cause of kidney injury is renal ischemia/reperfusion injury (IRI), which is gender-related. This study was designed to investigate the protective role of Γ-aminobutyric acid (GABA (against IRI in male and female rats. Thirty-six female and male wistar rats were assigned to six experimental groups. The IRI was induced by clamping renal vessels for 45 min then was performed reperfusion for 24 h. The group sex posed to IRI were pretreated with GABA and were compared with the control groups. Serum levels of creatinine and blood urea nitrogen, kidney weight, and kidney tissue damage score increased in the IRI alone groups, (P < 0.05), while GABA decreased these parameters in female significantly (P < 0.05), but not in male rats. Uterus weight decreased significantly in female rats treated with GABA. Testis weight did not alter in male rats. Serum level of nitrite and kidney level of malondialdehyde (MDA) had no significant change in both female and male rats. Kidney level of nitrite increased significantly in female rats experienced IRI and serum level of MDA increased significantly in males that were exposed to IRI (P < 0.05). GABA could ameliorate kidney injury induced by renal IRI in a gender dependent manner.

Intra-accumbens baclofen, but not muscimol, increases second order instrumental responding for food reward in rats.

PubMed

Pulman, Kim G T; Somerville, Elizabeth M; Clifton, Peter G

2012-01-01

Stimulation of either GABA(A) or GABA(B) receptors within the nucleus accumbens shell strongly enhances food intake in rats. However the effects of subtype-selective stimulation of GABA receptors on instrumental responses for food reward are less well characterized. Here we contrast the effects of the GABA(A) receptor agonist muscimol and GABA(B) receptor agonist baclofen on instrumental responding for food using a second order reinforcement schedule. Bilateral intra-accumbens administration of baclofen (220-440 pmol) stimulated responding but a higher dose (660 pmol) induced stereotyped oral behaviour that interfered with responding. Baclofen (220-660 pmol) also stimulated intake of freely available chow. Muscimol (220-660 pmol) was without effect on responding for food on this schedule but did stimulate intake of freely available chow. Unilateral administration of either baclofen or muscimol (220 pmol) induced similar patterns of c-fos immunoreactivity in several hypothalamic sites but differed in its induction in the central nucleus of the amygdala. We conclude that stimulation of GABA(A) or GABA(B) receptors in the nucleus accumbens shell of rats produces clearly distinguishable effects on operant responding for food.

Comparison of taurine, GABA, Glu, and Asp as scavengers of malondialdehyde in vitro and in vivo

NASA Astrophysics Data System (ADS)

Deng, Yan; Wang, Wei; Yu, Pingfeng; Xi, Zhijiang; Xu, Lijian; Li, Xiaolong; He, Nongyue

2013-04-01

The purpose of this study is to determine if amino acid neurotransmitters such as gamma-aminobutyric acid (GABA), taurine, glutamate (Glu), and aspartate (Asp) can scavenge activated carbonyl toxicants. In vitro, direct reaction between malondialdehyde (MDA) and amino acids was researched using different analytical methods. The results indicated that scavenging activated carbonyl function of taurine and GABA is very strong and that of Glu and Asp is very weak in pathophysiological situations. The results provided perspective into the reaction mechanism of taurine and GABA as targets of activated carbonyl such as MDA in protecting nerve terminals. In vivo, we studied the effect of taurine and GABA as antioxidants by detecting MDA concentration and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities. It was shown that MDA concentration was decreased significantly, and the activities of SOD and GSH-Px were increased significantly in the cerebral cortex and hippocampus of acute epileptic state rats, after the administration of taurine and GABA. The results indicated that the peripherally administered taurine and GABA can scavenge free radicals and protect the tissue against activated carbonyl in vivo and in vitro.

Combined glutamate and glutamine levels in pain-processing brain regions are associated with individual pain sensitivity.

PubMed

Zunhammer, Matthias; Schweizer, Lauren M; Witte, Vanessa; Harris, Richard E; Bingel, Ulrike; Schmidt-Wilcke, Tobias

2016-10-01

The relationship between glutamate and γ-aminobutyric acid (GABA) levels in the living human brain and pain sensitivity is unknown. Combined glutamine/glutamate (Glx), as well as GABA levels can be measured in vivo with single-voxel proton magnetic resonance spectroscopy. In this cross-sectional study, we aimed at determining whether Glx and/or GABA levels in pain-related brain regions are associated with individual differences in pain sensitivity. Experimental heat, cold, and mechanical pain thresholds were obtained from 39 healthy, drug-free individuals (25 men) according to the quantitative sensory testing protocol and summarized into 1 composite measure of pain sensitivity. The Glx levels were measured using point-resolved spectroscopy at 3 T, within a network of pain-associated brain regions comprising the insula, the anterior cingulate cortex, the mid-cingulate cortex, the dorsolateral prefrontal cortex, and the thalamus. GABA levels were measured using GABA-edited spectroscopy (Mescher-Garwood point-resolved spectroscopy) within the insula, the anterior cingulate cortex, and the mid-cingulate cortex. Glx and/or GABA levels correlated positively across all brain regions. Gender, weekly alcohol consumption, and depressive symptoms were significantly associated with Glx and/or GABA levels. A linear regression analysis including all these factors indicated that Glx levels pooled across pain-related brain regions were positively associated with pain sensitivity, whereas no appreciable relationship with GABA was found. In sum, we show that the levels of the excitatory neurotransmitter glutamate and its precursor glutamine across pain-related brain regions are positively correlated with individual pain sensitivity. Future studies will have to determine whether our findings also apply to clinical populations.

Antagonism of GABA-B but not GABA-A receptors in the VTA prevents stress- and intra-VTA CRF-induced reinstatement of extinguished cocaine seeking in rats.

PubMed

Blacktop, Jordan M; Vranjkovic, Oliver; Mayer, Matthieu; Van Hoof, Matthew; Baker, David A; Mantsch, John R

2016-03-01

Stress-induced reinstatement of cocaine seeking requires corticotropin releasing factor (CRF) actions in the ventral tegmental area (VTA). However the mechanisms through which CRF regulates VTA function to promote cocaine use are not fully understood. Here we examined the role of GABAergic neurotransmission in the VTA mediated by GABA-A or GABA-B receptors in the reinstatement of extinguished cocaine seeking by a stressor, uncontrollable intermittent footshock, or bilateral intra-VTA administration of CRF. Rats underwent repeated daily cocaine self-administration (1.0 mg/kg/ing; 14 × 6 h/day) and extinction and were tested for reinstatement in response to footshock (0.5 mA, 0.5" duration, average every 40 s; range 10-70 s) or intra-VTA CRF delivery (500 ng/side) following intra-VTA pretreatment with the GABA-A antagonist, bicuculline, the GABA-B antagonist, 2-hydroxysaclofen or vehicle. Intra-VTA bicuculline (1, 10 or 20 ng/side) failed to block footshock- or CRF-induced cocaine seeking at either dose tested. By contrast, 2-hydroxysaclofen (0.2 or 2 μg/side) prevented reinstatement by both footshock and intra-VTA CRF at a concentration that failed to attenuate food-reinforced lever pressing (45 mg sucrose-sweetened pellets; FR4 schedule) in a separate group of rats. These data suggest that GABA-B receptor-dependent CRF actions in the VTA mediate stress-induced cocaine seeking and that GABA-B receptor antagonists may have utility for the management of stress-induced relapse in cocaine addicts. Copyright © 2015 Elsevier Ltd. All rights reserved.

Assessment of anoxia tolerance and photoperiod dependence of GABAergic polarity in the pond snail Lymnaea stagnalis.

PubMed

Buck, Leslie T; Bond, Hilary C; Malik, Aqsa

2017-01-01

The pond snail Lymnaea stagnalis is reported to be anoxia-tolerant and if the tolerance mechanism is similar to that of the anoxia-tolerant painted turtle, GABA should play an important role. A potentially confounding factor investigating the role of GABA in anoxia tolerance are reports that GABA has both inhibitory and excitatory effects within L. stagnalis central ganglion. We therefore set out to determine if seasonality or photoperiod has an impact on: 1) the anoxia-tolerance of the intact pond snail, and 2) the response of isolated neuroganglia cluster F neurons to exogenous GABA application. L. stagnalis maintained on a natural summer light cycle were unable to survive any period of anoxic exposure, while those maintained on a natural winter light cycle survived a maximum of 4h. Using intracellular sharp electrode recordings from pedal ganglia cluster F neurons we show that there is a photoperiod dependent shift in the response to GABA. Snails exposed to a 16h:8h light:dark cycle in an environmental chamber (induced summer phenotype) exhibited hyperpolarizing inhibitory responses and those exposed to a 8h:16h light:dark cycle (induced winter phenotype) exhibited depolarizing excitatory responses to GABA application. Using gramicidin-perforated patch recordings we also found a photoperiod dependent shift in the reversal potential for GABA. We conclude that the opposing responses of L. stagnalis central neurons to GABA results from a shift in intracellular chloride concentration that is photoperiod dependent and is likely mediated through the relative efficacy of cation chloride co-transporters. Although the physiological ramifications of the photoperiod dependent shift are unknown this work potentially has important implications for the impact of artificial light pollution on animal health. Copyright © 2016 Elsevier Inc. All rights reserved.

Acute spinal cord injury (SCI) transforms how GABA affects nociceptive sensitization.

PubMed

Huang, Yung-Jen; Lee, Kuan H; Murphy, Lauren; Garraway, Sandra M; Grau, James W

2016-11-01

Noxious input can sensitize pain (nociceptive) circuits within the spinal cord, inducing a lasting increase in spinal cord neural excitability (central sensitization) that is thought to contribute to chronic pain. The development of spinally-mediated central sensitization is regulated by descending fibers and GABAergic interneurons. The current study provides evidence that spinal cord injury (SCI) transforms how GABA affects nociceptive transmission within the spinal cord, recapitulating an earlier developmental state wherein GABA has an excitatory effect. In spinally transected rats, noxious electrical stimulation and inflammation induce enhanced mechanical reactivity (EMR), a behavioral index of nociceptive sensitization. Pretreatment with the GABA A receptor antagonist bicuculline blocked these effects. Peripheral application of an irritant (capsaicin) also induced EMR. Both the induction and maintenance of this effect were blocked by bicuculline. Cellular indices of central sensitization [c-fos expression and ERK phosphorylation (pERK)] were also attenuated. In intact (sham operated) rats, bicuculline had the opposite effect. Pretreatment with a GABA agonist (muscimol) attenuated nociceptive sensitization in intact, but not spinally injured, rats. The effect of SCI on GABA function was linked to a reduction in the Cl - transporter, KCC2, leading to a reduction in intracellular Cl - that would attenuate GABA-mediated inhibition. Pharmacologically blocking the KCC2 channel (with i.t. DIOA) in intact rats mimicked the effect of SCI. Conversely, a pharmacological treatment (bumetanide) that should increase intracellular Cl - levels blocked the effect of SCI. The results suggest that GABAergic neurons drive, rather than inhibit, the development of nociceptive sensitization after spinal injury. Copyright © 2016 Elsevier Inc. All rights reserved.

Reduced Chrna7 expression in mice is associated with decreases in hippocampal markers of inhibitory function: implications for neuropsychiatric diseases.

PubMed

Adams, C E; Yonchek, J C; Schulz, K M; Graw, S L; Stitzel, J; Teschke, P U; Stevens, K E

2012-04-05

The α7* nicotinic acetylcholine receptor encoded by CHRNA7 (human)/Chrna7 (mice) regulates the release of both the inhibitory neurotransmitter GABA and the excitatory neurotransmitter glutamate in the hippocampal formation. A heterozygous (Het) deletion at 15q13.3 containing CHRNA7 is associated with increased risk for schizophrenia, autism, and epilepsy. Each of these diseases are characterized by abnormalities in excitatory and inhibitory hippocampal circuit function. Reduced Chrna7 expression results in decreased hippocampal α7* receptor density, abnormal hippocampal auditory sensory processing, and increased hippocampal CA3 pyramidal neuron activity in C3H mice Het for a null mutation in Chrna7. These abnormalities demonstrate that decreased Chrna7 expression alters hippocampal inhibitory circuit function. The current study examined the specific impact of reduced Chrna7 expression on hippocampal inhibitory circuits by measuring the levels of GABA, GABA(A) receptors, the GABA synthetic enzyme l-glutamic acid decarboxylase-65 (GAD-65), and the vesicular GABA transporter 1 (GAT-1) in wild-type (Chrna7 +/+) and Het (Chrna7 +/-) C3H α7 mice of both genders. GAD-65 levels were significantly decreased in male and female Het C3H α7 mice, whereas GABA(A) receptors were significantly reduced only in male Het C3H α7 mice. No changes in GABA and GAT-1 levels were detected. These data suggest that reduced CHRNA7 expression may contribute to the abnormalities in hippocampal inhibitory circuits observed in schizophrenia, autism, and/or epilepsy. Published by Elsevier Ltd.

Extracellular pH modulates GABAergic neurotransmission in rat hypothalamus.

PubMed

Chen, Z L; Huang, R Q

2014-06-20

Changes in extracellular pH have a modulatory effect on GABAA receptor function. It has been reported that pH sensitivity of the GABA receptor is dependent on subunit composition and GABA concentration. Most of previous investigations focused on GABA-evoked currents, which only reflect the postsynaptic receptors. The physiological relevance of pH modulation of GABAergic neurotransmission is not fully elucidated. In the present studies, we examined the influence of extracellular pH on the GABAA receptor-mediated inhibitory neurotransmission in rat hypothalamic neurons. The inhibitory postsynaptic currents (IPSCs), tonic currents, and the GABA-evoked currents were recorded with whole-cell patch techniques on the hypothalamic slices from Sprague-Dawley rats at 15-26 postnatal days. The amplitude and frequency of spontaneous GABA IPSCs were significantly increased while the external pH was changed from 7.3 to 8.4. In the acidic pH (6.4), the spontaneous GABA IPSCs were reduced in amplitude and frequency. The pH induced changes in miniature GABA IPSCs (mIPSCs) similar to that in spontaneous IPSCs. The pH effect on the postsynaptic GABA receptors was assessed with exogenously applied varying concentrations of GABA. The tonic currents and the currents evoked by sub-saturating concentration of GABA ([GABA]) (10 μM) were inhibited by acidic pH and potentiated by alkaline pH. In contrast, the currents evoked by saturating [GABA] (1mM) were not affected by pH changes. We also investigated the influence of pH buffers and buffering capacity on pH sensitivity of GABAA receptors on human recombinant α1β2γ2 GABAA receptors stably expressed in HEK 293 cells. The pH influence on GABAA receptors was similar in HEPES- and MES-buffered media, and not dependent on protonated buffers, suggesting that the observed pH effect on GABA response is a specific consequence of changes in extracellular protons. Our data suggest that the hydrogen ions suppress the GABAergic neurotransmission, which is mediated by both presynaptic and postsynaptic mechanisms. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

General, kappa, delta and mu opioid receptor antagonists mediate feeding elicited by the GABA-B agonist baclofen in the ventral tegmental area and nucleus accumbens shell in rats: reciprocal and regional interactions.

PubMed

Miner, Patricia; Shimonova, Lyudmila; Khaimov, Arthur; Borukhova, Yaffa; Ilyayeva, Ester; Ranaldi, Robert; Bodnar, Richard J

2012-03-14

Food intake is significantly increased following administration of agonists of GABA and opioid receptors into the nucleus accumbens shell (NACs) and ventral tegmental area (VTA). GABA-A or GABA-B receptor antagonist pretreatment within the VTA or NACs differentially affects mu-opioid agonist-induced feeding elicited from the same site. Correspondingly, general or selective opioid receptor antagonist pretreatment within the VTA or NACs differentially affects GABA agonist-induced feeding elicited from the same site. Regional interactions have been evaluated in feeding studies by administering antagonists in one site prior to agonist administration in a second site. Thus, opioid antagonist-opioid agonist and GABA antagonist-GABA agonist feeding interactions have been identified between the VTA and NACs. However, pretreatment with GABA-A or GABA-B receptor antagonists in the VTA failed to affect mu opioid agonist-induced feeding elicited from the NACs, and correspondingly, these antagonists administered in the NACs failed to affect mu opioid-induced feeding elicited from the VTA. To evaluate whether regional and reciprocal VTA and NACs feeding interactions occur for opioid receptor modulation of GABA agonist-mediated feeding, the present study examined whether feeding elicited by the GABA-B agonist, baclofen microinjected into the NACs was dose-dependently blocked by pretreatment with general (naltrexone: NTX), mu (beta-funaltrexamine: BFNA), kappa (nor-binaltorphamine: NBNI) or delta (naltrindole: NTI) opioid antagonists in the VTA, and correspondingly, whether VTA baclofen-induced feeding was dose-dependently blocked by NACs pretreatment with NTX, BFNA, NBNI or NTI in rats. Bilateral pairs of cannulae aimed at the VTA and NACs were stereotaxically implanted in rats, and their food intakes were assessed following vehicle and baclofen (200 ng) in each site. Baclofen produced similar magnitudes of increased food intake following VTA and NACs treatment. Baclofen administration in the VTA or NACs was also preceded by administration of NTX (0.1, 1, 5 μg, 0.5 h), BFNA (0.4, 4 μg, 24 h), NBNI (0.6, 6 μg, 0.5 h) or NTI (0.4, 4 μg, 0.5 h) into the other site with intake measured 1, 2 and 4 h after agonist treatment. VTA NTX significantly reduced NACs baclofen-induced feeding. Correspondingly, NACs NTX significantly reduced VTA baclofen-induced feeding, indicating a robust and bidirectional general opioid and GABA-B receptor feeding interaction. Whereas the high, but not low VTA BFNA dose reduced NACs baclofen-induced feeding, NACs BFNA failed to affect VTA baclofen-induced feeding, indicating a unidirectional mu opioid and GABA-B receptor feeding interaction. Whereas VTA NBNI at both doses reduced NACs baclofen-induced feeding, the high, but not low NACs NBNI dose significantly reduced VTA baclofen-induced feeding, indicating a bidirectional kappa opioid and GABA-B receptor feeding interaction. Whereas VTA NTI only transiently reduced NACs baclofen-induced feeding, NACs NTI failed to affect VTA baclofen-induced feeding, indicating a weak unidirectional delta opioid and GABA-B receptor interaction. Whereas administration of NTX or BFNA into the NACs or VTA marginally reduced spontaneous food intake, NBNI or NTI into the same sites failed to alter food intake alone. Therefore, the present study suggests that GABA employs a distributed brain network in mediating its ingestive effects that is dependent upon intact opioid receptor signaling with kappa opioid receptors more involved than mu and delta opioid receptors underlying these regional effects. An alternative hypothesis to be considered is that these effects could be the sum of two independent drug effects (opioid antagonists decreasing and baclofen increasing food intake). Copyright © 2012 Elsevier B.V. All rights reserved.

[Single and combining effects of Calculus Bovis and zolpidem on inhibitive neurotransmitter of rat striatum corpora].

PubMed

Liu, Ping; He, Xinrong; Guo, Mei

2010-04-01

To investigate the correlation effects between single or combined administration of Calculus Bovis or zolpidem and changes of inhibitive neurotransmitter in rat striatum corpora. Sampling from rat striatum corpora was carried out through microdialysis. The content of two inhibitive neurotransmitters in rat corpus striatum- glycine (Gly) and gama aminobutyric acid (GABA), was determined by HPLC, which involved pre-column derivation with orthophthaladehyde, reversed-phase gradient elution and fluorescence detection. GABA content of rat striatum corpora in Calculus Bovis group was significantly increased compared with saline group (P < 0.01). GABA content of zolpidem group and Calculus Boris plus zolpidem group were increased largely compared with saline group as well (P < 0.05). GABA content of Calculus Bovis group was higher than combination group (P < 0.05). GABA content of zolpidem group was not significantly different from combination group. Gly content of Calculus Bovis or zolpidem group was markedly increased compared with saline group or combination group (P < 0.05). Contents of two inhibitive neurotransmitters in rat striatum corpora were all significantly increased in Calculus Bovis group, zolpidem group and combination group. The magnitude of increase was lower in combination group than in Calculus Bovis group and Zolpidem group, suggesting that Calculus Bovis promoted encephalon inhibition is more powerful than zolpidem. The increase in two inhibitive neurotransmitters did not show reinforcing effect in combination group, suggesting that Calculus Bovis and zolpidem may compete the same receptors. Therefore, combination of Calculus Bovis containing drugs and zolpidem has no clinical significance. Calculus Bovis shouldn't as an aperture-opening drugs be used for resuscitation therapy.

The postnatal 5-HT1A receptor regulates adult anxiety and depression differently via multiple molecules.

PubMed

Ishikawa, Chihiro; Shiga, Takashi

2017-08-01

Serotonin (5-HT) and the 5-HT 1A receptor during development are known to modulate anxiety and depression in later life. However, the brain mechanisms linking the postnatal 5-HT system and adult behavior remain unknown. Here, we examined the effects of pharmacological 5-HT 1A receptor activation during the postnatal period on anxiety and depression-like behavior in adult BALB/c male mice. To elucidate the underlying mechanisms, we measured mRNA expression of the 5-HT 1A receptor, brain-derived neurotrophic factor (BDNF), GABA A receptor subunits, and AMPA receptor subunits in the medial prefrontal cortex (mPFC), amygdala, and hippocampus. Treatment with the selective 5-HT reuptake inhibitor (fluoxetine) and 5-HT 1A receptor agonist (8-OH-DPAT) during the postnatal period decreased anxiety-like behavior in adulthood, whereas only 8-OH-DPAT treatment increased depression-like behavior. Concomitantly with the behavioral effects, postnatal treatment with fluoxetine and 8-OH-DPAT decreased the mRNA expression of the GABA A receptor α3 subunit in the mPFC and ventral hippocampus in adulthood, while 8-OH-DPAT, but not fluoxetine, decreased the mRNA expression of the 5-HT 1A receptor and BDNF in the mPFC and the GABA A receptor α2 subunit in the mPFC and ventral hippocampus. On the basis of the correlative changes between behavior and mRNA expression, these results suggest that the GABA A receptor α3 subunit in the mPFC and ventral hippocampus may regulate anxiety-like behavior. In contrast, depression-like behavior may be regulated by the 5-HT 1A receptor and BDNF in the mPFC and by the GABA A receptor α2 subunit in the mPFC and ventral hippocampus. In summary, activation of the 5-HT 1A receptor during the postnatal period may reduce anxiety levels, but increase depression levels during adulthood via different multiple molecules in the mPFC and ventral hippocampus. Copyright © 2017 Elsevier Inc. All rights reserved.

The Protective Effect of γ-aminobutyric Acid on Kidney Injury Induced by Renal Ischemia-reperfusion in Ovariectomized Estradiol-treated Rats.

PubMed

Talebi, Nahid; Nematbakhsh, Mehdi; Monajemi, Ramesh; Mazaheri, Safoora; Talebi, Ardeshir; Vafapour, Marzieh

2016-01-01

Renal ischemia-reperfusion injury (IRI) is one of the most important causes of kidney injury, which is possibly gender-related. This study was designed to investigate the role of γ-aminobutyric acid (GABA) against IRI in ovariectomized estradiol-treated rats. Thirty-five ovariectomized Wistar rats were used in six experimental groups. The first three groups did not subject to estradiol treatment and assigned as sham-operated, control, and GABA-treated groups. GABA (50 μmol/kg) and saline were injected in the treated and control groups 30 min before the surgery, respectively. The second three groups received the same treatments but received estradiol valerate (500 μg/kg, intramuscularly) 3 days prior to the surgery. The IRI was induced in the control and treated groups by clamping the renal artery for 45 min and then 24 h of reperfusion. All animals were sacrificed for the measurements. The serum levels of creatinine and blood urea nitrogen, kidney weight, and kidney tissue damage score significantly increased in the IRI rats (P < 0.05). GABA significantly decreased the aforementioned parameters (P < 0.05). The uterus weight increased significantly in rats that received estradiol (P < 0.05). Serum and kidney levels of nitrite (nitric oxide metabolite) did not alter significantly. Serum level of malondialdehyde increased significantly in the ovariectomized rats exposed to IRI (P < 0.05). It seems that GABA improved IRI in ovariectomized rats. Estradiol was also nephroprotective against IRI. However, co-administration of estradiol and GABA could not protect the kidney against IRI.

Nitrate uptake and utilization is modulated by exogenous gamma-aminobutyric acid in Arabidopsis thaliana seedlings.

PubMed

Barbosa, Jose M; Singh, Narendra K; Cherry, Joe H; Locy, Robert D

2010-06-01

Exogenously applied GABA modulates root growth by inhibition of root elongation when seedlings were grown in vitro on full-strength Murashige and Skoog (MS) salts, but root elongation was stimulated when seedlings were grown on 1/8 strength MS salts. When the concentration of single ions in MS salts was individually varied, the control of growth between inhibition and stimulation was found to be related to the level of nitrate (NO(3)(-)) in the growth medium. At NO(3)(-) concentrations below 40 mM (full-strength MS salts level), root growth was stimulated by the addition of GABA to the growth medium; whereas at concentrations above 40 mM NO(3)(-), the addition of GABA to the growth medium inhibited root elongation. GABA promoted NO(3)(-) uptake at low NO(3)(-), while GABA inhibited NO(3)(-) uptake at high NO(3)(-). Activities of several enzymes involved in nitrogen and carbon metabolism including nitrate reductase (NR), glutamine synthetase (GS), glutamate synthase (NADH-GOGAT), NADP-dependent isocitrate dehydrogenase (NADP-ICDH), and phosphoenol pyruvate carboxylase (PEPCase) were regulated by GABA in the growth medium. Supplementing 1/8 strength MS medium with 50 mM GABA enhanced the activities of all of the above enzymes except ICDH activities in root tissues. However, at full-strength MS, GABA showed no inhibitory effect on the activities of these enzymes, except on GS in both root and shoot tissues, and PEPCase activity in shoot tissues. Exogenous GABA increased the amount of NR protein rather than its activation status in the tissues. This study shows that GABA affects the growth of Arabidopsis, possibly by acting as a signaling molecule, modulating the activity of enzymes involved in primary nitrogen metabolism and nitrate uptake.

Individual Differences in Resting Corticospinal Excitability Are Correlated with Reaction Time and GABA Content in Motor Cortex

PubMed Central

Ivry, Richard B.

2017-01-01

Individuals differ in the intrinsic excitability of their corticospinal pathways and, perhaps more generally, their entire nervous system. At present, we have little understanding of the mechanisms underlying these differences and how variation in intrinsic excitability relates to behavior. Here, we examined the relationship between individual differences in intrinsic corticospinal excitability, local cortical GABA levels, and reaction time (RT) in a group of 20 healthy human adults. We measured corticospinal excitability at rest with transcranial magnetic stimulation, local concentrations of basal GABA with magnetic resonance spectroscopy, and RT with a behavioral task. All measurements were repeated in two separate sessions, and tests of reliability confirmed the presence of stable individual differences. There was a negative correlation between corticospinal excitability and RT, such that larger motor-evoked potentials (MEPs) measured at rest were associated with faster RTs. Interestingly, larger MEPs were associated with higher levels of GABA in M1, but not in three other cortical regions. Together, these results suggest that individuals with more excitable corticospinal pathways are faster to initiate planned responses and have higher levels of GABA within M1, possibly to compensate for a more excitable motor system. SIGNIFICANCE STATEMENT This study brings together physiological, behavioral, and neurochemical evidence to examine variability in the excitability of the human motor system. Previous work has focused on state-based factors (e.g., preparedness, uncertainty), with little attention given to the influence of inherent stable characteristics. Here, we examined how the excitability of the motor system relates to reaction time and the regional content of the inhibitory neurotransmitter GABA. Importantly, motor pathway excitability and GABA concentrations were measured at rest, outside a task context, providing assays of intrinsic properties of the individuals. Individuals with more excitable motor pathways had faster reaction times and, paradoxically, higher concentrations of GABA. We propose that greater GABA capacity in the motor cortex counteracts an intrinsically more excitable motor system. PMID:28179557

Altered Cortical GABA in Female Veterans with Suicidal Behavior: Sex Differences and Clinical Correlates.

PubMed

Prescot, Andrew; Sheth, Chandni; Legarreta, Margaret; Renshaw, Perry F; McGlade, Erin; Yurgelun-Todd, Deborah

2018-01-01

Suicide is a public health concern in the civilian and veteran populations. Stressful life events are precipitating factors for suicide. The neurochemical underpinnings of the association between stress/trauma and suicide risk are unclear, especially in regards to sex differences. We hypothesized that gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter may be a neurochemical candidate that is critical in the association between stress and suicide risk in veterans. Proton magnetic resonance spectroscopy ( 1 H MRS) at 3.0 Tesla was used to measure in vivo neurochemistry in the anterior cingulate cortex (ACC; predominantly the dorsal ACC) of 81 veterans (16 females), including 57 (11 females) who endorsed past suicidal ideation (SI) and/or suicide attempt (SA) and 24 (5 females) with no history of SI and/or SA. Suicidal behavior (SB) was defined as the presence of SI and/or SA. We observed no significant differences in GABA/ Creatine+phosphocreatine (Cr+PCr) between veterans with SB (SB+) and without SB (SB-). However, the female SB+ group showed significantly reduced GABA/Cr+PCr vs. the female SB- group. We observed a trend-level significant negative correlation between GABA/Cr+PCr and the defensive avoidance (DA) subscale on the Trauma Symptom Inventory (TSI) in the SB+ group. In contrast, the SB- group exhibited a positive relationship between the two variables. Furthermore, we found significant negative correlations between GABA/Cr+PCr and Hamilton Rating Scale for Depression (HAM-D) scores as well as between GABA/Cr+PCr and several subscales of the TSI in female veterans. This study suggests that reduced GABA/Cr+ PCr ratio in the ACC, which may be related to altered inhibitory capacity, may underlie suicide risk in female veterans. Further, the negative association between GABA/Cr+PCr and stress symptomatology and depression scores suggests that MRS studies may shed light on intermediate phenotypes of SB.

Immunoreactivity for GABA, GAD65, GAD67 and Bestrophin-1 in the meninges and the choroid plexus: implications for non-neuronal sources for GABA in the developing mouse brain.

PubMed

Tochitani, Shiro; Kondo, Shigeaki

2013-01-01

Neural progenitors in the developing neocortex, neuroepithelial cells and radial glial cells, have a bipolar shape with a basal process contacting the basal membrane of the meninge and an apical plasma membrane facing the lateral ventricle, which the cerebrospinal fluid is filled with. Recent studies revealed that the meninges and the cerebrospinal fluid have certain roles to regulate brain development. γ-aminobutyric acid (GABA) is a neurotransmitter which appears first during development and works as a diffusible factor to regulate the properties of neural progenitors. In this study, we examined whether GABA can be released from the meninges and the choroid plexus in the developing mouse brain. Immunohistochemical analyses showed that glutamic acid decarboxylase 65 and 67 (GAD65 and GAD67), both of which are GABA-synthesizing enzymes, are expressed in the meninges. The epithelial cells in the choroid plexus express GAD65. GABA immunoreactivity could be observed beneath the basal membrane of the meninge and in the epithelial cells of the choroid plexus. Expression analyses on Bestrophin-1, which is known as a GABA-permeable channel in differentiated glial cells, suggested that the cells in the meninges and the epithelial cells in the choroid plexus have the channels able to permeate non-synaptic GABA into the extracellular space. Further studies showed that GAD65/67-expressing meningeal cells appear in a manner with rostral to caudal and lateral to dorsal gradient to cover the entire neocortex by E14.5 during development, while the cells in the choroid plexus in the lateral ventricle start to express GAD65 on E11-E12, the time when the choroid plexus starts to develop in the developing brain. These results totally suggest that the meninges and the choroid plexus can work as non-neuronal sources for ambient GABA which can modulate the properties of neural progenitors during neocortical development.

Immunoreactivity for GABA, GAD65, GAD67 and Bestrophin-1 in the Meninges and the Choroid Plexus: Implications for Non-Neuronal Sources for GABA in the Developing Mouse Brain

PubMed Central

Tochitani, Shiro; Kondo, Shigeaki

2013-01-01

Neural progenitors in the developing neocortex, neuroepithelial cells and radial glial cells, have a bipolar shape with a basal process contacting the basal membrane of the meninge and an apical plasma membrane facing the lateral ventricle, which the cerebrospinal fluid is filled with. Recent studies revealed that the meninges and the cerebrospinal fluid have certain roles to regulate brain development. γ-aminobutyric acid (GABA) is a neurotransmitter which appears first during development and works as a diffusible factor to regulate the properties of neural progenitors. In this study, we examined whether GABA can be released from the meninges and the choroid plexus in the developing mouse brain. Immunohistochemical analyses showed that glutamic acid decarboxylase 65 and 67 (GAD65 and GAD67), both of which are GABA-synthesizing enzymes, are expressed in the meninges. The epithelial cells in the choroid plexus express GAD65. GABA immunoreactivity could be observed beneath the basal membrane of the meninge and in the epithelial cells of the choroid plexus. Expression analyses on Bestrophin-1, which is known as a GABA-permeable channel in differentiated glial cells, suggested that the cells in the meninges and the epithelial cells in the choroid plexus have the channels able to permeate non-synaptic GABA into the extracellular space. Further studies showed that GAD65/67-expressing meningeal cells appear in a manner with rostral to caudal and lateral to dorsal gradient to cover the entire neocortex by E14.5 during development, while the cells in the choroid plexus in the lateral ventricle start to express GAD65 on E11–E12, the time when the choroid plexus starts to develop in the developing brain. These results totally suggest that the meninges and the choroid plexus can work as non-neuronal sources for ambient GABA which can modulate the properties of neural progenitors during neocortical development. PMID:23437266

Hap1 and GABA: thinking about food intake.

PubMed

Woods, Stephen C; Seeley, Randy J

2006-06-01

GABA stimulation of hypothalamic GABAA receptors increases food intake and body weight. Huntingtin-associated protein-1 (Hap1), is highly expressed in the hypothalamus and increases activity at GABAA receptors; mice lacking Hap1 are hypophagic. A recent paper (Sheng et al.,2006) further explores the role of Hap1 in the control of food intake.

GABA-BZD Receptor Modulating Mechanism of Panax quinquefolius against 72-h Sleep Deprivation Induced Anxiety like Behavior: Possible Roles of Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation

PubMed Central

Chanana, Priyanka; Kumar, Anil

2016-01-01

Rationale: Panax quinquefolius (American Ginseng) is known for its therapeutic potential against various neurological disorders, but its plausible mechanism of action still remains undeciphered. GABA (Gamma Amino Butyric Acid) plays an important role in sleep wake cycle homeostasis. Thus, there exists rationale in exploring the GABA-ergic potential of Panax quinquefolius as neuroprotective strategy in sleep deprivation induced secondary neurological problems. Objective: The present study was designed to explore the possible GABA-ergic mechanism in the neuro-protective effect of Panax quinquefolius against 72-h sleep deprivation induced anxiety like behavior, oxidative stress, mitochondrial dysfunction, HPA-axis activation and neuroinflammation. Materials and Methods: Male laca mice were sleep deprived for 72-h by using Grid suspended over water method. Panax quinquefolius (American Ginseng 50, 100, and 200 mg/kg) was administered alone and in combination with GABA modulators (GABA Cl− channel inhibitor, GABA-benzodiazepine receptor inhibitor and GABAA agonist) for 8 days, starting 5 days prior to 72-h sleep deprivation period. Various behavioral (locomotor activity, mirror chamber test), biochemical (lipid peroxidation, reduced glutathione, catalase, nitrite levels), mitochondrial complexes, neuroinflammation marker (Tumor Necrosis Factor, TNF-alpha), serum corticosterone, and histopathological sections of brains were assessed. Results: Seventy two hours sleep deprivation significantly impaired locomotor activity, caused anxiety-like behavior, conditions of oxidative stress, alterations in mitochondrial enzyme complex activities, raised serum corticosterone levels, brain TNFα levels and led to neuroinflammation like signs in discrete brain areas as compared to naive group. Panax quinquefolius (100 and 200 mg/kg) treatment restored the behavioral, biochemical, mitochondrial, molecular and histopathological alterations. Pre-treatment of GABA Cl− channel inhibitor as well as GABA-benzodiazepine receptor inhibitor, significantly reversed the protective effect of P. quinquefolius (100 mg/kg) in 72-h sleep deprived animals (P < 0.05). However, pretreatment with GABAA agonist, potentiated Panax quinquefolius's protective effect which was significant as compared to their effect per se (p < 0.05). Conclusion: GABA-ergic mechanism could be involved in the neuroprotective effect of P.quinquefolius against sleep deprivation induced anxiety-like behavior, oxidative stress, mitochondrial dysfunction, HPA axis activation and neuroinflammation. PMID:27013946

K+ channel TASK-1 knockout mice show enhanced sensitivities to ataxic and hypnotic effects of GABA(A) receptor ligands.

PubMed

Linden, Anni-Maija; Aller, M Isabel; Leppä, Elli; Rosenberg, Per H; Wisden, William; Korpi, Esa R

2008-10-01

TASK two-pore-domain leak K(+) channels occur throughout the brain. However, TASK-1 and TASK-3 knockout (KO) mice have few neurological impairments and only mildly reduced sensitivities to inhalational anesthetics, contrasting with the anticipated functions and importance of these channels. TASK-1/-3 channel expression can compensate for the absence of GABA(A) receptors in GABA(A) alpha6 KO mice. To investigate the converse, we analyzed the behavior of TASK-1 and -3 KO mice after administering drugs with preferential efficacies at GABA(A) receptor subtypes: benzodiazepines (diazepam and flurazepam, active at alpha1betagamma2, alpha2betagamma2, alpha3betagamma2, and alpha5betagamma2 subtypes), zolpidem (alpha1betagamma2 subtype), propofol (beta2-3-containing receptors), gaboxadol (alpha4betadelta and alpha6betadelta subtypes), pregnanolone, and pentobarbital (many subtypes). TASK-1 KO mice showed increased motor impairment in rotarod and beam-walking tests after diazepam and flurazepam administration but not after zolpidem. They also showed prolonged loss of righting reflex induced by propofol and pentobarbital. Autoradiography indicated no change in GABA(A) receptor ligand binding levels. These altered behavioral responses to GABAergic drugs suggest functional up-regulation of alpha2beta2/3gamma2 and alpha3beta2/3gamma2 receptor subtypes in TASK-1 KO mice. In addition, female, but not male, TASK-1 KO mice were more sensitive to gaboxadol, suggesting an increased influence of alpha4betadelta or alpha6betadelta subtypes. The benzodiazepine sensitivity of TASK-3 KO mice was marginally increased. Our results underline that TASK-1 channels perform such key functions in the brain that compensation is needed for their absence. Furthermore, because inhalation anesthetics act partially through GABA(A) receptors, the up-regulation of GABA(A) receptor function in TASK-1 KO mice might mask TASK-1 channel's significance as a target for inhalation anesthetics.

Selective activation of group III metabotropic glutamate receptor subtypes produces different patterns of γ-aminobutyric acid immunoreactivity and glutamate release in the retina.

PubMed

Guimarães-Souza, E M; Calaza, K C

2012-12-01

Glutamate, the major excitatory neurotransmitter in the retina, functions by activation of both ionotropic (iGluR) and metabotropic (mGluR) glutamate receptors. Group III mGluRs, except for mGluR6, are mostly found in the inner plexiform layer (IPL), and their retinal functions are not well known. Therefore, we decided to investigate the effect of mGluRIII on glutamate release and GABAergic amacrine cells in the chick retina. The nonselective mGluRIII agonist L-SOP promoted a decrease in the number of γ-aminobutyric acid (GABA)-positive cells and in the GABA immunoreactivity in all sublayers of the IPL. This effect was prevented by the antagonist MAP-4, by GAT-1 inhibitor, and by antagonists of iGluR. Under the conditions used, L-SOP did not alter endogenous glutamate release. VU0155041, an mGluR4-positive allosteric modulator, reduced GABA immunoreactivity in amacrine cells and in sublayers 2 and 4 of the IPL but evoked an increase in the glutamate released. VU0155041's effect was inhibited by the absence of calcium. AMN082, a selective mGluR7-positive allosteric modulator, also decreased GABA immunoreactivity in amacrine cells and sublayers 1, 2, and 3 and increased glutamate release, and this effect was also inhibited by calcium absence. DCPG, an mGluR8-selective agonist, did not significantly alter GABA immunoreactivity in amacrine cells or glutamate release. However, it did significantly increase GABA immunoreactivity in sublayers 4 and 5. The results suggest that mGluRIIIs are involved in the modulation of glutamate and GABA release in the retina, possibly participating in distinct visual pathways: mGluR4 might be involved with cholinergic circuitry, whereas mGluR7 and mGluR8 might participate, respectively, in the OFF and the ON pathways. Copyright © 2012 Wiley Periodicals, Inc.

GABAA receptor positive allosteric modulators modify the abuse-related behavioral and neurochemical effects of methamphetamine in rhesus monkeys.

PubMed

Berro, Laís F; Andersen, Monica L; Tufik, Sergio; Howell, Leonard L

2017-09-01

GABA A receptor positive allosteric modulators (GABA A receptor modulators) are commonly used for the treatment of insomnia. Nevertheless, the effects of these compounds on psychostimulant-induced sleep impairment are poorly understood. Because GABA A receptor modulators have been shown to decrease the abuse-related effects of psychostimulants, the aim of the present study was to evaluate the effects of temazepam (0.3, 1.0 or 3.0 mg/kg) and eszopiclone (0.3, 1.0 or 3.0 mg/kg), two GABA A receptor modulators, on the behavioral neuropharmacology of methamphetamine in adult rhesus macaques (n = 5). Sleep-like measures and general daytime activity were evaluated with Actiwatch monitors. Methamphetamine self-administration (0.03 mg/kg/inf) was evaluated during morning sessions. Methamphetamine-induced dopamine overflow was assessed through in vivo microdialysis targeting the nucleus accumbens. Nighttime treatment with either temazepam or eszopiclone was ineffective in improving sleep-like measures disrupted by methamphetamine self-administration. Acute pretreatment with a low dose of temazepam before self-administration sessions increased methamphetamine self-administration without affecting normal daytime home-cage activity. At a high dose, acute temazepam pretreatment decreased methamphetamine self-administration and attenuated methamphetamine-induced increases in dopamine in the nucleus accumbens, without decreasing general daytime activity. Acute eszopiclone treatment exerted no effects on methamphetamine intake or drug-induced increases in dopamine. Our study suggests that treatments based on GABA A receptor modulators are not effective for the treatment of sleep disruption in the context of psychostimulant use. In addition, distinct GABA A receptor modulators differentially modulated the abuse-related effects of methamphetamine, with acute treatment with the high efficacy GABA A receptor modulator temazepam decreasing the behavioral and neurochemical effects of methamphetamine. Copyright © 2017 Elsevier Ltd. All rights reserved.

Testing the excitation/inhibition imbalance hypothesis in a mouse model of the autism spectrum disorder: in vivo neurospectroscopy and molecular evidence for regional phenotypes.

PubMed

Gonçalves, Joana; Violante, Inês R; Sereno, José; Leitão, Ricardo A; Cai, Ying; Abrunhosa, Antero; Silva, Ana Paula; Silva, Alcino J; Castelo-Branco, Miguel

2017-01-01

Excitation/inhibition (E/I) imbalance remains a widely discussed hypothesis in autism spectrum disorders (ASD). The presence of such an imbalance may potentially define a therapeutic target for the treatment of cognitive disabilities related to this pathology. Consequently, the study of monogenic disorders related to autism, such as neurofibromatosis type 1 (NF1), represents a promising approach to isolate mechanisms underlying ASD-related cognitive disabilities. However, the NF1 mouse model showed increased γ-aminobutyric acid (GABA) neurotransmission, whereas the human disease showed reduced cortical GABA levels. It is therefore important to clarify whether the E/I imbalance hypothesis holds true. We hypothesize that E/I may depend on distinct pre- and postsynaptic push-pull mechanisms that might be are region-dependent. In current study, we assessed two critical components of E/I regulation: the concentration of neurotransmitters and levels of GABA(A) receptors. Measurements were performed across the hippocampi, striatum, and prefrontal cortices by combined in vivo magnetic resonance spectroscopy (MRS) and molecular approaches in this ASD-related animal model, the Nf1 +/- mouse. Cortical and striatal GABA/glutamate ratios were increased. At the postsynaptic level, very high receptor GABA(A) receptor expression was found in hippocampus, disproportionately to the small reduction in GABA levels. Gabaergic tone (either by receptor levels change or GABA/glutamate ratios) seemed therefore to be enhanced in all regions, although by a different mechanism. Our data provides support for the hypothesis of E/I imbalance in NF1 while showing that pre- and postsynaptic changes are region-specific. All these findings are consistent with our previous physiological evidence of increased inhibitory tone. Such heterogeneity suggests that therapeutic approaches to address neurochemical imbalance in ASD may need to focus on targets where convergent physiological mechanisms can be found.

Activation of postsynaptic GABAB receptors modulates the bursting pattern and synaptic activity of olfactory bulb juxtaglomerular neurons.

PubMed

Karpuk, Nikolay; Hayar, Abdallah

2008-01-01

Olfactory bulb glomeruli are formed by a network of three major types of neurons collectively called juxtaglomerular (JG) cells, which include external tufted (ET), periglomerular (PG), and short axon (SA) cells. There is solid evidence that gamma-aminobutyric acid (GABA) released from PG neurons presynaptically inhibits glutamate release from olfactory nerve terminals via activation of GABA(B) receptors (GABA(B)-Rs). However, it is still unclear whether ET cells have GABA(B)-Rs. We have investigated whether ET cells have functional postsynaptic GABA(B)-Rs using extracellular and whole cell recordings in olfactory bulb slices. In the presence of fast synaptic blockers (CNQX, APV, and gabazine), the GABA(B)-R agonist baclofen either completely inhibited the bursting or reduced the bursting frequency and increased the burst duration and the number of spikes/burst in ET cells. In the presence of fast synaptic blockers and tetrodotoxin, baclofen induced an outward current in ET cells, suggesting a direct postsynaptic effect. Baclofen reduced the frequency and amplitude of spontaneous EPSCs in PG and SA cells. In the presence of sodium and potassium channel blockers, baclofen reduced the frequency of miniature EPSCs, which were inhibited by the calcium channel blocker cadmium. All baclofen effects were reversed by application of the GABA(B)-R antagonist CGP55845. We suggest that activation of GABA(B)-Rs directly inhibits ET cell bursting and decreases excitatory dendrodendritic transmission from ET to PG and SA cells. Thus the postsynaptic GABA(B)-Rs on ET cells may play an important role in shaping the activation pattern of the glomeruli during olfactory coding.

Endogenous concentrations, pharmacokinetics, and selected pharmacodynamic effects of a single dose of exogenous GABA in horses.

PubMed

Knych, H K; Steinmetz, S J; McKemie, D S

2015-04-01

The anti-anxiety and calming effects following activation of the GABA receptor have been exploited in performance horses by administering products containing GABA. The primary goal of the study reported here was to describe endogenous concentrations of GABA in horses and the pharmacokinetics, selected pharmacodynamic effects, and CSF concentrations following administration of a GABA-containing product. The mean (±SD) endogenous GABA level was 36.4 ± 12.5 ng/mL (n = 147). Sixteen of these horses received a single intravenous and oral dose of GABA (1650 mg). Blood, urine, and cerebrospinal fluid (n = 2) samples were collected at time 0 and at various times for up to 48 h and analyzed using LC-MS. Plasma clearance and volume of distribution was 155.6 and 147.6 L/h and 0.154 and 7.39 L for the central and peripheral compartments, respectively. Terminal elimination half-life was 22.1 (intravenous) and 25.1 (oral) min. Oral bioavailability was 9.81%. Urine GABA concentrations peaked rapidly returning to baseline levels by 3 h. Horses appeared behaviorally unaffected following oral administration, while sedative-like changes following intravenous administration were transient. Heart rate was increased for 1 h postintravenous administration, and gastrointestinal sounds decreased for approximately 30 min following both intravenous and oral administration. Based on a limited number of horses and time points, exogenously administered GABA does not appear to enter the CSF to an appreciable extent. © 2014 John Wiley & Sons Ltd.

Central pipecolic acid increases food intake under ad libitum feeding conditions in the neonatal chick.

PubMed

Takagi, Tomo; Tachibana, Tetsuya; Saito, Ei-Suke; Tomonaga, Shouzou; Saito, Shin; Bungo, Takashi; Denbow, D Michael; Furuse, Mitsuhiro

2003-08-21

It has been demonstrated that L-pipecolic acid (L-PA) is a major metabolic intermediate of L-lysine in the mammalian and chicken brain. A previous study showed that intracerebroventricular (i.c.v.) injection of L-PA suppressed feeding in neonatal chicks, and the actions were associated with gamma-aminobutyric acid (GABA)-B receptor activation. It has been reported that endogenous L-PA in the brain fluctuated under different feeding conditions. In the present study, we investigated the effect of i.c.v. injection of L-PA on food intake in the neonatal chick under ad libitum feeding conditions. The food intake was increased by 0.5 or 1.0 mg L-PA under ad libitum feeding conditions contrary to previous studies using fasted birds. A hyperphagic effect of L-PA (0.5 mg) was attenuated by both GABA-A receptor antagonist (picrotoxin, 0.5 microg) and GABA-B receptor antagonist (CGP54626, 21.0 ng). These results indicate that a hyperphagic effect of L-PA is mediated by both GABA-A and GABA-B receptors and L-PA differentially affects food intake under different feeding conditions in the neonatal chick.

GABA/benzodiazepine receptor complex in long-sleep and short-sleep mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marley, R.J.

LS mice are more sensitive to benzodiazepine-induced anesthesia; however, the two lines do not differ in their hypothermic response to flurazepam. SS mice are more resistant to 3-mercaptopropionic acid-induced seizures and more sensitive to the anticonvulsant effects of benzodiazepines. The various correlates of GABA and benzodiazepine actions probably are the results of different mechanisms of action and/or differential regional control. Bicuculline competition for /sup 3/H-GABA binding sites is greater in SS cerebellar tissue and /sup 3/H-flunitrazepam binding is greater in the mid-brain region of LS mice. GABA enhancement of /sup 3/H-flunitrazepma binding is greater in SS mice. Ethanol also enhancesmore » /sup 3/H-flunitrazepam binding and increases the levels of /sup 3/H-flunitrazepam binding above those observed for GABA. Using correlational techniques on data from LS and SS mice and several inbred mouse strains, it was demonstrated that a positive relationship exists between the degree of receptor coupling within the GABA receptor complex and the degree of resistance to seizures.« less

GABA and glutamate immunoreactivity in tentacles of the sea anemone Phymactis papillosa (LESSON 1830).

PubMed

Delgado, Luz M; Couve, Eduardo; Schmachtenberg, Oliver

2010-07-01

Sea anemones have a structurally simple nervous system that controls behaviors like feeding, locomotion, aggression, and defense. Specific chemical and tactile stimuli are transduced by ectodermal sensory cells and transmitted via a neural network to cnidocytes and epithelio-muscular cells, but the nature of the neurotransmitters operating in these processes is still under discussion. Previous studies demonstrated an important role of peptidergic transmission in cnidarians, but during the last decade the contribution of conventional neurotransmitters became increasingly evident. Here, we used immunohistochemistry on light and electron microscopical preparations to investigate the localization of glutamate and GABA in tentacle cross-sections of the sea anemone Phymactis papillosa. Our results demonstrate strong glutamate immunoreactivity in the nerve plexus, while GABA labeling was most prominent in the underlying epithelio-muscular layer. Immunoreactivity for both molecules was also found in glandular epithelial cells, and putative sensory cells were GABA positive. Under electron microscopy, both glutamate and GABA immunogold labeling was found in putative neural processes within the neural plexus. These data support a function of glutamate and GABA as signaling molecules in the nervous system of sea anemones.

Structure and functional interaction of the extracellular domain of human GABA[subscript B] receptor GBR2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Geng, Yong; Xiong, Dazhi; Mosyak, Lidia

2012-10-24

Inhibitory neurotransmission is mediated primarily by GABA. The metabotropic GABA{sub B} receptor is a G protein-coupled receptor central to mammalian brain function. Malfunction of GABA{sub B} receptor has been implicated in several neurological disorders. GABA{sub B} receptor functions as a heterodimeric assembly of GBR1 and GBR2 subunits, where GBR1 is responsible for ligand-binding and GBR2 is responsible for G protein coupling. Here we demonstrate that the GBR2 ectodomain directly interacts with the GBR1 ectodomain to increase agonist affinity by selectively stabilizing the agonist-bound conformation of GBR1. We present the crystal structure of the GBR2 ectodomain, which reveals a polar heterodimericmore » interface. We also identify specific heterodimer contacts from both subunits, and GBR1 residues involved in ligand recognition. Lastly, our structural and functional data indicate that the GBR2 ectodomain adopts a constitutively open conformation, suggesting a structural asymmetry in the active state of GABA{sub B} receptor that is unique to the GABAergic system.« less

Time dependent effects of haloperidol on glutamine and GABA homeostasis and astrocyte activity in the rat brain

PubMed Central

Konopaske, Glenn T.; Bolo, Nicolas R.; Basu, Alo C.; Renshaw, Perry F.; Coyle, Joseph T.

2013-01-01

Rationale Schizophrenia is a severe, persistent, and fairly common mental illness. Haloperidol is widely used and is effective against the symptoms of psychosis seen in schizophrenia. Chronic oral haloperidol administration decreased the number of astrocytes in the parietal cortex of macaque monkeys (Konopaske et al. Biol Psych, 2008). Since astrocytes play a key role in glutamate metabolism, chronic haloperidol administration was hypothesized to modulate astrocyte metabolic function and glutamate homeostasis. Objectives This study investigated the effects of chronic haloperidol administration on astrocyte metabolic activity and glutamate, glutamine, and GABA homeostasis. Methods We used ex vivo 13C magnetic resonance spectroscopy along with high performance liquid chromatography after [1-13C]glucose and [1,2-13C]acetate administration to analyze forebrain tissue from rats administered oral haloperidol for 1 or 6 months. Results Administration of haloperidol for 1 month produced no changes in 13C labeling of glutamate, glutamine, or GABA, or in their total levels. However, a 6 month haloperidol administration increased 13C labeling of glutamine by [1,2-13C]acetate. Moreover, total GABA levels were also increased. Haloperidol administration also increased the acetate/glucose utilization ratio for glutamine in the 6 month cohort. Conclusions Chronic haloperidol administration in rats appears to increase forebrain GABA production along with astrocyte metabolic activity. Studies exploring these processes in subjects with schizophrenia should take into account the potential confounding effects of antipsychotic medication treatment. PMID:23660600

Ethanol increases GABAergic transmission at both pre- and postsynaptic sites in rat central amygdala neurons

PubMed Central

Roberto, Marisa; Madamba, Samuel G.; Moore, Scott D.; Tallent, Melanie K.; Siggins, George R.

2003-01-01

We examined the interaction of ethanol with the γ-aminobutyric acid (GABA)ergic system in neurons of slices of the rat central amygdala nucleus (CeA), a brain region thought to be critical for the reinforcing effects of ethanol. Brief superfusion of 11–66 mM ethanol significantly increased GABA type A (GABAA) receptor-mediated inhibitory postsynaptic potentials (IPSPs) and currents (IPSCs) in most CeA neurons, with a low apparent EC50 of 20 mM. Acute superfusion of 44 mM ethanol increased the amplitude of evoked GABAA IPSPs and IPSCs in 70% of CeA neurons. The ethanol enhancement of IPSPs and IPSCs occurred to a similar extent in the presence of the GABA type B (GABAB) receptor antagonist CGP 55845A, suggesting that this receptor is not involved in the ethanol effect on CeA neurons. Ethanol superfusion also decreased paired-pulse facilitation of evoked GABAA IPSPs and IPSCs and always increased the frequency and sometimes the amplitude of spontaneous miniature GABAA IPSCs as well as responses to local GABA application, indicating both presynaptic and postsynaptic sites of action for ethanol. Thus, the CeA is the first brain region to reveal, without conditional treatments such as GABAB antagonists, consistent, low-dose ethanol enhancement of GABAergic transmission at both pre- and postsynaptic sites. These findings add further support to the contention that the ethanol–GABA interaction in CeA plays an important role in the reinforcing effects of ethanol. PMID:12566570

Developmental excitatory-to-inhibitory GABA polarity switch is delayed in Ts65Dn mice, a genetic model of Down syndrome.

PubMed

Lysenko, Larisa V; Kim, Jeesun; Madamba, Francisco; Tyrtyshnaia, Anna A; Ruparelia, Aarti; Kleschevnikov, Alexander M

2018-07-01

Down syndrome (DS) is the most frequent genetic cause of developmental abnormalities leading to intellectual disability. One notable phenomenon affecting the formation of nascent neural circuits during late developmental periods is developmental switch of GABA action from depolarizing to hyperpolarizing mode. We examined properties of this switch in DS using primary cultures and acute hippocampal slices from Ts65Dn mice, a genetic model of DS. Cultures of DIV3-DIV13 Ts65Dn and control normosomic (2 N) neurons were loaded with FURA-2 AM, and GABA action was assessed using local applications. In 2 N cultures, the number of GABA-activated cells dropped from ~100% to 20% between postnatal days 3-13 (P3-P13) reflecting the switch in GABA action polarity. In Ts65Dn cultures, the timing of this switch was delayed by 2-3 days. Next, microelectrode recordings of multi-unit activity (MUA) were performed in CA3 slices during bath application of the GABA A agonist isoguvacine. MUA frequency was increased in P8-P12 and reduced in P14-P22 slices reflecting the switch of GABA action from excitatory to inhibitory mode. The timing of this switch was delayed in Ts65Dn by approximately 2 days. Finally, frequency of giant depolarizing potentials (GDPs), a form of primordial neural activity, was significantly increased in slices from Ts65Dn pups at P12 and P14. These experimental evidences show that GABA action polarity switch is delayed in Ts65Dn model of DS, and that these changes lead to a delay in maturation of nascent neural circuits. These alterations may affect properties of neural circuits in adult animals and, therefore, represent a prospective target for pharmacotherapy of cognitive impairment in DS. Copyright © 2018 Elsevier Inc. All rights reserved.

The role of GABAergic system on the inhibitory effect of ghrelin on food intake in neonatal chicks.

PubMed

Jonaidi, H; Abbassi, L; Yaghoobi, M M; Kaiya, H; Denbow, D M; Kamali, Y; Shojaei, B

2012-06-27

Ghrelin is a gut-brain peptide that has a stimulatory effect on food intake in mammals. In contrast, this peptide decreases food intake in neonatal chicks when injected intracerebroventricularly (ICV). In mammals, neuropeptide Y (NPY) mediates the orexigenic effect of ghrelin whereas in chicks it appears that corticotrophin releasing factor (CRF) is partially involved in the inhibitory effect of ghrelin on food intake. Gamma aminobutyric acid (GABA) has a stimulatory effect on food intake in mammals and birds. In this study we investigated whether the anorectic effect of ghrelin is mediated by the GABAergic system. In Experiment 1, 3h-fasted chicks were given an ICV injection of chicken ghrelin and picrotoxin, a GABA(A) receptors antagonist. Picrotoxin decreased food intake compared to the control chicks indicating a stimulatory effect of GABA(A) receptors on food intake. However, picrotoxin did not alter the inhibitory effect of ghrelin on food intake. In Experiment 2, THIP hydrochloride, a GABA(A) receptor agonist, was used in place of picrotoxin. THIP hydrochloride appeared to partially attenuate the decrease in food intake induced by ghrelin at 30 min postinjection. In Experiment 3, the effect of ICV injection of chicken ghrelin on gene expression of glutamate decarboxylase (GAD)(1) and GAD(2), GABA synthesis enzymes in the brain stem including hypothalamus, was investigated. The ICV injection of chicken ghrelin significantly reduced GAD(2) gene expression. These findings suggest that ghrelin may decrease food intake in neonatal chicks by reducing GABA synthesis and thereby GABA release within brain feeding centers. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

GABA content within the ventromedial prefrontal cortex is related to trait anxiety.

PubMed

Delli Pizzi, Stefano; Padulo, Caterina; Brancucci, Alfredo; Bubbico, Giovanna; Edden, Richard A; Ferretti, Antonio; Franciotti, Raffaella; Manippa, Valerio; Marzoli, Daniele; Onofrj, Marco; Sepede, Gianna; Tartaro, Armando; Tommasi, Luca; Puglisi-Allegra, Stefano; Bonanni, Laura

2016-05-01

The ventromedial prefrontal cortex (vmPFC) plays a key role in emotion processing and regulation. vmPFC dysfunction may lead to disinhibition of amygdala causing high anxiety levels. γ-Aminobutyric acid (GABA) inter-neurons within vmPFC shape the information flow to amygdala. Thus, we hypothesize that GABA content within vmPFC could be relevant to trait anxiety. Forty-three healthy volunteers aged between 20 and 88 years were assessed for trait anxiety with the Subscale-2 of the State-Trait-Anxiety Inventory (STAI-Y2) and were studied with proton magnetic resonance spectroscopy to investigate GABA and Glx (glutamate+glutamine) contents within vmPFC. Total creatine (tCr) was used as internal reference. Partial correlations assessed the association between metabolite levels and STAI-Y2 scores, removing the effect of possible nuisance factors including age, educational level, volumes of gray matter and white matter within magnetic resonance spectroscopy voxel. We observed a positive relationship between GABA/tCr and STAI-Y2 scores. No significant relationships were found between Glx/tCr and STAI-Y2 and between tCr/water and STAI-Y2. No differences were found between males and females as regards to age, STAI-Y2, GABA/tCr, Glx/tCr, tCr/water, gray matter and white matter volumes. We suggest a close relationship between GABA content within vmPFC and trait anxiety providing new insights in the physiology of emotional brain. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Regulation of Local Ambient GABA Levels via Transporter-Mediated GABA Import and Export for Subliminal Learning.

PubMed

Hoshino, Osamu

2015-06-01

Perception of supraliminal stimuli might in general be reflected in bursts of action potentials (spikes), and their memory traces could be formed through spike-timing-dependent plasticity (STDP). Memory traces for subliminal stimuli might be formed in a different manner, because subliminal stimulation evokes a fraction (but not a burst) of spikes. Simulations of a cortical neural network model showed that a subliminal stimulus that was too brief (10 msec) to perceive transiently (more than about 500 msec) depolarized stimulus-relevant principal cells and hyperpolarized stimulus-irrelevant principal cells in a subthreshold manner. This led to a small increase or decrease in ongoing-spontaneous spiking activity frequency (less than 1 Hz). Synaptic modification based on STDP during this period effectively enhanced relevant synaptic weights, by which subliminal learning was improved. GABA transporters on GABAergic interneurons modulated local levels of ambient GABA. Ambient GABA molecules acted on extrasynaptic receptors, provided principal cells with tonic inhibitory currents, and contributed to achieving the subthreshold neuronal state. We suggest that ongoing-spontaneous synaptic alteration through STDP following subliminal stimulation may be a possible neuronal mechanism for leaving its memory trace in cortical circuitry. Regulation of local ambient GABA levels by transporter-mediated GABA import and export may be crucial for subliminal learning.

Cortical Proteins are Chemokinetic to Cells from the Medial Ganglionic Eminence

DTIC Science & Technology

2011-05-28

et al., 2009). Disruption of interneuron migration can lead to improper distribution within the cortex and is associated with schizophrenia, autism ...include the neurotrophins; the growth factors NRG1 and GDNF, the chemokine, SDF-1 and neurotransmitters, glutamate, GABA, and dopamine (Stumm et al...Bhide PG ( Dopamine receptor activation modulates GABA neuron migration from the basal forebrain to the cerebral cortex. J Neurosci 27:3813-3822.2007

Binge Toluene Exposure Alters Glutamate, Glutamine and GABA in the Adolescent Rat Brain as Measured by Proton Magnetic Resonance Spectroscopy*

PubMed Central

Perrine, Shane A.; O'Leary-Moore, Shonagh K.; Galloway, Matthew P.; Hannigan, John H.; Bowen, Scott E.

2010-01-01

Despite the high incidence of toluene abuse in adolescents, little is known regarding the effect of binge exposure on neurochemical profiles during this developmental stage. In the current study, the effects of binge toluene exposure during adolescence on neurotransmitter levels were determined using high-resolution proton magnetic resonance spectroscopy ex vivo at 11.7 T. Adolescent male Sprague-Dawley rats were exposed to toluene (0, 8,000 , or 12,000 ppm) for 15 min twice daily from postnatal day 28 (P28) through P34 and then euthanized either one or seven days later (on P35 or P42) to assess glutamate, glutamine, and GABA levels in intact tissue punches from the medial prefrontal cortex (mPFC), anterior striatum and hippocampus. In the mPFC, toluene reduced glutamate one day after exposure, with no effect on GABA, while after seven days, glutamate was no longer affected but there was an increase in GABA levels. In the hippocampus, neither GABA nor glutamate was altered one day after exposure, whereas seven days after exposure, increases were observed in GABA and glutamate. Striatal glutamate and GABA levels measured after either one or seven days were not altered after toluene exposure. These findings show that one week of binge toluene inhalation selectively alters these neurotransmitters in the mPFC and hippocampus in adolescent rats, and that some of these effects endure at least one week after the exposure. The results suggest that age-dependent, differential neurochemical responses to toluene may contribute to the unique behavioral patterns associated with drug abuse among older children and young teens. PMID:21126832

Estradiol and luteinizing hormone regulate recognition memory following subchronic phencyclidine: Evidence for hippocampal GABA action.

PubMed

Riordan, Alexander J; Schaler, Ari W; Fried, Jenny; Paine, Tracie A; Thornton, Janice E

2018-05-01

The cognitive symptoms of schizophrenia are poorly understood and difficult to treat. Estrogens may mitigate these symptoms via unknown mechanisms. To examine these mechanisms, we tested whether increasing estradiol (E) or decreasing luteinizing hormone (LH) could mitigate short-term episodic memory loss in a phencyclidine (PCP) model of schizophrenia. We then assessed whether changes in cortical or hippocampal GABA may underlie these effects. Female rats were ovariectomized and injected subchronically with PCP. To modulate E and LH, animals received estradiol capsules or Antide injections. Short-term episodic memory was assessed using the novel object recognition task (NORT). Brain expression of GAD67 was analyzed via western blot, and parvalbumin-containing cells were counted using immunohistochemistry. Some rats received hippocampal infusions of a GABA A agonist, GABA A antagonist, or GAD inhibitor before behavioral testing. We found that PCP reduced hippocampal GAD67 and abolished recognition memory. Antide restored hippocampal GAD67 and rescued recognition memory in PCP-treated animals. Estradiol prevented PCP's amnesic effect in NORT but failed to restore hippocampal GAD67. PCP did not cause significant differences in number of parvalbumin-expressing cells or cortical expression of GAD67. Hippocampal infusions of a GABA A agonist restored recognition memory in PCP-treated rats. Blocking hippocampal GAD or GABA A receptors in ovx animals reproduced recognition memory loss similar to PCP and inhibited estradiol's protection of recognition memory in PCP-treated animals. In summary, decreasing LH or increasing E can lessen short-term episodic memory loss, as measured by novel object recognition, in a PCP model of schizophrenia. Alterations in hippocampal GABA may contribute to both PCP's effects on recognition memory and the hormones' ability to prevent or reverse them. Copyright © 2018 Elsevier Ltd. All rights reserved.

An autocrine γ-aminobutyric acid signaling system exists in pancreatic β-cell progenitors of fetal and postnatal mice.

PubMed

Feng, Mary M; Xiang, Yun-Yan; Wang, Shuanglian; Lu, Wei-Yang

2013-01-01

Gamma-aminobutyric acid (GABA) is produced and secreted by adult pancreatic β-cells, which also express GABA receptors mediating autocrine signaling and regulating β-cell proliferation. However, whether the autocrine GABA signaling involves in β-cell progenitor development or maturation remains uncertain. By means of immunohistochemistry we analyzed the expression profiles of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) and the α1-subunit of type-A GABA receptor (GABAARα1) in the pancreas of mice at embryonic day 15.5 (E15.5), E18.5, postnatal day 1 (P1) and P7. Our data showed that at E15.5 the pancreatic and duodenum homeobox-1 (Pdx1) was expressed in the majority of cells in the developing pancreata. Notably, insulin immunoreactivity was identified in a subpopulation of pancreatic cells with a high level of Pdx1 expression. About 80% of the high-level Pdx-1 expressing cells in the pancreas expressed GAD and GABAARα1 at all pancreatic developmental stages. In contrast, only about 30% of the high-level Pdx-1 expressing cells in the E15.5 pancreas expressed insulin; i.e., a large number of GAD/GABAARα1-expressing cells did not express insulin at this early developmental stage. The expression level of GAD and GABAARα1 increased steadily, and progressively more GAD/GABAARα1-expressing cells expressed insulin in the course of pancreatic development. These results suggest that 1) GABA signaling proteins appear in β-cell progenitors prior to insulin expression; and 2) the increased expression of GABA signaling proteins may be involved in β-cell progenitor maturation.

Altered neurotransmitter metabolism in adolescents with high-functioning autism

PubMed Central

Drenthen, Gerhard S.; Barendse, Evelien M.; Aldenkamp, Albert P.; van Veenendaal, Tamar M.; Puts, Nicolaas A.J.; Edden, Richard A.E.; Zinger, Svitlana; Thoonen, Geert; Hendriks, Marc P.H.; Kessels, Roy P.C.; Jansen, Jacobus F.A.

2017-01-01

Previous studies have suggested that alterations in excitatory/inhibitory neurotransmitters might play a crucial role in autism spectrum disorder (ASD). Proton magnetic resonance spectroscopy (1H-MRS) can provide valuable information about abnormal brain metabolism and neurotransmitter concentrations. However, few 1H-MRS studies have been published on the imbalance of the two most abundant neurotransmitters in ASD: glutamate (Glu) and gamma-aminobutyric acid (GABA). Moreover, to our knowledge none of these published studies is performed with a study population consisting purely of high-functioning autism (HFA) adolescents. Selecting only individuals with HFA eliminates factors possibly related to intellectual impairment instead of ASD. This study aims to assess Glu and GABA neurotransmitter concentrations in HFA. Occipital concentrations of Glu and GABA plus macromolecules (GABA+) were obtained using 1H-MRS relative to creatine (Cr) in adolescents with HFA (n=15 and n=13 respectively) and a healthy control group (n=17). Multiple linear regression revealed significantly higher Glu/Cr and lower GABA+/Glu concentrations in the HFA group compared to the controls. These results imply that imbalanced neurotransmitter levels of excitation and inhibition are associated with HFA in adolescents. PMID:27685800

Structure-Function Evaluation of Imidazopyridine Derivatives Selective for δ-Subunit-Containing γ-Aminobutyric Acid Type A (GABAA) Receptors.

PubMed

Yakoub, Kirsten; Jung, Sascha; Sattler, Christian; Damerow, Helen; Weber, Judith; Kretzschmann, Annika; Cankaya, Aylin S; Piel, Markus; Rösch, Frank; Haugaard, Anne S; Frølund, Bente; Schirmeister, Tanja; Lüddens, Hartmut

2018-03-08

δ-Selective compounds 1 and 2 (DS1, compound 22; DS2, compound 16) were introduced as functionally selective modulators of δ-containing GABA type A receptors (GABA A R). In our hands, [ 3 H]EBOB-binding experiments with recombinant GABA A R and compound 22 showed no proof of δ-selectivity, although there was a minimally higher preference for the α4β3δ and α6β2/3δ receptors with respect to potency. In order to delineate the structural determinants of δ preferences, we synthesized 25 derivatives of DS1 and DS2, and investigated their structure-activity relationships (SAR). Four of our derivatives showed selectivity for α6β3δ receptors (29, 38, 39, and 41). For all of them, the major factors that distinguished them from compound 22 were variations at the para-positions of their benzamide groups. However, two compounds (29 and 39), when tested in the presence of GABA, revealed effects at several additional GABA A R. The newly synthesized compounds will still serve as useful tools to investigate α6β3δ receptors.

Opiate-induced motor stimulation is regulated by gamma-aminobutyric acid type B receptors found in the ventral tegmental area in mice.

PubMed

Leite-Morris, Kimberly A; Fukudome, Eugene Y; Kaplan, Gary B

2002-01-14

Recent studies suggest that gamma-aminobutyric acid type B (GABA(B)) receptors located on dopaminergic cells in the ventral tegmental area (VTA) regulate mesolimbic dopaminergic (A10) activity. In the current study, we identified GABA(B) receptor subtypes in the area of the VTA and examined their role in modulating acute opiate actions. We studied the effects of intra-VTA infusions of the selective GABA(B) agonist baclofen on morphine-induced locomotor stimulation and A10 neuronal activation. Drug treatments were followed by ambulatory activity monitoring for 180 min. Intra-VTA baclofen treatment produced a 70% inhibition of morphine-stimulated locomotor activity. Furthermore, functional activation of A10 neurons was assessed by immunohistochemical staining of c-Fos in the nucleus accumbens (NAc), where A10 neurons terminate. We found that morphine treatment increased the levels of Fos-positive nuclei in the NAc, while intra-VTA baclofen treatment reversed morphine's effects. Finally, GABA(B) receptor subtypes and isoforms were identified in the ventromedial mesencephalon using immunoblotting. We demonstrated the presence of GABA(B)R1a (130 kDa), GABA(B)R1b (100 kDa), and GABA(B)R2 (120 kDa) receptor subtypes in this region. These results suggest that GABA(B) receptor isoforms are found in the VTA and their activation results in the blockade of behavioral effects of opiates via inhibition of dopaminergic neurotransmission.

Application of Baechu-Kimchi Powder and GABA-Producing Lactic Acid Bacteria for the Production of Functional Fermented Sausages

PubMed Central

Choi, Ji Hun; Kang, Ki Moon

2017-01-01

This study was carried out to determine the physicochemical, microbiological, and quality characteristics of a new type of fermented sausage manufactured by incorporating Baechu-kimchi powder and gamma-aminobutyric acid (GABA)-producing lactic acid bacteria (LAB). The LAB count was at the maximum level by day nine of ripening in inoculated sausages, accompanied by a rapid decrease in the pH. The addition of kimchi powder decreased the lightness (L*) and increased the redness (a*) and, yellowness (b*) values, while also significantly increasing the hardness and chewiness of the sausage (p<0.05). Moreover, although the thiobarbituric acid reactive substances values increased in all samples during the study period, this increase was lower in the kimchi-treated samples, indicating a reduction in lipid oxidation. Overall, our results show that the addition of Baechu-kimchi powder to sausages reduced the off-flavor properties and improved the taste profile of the fermented sausage in sensory evaluations. The GABA content of all fermented sausages increased from 17.42-25.14 mg/kg on the third day of fermentation to 60.95-61.47 mg/kg on the thirtieth day. These results demonstrate that Baechu-kimchi powder and GABA-producing LAB could be functional materials in fermented sausage to improve quality characteristics. PMID:29725201

[Effect of gamma-aminobutyric acid on peripheral mechanisms regulating autonomic functions].

PubMed

Godovalova, L A

1976-01-01

Experiments with cats ascertained the potentiating action of GABA (100,300,500 mg/kg) on the pressor reactions of the small intestine vessels, the systemic arterial pressure, depressing (100 mg/kg) and facilitating (500 mg/kg) effect upon the reactions of inhibition of the small intestine motor activity evoked by the efferent stimulation of the celiac nerve. Adrenolytics (dihydroergotoxin, inderal) abolished the facilitating effects of GABA. The latter (0.01 solution) inhibited spontaneous contractions of isolated small intestine lengths. As proved histochemically GABA (500 mg/kg) reduces the catecholamines content in the suprarenals, in the solar plexus ganglia and in vessles "in vivo". It also increases the catecholamines content in the small intestine wall in experiments in vivo and reduces in vitro tests. The potentiating action of GABA on the vegetative reactions in efferent stimulation of the ciliac nerve occurs, apparently, due to an increased ejection of catecholamines by suprarenals and lowered the content of catecholamines in the solar plexus ganglia, which causes facilitated conduction of excitation in the ganglia.

Changes of tocopherols, tocotrienols, γ-oryzanol, and γ-aminobutyric acid levels in the germinated brown rice of pigmented and nonpigmented cultivars.

PubMed

Ng, Lean-Teik; Huang, Shao-Hua; Chen, Yen-Ting; Su, Chun-Han

2013-12-26

This study examined the changes of tocopherols (Toc), tocotrienols (T3), γ-oryzanol (GO), and γ-aminobutyric acid (GABA) contents in germinated brown rice (GBR) of pigmented and nonpigmented cultivars under different germination conditions. Results showed that the Toc and T3 contents in GBR were significantly different between treatments in both rice cultivars. The pigmented GBR possessed higher total vitamin E, total Toc, total T3, and GO contents than the nonpigmented GBR; however, its level of GABA was lower. The order of the three highest vitamin E homologues in pigmented and nonpigmented GBR was γ-T3 > γ-Toc > α-Toc and α-Toc > γ-T3 > α-T3, respectively; β-Toc, β-T3, δ-Toc, and δ-T3 were present in only small amounts (≤1.0 mg/kg) in GBR of both cultivars. Although both cultivars showed an increase in GABA contents with increasing germination time, the GABA content in nonpigmented GBR was higher.

Sodium p-Aminosalicylic Acid Reverses Sub-Chronic Manganese-Induced Impairments of Spatial Learning and Memory Abilities in Rats, but Fails to Restore γ-Aminobutyric Acid Levels.

PubMed

Li, Shao-Jun; Ou, Chao-Yan; He, Sheng-Nan; Huang, Xiao-Wei; Luo, Hai-Lan; Meng, Hao-Yang; Lu, Guo-Dong; Jiang, Yue-Ming; Vieira Peres, Tanara; Luo, Yi-Ni; Deng, Xiang-Fa

2017-04-10

Excessive manganese (Mn) exposure is not only a health risk for occupational workers, but also for the general population. Sodium para-aminosalicylic acid (PAS-Na) has been successfully used in the treatment of manganism, but the involved molecular mechanisms have yet to be determined. The present study aimed to investigate the effects of PAS-Na on sub-chronic Mn exposure-induced impairments of spatial learning and memory, and determine the possible involvements of γ-aminobutyric acid (GABA) metabolism in vivo. Sprague-Dawley male rats received daily intraperitoneal injections MnCl₂ (as 6.55 mg/kg Mn body weight, five days per week for 12 weeks), followed by daily subcutaneous injections of 100, 200, or 300 mg/kg PAS-Na for an additional six weeks. Mn exposure significantly impaired spatial learning and memory ability, as noted in the Morris water maze test, and the following PAS-Na treatment successfully restored these adverse effects to levels indistinguishable from controls. Unexpectedly, PAS-Na failed to recover the Mn-induced decrease in the overall GABA levels, although PAS-Na treatment reversed Mn-induced alterations in the enzyme activities directly responsible for the synthesis and degradation of GABA (glutamate decarboxylase and GABA-transaminase, respectively). Moreover, Mn exposure caused an increase of GABA transporter 1 (GAT-1) and decrease of GABA A receptor (GABA A ) in transcriptional levels, which could be reverted by the highest dose of 300 mg/kg PAS-Na treatment. In conclusion, the GABA metabolism was interrupted by sub-chronic Mn exposure. However, the PAS-Na treatment mediated protection from sub-chronic Mn exposure-induced neurotoxicity, which may not be dependent on the GABA metabolism.

A molecular characterization of the agonist binding site of a nematode cys-loop GABA receptor

PubMed Central

Kaji, Mark D; Kwaka, Ariel; Callanan, Micah K; Nusrat, Humza; Desaulniers, Jean-Paul; Forrester, Sean G

2015-01-01

Background and Purpose Cys-loop GABA receptors represent important targets for human chemotherapeutics and insecticides and are potential targets for novel anthelmintics (nematicides). However, compared with insect and mammalian receptors, little is known regarding the pharmacological characteristics of nematode Cys-loop GABA receptors. Here we have investigated the agonist binding site of the Cys-loop GABA receptor UNC-49 (Hco-UNC-49) from the parasitic nematode Haemonchus contortus. Experimental Approach We used two-electrode voltage-clamp electrophysiology to measure channel activation by classical GABA receptor agonists on Hco-UNC-49 expressed in Xenopus laevis oocytes, along with site-directed mutagenesis and in silico homology modelling. Key Results The sulphonated molecules P4S and taurine had no effect on Hco-UNC-49. Other classical Cys-loop GABAA receptor agonists tested on the Hco-UNC-49B/C heteromeric channel had a rank order efficacy of GABA > trans-4-aminocrotonic acid > isoguvacine > imidazole-4-acetic acid (IMA) > (R)-(−)-4-amino-3-hydroxybutyric acid [R(−)-GABOB] > (S)-(+)-4-amino-3-hydroxybutyric acid [S(+)-GABOB] > guanidinoacetic acid > isonipecotic acid > 5-aminovaleric acid (DAVA) (partial agonist) > β-alanine (partial agonist). In silico ligand docking revealed some variation in binding between agonists. Mutagenesis of a key serine residue in binding loop C to threonine had minimal effects on GABA and IMA but significantly increased the maximal response to DAVA and decreased twofold the EC50 for R(−)- and S(+)-GABOB. Conclusions and Implications The pharmacological profile of Hco-UNC-49 differed from that of vertebrate Cys-loop GABA receptors and insect resistance to dieldrin receptors, suggesting differences in the agonist binding pocket. These findings could be exploited to develop new drugs that specifically target GABA receptors of parasitic nematodes. PMID:25850584

GABA transaminases from Saccharomyces cerevisiae and Arabidopsis thaliana complement function in cytosol and mitochondria.

PubMed

Cao, Juxiang; Barbosa, Jose M; Singh, Narendra; Locy, Robert D

2013-07-01

GABA transaminase (GABA-T) catalyses the conversion of GABA to succinate semialdehyde (SSA) in the GABA shunt pathway. The GABA-T from Saccharomyces cerevisiae (ScGABA-TKG) is an α-ketoglutarate-dependent enzyme encoded by the UGA1 gene, while higher plant GABA-T is a pyruvate/glyoxylate-dependent enzyme encoded by POP2 in Arabidopsis thaliana (AtGABA-T). The GABA-T from A. thaliana is localized in mitochondria and mediated by an 18-amino acid N-terminal mitochondrial targeting peptide predicated by both web-based utilities TargetP 1.1 and PSORT. Yeast UGA1 appears to lack a mitochondrial targeting peptide and is localized in the cytosol. To verify this bioinformatic analysis and examine the significance of ScGABA-TKG and AtGABA-T compartmentation and substrate specificity on physiological function, expression vectors were constructed to modify both ScGABA-TKG and AtGABA-T, so that they express in yeast mitochondria and cytosol. Physiological function was evaluated by complementing yeast ScGABA-TKG deletion mutant Δuga1 with AtGABA-T or ScGABA-TKG targeted to the cytosol or mitochondria for the phenotypes of GABA growth defect, thermosensitivity and heat-induced production of reactive oxygen species (ROS). This study demonstrates that AtGABA-T is functionally interchangeable with ScGABA-TKG for GABA growth, thermotolerance and limiting production of ROS, regardless of location in mitochondria or cytosol of yeast cells, but AtGABA-T is about half as efficient in doing so as ScGABA-TKG. These results are consistent with the hypothesis that pyruvate/glyoxylate-limited production of NADPH mediates the effect of the GABA shunt in moderating heat stress in Saccharomyces. Copyright © 2013 John Wiley & Sons, Ltd.

GABA-CREB signalling regulates maturation and survival of newly generated neurons in the adult hippocampus

PubMed Central

Jagasia, Ravi; Steib, Kathrin; Englberger, Elisabeth; Herold, Sabine; Faus-Kessler, Theresa; Saxe, Michael; Gage, Fred H.; Song, Hongjun; Lie, D. Chichung

2009-01-01

Survival and integration of new neurons in the hippocampal circuit are rate-limiting steps in adult hippocampal neurogenesis. Neuronal network activity is a major regulator of these processes, yet little is known about the respective downstream signalling pathways. Here, we investigate the role of CREB signalling in adult hippocampal neurogenesis. CREB is activated in new granule neurons during a distinct developmental period. Loss of CREB function in a cell-autonomous fashion impairs dendritic development, decreases the expression of the neurogenic transcription factor NeuroD and of the neuronal microtubule associated protein, DCX, and compromises the survival of newborn neurons. In addition, GABA-mediated excitation regulates CREB activation at early developmental stages. Importantly, developmental defects following loss of GABA-mediated excitation can be compensated by enhanced CREB signalling. These results indicate that CREB signalling is a central pathway in adult hippocampal neurogenesis, regulating the development and survival of new hippocampal neurons downstream of GABA-mediated excitation. PMID:19553437

Correction of respiratory disorders in a mouse model of Rett syndrome

PubMed Central

Abdala, Ana P. L.; Dutschmann, Mathias; Bissonnette, John M.; Paton, Julian F. R.

2010-01-01

Rett syndrome (RTT) is an autism spectrum disorder caused by mutations in the X-linked gene that encodes the transcription factor methyl-CpG-binding protein 2 (MeCP2). A major debilitating phenotype in affected females is frequent apneas, and heterozygous Mecp2-deficient female mice mimic the human respiratory disorder. GABA defects have been demonstrated in the brainstem of Mecp2-deficient mice. Here, using an intact respiratory network, we show that apnea in RTT mice is characterized by excessive excitatory activity in expiratory cranial and spinal nerves. Augmenting GABA markedly improves the respiratory phenotype. In addition, a serotonin 1a receptor agonist that depresses expiratory neuron activity also reduces apnea, corrects the irregular breathing pattern, and prolongs survival in MeCP2 null males. Combining a GABA reuptake blocker with a serotonin 1a agonist in heterozygous females completely corrects their respiratory defects. The results indicate that GABA and serotonin 1a receptor activity are candidates for treatment of the respiratory disorders in Rett syndrome. PMID:20921395

Brain infection with Staphylococcus aureus leads to high extracellular levels of glutamate, aspartate, γ-aminobutyric acid, and zinc.

PubMed

Hassel, Bjørnar; Dahlberg, Daniel; Mariussen, Espen; Goverud, Ingeborg Løstegaard; Antal, Ellen-Ann; Tønjum, Tone; Maehlen, Jan

2014-12-01

Staphylococcal brain infections may cause mental deterioration and epileptic seizures, suggesting interference with normal neurotransmission in the brain. We injected Staphylococcus aureus into rat striatum and found an initial 76% reduction in the extracellular level of glutamate as detected by microdialysis at 2 hr after staphylococcal infection. At 8 hr after staphylococcal infection, however, the extracellular level of glutamate had increased 12-fold, and at 20 hr it had increased >30-fold. The extracellular level of aspartate and γ-aminobutyric acid (GABA) also increased greatly. Extracellular Zn(2+) , which was estimated at ∼2.6 µmol/liter in the control situation, was increased by 330% 1-2.5 hr after staphylococcal infection and by 100% at 8 and 20 hr. The increase in extracellular glutamate, aspartate, and GABA appeared to reflect the degree of tissue damage. The area of tissue damage greatly exceeded the area of staphylococcal infiltration, pointing to soluble factors being responsible for cell death. However, the N-methyl-D-aspartate receptor antagonist MK-801 ameliorated neither tissue damage nor the increase in extracellular neuroactive amino acids, suggesting the presence of neurotoxic factors other than glutamate and aspartate. In vitro staphylococci incubated with glutamine and glucose formed glutamate, so bacteria could be an additional source of infection-related glutamate. We conclude that the dramatic increase in the extracellular concentration of neuroactive amino acids and zinc could interfere with neurotransmission in the surrounding brain tissue, contributing to mental deterioration and a predisposition to epileptic seizures, which are often seen in brain abscess patients. © 2014 Wiley Periodicals, Inc.

Cocaine disinhibits dopamine neurons in the ventral tegmental area via use-dependent blockade of GABA neuron voltage-sensitive sodium channels

PubMed Central

Steffensen, Scott C.; Taylor, Seth R.; Horton, Malia L.; Barber, Elise N.; Lyle, Laura T.; Stobbs, Sarah H.; Allison, David W.

2010-01-01

The aim of this study was to evaluate the effects of cocaine on γ-aminobutyric acid (GABA) and dopamine (DA) neurons in the ventral tegmental area (VTA). Utilizing single-unit recordings in vivo, microelectrophoretic administration of DA enhanced the firing rate of VTA GABA neurons via D2/D3 DA receptor activation. Lower doses of intravenous cocaine (0.25–0.5 mg/kg), or the DA transporter (DAT) blocker methamphetamine, enhanced VTA GABA neuron firing rate via D2/D3 receptor activation. Higher doses of cocaine (1.0–2.0 mg/kg) inhibited their firing rate, which was not sensitive to the D2/D3 antagonist eticlopride. The voltage-sensitive sodium channel (VSSC) blocker lidocaine inhibited the firing rate of VTA GABA neurons at all doses tested (0.25–2.0 mg/kg). Cocaine or lidocaine reduced VTA GABA neuron spike discharges induced by stimulation of the internal capsule (ICPSDs) at dose levels 0.25–2 mg/kg (IC50 1.2 mg/kg). There was no effect of DA or methamphetamine on ICPSDs, or of DA antagonists on cocaine inhibition of ICPSDs. In VTA GABA neurons in vitro, cocaine reduced (IC50 13 μm) current-evoked spikes and TTX-sensitive sodium currents in a use-dependent manner. In VTA DA neurons, cocaine reduced IPSCs (IC50 13 μm), increased IPSC paired-pulse facilitation and decreased spontaneous IPSC frequency, without affecting miniature IPSC frequency or amplitude. These findings suggest that cocaine acts on GABA neurons to reduce activity-dependent GABA release on DA neurons in the VTA, and that cocaine's use-dependent blockade of VTA GABA neuron VSSCs may synergize with its DAT inhibiting properties to enhance mesolimbic DA transmission implicated in cocaine reinforcement. PMID:19046384

Altered expression of genes involved in GABAergic transmission and neuromodulation of granule cell activity in the cerebellum of schizophrenia patients.

PubMed

Bullock, W Michael; Cardon, Karen; Bustillo, Juan; Roberts, Rosalinda C; Perrone-Bizzozero, Nora I

2008-12-01

Deficits in gamma-aminobutyric acid (GABA) signaling have been described in the prefrontal cortex, limbic system, and cerebellum in individuals with schizophrenia. The purpose of the present study was to further investigate cerebellar gene expression alterations as they relate to decreases in GABAergic transmission by examining the expression of GABAergic markers, N-methyl-d-aspartic-acid (NMDA) receptor subunits, and cerebellum neuromodulators in individuals with schizophrenia. Subjects were postmortem men with a diagnosis of schizophrenia (N=13) and a postmortem interval-matched non-psychiatric male comparison group (N=13). The authors utilized real-time-quantitative polymerase chain reaction (PCR) to measure mRNA levels of the following GABAergic markers: glutamic acid decarboxylase (GAD) 65 and 67; GABA plasma membrane transporter-1 (GAT-1); GABA type A (GABA(A)) receptor subunits alpha(6), beta(3), and delta; and parvalbumin. In addition, real-time-quantitative PCR was utilized to assess mRNA levels of the NMDA receptor (NR) subunits NR1, NR2-A, NR2-B, NR2-C, and NR2-D as well as the cerebellar neuromodulators glutamate receptor (GluR)-6, kainate-preferring glutamate receptor subunit-2 (KA2), metabotropic glutamate receptor (mGluR)-2 and mGluR3, and neuronal nitric oxide synthase. Measurements for mRNA levels were determined using lateral cerebellar hemisphere tissue from both schizophrenia and comparison subjects. Schizophrenia subjects showed significant decreases in mRNA levels of GAD(67), GAD(65), GAT-1, mGluR2, and neuronal nitric oxide synthase. Increases in GABA(A)-alpha(6 )and GABA(A)-delta as well as GluR6 and KA2 were also observed. Medication effects on the expression of the same genes were examined in rats treated with either haloperidol (Sprague-Dawley rats [N=16]) or clozapine (Long-Evans rats [N=20]). Both haloperidol and clozapine increased the levels of GAD(67) in the cerebellum and altered the expression of other cerebellar mRNAs. These findings suggest that GABA transmission is decreased in the cerebellar cortices in individuals with schizophrenia and additional gene expression changes may reflect an attempt to increase GABA neurotransmission at the cerebellar glomerulus.

Hypoxia and GABA shunt activation in the pathogenesis of Alzheimer's disease.

PubMed

Salminen, Antero; Jouhten, Paula; Sarajärvi, Timo; Haapasalo, Annakaisa; Hiltunen, Mikko

2016-01-01

We have previously observed that the conversion of mild cognitive impairment to definitive Alzheimer's disease (AD) is associated with a significant increase in the serum level of 2,4-dihydroxybutyrate (2,4-DHBA). The metabolic generation of 2,4-DHBA is linked to the activation of the γ-aminobutyric acid (GABA) shunt, an alternative energy production pathway activated during cellular stress, when the function of Krebs cycle is compromised. The GABA shunt can be triggered by local hypoperfusion and subsequent hypoxia in AD brains caused by cerebral amyloid angiopathy. Succinic semialdehyde dehydrogenase (SSADH) is a key enzyme in the GABA shunt, converting succinic semialdehyde (SSA) into succinate, a Krebs cycle intermediate. A deficiency of SSADH activity stimulates the conversion of SSA into γ-hydroxybutyrate (GHB), an alternative route from the GABA shunt. GHB can exert not only acute neuroprotective activities but unfortunately also chronic detrimental effects which may lead to cognitive impairment. Subsequently, GHB can be metabolized to 2,4-DHBA and secreted from the brain. Thus, the activation of the GABA shunt and the generation of GHB and 2,4-DHBA can have an important role in the early phase of AD pathogenesis. Copyright © 2015 Elsevier Ltd. All rights reserved.

Self-enhancement of GABA in rice bran using various stress treatments.

PubMed

Kim, Hyun Soo; Lee, Eun Jung; Lim, Seung-Taik; Han, Jung-Ah

2015-04-01

Gamma-aminobutyric acid (GABA) may be synthesized in plant tissues when the organism is under stressful conditions. Rice bran byproduct obtained from the milling of brown rice was treated under anaerobic storage with nitrogen at different temperatures (20-60 °C) and moisture contents (10-50%) up to 12h. For the GABA synthesis, the storage at 30% moisture content and 40 °C appeared optimal. Utilisation of an electrolyzed oxidizing water (EOW, pH 3.3) for moisture adjustment and addition of glutamic acid increased the GABA content in rice bran. The maximum GABA content in rice bran (523 mg/100g) could be achieved by the anaerobic storage at 30% EOW for 5h at 40 °C after an addition of glutamic acid (5mM). This amount was approximately 17 times higher than that in the control (30 mg/100g). The use of EOW also prevented bacterial growth by decreasing the colony counts almost by half. Copyright © 2014 Elsevier Ltd. All rights reserved.

Contribution of polyamines metabolism and GABA shunt to chilling tolerance induced by nitric oxide in cold-stored banana fruit.

PubMed

Wang, Yansheng; Luo, Zisheng; Mao, Linchun; Ying, Tiejin

2016-04-15

Effect of exogenous nitric oxide (NO) on polyamines (PAs) catabolism, γ-aminobutyric acid (GABA) shunt, proline accumulation and chilling injury of banana fruit under cold storage was investigated. Banana fruit treated with NO sustained lower chilling injury index than the control. Notably elevated nitric oxide synthetase activity and endogenous NO level were observed in NO-treated banana fruit. PAs contents in treated fruit were significantly higher than control fruit, due to the elevated activities of arginine decarboxylase and ornithine decarboxylase. NO treatment increased the activities of diamine oxidase, polyamine oxidase and glutamate decarboxylase, while reduced GABA transaminase activity to lower levels compared with control fruit, which resulted the accumulation of GABA. Besides, NO treatment upregulated proline content and significantly enhanced the ornithine aminotransferase activity. These results indicated that the chilling tolerance induced by NO treatment might be ascribed to the enhanced catabolism of PAs, GABA and proline. Copyright © 2015 Elsevier Ltd. All rights reserved.

GABAA receptor dependent synaptic inhibition rapidly tunes KCC2 activity via the Cl--sensitive WNK1 kinase.

PubMed

Heubl, Martin; Zhang, Jinwei; Pressey, Jessica C; Al Awabdh, Sana; Renner, Marianne; Gomez-Castro, Ferran; Moutkine, Imane; Eugène, Emmanuel; Russeau, Marion; Kahle, Kristopher T; Poncer, Jean Christophe; Lévi, Sabine

2017-11-24

The K + -Cl - co-transporter KCC2 (SLC12A5) tunes the efficacy of GABA A receptor-mediated transmission by regulating the intraneuronal chloride concentration [Cl - ] i . KCC2 undergoes activity-dependent regulation in both physiological and pathological conditions. The regulation of KCC2 by synaptic excitation is well documented; however, whether the transporter is regulated by synaptic inhibition is unknown. Here we report a mechanism of KCC2 regulation by GABA A receptor (GABA A R)-mediated transmission in mature hippocampal neurons. Enhancing GABA A R-mediated inhibition confines KCC2 to the plasma membrane, while antagonizing inhibition reduces KCC2 surface expression by increasing the lateral diffusion and endocytosis of the transporter. This mechanism utilizes Cl - as an intracellular secondary messenger and is dependent on phosphorylation of KCC2 at threonines 906 and 1007 by the Cl - -sensing kinase WNK1. We propose this mechanism contributes to the homeostasis of synaptic inhibition by rapidly adjusting neuronal [Cl - ] i to GABA A R activity.

Contributions of GABA to alcohol responsivity during adolescence: Insights from preclinical and clinical studies

PubMed Central

Silveri, Marisa M.

2015-01-01

There is a considerable body of literature demonstrating that adolescence is a unique age period, which includes rapid and dramatic maturation of behavioral, cognitive, hormonal and neurobiological systems. Most notably, adolescence is also a period of unique responsiveness to alcohol effects, with both hyposensitivity and hypersensitivity observed to the various effects of alcohol. Multiple neurotransmitter systems are undergoing fine-tuning during this critical period of brain development, including those that contribute to the rewarding effects of drugs of abuse. The role of developmental maturation of the γ-amino-butyric acid (GABA) system, however, has received less attention in contributing to age-specific alcohol sensitivities. This review integrates GABA findings from human magnetic resonance spectroscopy studies as they may translate to understanding adolescent-specific responsiveness to alcohol effects. Better understanding of the vulnerability of the GABA system both during adolescent development, and in psychiatric conditions that include alcohol dependence, could point to a putative mechanism, boosting brain GABA, that may have increased effectiveness for treating alcohol abuse disorders. PMID:24631274

Anxiolytic effect of Kami-Shoyo-San (TJ-24) in mice: possible mediation of neurosteroid synthesis.

PubMed

Mizowaki, M; Toriizuka, K; Hanawa, T

2001-09-21

We assessed the anxiolytic effect of Kami-Shoyo-San (Jia-wei-xiao-yao-san; TJ-24), one of a traditional Chinese herbal medicine used for the treatment of menopausal anxiety, by the social interaction (SI) test in male mice. Acute administration of TJ-24 (25-100 mg/kg, p.o.), as well as the gamma-amino-butyric acidA/benzodiazepine (GABA(A)/BZP) receptor agonist diazepam (1-3 mg/kg, i.p.), dose dependently increased the SI time, respectively. The GABA(A) receptor antagonist picrotoxin blocked the effects of TJ-24 and diazepam. TJ-24-induced SI behavior was significantly blocked by the GABA(A)/BZP receptor inverse agonist Ro 15-4513 and the GABA(A)/BZP receptor antagonist flumazenil. In addition, 5alpha-reductase inhibitor finasteride potently blocked the effect of TJ-24 without attenuating the basal level by itself. These findings suggest that TJ-24 shows the anxiolytic effect through the neurosteroid synthesis followed by GABA(A)/BDZ receptor stimulations.

RNA editing of the GABAA receptor α3 subunit alters the functional properties of recombinant receptors

PubMed Central

Nimmich, Mitchell L.; Heidelberg, Laura S.; Fisher, Janet L.

2009-01-01

RNA editing provides a post-transcriptional mechanism to increase structural heterogeneity of gene products. Recently, the α3 subunit of the GABAA receptors has been shown to undergo RNA editing. As a result, a highly conserved isoleucine residue in the third transmembrane domain is replaced with a methionine. To determine the effect of this structural change on receptor function, we compared the GABA sensitivity, pharmacological properties and macroscopic kinetics of recombinant receptors containing either the edited or unedited forms of the α3 subunit along with β3 and γ2L. Editing substantially altered the GABA sensitivity and deactivation rate of the receptors, with the unedited form showing a lower GABA EC50 and slower decay. Comparable effects were observed with a mutation at the homologous location in the α1 subunit, suggesting a common role for this site in regulation of channel gating. Except for the response to GABA, the pharmacological properties of the receptor were unaffected by editing, with similar enhancement by a variety of modulators. Since RNA editing of the α3 subunit increases through development, our findings suggest that GABAergic neurotransmission may be more effective early in development, with greater GABA sensitivity and slower decay rates conferred by the unedited α3 subunit. PMID:19367790

Women with PTSD have a changed sensitivity to GABA-A receptor active substances.

PubMed

Möller, Anna Tiihonen; Bäckström, Torbjörn; Nyberg, Sigrid; Söndergaard, Hans Peter; Helström, Lotti

2016-06-01

The use of benzodiazepines in treating anxiety symptoms in patients with posttraumatic stress disorder (PTSD) has been debated. Studies on other anxiety disorders have indicated changed sensitivity to GABA-A receptor active substances. In the present study, we investigated the GABA receptor sensitivity in PTSD patients. Injections of allopreganolone, diazepam, and flumazenil were carried out, each on separate occasions, in 10 drug naïve patients with PTSD compared to 10 healthy controls. Effects were measured in saccadic eye velocity (SEV) and in subjective ratings of sedation. The PTSD patients were less sensitive to allopregnanolone compared with healthy controls. This was seen as a significant difference in SEV between the groups (p = 0.047). Further, the patients were less sensitive to diazepam, with a significant less increase in sedation compared to controls (p = 0.027). After flumazenil injection, both patients and controls had a significant agonistic effect on SEV, leading to decreased SEV after injection. The patients also responded with an increase in sedation after flumazenil injection, while this was not seen in the controls. Patients with PTSD have a changed sensitivity to GABA-A receptor active substances. As a consequence of this, benzodiazepines and other GABA-A receptor active compounds such as sleeping pills will be less useful for this group of patients.

Increased Cortical Gamma-Aminobutyric Acid Precedes Incomplete Extinction of Conditioned Fear and Increased Hippocampal Excitatory Tone in a Mouse Model of Mild Traumatic Brain Injury.

PubMed

Schneider, Brandy L; Ghoddoussi, Farhad; Charlton, Jennifer L; Kohler, Robert J; Galloway, Matthew P; Perrine, Shane A; Conti, Alana C

2016-09-01

Mild traumatic brain injury (mTBI) contributes to development of affective disorders, including post-traumatic stress disorder (PTSD). Psychiatric symptoms typically emerge in a tardive fashion post-TBI, with negative effects on recovery. Patients with PTSD, as well as rodent models of PTSD, demonstrate structural and functional changes in brain regions mediating fear learning, including prefrontal cortex (PFC), amygdala (AMYG), and hippocampus (HC). These changes may reflect loss of top-down control by which PFC normally exhibits inhibitory influence over AMYG reactivity to fearful stimuli, with HC contribution. Considering the susceptibility of these regions to injury, we examined fear conditioning (FC) in the delayed post-injury period, using a mouse model of mTBI. Mice with mTBI displayed enhanced acquisition and delayed extinction of FC. Using proton magnetic resonance spectroscopy ex vivo, we examined PFC, AMYG, and HC levels of gamma-aminobutyric acid (GABA) and glutamate as surrogate measures of inhibitory and excitatory neurotransmission, respectively. Eight days post-injury, GABA was increased in PFC, with no significant changes in AMYG. In animals receiving FC and mTBI, glutamate trended toward an increase and the GABA/glutamate ratio decreased in ventral HC at 25 days post-injury, whereas GABA decreased and GABA/glutamate decreased in dorsal HC. These neurochemical changes are consistent with early TBI-induced PFC hypoactivation facilitating the fear learning circuit and exacerbating behavioral fear responses. The latent emergence of overall increased excitatory tone in the HC, despite distinct plasticity in dorsal and ventral HC fields, may be associated with disordered memory function, manifested as incomplete extinction and enhanced FC recall.

In vivo transgenic expression of collybistin in neurons of the rat cerebral cortex.

PubMed

Fekete, Christopher D; Goz, Roman U; Dinallo, Sean; Miralles, Celia P; Chiou, Tzu-Ting; Bear, John; Fiondella, Christopher G; LoTurco, Joseph J; De Blas, Angel L

2017-04-01

Collybistin (CB) is a guanine nucleotide exchange factor selectively localized to γ-aminobutyric acid (GABA)ergic and glycinergic postsynapses. Active CB interacts with gephyrin, inducing the submembranous clustering and the postsynaptic accumulation of gephyrin, which is a scaffold protein that recruits GABA A receptors (GABA A Rs) at the postsynapse. CB is expressed with or without a src homology 3 (SH3) domain. We have previously reported the effects on GABAergic synapses of the acute overexpression of CB SH3- or CB SH3+ in cultured hippocampal (HP) neurons. In the present communication, we are studying the effects on GABAergic synapses after chronic in vivo transgenic expression of CB2 SH3- or CB2 SH3+ in neurons of the adult rat cerebral cortex. The embryonic precursors of these cortical neurons were in utero electroporated with CB SH3- or CB SH3+ DNAs, migrated to the appropriate cortical layer, and became integrated in cortical circuits. The results show that: 1) the strength of inhibitory synapses in vivo can be enhanced by increasing the expression of CB in neurons; and 2) there are significant differences in the results between in vivo and in culture studies. J. Comp. Neurol. 525:1291-1311, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Solute accumulation and elastic modulus changes in six radiata pine breeds exposed to drought.

PubMed

De Diego, N; Sampedro, M C; Barrio, R J; Saiz-Fernández, I; Moncaleán, P; Lacuesta, M

2013-01-01

Drought is one of the main abiotic factors that determine forest species growth, survival and productivity. For this reason, knowledge of plant drought response and the identification of physiological traits involved in stress tolerance will be of interest to breeding programs. In this work, several Pinus radiata D. Don breeds from different geographical origins were evaluated along a water stress period (4 weeks) and subsequent rewatering (1 week), showing different responses among them. Leaf water potential (Ψ(leaf)) and osmotic potential decreases were accompanied by a variation in the total relative water content (RWC, %). The most tolerant breeds presented the lowest leaf water potential and RWC at turgor loss point, and showed the lowest elastic modulus (ε) values. A high ε value was a characteristic of a less-drought-tolerant plant and was related to membrane alterations (high electrolyte leakage percentages) that could favor cell water loss. Of the group of solutes that contributed to osmotic adjustment, soluble carbohydrates were the most abundant, although stressed plants also increased their content of free amino acids [mainly proline (Pro) and glutamic acid (Glu), and γ-aminobutyric acid (GABA)] and free polyamines. In addition, the most sensitive breeds had a higher GABA/Glu ratio. After rewatering, Pro and GABA were higher in rehydrated plants than in controls.

Control of cortical neuronal migration by glutamate and GABA

PubMed Central

Luhmann, Heiko J.; Fukuda, A.; Kilb, W.

2015-01-01

Neuronal migration in the cortex is controlled by the paracrine action of the classical neurotransmitters glutamate and GABA. Glutamate controls radial migration of pyramidal neurons by acting primarily on NMDA receptors and regulates tangential migration of inhibitory interneurons by activating non-NMDA and NMDA receptors. GABA, acting on ionotropic GABAA-rho and GABAA receptors, has a dichotomic action on radially migrating neurons by acting as a GO signal in lower layers and as a STOP signal in upper cortical plate (CP), respectively. Metabotropic GABAB receptors promote radial migration into the CP and tangential migration of interneurons. Besides GABA, the endogenous GABAergic agonist taurine is a relevant agonist controlling radial migration. To a smaller extent glycine receptor activation can also influence radial and tangential migration. Activation of glutamate and GABA receptors causes increases in intracellular Ca2+ transients, which promote neuronal migration by acting on the cytoskeleton. Pharmacological or genetic manipulation of glutamate or GABA receptors during early corticogenesis induce heterotopic cell clusters in upper layers and loss of cortical lamination, i.e., neuronal migration disorders which can be associated with neurological or neuropsychiatric diseases. The pivotal role of NMDA and ionotropic GABA receptors in cortical neuronal migration is of major clinical relevance, since a number of drugs acting on these receptors (e.g., anti-epileptics, anesthetics, alcohol) may disturb the normal migration pattern when present during early corticogenesis. PMID:25688185

Effect of oral administration of GABA on temperature regulation in humans during rest and exercise at high ambient temperature.

PubMed

Miyazawa, Taiki; Kawabata, Takashi; Suzuki, Takashi; Imai, Daiki; Hamamoto, Takeshi; Yoshikawa, Takahiro; Miyagawa, Toshiaki

2009-12-01

Centric administration of gamma-aminobutyric acid (GABA) has been implicated to affect temperature regulation in animals during rest or under anesthesia. However, there are few reports concerning the effects of the oral administration of GABA on temperature regulation in humans during rest and exercise. In order to clarify the effects and underlying mechanisms, we measured several parameters related to temperature regulation of humans during rest and exercise at high ambient temperature (35 degrees C). On two occasions, eight endurance-trained men rested for 20 min and cycled at 65% VO2peak for 30 min. In control trial (trial-C), subjects drank the sample which was a sports drink of 200 mL (placebo) before the rest period. In another trial (trial-G), subjects drank the sample which was a sports drink containing 1000 mg of GABA (GABA drink) before the rest period. In trial-G, the plasma GABA concentrations were maintained higher than those in trial-C during the experiment. An increase of esophageal temperature during rest and exercise was inhibited in trial-G. Sweat rate, and plasma catecholamine concentrations during exercise were inhibited in trial-G. Esophageal temperature inhibition is suggested to be induced by the suppression of cold-sensitive neurons during rest, and the inhibition of plasma catecholamine concentrations caused by the GABA-induced attenuation of the sympathetic nervous system during exercise.

Accumulation of γ‐aminobutyric acid by E nterococcus avium 9184 in scallop solution in a two‐stage fermentation strategy

PubMed Central

Yang, Haoyue; Hu, Linfeng; Liu, Song

2015-01-01

Summary In this study, a new bacterial strain having a high ability to produce γ‐aminobutyric acid (GABA) was isolated from naturally fermented scallop solution and was identified as E nterococcus avium. To the best of our knowledge, this is the first study to prove that E . avium possesses glutamate decarboxylase activity. The strain was then mutagenized with UV radiation and was designated as E . avium 9184. Scallop solution was used as the culture medium to produce GABA. A two‐stage fermentation strategy was applied to accumulate GABA. In the first stage, cell growth was regulated. Optimum conditions for cell growth were pH, 6.5; temperature, 37°C; and glucose concentration, 10 g·L−1. This produced a maximum dry cell mass of 2.10 g·L−1. In the second stage, GABA formation was regulated. GABA concentration reached 3.71 g·L−1 at 96 h pH 6.0, 37°C and initial l‐monosodium glutamate concentration of 10 g·L−1. Thus, compared with traditional one‐stage fermentation, the two‐stage fermentation significantly increased GABA accumulation. These results provide preliminary data to produce GABA using E . avium and also provide a new approach to process and utilize shellfish. PMID:26200650

Transition from androgenic to neurosteroidal action of 5α-androstane-3α, 17β-diol through the type A γ-aminobutyric acid receptor in prostate cancer progression.

PubMed

Xia, Ding; Lai, Doan V; Wu, Weijuan; Webb, Zachary D; Yang, Qing; Zhao, Lichao; Yu, Zhongxin; Thorpe, Jessica E; Disch, Bryan C; Ihnat, Michael A; Jayaraman, Muralidharan; Dhanasekaran, Danny N; Stratton, Kelly L; Cookson, Michael S; Fung, Kar-Ming; Lin, Hsueh-Kung

2018-04-01

Androgen ablation is the standard of care prescribed to patients with advanced or metastatic prostate cancer (PCa) to slow down disease progression. Unfortunately, a majority of PCa patients under androgen ablation progress to castration-resistant prostate cancer (CRPC). Several mechanisms including alternative intra-prostatic androgen production and androgen-independent androgen receptor (AR) activation have been proposed for CRPC progression. Aldo-keto reductase family 1 member C3 (AKR1C3), a multi-functional steroid metabolizing enzyme, is specifically expressed in the cytoplasm of PCa cells; and positive immunoreactivity of the type A γ-aminobutyric acid receptor (GABA A R), an ionotropic receptor and ligand-gated ion channel, is detected on the membrane of PCa cells. We studied a total of 72 radical prostatectomy cases by immunohistochemistry, and identified that 21 cases exhibited positive immunoreactivities for both AKR1C3 and GABA A R. In the dual positive cancer cases, AKR1C3 and GABA A R subunit α 1 were either expressed in the same cells or in neighboring cells. Among several possible substrates, AKR1C3 reduces 5α-dihydrotesterone (DHT) to form 5α-androstane-3α, 17β-diol (3α-diol). 3α-diol is a neurosteroid that acts as a positive allosteric modulator of the GABA A R in the central nervous system (CNS). We examined the hypothesis that 3α-diol-regulated pathological effects in the prostate are GABA A R-dependent, but are independent of the AR. In GABA A R-positive, AR-negative human PCa PC-3 cells, 3α-diol significantly stimulated cell growth in culture and the in ovo chorioallantoic membrane (CAM) xenograft model. 3α-diol also up-regulated expression of the epidermal growth factor (EGF) family of growth factors and activation of EGF receptor (EGFR) and Src as measured by quantitative polymerase chain reaction and immunoblotting, respectively. Inclusion of GABA A R antagonists reversed 3α-diol-stimulated tumor cell growth, expression of EGF family members, and activation of EGFR and Src to the level observed in untreated cells. Results from the present study suggest that 3α-diol may act as an alternative intra-prostatic neurosteroid that activates AR-independent PCa progression. The involvement of AKR1C3-mediated steroid metabolisms in modulating GABA A R activation and promoting PCa progression requires continued studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Regulation of α3-containing GABAA receptors in guinea-pig adrenal medullary cells by adrenal steroids.

PubMed

Inoue, M; Harada, K; Nakamura, J; Matsuoka, H

2013-12-03

GABA is thought to function as a paracrine factor in adrenal medullary (AM) cells. Thus, we electrophysiologically and immunologically examined the properties of GABAA receptors (GABAARs) in guinea-pig AM cells. Bath application of GABA produced an inward current at -60 mV in a dose-dependent manner with an EC50 of 32.3 μM. This GABA-induced current was enhanced by allopregnanolone at concentrations of 0.01 μM and more. A prior exposure to allopregnanolone resulted in a decrease in an EC50 for GABA in activating GABAARs. The GABA-induced current was suppressed by Zn(2+) in a dose-dependent manner with an IC50 of 18 μM, whereas it was enhanced by 100 μM La(3+). The benzodiazepine analog diazepam was three times more potent than zolpidem in enhancing the GABA current, and it was also augmented by L-838,417, which has no action on α1-containing GABAARs. The GABAAR α3, but not α1, and γ2 subunits were immunologically detected at the cell periphery. The expression of α3 subunits in PC12 cells was enhanced by glucocorticoid activity. The results indicated that GABAARs in guinea-pig AM cells mainly comprise α3, β, and γ2 subunits and are enhanced by allopreganalone and glucocorticoids may play a major role in the expression of α3 subunits. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Effect of taurine on the concentrations of glutamate, GABA, glutamine and alanine in the rat striatum and hippocampus.

PubMed

Molchanova, Svetlana M; Oja, Simos S; Saransaari, Pirjo

2007-01-01

Taurine, a non-protein amino acid, acts as an osmoregulator and inhibitory neuromodulator in the brain. Here we studied the effects of intraperitoneal injections of taurine on the concentrations of glutamate and GABA, and their precursors, glutamine and alanine, in the rat striatum and hippocampus. Injections of 0.25, 0.5 and 1 g/kg taurine led to a gradual increase in taurine tissue concentrations in both hippocampus and striatum. Glutamate and GABA also increased in the hippocampus, but not in the striatum. Glutamine increased and alanine decreased markedly in both brain structures. The results corroborate the neuromodulatory role of taurine in the brain. Taurine administration results in an imbalance in inhibitory and excitatory neurotransmission in the glutamatergic (hippocampus) and GABAergic (striatum) brain structures, affecting more markedly the neurotransmitter precursors.

Alpha1- and alpha2-containing GABAA receptor modulation is not necessary for benzodiazepine-induced hyperphagia.

PubMed

Morris, H V; Nilsson, S; Dixon, C I; Stephens, D N; Clifton, P G

2009-06-01

Benzodiazepines increase food intake, an effect attributed to their ability to enhance palatability. We investigated which GABA(A) receptor subtypes may be involved in mediating benzodiazepine-induced hyperphagia. The role of the alpha2 subtype was investigated by observing the effects of midazolam, on the behavioural satiety sequence in mice with targeted deletion of the alpha2 gene (alpha2 knockout). Midazolam (0.125, 0.25 and 0.5mg/kg) increased food intake and the amount of time spent feeding in alpha2 knockout mice, suggesting that BZ-induced hyperphagia does not involve alpha2-containing GABA(A) receptors. We further investigated the roles of alpha1- and alpha3-containing GABA(A) receptors in mediating BZ-induced hyperphagia. We treated alpha2(H101R) mice, in which alpha2-containing receptors are rendered benzodiazepine insensitive, with L-838417, a compound which acts as a partial agonist at alpha2-, alpha3- and alpha5-receptors but is inactive at alpha1-containing receptors. L-838417 (10 and 30 mg/kg) increased food intake and the time spent feeding in both wildtype and alpha2(H101R) mice, demonstrating that benzodiazepine-induced hyperphagia does not require alpha1- and alpha2-containing GABA(A) receptors. These observations, together with evidence against the involvement of alpha5-containing GABA(A) receptors, suggest that alpha3-containing receptors mediate BZ-induced hyperphagia in the mouse.

A tonoplast Glu/Asp/GABA exchanger that affects tomato fruit amino acid composition.

PubMed

Snowden, Christopher J; Thomas, Benjamin; Baxter, Charles J; Smith, J Andrew C; Sweetlove, Lee J

2015-03-01

Vacuolar accumulation of acidic metabolites is an important aspect of tomato fruit flavour and nutritional quality. The amino acids Asp and Glu accumulate to high concentrations during ripening, while γ-aminobutyrate (GABA) shows an approximately stoichiometric decline. Given that GABA can be catabolised to form Glu and subsequently Asp, and the requirement for the fruit to maintain osmotic homeostasis during ripening, we hypothesised the existence of a tonoplast transporter that exports GABA from the vacuole in exchange for import of either Asp or Glu. We show here that the tomato vacuolar membrane possesses such a transport property: transport of Glu across isolated tonoplast vesicle membranes was trans-stimulated in counterexchange mode by GABA, Glu and Asp. We identified SlCAT9 as a candidate protein for this exchanger using quantitative proteomics of a tonoplast-enriched membrane fraction. Transient expression of a SlCAT9-YFP fusion in tobacco confirmed a tonoplast localisation. The function of the protein was examined by overexpression of SlCAT9 in transgenic tomato plants. Tonoplast vesicles isolated from transgenic plants showed higher rates of Glu and GABA transport than wild-type (WT) only when assayed in counterexchange mode with Glu, Asp, or GABA. Moreover, there were substantial increases in the content of all three cognate amino acids in ripe fruit from the transgenic plants. We conclude that SlCAT9 is a tonoplast Glu/Asp/GABA exchanger that strongly influences the accumulation of these amino acids during fruit development. © 2015 The Authors The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.

Inhibitory actions of the gamma-aminobutyric acid in pediatric Sturge-Weber syndrome.

PubMed

Tyzio, Roman; Khalilov, Ilgam; Represa, Alfonso; Crepel, Valerie; Zilberter, Yuri; Rheims, Sylvain; Aniksztejn, Laurent; Cossart, Rosa; Nardou, Romain; Mukhtarov, Marat; Minlebaev, Marat; Epsztein, Jérôme; Milh, Mathieu; Becq, Helene; Jorquera, Isabel; Bulteau, Christine; Fohlen, Martine; Oliver, Viviana; Dulac, Olivier; Dorfmüller, Georg; Delalande, Olivier; Ben-Ari, Yehezkel; Khazipov, Roustem

2009-08-01

The mechanisms of epileptogenesis in Sturge-Weber syndrome (SWS) are unknown. We explored the properties of neurons from human pediatric SWS cortex in vitro and tested in particular whether gamma-aminobutyric acid (GABA) excites neurons in SWS cortex, as has been suggested for various types of epilepsies. Patch-clamp and field potential recordings and dynamic biphoton imaging were used to analyze cortical tissue samples obtained from four 6- to 14-month-old pediatric SWS patients during surgery. Neurons in SWS cortex were characterized by a relatively depolarized resting membrane potential, as was estimated from cell-attached recordings of N-methyl-D-aspartate channels. Many cells spontaneously fired action potentials at a rate proportional to the level of neuronal depolarization. The reversal potential for GABA-activated currents, assessed by cell-attached single channel recordings, was close to the resting membrane potential. All spontaneously firing neurons recorded in cell-attached mode or imaged with biphoton microscopy were inhibited by GABA. Spontaneous epileptiform activity in the form of recurrent population bursts was suppressed by glutamate receptor antagonists, the GABA(A) receptor agonist isoguvacine, and the positive allosteric GABA(A) modulator diazepam. Blockade of GABA(A) receptors aggravated spontaneous epileptiform activity. The NKCC1 antagonist bumetanide had little effect on epileptiform activity. SWS cortical neurons have a relatively depolarized resting membrane potential and spontaneously fire action potentials that may contribute to increased network excitability. In contrast to previous data depicting excitatory and proconvulsive actions of GABA in certain pediatric and adult epilepsies, GABA plays mainly an inhibitory and anticonvulsive role in SWS pediatric cortex.

GABA, 5-HT and amino acids in the rotifers Brachionus plicatilis and Brachionus rotundiformis.

PubMed

Gallardo, W G; Hagiwara, A; Hara, K; Soyano, K; Snell, T W

2000-11-01

gamma-Aminobutyric acid (GABA) and 5-hydroxytryptamine (5-HT) have been shown to increase the reproduction of the Brachionus plicatilis (NH3L strain). In the present study, the endogenous presence of GABA and 5-HT in the rotifers B. plicatilis (NH3L and Kamiura strains) and Brachionus rotundiformis (Langkawi strain) were confirmed by dot blot immunoassay and high-performance liquid chromatography (HPLC). HPLC showed that GABA and 5-HT concentrations in the three rotifer strains range from 71 to 188 pmol/mg and from 12 to 64 pmol/mg, respectively. A total of 33 amino acids were also detected in B. plicatilis and B. rotundiformis, with glutamic acid, serine, glycine, taurine, threonine, alanine, arginine, proline, valine and isoleucine in high concentrations relative to other amino acids.

Astrocytic GABA transporter activity modulates excitatory neurotransmission

PubMed Central

Boddum, Kim; Jensen, Thomas P.; Magloire, Vincent; Kristiansen, Uffe; Rusakov, Dmitri A.; Pavlov, Ivan; Walker, Matthew C.

2016-01-01

Astrocytes are ideally placed to detect and respond to network activity. They express ionotropic and metabotropic receptors, and can release gliotransmitters. Astrocytes also express transporters that regulate the extracellular concentration of neurotransmitters. Here we report a previously unrecognized role for the astrocytic GABA transporter, GAT-3. GAT-3 activity results in a rise in astrocytic Na+ concentrations and a consequent increase in astrocytic Ca2+ through Na+/Ca2+ exchange. This leads to the release of ATP/adenosine by astrocytes, which then diffusely inhibits neuronal glutamate release via activation of presynaptic adenosine receptors. Through this mechanism, increases in astrocytic GAT-3 activity due to GABA released from interneurons contribute to 'diffuse' heterosynaptic depression. This provides a mechanism for homeostatic regulation of excitatory transmission in the hippocampus. PMID:27886179

Neuroinflammation increases GABAergic tone and impairs cognitive and motor function in hyperammonemia by increasing GAT-3 membrane expression. Reversal by sulforaphane by promoting M2 polarization of microglia.

PubMed

Hernandez-Rabaza, Vicente; Cabrera-Pastor, Andrea; Taoro-Gonzalez, Lucas; Gonzalez-Usano, Alba; Agusti, Ana; Balzano, Tiziano; Llansola, Marta; Felipo, Vicente

2016-04-18

Hyperammonemia induces neuroinflammation and increases GABAergic tone in the cerebellum which contributes to cognitive and motor impairment in hepatic encephalopathy (HE). The link between neuroinflammation and GABAergic tone remains unknown. New treatments reducing neuroinflammation and GABAergic tone could improve neurological impairment. The aims were, in hyperammonemic rats, to assess whether: (a) Enhancing endogenous anti-inflammatory mechanisms by sulforaphane treatment reduces neuroinflammation and restores learning and motor coordination. (b) Reduction of neuroinflammation by sulforaphane normalizes extracellular GABA and glutamate-NO-cGMP pathway and identify underlying mechanisms. (c) Identify steps by which hyperammonemia-induced microglial activation impairs cognitive and motor function and how sulforaphane restores them. We analyzed in control and hyperammonemic rats, treated or not with sulforaphane, (a) learning in the Y maze; (b) motor coordination in the beam walking; (c) glutamate-NO-cGMP pathway and extracellular GABA by microdialysis; (d) microglial activation, by analyzing by immunohistochemistry or Western blot markers of pro-inflammatory (M1) (IL-1b, Iba-1) and anti-inflammatory (M2) microglia (Iba1, IL-4, IL-10, Arg1, YM-1); and (e) membrane expression of the GABA transporter GAT-3. Hyperammonemia induces activation of astrocytes and microglia in the cerebellum as assessed by immunohistochemistry. Hyperammonemia-induced neuroinflammation is associated with increased membrane expression of the GABA transporter GAT-3, mainly in activated astrocytes. This is also associated with increased extracellular GABA in the cerebellum and with motor in-coordination and impaired learning ability in the Y maze. Sulforaphane promotes polarization of microglia from the M1 to the M2 phenotype, reducing IL-1b and increasing IL-4, IL-10, Arg1, and YM-1 in the cerebellum. This is associated with astrocytes deactivation and normalization of GAT-3 membrane expression, extracellular GABA, glutamate-nitric oxide-cGMP pathway, and learning and motor coordination. Neuroinflammation increases GABAergic tone in the cerebellum by increasing GAT-3 membrane expression. This impairs motor coordination and learning in the Y maze. Sulforaphane could be a new therapeutic approach to improve cognitive and motor function in hyperammonemia, hepatic encephalopathy, and other pathologies associated with neuroinflammation by promoting microglia differentiation from M1 to M2.

Dietary Restriction Affects Neuronal Response Property and GABA Synthesis in the Primary Visual Cortex.

PubMed

Yang, Jinfang; Wang, Qian; He, Fenfen; Ding, Yanxia; Sun, Qingyan; Hua, Tianmiao; Xi, Minmin

2016-01-01

Previous studies have reported inconsistent effects of dietary restriction (DR) on cortical inhibition. To clarify this issue, we examined the response properties of neurons in the primary visual cortex (V1) of DR and control groups of cats using in vivo extracellular single-unit recording techniques, and assessed the synthesis of inhibitory neurotransmitter GABA in the V1 of cats from both groups using immunohistochemical and Western blot techniques. Our results showed that the response of V1 neurons to visual stimuli was significantly modified by DR, as indicated by an enhanced selectivity for stimulus orientations and motion directions, decreased visually-evoked response, lowered spontaneous activity and increased signal-to-noise ratio in DR cats relative to control cats. Further, it was shown that, accompanied with these changes of neuronal responsiveness, GABA immunoreactivity and the expression of a key GABA-synthesizing enzyme GAD67 in the V1 were significantly increased by DR. These results demonstrate that DR may retard brain aging by increasing the intracortical inhibition effect and improve the function of visual cortical neurons in visual information processing. This DR-induced elevation of cortical inhibition may favor the brain in modulating energy expenditure based on food availability.

Dietary Restriction Affects Neuronal Response Property and GABA Synthesis in the Primary Visual Cortex

PubMed Central

Sun, Qingyan; Hua, Tianmiao; Xi, Minmin

2016-01-01

Previous studies have reported inconsistent effects of dietary restriction (DR) on cortical inhibition. To clarify this issue, we examined the response properties of neurons in the primary visual cortex (V1) of DR and control groups of cats using in vivo extracellular single-unit recording techniques, and assessed the synthesis of inhibitory neurotransmitter GABA in the V1 of cats from both groups using immunohistochemical and Western blot techniques. Our results showed that the response of V1 neurons to visual stimuli was significantly modified by DR, as indicated by an enhanced selectivity for stimulus orientations and motion directions, decreased visually-evoked response, lowered spontaneous activity and increased signal-to-noise ratio in DR cats relative to control cats. Further, it was shown that, accompanied with these changes of neuronal responsiveness, GABA immunoreactivity and the expression of a key GABA-synthesizing enzyme GAD67 in the V1 were significantly increased by DR. These results demonstrate that DR may retard brain aging by increasing the intracortical inhibition effect and improve the function of visual cortical neurons in visual information processing. This DR-induced elevation of cortical inhibition may favor the brain in modulating energy expenditure based on food availability. PMID:26863207

Laser photolysis of DPNI-GABA, a tool for investigating the properties and distribution of GABA receptors and for silencing neurons in situ.

PubMed

Trigo, Federico F; Papageorgiou, George; Corrie, John E T; Ogden, David

2009-07-30

Laser photolysis to release GABA at precisely defined times and locations permits investigation of the distribution of functional GABA(A) receptors in neuronal compartments, the activation kinetics and pharmacology of GABA(A) receptors in situ, and the role of individual neurons in neural circuits by selective silencing with low GABA concentrations. We describe the experimental evaluation and applications of a new nitroindoline-caged GABA, DPNI-GABA, modified to minimize the pharmacological interference commonly found with caged GABA reagents, but retaining the advantages of nitroindoline cages. Unlike the 5-methoxycarbonylmethyl-7-nitroindolinyl-GABA tested previously, DPNI-GABA inhibited GABA(A) receptors with much lower affinity, reducing peak GABA-evoked responses with an IC(50) of approximately 0.5 mM. Most importantly, the kinetics of receptor activation, determined as 10-90% rise-times, were comparable to synaptic events and were little affected by DPNI-GABA present at 1mM concentration, permitting photolysis of DPNI-GABA to mimic synaptic activation of GABA(A) receptors. With a laser spot of 1 microm applied to cerebellar molecular layer interneurons, the spatial resolution of uncaging DPNI-GABA in dendrites was estimated as 2 microm laterally and 7.5 microm focally. Finally, at low DPNI-GABA concentration, photorelease restricted to the area of the soma suppressed spiking in single Purkinje neurons or molecular layer interneurons for periods controlled by the flash intensity and duration. DPNI-GABA has properties better adapted for fast kinetic studies with laser photolysis at GABA(A) receptors than previously reported caged GABA reagents, and can be used in experiments where spatial resolution is determined by the dimensions of the laser light spot.

Systematic Analysis of γ-Aminobutyric Acid (GABA) Metabolism and Function in the Social Amoeba Dictyostelium discoideum*

PubMed Central

Wu, Yuantai; Janetopoulos, Chris

2013-01-01

While GABA has been suggested to regulate spore encapsulation in the social amoeba Dictyostelium discoideum, the metabolic profile and other potential functions of GABA during development remain unclear. In this study, we investigated the homeostasis of GABA metabolism by disrupting genes related to GABA metabolism and signaling. Extracellular levels of GABA are tightly regulated during early development, and GABA is generated by the glutamate decarboxylase, GadB, during growth and in early development. However, overexpression of the prespore-specific homologue, GadA, in the presence of GadB reduces production of extracellular GABA. Perturbation of extracellular GABA levels delays the process of aggregation. Cytosolic GABA is degraded by the GABA transaminase, GabT, in the mitochondria. Disruption of a putative vesicular GABA transporter (vGAT) homologue DdvGAT reduces secreted GABA. We identified the GABAB receptor-like family member GrlB as the major GABA receptor during early development, and either disruption or overexpression of GrlB delays aggregation. This delay is likely the result of an abolished pre-starvation response and late expression of several “early” developmental genes. Distinct genes are employed for GABA generation during sporulation. During sporulation, GadA alone is required for generating GABA and DdvGAT is likely responsible for GABA secretion. GrlE but not GrlB is the GABA receptor during late development. PMID:23548898

Prefrontal Cortical GABA Modulation of Spatial Reference and Working Memory

PubMed Central

Auger, Meagan L.

2015-01-01

Background: Dysfunction in prefrontal cortex (PFC) GABA transmission has been proposed to contribute to cognitive dysfunction in schizophrenia, yet how this system regulates different cognitive and mnemonic functions remains unclear. Methods: We assessed the effects of pharmacological reduction of GABAA signaling in the medial PFC of rats on spatial reference/working memory using different versions of the radial-arm maze task. We used a massed-trials procedure to probe how PFC GABA regulates susceptibility to proactive interference. Male rats were well-trained to retrieve food from the same 4 arms of an 8-arm maze, receiving 5 trials/day (1–2min intervals). Results: Infusions of the GABAA receptor antagonist bicuculline (12.5–50ng) markedly increased working and reference memory errors and response latencies. Similar treatments also impaired short-term memory on an 8-baited arm task. These effects did not appear to be due to increased susceptibility to proactive interference. In contrast, PFC inactivation via infusion of GABA agonists baclofen/muscimol did not affect reference/working memory. In comparison to the pronounced effects on the 8-arm maze tasks, PFC GABAA antagonism only causes a slight and transient decrease in accuracy on a 2-arm spatial discrimination. Conclusions: These findings demonstrate that prefrontal GABA hypofunction severely disrupts spatial reference and short-term memory and that disinhibition of the PFC can, in some instances, perturb memory processes not normally dependent on the frontal lobes. Moreover, these impairments closely resemble those observed in schizophrenic patients, suggesting that perturbation in PFC GABA signaling may contribute to these types of cognitive deficits associated with the disorder. PMID:25552433

Role of GABA Deficit in Sensitivity to the Psychotomimetic Effects of Amphetamine.

PubMed

Ahn, Kyung-Heup; Sewell, Andrew; Elander, Jacqueline; Pittman, Brian; Ranganathan, Mohini; Gunduz-Bruce, Handan; Krystal, John; D'Souza, Deepak Cyril

2015-11-01

Some schizophrenia patients are more sensitive to amphetamine (AMPH)-induced exacerbations in psychosis-an effect that correlates with higher striatal dopamine release. This enhanced vulnerability may be related to gamma-aminobutyric acid (GABA) deficits observed in schizophrenia. We hypothesized that a pharmacologically induced GABA deficit would create vulnerability to the psychotomimetic effects to the 'subthreshold' dose of AMPH in healthy subjects, which by itself would not induce clinically significant increase in positive symptoms. To test this hypothesis, a GABA deficit was induced by intravenous infusion of iomazenil (IOM; 3.7 μg/kg), an antagonist and partial inverse agonist of benzodiazepine receptor. A subthreshold dose of AMPH (0.1 mg/kg) was administered by intravenous infusion. Healthy subjects received placebo IOM followed by placebo AMPH, active IOM followed by placebo AMPH, placebo IOM followed by active AMPH, and active IOM followed by active AMPH in a randomized, double-blind crossover design over 4 test days. Twelve healthy subjects who had a subclinical response to active AMPH alone were included in the analysis. Psychotomimetic effects (Positive and Negative Syndrome Scale (PANSS)), perceptual alterations (Clinician Administered Dissociative Symptoms Scale (CADSS)), and subjective effects (visual analog scale) were captured before and after the administration of drugs. IOM significantly augmented AMPH-induced peak changes in PANSS positive symptom subscale and both subjective and objective CADSS scores. There were no pharmacokinetic interactions. In conclusion, GABA deficits increased vulnerability to amphetamine-induced psychosis-relevant effects in healthy subjects, suggesting that pre-existing GABA deficits may explain why a subgroup of schizophrenia patients are vulnerable to AMPH.

Dietary supplementation with glutamine and γ-aminobutyric acid improves growth performance and serum parameters in 22- to 35-day-old broilers exposed to hot environment.

PubMed

Hu, H; Bai, X; Shah, A A; Wen, A Y; Hua, J L; Che, C Y; He, S J; Jiang, J P; Cai, Z H; Dai, S F

2016-04-01

This study was designed using 360 21-day-old chicks to determine the influences of diet supplementation with glutamine (5 g/kg), γ-aminobutyric acid (GABA, 100 mg/kg) or their combinations on performance and serum parameters exposed to cycling high temperatures. From 22 to 35 days, the experimental groups (2 × 2) were subjected to circular heat stress by exposing them to 30-34 °C cycling, while the positive control group was exposed to 23 °C constant. The blood of broilers was collected to detect serum parameters on days 28 and 35. Compared with the positive control group, the cycling high temperature decreased (p < 0.05) the feed consumption, weight gain and serum total protein (TP), glucose, thyroxine (T4), insulin, alkaline phosphatase (ALP), glutamine, GABA and glutamate levels, while increased (p < 0.05) the serum triglyceride (TG), corticosterone (CS), glucagon (GN), creatine kinase (CK), glutamic oxaloacetic transaminase (GOT), nitric oxide synthase (NOS), glutamate pyruvate transaminase (GPT) and lactate dehydrogenase (LDH) levels during 22-35 days. However, dietary glutamine (5 g/kg) increased (p < 0.05) the feed consumption, weight gain and serum levels of glutamine, TP, insulin and ALP, but decreased (p < 0.05) the serum TG, CK, GOT, NOS and GPT levels. Diet supplemented with GABA also increased (p < 0.05) weight gain and the serum levels of TP, T4, ALP, GABA and glutamine. In addition, the significant interactions (p < 0.05) between glutamine and GABA were found in the feed consumption, weight gain and the serum ALP, CK, LDH, GABA, T3 and T4 levels of heat-stressed chickens. This research indicated that dietary glutamine and GABA improved the antistress ability in performance and serum parameters of broilers under hot environment. Journal of Animal Physiology and Animal Nutrition © 2015 Blackwell Verlag GmbH.

Context-Dependent Modulation of GABAAR-Mediated Tonic Currents.

PubMed

Patel, Bijal; Bright, Damian P; Mortensen, Martin; Frølund, Bente; Smart, Trevor G

2016-01-13

Tonic GABA currents mediated by high-affinity extrasynaptic GABAA receptors, are increasingly recognized as important regulators of cell and neuronal network excitability. Dysfunctional GABAA receptor signaling that results in modified tonic GABA currents is associated with a number of neurological disorders. Consequently, developing compounds to selectively modulate the activity of extrasynaptic GABAA receptors underlying tonic inhibition is likely to prove therapeutically useful. Here, we examine the GABAA receptor subtype selectivity of the weak partial agonist, 5-(4-piperidyl)isoxazol-3-ol (4-PIOL), as a potential mechanism for modulating extrasynaptic GABAA receptor-mediated tonic currents. By using recombinant GABAA receptors expressed in HEK293 cells, and native GABAA receptors of cerebellar granule cells, hippocampal neurons, and thalamic relay neurons, 4-PIOL evidently displayed differential agonist and antagonist-type profiles, depending on the extrasynaptic GABAA receptor isoforms targeted. For neurons, this resulted in differential modulation of GABA tonic currents, depending on the cell type studied, their respective GABAA receptor subunit compositions, and critically, on the ambient GABA levels. Unexpectedly, 4-PIOL revealed a significant population of relatively low-affinity γ2 subunit-containing GABAA receptors in the thalamus, which can contribute to tonic inhibition under specific conditions when GABA levels are raised. Together, these data indicate that partial agonists, such as 4-PIOL, may be useful for modulating GABAA receptor-mediated tonic currents, but the direction and extent of this modulation is strongly dependent on relative expression levels of different extrasynaptic GABAA receptor subtypes, and on the ambient GABA levels. A background level of inhibition (tonic) is important in the brain for controlling neuronal excitability. Increased levels of tonic inhibition are associated with some neurological disorders but there are no specific ligands capable of selectively reducing tonic inhibition. Here we explore the use of a GABA partial agonist as a selective chemical tool in three different brain regions. We discover that the activity of a partial agonist is heavily dependent upon the GABAA receptor subunit composition underpinning tonic inhibition, and on the ambient levels of GABA in the brain. Copyright © 2016 Patel et al.

Context-Dependent Modulation of GABAAR-Mediated Tonic Currents

PubMed Central

Patel, Bijal; Bright, Damian P.; Mortensen, Martin; Frølund, Bente

2016-01-01

Tonic GABA currents mediated by high-affinity extrasynaptic GABAA receptors, are increasingly recognized as important regulators of cell and neuronal network excitability. Dysfunctional GABAA receptor signaling that results in modified tonic GABA currents is associated with a number of neurological disorders. Consequently, developing compounds to selectively modulate the activity of extrasynaptic GABAA receptors underlying tonic inhibition is likely to prove therapeutically useful. Here, we examine the GABAA receptor subtype selectivity of the weak partial agonist, 5-(4-piperidyl)isoxazol-3-ol (4-PIOL), as a potential mechanism for modulating extrasynaptic GABAA receptor-mediated tonic currents. By using recombinant GABAA receptors expressed in HEK293 cells, and native GABAA receptors of cerebellar granule cells, hippocampal neurons, and thalamic relay neurons, 4-PIOL evidently displayed differential agonist and antagonist-type profiles, depending on the extrasynaptic GABAA receptor isoforms targeted. For neurons, this resulted in differential modulation of GABA tonic currents, depending on the cell type studied, their respective GABAA receptor subunit compositions, and critically, on the ambient GABA levels. Unexpectedly, 4-PIOL revealed a significant population of relatively low-affinity γ2 subunit-containing GABAA receptors in the thalamus, which can contribute to tonic inhibition under specific conditions when GABA levels are raised. Together, these data indicate that partial agonists, such as 4-PIOL, may be useful for modulating GABAA receptor-mediated tonic currents, but the direction and extent of this modulation is strongly dependent on relative expression levels of different extrasynaptic GABAA receptor subtypes, and on the ambient GABA levels. SIGNIFICANCE STATEMENT A background level of inhibition (tonic) is important in the brain for controlling neuronal excitability. Increased levels of tonic inhibition are associated with some neurological disorders but there are no specific ligands capable of selectively reducing tonic inhibition. Here we explore the use of a GABA partial agonist as a selective chemical tool in three different brain regions. We discover that the activity of a partial agonist is heavily dependent upon the GABAA receptor subunit composition underpinning tonic inhibition, and on the ambient levels of GABA in the brain. PMID:26758848

Hyperammonemia induces glial activation, neuroinflammation and alters neurotransmitter receptors in hippocampus, impairing spatial learning: reversal by sulforaphane.

PubMed

Hernández-Rabaza, Vicente; Cabrera-Pastor, Andrea; Taoro-González, Lucas; Malaguarnera, Michele; Agustí, Ana; Llansola, Marta; Felipo, Vicente

2016-02-16

Patients with liver cirrhosis and minimal hepatic encephalopathy (MHE) show mild cognitive impairment and spatial learning dysfunction. Hyperammonemia acts synergistically with inflammation to induce cognitive impairment in MHE. Hyperammonemia-induced neuroinflammation in hippocampus could contribute to spatial learning impairment in MHE. Two main aims of this work were: (1) to assess whether chronic hyperammonemia increases inflammatory factors in the hippocampus and if this is associated with microglia and/or astrocytes activation and (2) to assess whether hyperammonemia-induced neuroinflammation in the hippocampus is associated with altered membrane expression of glutamate and GABA receptors and spatial learning impairment. There are no specific treatments for cognitive alterations in patients with MHE. A third aim was to assess whether treatment with sulforaphane enhances endogenous the anti-inflammatory system, reduces neuroinflammation in the hippocampus of hyperammonemic rats, and restores spatial learning and if normalization of receptor membrane expression is associated with learning improvement. We analyzed the following in control and hyperammonemic rats, treated or not with sulforaphane: (1) microglia and astrocytes activation by immunohistochemistry, (2) markers of pro-inflammatory (M1) (IL-1β, IL-6) and anti-inflammatory (M2) microglia (Arg1, YM-1) by Western blot, (3) membrane expression of GABA, AMPA, and NMDA receptors using the BS3 cross-linker, and (4) spatial learning using the radial maze. The results reported show that hyperammonemia induces astrocytes and microglia activation in the hippocampus, increasing pro-inflammatory cytokines IL-1β and IL-6. This is associated with altered membrane expression of AMPA, NMDA, and GABA receptors which would be responsible for altered neurotransmission and impairment of spatial learning in the radial maze. Treatment with sulforaphane promotes microglia differentiation from pro-inflammatory M1 to anti-inflammatory M2 phenotype and reduces activation of astrocytes in hyperammonemic rats. This reduces neuroinflammation, normalizes membrane expression of glutamate and GABA receptors, and restores spatial learning in hyperammonemic rats. Hyperammonemia-induced neuroinflammation impairs glutamatergic and GABAergic neurotransmission by altering membrane expression of glutamate and GABA receptors, resulting in impaired spatial learning. Sulforaphane reverses all these effects. Treatment with sulforaphane could be useful to improve cognitive function in cirrhotic patients with minimal or clinical hepatic encephalopathy.

A Sensitive Period of Mice Inhibitory System to Neonatal GABA Enhancement by Vigabatrin is Brain Region Dependent

PubMed Central

Levav-Rabkin, Tamar; Melamed, Osnat; Clarke, Gerard; Farber, Malca; Cryan, John F; Dinan, Timothy G; Grossman, Yoram; Golan, Hava M

2010-01-01

Neurodevelopmental disorders, such as schizophrenia and autism, have been associated with disturbances of the GABAergic system in the brain. We examined immediate and long-lasting influences of exposure to the GABA-potentiating drug vigabatrin (GVG) on the GABAergic system in the hippocampus and cerebral cortex, before and during the developmental switch in GABA function (postnatal days P1–7 and P4–14). GVG induced a transient elevation of GABA levels. A feedback response to GABA enhancement was evident by a short-term decrease in glutamate decarboxylase (GAD) 65 and 67 levels. However, the number of GAD65/67-immunoreactive (IR) cells was greater in 2-week-old GVG-treated mice. A long-term increase in GAD65 and GAD67 levels was dependent on brain region and treatment period. Vesicular GABA transporter was insensitive to GVG. The overall effect of GVG on the Cl− co-transporters NKCC1 and KCC2 was an enhancement of their synthesis, which was dependent on the treatment period and brain region studied. In addition, a short-term increase was followed by a long-term decrease in KCC2 oligomerization in the cell membrane of P4–14 hippocampi and cerebral cortices. Analysis of the Ca2+ binding proteins expressed in subpopulations of GABAergic cells, parvalbumin and calbindin, showed region-specific effects of GVG during P4–14 on parvalbumin-IR cell density. Moreover, calbindin levels were elevated in GVG mice compared to controls during this period. Cumulatively, these results suggest a particular susceptibility of the hippocampus to GVG when exposed during days P4–14. In conclusion, our studies have identified modifications of key components in the inhibitory system during a critical developmental period. These findings provide novel insights into the deleterious consequences observed in children following prenatal and neonatal exposure to GABA-potentiating drugs. PMID:20043003

Stimulation of accumbal GABAA receptors inhibits delta2-, but not delta1-, opioid receptor-mediated dopamine efflux in the nucleus accumbens of freely moving rats.

PubMed

Aono, Yuri; Kiguchi, Yuri; Watanabe, Yuriko; Waddington, John L; Saigusa, Tadashi

2017-11-15

The nucleus accumbens contains delta-opioid receptors that may reduce inhibitory neurotransmission. Reduction in GABA A receptor-mediated inhibition of accumbal dopamine release due to delta-opioid receptor activation should be suppressed by stimulating accumbal GABA A receptors. As delta-opioid receptors are divided into delta2- and delta1-opioid receptors, we analysed the effects of the GABA A receptor agonist muscimol on delta2- and delta1-opioid receptor-mediated accumbal dopamine efflux in freely moving rats using in vivo microdialysis. Drugs were administered intracerebrally through the dialysis probe. Doses of compounds indicate total amount administered (mol) during 25-50min infusions. The delta2-opioid receptor agonist deltorphin II (25.0nmol)- and delta1-opioid receptor agonist DPDPE (5.0nmol)-induced increases in dopamine efflux were inhibited by the delta2-opioid receptor antagonist naltriben (1.5nmol) and the delta1-opioid receptor antagonist BNTX (150.0pmol), respectively. Muscimol (250.0pmol) inhibited deltorphin II (25.0nmol)-induced dopamine efflux. The GABA A receptor antagonist bicuculline (50.0pmol), which failed to affect deltorphin II (25.0nmol)-induced dopamine efflux, counteracted the inhibitory effect of muscimol on deltorphin II-induced dopamine efflux. Neither muscimol (250.0pmol) nor bicuculline (50.0 and 500.0pmol) altered DPDPE (5.0nmol)-induced dopamine efflux. The present results show that reduction in accumbal GABA A receptor-mediated inhibition of dopaminergic activity is necessary to produce delta2-opioid receptor-induced increase in accumbal dopamine efflux. This study indicates that activation of delta2- but not delta1-opioid receptors on the cell bodies and/or terminals of accumbal GABAergic interneurons inhibits GABA release and, accordingly, decreases GABA A receptor-mediated inhibition of dopaminergic terminals, resulting in enhanced accumbal dopamine efflux. Copyright © 2017 Elsevier B.V. All rights reserved.

Interactions between hypocretinergic and GABAergic systems in the control of activity of neurons in the cat pontine reticular formation.

PubMed

Xi, M; Fung, S J; Yamuy, J; Chase, M H

2015-07-09

Anatomical studies have demonstrated that hypocretinergic and GABAergic neurons innervate cells in the nucleus pontis oralis (NPO), a nucleus responsible for the generation of active (rapid eye movement (REM)) sleep (AS) and wakefulness (W). Behavioral and electrophysiological studies have shown that hypocretinergic and GABAergic processes in the NPO are involved in the generation of AS as well as W. An increase in hypocretin in the NPO is associated with both AS and W, whereas GABA levels in the NPO are elevated during W. We therefore examined the manner in which GABA modulates NPO neuronal responses to hypocretin. We hypothesized that interactions between the hypocretinergic and GABAergic systems in the NPO play an important role in determining the occurrence of AS or W. To determine the veracity of this hypothesis, we examined the effects of the juxtacellular application of hypocretin-1 and GABA on the activity of NPO neurons, which were recorded intracellularly, in chloralose-anesthetized cats. The juxtacellular application of hypocretin-1 significantly increased the mean amplitude of spontaneous EPSPs and the frequency of discharge of NPO neurons; in contrast, the juxtacellular microinjection of GABA produced the opposite effects, i.e., there was a significant reduction in the mean amplitude of spontaneous EPSPs and a decrease in the discharge of these cells. When hypocretin-1 and GABA were applied simultaneously, the inhibitory effect of GABA on the activity of NPO neurons was reduced or completely blocked. In addition, hypocretin-1 also blocked GABAergic inhibition of EPSPs evoked by stimulation of the laterodorsal tegmental nucleus. These data indicate that hypocretin and GABA function within the context of a neuronal gate that controls the activity of AS-on neurons. Therefore, we suggest that the occurrence of either AS or W depends upon interactions between hypocretinergic and GABAergic processes as well as inputs from other sites that project to AS-on neurons in the NPO. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Functional reorganization of visual cortex maps after ischemic lesions is accompanied by changes in expression of cytoskeletal proteins and NMDA and GABA(A) receptor subunits.

PubMed

Zepeda, Angelica; Sengpiel, Frank; Guagnelli, Miguel Angel; Vaca, Luis; Arias, Clorinda

2004-02-25

Reorganization of cortical representations after focal visual cortex lesions has been documented. It has been suggested that functional reorganization may rely on cellular mechanisms involving modifications in the excitatory/inhibitory neurotransmission balance and on morphological changes of neurons peripheral to the lesion. We explored functional reorganization of cortical retinotopic maps after a focal ischemic lesion in primary visual cortex of kittens using optical imaging of intrinsic signals. After 1, 2, and 5 weeks postlesion (wPL), we addressed whether functional reorganization correlated in time with changes in the expression of MAP-2, GAP-43, GFAP, GABA(A) receptor subunit alpha1 (GABA(A)alpha1), subunit 1 of the NMDA receptor (NMDAR1), and in neurotransmitter levels at the border of the lesion. Our results show that: (1) retinotopic maps reorganize with time after an ischemic lesion; (2) MAP-2 levels increase gradually from 1wPL to 5wPL; (3) MAP-2 upregulation is associated with an increase in dendritic-like structures surrounding the lesion and a decrease in GFAP-positive cells; (4) GAP-43 levels reach the highest point at 2wPL; (5) NMDAR1 and glutamate contents increase in parallel from 1wPL to 5wPL; (6) GABA(A)alpha1 levels increase from 1wPL to 2wPL but do not change after this time point; and (7) GABA contents remain low from 1wPL to 5wPL. This is a comprehensive study showing for the first time that functional reorganization correlates in time with dendritic sprouting and with changes in the excitatory/inhibitory neurotransmission systems previously proposed to participate in cortical remodeling and suggests mechanisms by which plasticity of cortical representations may occur.

Mefloquine effects on ventral tegmental area dopamine and GABA neuron inhibition: a physiologic role for connexin-36 GAP junctions.

PubMed

Allison, David W; Wilcox, Rebecca S; Ellefsen, Kyle L; Askew, Caitlin E; Hansen, David M; Wilcox, Jeffrey D; Sandoval, Stephanie S; Eggett, Dennis L; Yanagawa, Yuchio; Steffensen, Scott C

2011-08-01

Connexin-36 (Cx36) gap junctions (GJs) appear to be involved in the synchronization of GABA interneurons in many brain areas. We have previously identified a population of Cx36-connected ventral tegmental area (VTA) GABA neurons that may regulate mesolimbic dopamine (DA) neurotransmission, a system implicated in reward from both natural behaviors and drugs of abuse. The aim of this study was to determine the effect mefloquine (MFQ) has on midbrain DA and GABA neuron inhibition, and the role Cx36 GJs play in regulating midbrain VTA DA neuron activity in mice. In brain slices from adolescent wild-type (WT) mice the Cx36-selective GJ blocker mefloquine (MFQ, 25 μM) increased VTA DA neuron sIPSC frequency sixfold, and mIPSC frequency threefold. However, in Cx36 KO mice, MFQ only increased sIPSC and mIPSC frequency threefold. The nonselective GJ blocker carbenoxolone (CBX, 100 μM) increased DA neuron sIPSC frequency twofold in WT mice, did not affect Cx36 KO mouse sIPSCs, and did not affect mIPSCs in WT or Cx36 KO mice. Interestingly, MFQ had no effect on VTA GABA neuron sIPSC frequency. We also examined MFQ effects on VTA DA neuron firing rate and current-evoked spiking in WT and Cx36 KO mice, and found that MFQ decreased WT DA neuron firing rate and current-evoked spiking, but did not alter these measures in Cx36 KO mice. Taken together these findings suggest that blocking Cx36 GJs increases VTA DA neuron inhibition, and that GJs play in key role in regulating inhibition of VTA DA neurons. Synapse, 2011. © 2011 Wiley-Liss, Inc. Copyright © 2011 Wiley-Liss, Inc.

Honokiol promotes non-rapid eye movement sleep via the benzodiazepine site of the GABA(A) receptor in mice.

PubMed

Qu, Wei-Min; Yue, Xiao-Fang; Sun, Yu; Fan, Kun; Chen, Chang-Rui; Hou, Yi-Ping; Urade, Yoshihiro; Huang, Zhi-Li

2012-10-01

Decoctions of the Chinese herb houpu contain honokiol and are used to treat a variety of mental disorders, including depression. Depression commonly presents alongside sleep disorders and sleep disturbances, which appear to be a major risk factor for depression. Here, we have evaluated the somnogenic effect of honokiol and the mechanisms involved. Honokiol was administered i.p. at 20:00 h in mice. Flumazenil, an antagonist at the benzodiazepine site of the GABA(A) receptor, was administered i.p. 15 min before honokiol. The effects of honokiol were measured by EEG and electromyogram (EMG), c-Fos expression and in vitro electrophysiology. Honokiol (10 and 20 mg·kg⁻¹) significantly shortened the sleep latency to non-rapid eye movement (non-REM, NREM) sleep and increased the amount of NREM sleep. Honokiol increased the number of state transitions from wakefulness to NREM sleep and, subsequently, from NREM sleep to wakefulness. However, honokiol had no effect on either the amount of REM sleep or EEG power density of both NREM and REM sleep. Honokiol increased c-Fos expression in ventrolateral preoptic area (VLPO) neurons, as examined by immunostaining, and excited sleep-promoting neurons in the VLPO by whole-cell patch clamping in the brain slice. Pretreatment with flumazenil abolished the somnogenic effects and activation of the VLPO neurons by honokiol. Honokiol promoted NREM sleep by modulating the benzodiazepine site of the GABA(A) receptor, suggesting potential applications in the treatment of insomnia, especially for patients who experience difficulty in falling and staying asleep. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Protection against cyanide-induced convulsions with alpha-ketoglutarate.

PubMed

Yamamoto, H

1990-04-30

Protection against convulsions induced by cyanide was observed after treatment with alpha-ketoglutarate, either alone or in combination with sodium thiosulfate, a classical antagonist for cyanide intoxication. However, sodium thiosulfate alone did not protect against cyanide (30 mg/kg)-induced convulsions. gamma-Aminobutyric acid (GABA) levels in brain were decreased by 31% in KCN-treated mice exhibiting convulsions. The combined administration of alpha-ketoglutarate and sodium thiosulfate completely abolished the decrease of GABA levels induced by cyanide. Furthermore, sodium thiosulfate alone also completely abolished the decrease of GABA levels. These results suggest that the depletion of brain GABA levels may not directly contribute to the development of convulsions induced by cyanide. On the other hand, cyanide increased calcium levels by 32% in brain crude mitochondrial fractions in mice with convulsions. The increased calcium levels were completely abolished by the combined administration of alpha-ketoglutarate and sodium thiosulfate, but not affected by sodium thiosulfate alone. These findings support the hypothesis proposed by Johnson et al. (Toxicol. Appl. Pharmacol., 84 (1986) 464) and Robinson et al. (Toxicology, 35 (1985) 59) that calcium may play an important role in mediating cyanide neurotoxicity.

GABA-B receptor activation and conflict behavior

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ketelaars, C.E.J.; Bollen, E.L.; Rigter, H.

1988-01-01

Baclofen and oxazepam enhance extinction of conflict behavior in the Geller-Seifter test while baclofen and diazepam release punished behavior in Vogel's conflict test. In order to investigate the possibility that the effect of the selective GABA-B receptor agonist baclofen is mediated indirectly via the GABA-A/benzodiazepine receptor complex, the effect of pretreatment of rats with baclofen on (/sup 3/H)-diazepam binding to washed and unwashed cortical and cerebellar membranes of rats has been studied. Baclofen pretreatment increase Bmax in washed cerebellar membranes when bicuculline was present in the incubation mixture. No effect was seen in cortical membranes. The present results render itmore » unlikely that the effect of baclofen on extinction of conflict behavior and punished drinking is mediated via the GABA-A/benzodiazepine receptor complex. 50 references, 1 figure, 4 tables.« less

Successful combination immunotherapy of anti-gamma aminobutyric acid (GABA)A receptor antibody-positive encephalitis with extensive multifocal brain lesions.

PubMed

Fukami, Yuki; Okada, Hiroaki; Yoshida, Mari; Yamaguchi, Keiji

2017-08-31

A 78-year old woman who presented with akinetic mutism was admitted to our hospital. Brain MRI showed multifocal increased T 2 /FLAIR signal with extensive cortical-subcortical involvement. We suspected autoimmune encephalitis and the patient received methylprednisolone pulse. Her conscious level gradually recovered, but later relapsed again and presented with refractory status epilepticus. We treated her with intravenous immunoglobulin, plasma exchange and pulsed cyclophosphamide, with satisfactory response. A brain biopsy showed perivascular lymphocytic infiltrates and reactive gliosis. Anti-gamma aminobutyric acid (GABA) A receptor antibodies test came back to be positive after her recovery, and the diagnosis of anti-GABA A receptor antibody-positive encephalitis was made. This is a very rare case where brain biopsies were performed in a patient with anti-GABA A receptor antibody-positive encephalitis.

Morphine history sensitizes postsynaptic GABA receptors on dorsal raphe serotonin neurons in a stress-induced relapse model in rats.

PubMed

Staub, D R; Lunden, J W; Cathel, A M; Dolben, E L; Kirby, L G

2012-06-01

The serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in stress-related psychiatric disorders and substance abuse. Previous work has shown that the dorsal raphe nucleus (DR)-5-HT system is inhibited by swim stress via stimulation of GABA synaptic activity by the stress neurohormone corticotropin-releasing factor (CRF). Additionally, the DR 5-HT system is regulated by opioids. The present study tests the hypothesis that the DR 5-HT system regulates stress-induced opioid relapse. In the first experiment, electrophysiological recordings of GABA synaptic activity in 5-HT DR neurons were conducted in brain slices from Sprague-Dawley rats that were exposed to swim stress-induced reinstatement of previously extinguished morphine conditioned place preference (CPP). Behavioral data indicate that swim stress triggers reinstatement of morphine CPP. Electrophysiology data indicate that 5-HT neurons in the morphine-conditioned group exposed to stress had increased amplitude of inhibitory postsynaptic currents (IPSCs), which would indicate greater postsynaptic GABA receptor density and/or sensitivity, compared to saline controls exposed to stress. In the second experiment, rats were exposed to either morphine or saline CPP and extinction, and then 5-HT DR neurons from both groups were examined for sensitivity to CRF in vitro. CRF induced a greater inward current in 5-HT neurons from morphine-conditioned subjects compared to saline-conditioned subjects. These data indicate that morphine history sensitizes 5-HT DR neurons to the GABAergic inhibitory effects of stress as well as to some of the effects of CRF. These mechanisms may sensitize subjects with a morphine history to the dysphoric effects of stressors and ultimately confer an enhanced vulnerability to stress-induced opioid relapse. Copyright © 2011 Elsevier Ltd. All rights reserved.

Upregulation of genes related to bone formation by γ-amino butyric acid and γ-oryzanol in germinated brown rice is via the activation of GABAB-receptors and reduction of serum IL-6 in rats.

PubMed

Muhammad, Sani Ismaila; Maznah, Ismail; Mahmud, Rozi; Zuki, Abu Bakar Zakaria; Imam, Mustapha Umar

2013-01-01

Osteoporosis and other bone degenerative diseases are among the most challenging non-communicable diseases to treat. Previous works relate bone loss due to osteoporosis with oxidative stress generated by free radicals and inflammatory cytokines. Alternative therapy to hormone replacement has been an area of interest to researchers for almost three decades due to hormone therapy-associated side effects. In this study, we investigated the effects of gamma-amino butyric acid (GABA), gamma-oryzanol (ORZ), acylated steryl glucosides (ASG), and phenolic extracts from germinated brown rice (GBR) on the expression of genes related to bone metabolism, such as bone morphogenic protein-2 (BMP-2), secreted protein acidic and rich in cysteine (SPARC), runt-related transcription factor 2 (RUNX-2), osteoblast-specific transcription factor osterix (Osx), periostin, osteoblast specific factor (Postn), collagen 1&2 (Col1&2), calcitonin receptor gene (CGRP); body weight measurement and also serum interleukin-6 (IL-6) and osteocalcin, in serum and bone. Rats were treated with GBR, ORZ, GABA, and ASG at (100 and 200 mg/kg); estrogen (0.2 mg/kg), or remifemin (10 and 20 mg/kg), compared to ovariectomized non-treated group as well as non-ovariectomized non-treated (sham) group. Enzyme-linked immunosorbent assay was used to measure the IL-6 and osteocalcin levels at week 2, 4, and 8, while the gene expression in the bone tissue was determined using the Genetic Analysis System (Beckman Coulter Inc., Brea, CA, USA). The results indicate that groups treated with GABA (100 and 200 mg/kg) showed significant upregulation of SPARC, calcitonin receptor, and BMP-2 genes (P < 0.05), while the ORZ-treated group (100 and 200 mg/kg) revealed significant (P < 0.05) upregulation of Osx, Postn, RUNX-2, and Col1&2. Similarly, IL-6 concentration decreased, while osteocalcin levels increased significantly (P < 0.05) in the treated groups as compared to ovariectomized non-treated groups. GABA and ORZ from GBR stimulates osteoblastogenesis by upregulation of bone formation genes, possibly via the activation of GABAB receptors and by inhibiting the activity of inflammatory cytokines and reactive oxygen species. Therefore, it could be used effectively in the management of osteoporosis.

Upregulation of genes related to bone formation by γ-amino butyric acid and γ-oryzanol in germinated brown rice is via the activation of GABAB-receptors and reduction of serum IL-6 in rats

PubMed Central

Muhammad, Sani Ismaila; Maznah, Ismail; Mahmud, Rozi; Zuki, Abu Bakar Zakaria; Imam, Mustapha Umar

2013-01-01

Background Osteoporosis and other bone degenerative diseases are among the most challenging non-communicable diseases to treat. Previous works relate bone loss due to osteoporosis with oxidative stress generated by free radicals and inflammatory cytokines. Alternative therapy to hormone replacement has been an area of interest to researchers for almost three decades due to hormone therapy-associated side effects. Methods In this study, we investigated the effects of gamma-amino butyric acid (GABA), gamma-oryzanol (ORZ), acylated steryl glucosides (ASG), and phenolic extracts from germinated brown rice (GBR) on the expression of genes related to bone metabolism, such as bone morphogenic protein-2 (BMP-2), secreted protein acidic and rich in cysteine (SPARC), runt-related transcription factor 2 (RUNX-2), osteoblast-specific transcription factor osterix (Osx), periostin, osteoblast specific factor (Postn), collagen 1&2 (Col1&2), calcitonin receptor gene (CGRP); body weight measurement and also serum interleukin-6 (IL-6) and osteocalcin, in serum and bone. Rats were treated with GBR, ORZ, GABA, and ASG at (100 and 200 mg/kg); estrogen (0.2 mg/kg), or remifemin (10 and 20 mg/kg), compared to ovariectomized non-treated group as well as non-ovariectomized non-treated (sham) group. Enzyme-linked immunosorbent assay was used to measure the IL-6 and osteocalcin levels at week 2, 4, and 8, while the gene expression in the bone tissue was determined using the Genetic Analysis System (Beckman Coulter Inc., Brea, CA, USA). Results The results indicate that groups treated with GABA (100 and 200 mg/kg) showed significant upregulation of SPARC, calcitonin receptor, and BMP-2 genes (P < 0.05), while the ORZ-treated group (100 and 200 mg/kg) revealed significant (P < 0.05) upregulation of Osx, Postn, RUNX-2, and Col1&2. Similarly, IL-6 concentration decreased, while osteocalcin levels increased significantly (P < 0.05) in the treated groups as compared to ovariectomized non-treated groups. Conclusion GABA and ORZ from GBR stimulates osteoblastogenesis by upregulation of bone formation genes, possibly via the activation of GABAB receptors and by inhibiting the activity of inflammatory cytokines and reactive oxygen species. Therefore, it could be used effectively in the management of osteoporosis. PMID:24098073

Hypoglycemia induced behavioural deficit and decreased GABA receptor, CREB expression in the cerebellum of streptozoticin induced diabetic rats.

PubMed

Sherin, A; Peeyush, K T; Naijil, G; Chinthu, R; Paulose, C S

2010-11-20

Intensive glycemic control during diabetes is associated with an increased incidence of hypoglycemia, which is the major barrier in blood glucose homeostasis during diabetes therapy. The CNS neurotransmitters play an important role in the regulation of glucose homeostasis. In the present study, we showed the effects of hypoglycemia in diabetic and non- diabetic rats on motor functions and alterations of GABA receptor and CREB expression in the cerebellum. Cerebellar dysfunction is associated with seizure generation, motor deficits and memory impairment. Scatchard analysis of [(3)H]GABA binding in the cerebellum of diabetic hypoglycemic and control hypoglycemic rats showed significant (P<0.01) decrease in B(max) and K(d) compared to diabetic and control rats. Real-time PCR amplification of GABA receptor subunit GABA(Aα1) and GAD showed significant (P<0.001) down-regulation in the cerebellum of hypoglycemic rats compared to diabetic and control rats. Confocal imaging study confirmed the decreased GABA receptors in hypoglycemic rats. CREB mRNA expression was down-regulated during recurrent hypoglycemia. Both diabetic and non-diabetic hypoglycemic rats showed impaired performance in grid walk test compared to diabetic and control. Impaired GABA receptor and CREB expression along with motor function deficit were more prominent in hypoglycemic rats than hyperglycemic which showed that hypoglycemia is causing more neuronal damage at molecular level. These molecular changes observed during hypo/hyperglycemia contribute to motor and learning deficits which has clinical significance in diabetes treatment. 2010 Elsevier Inc. All rights reserved.

Neonatal maternal separation delays the GABA excitatory-to-inhibitory functional switch by inhibiting KCC2 expression.

PubMed

Furukawa, Minami; Tsukahara, Takao; Tomita, Kazuo; Iwai, Haruki; Sonomura, Takahiro; Miyawaki, Shouichi; Sato, Tomoaki

2017-11-25

The excitatory-to-inhibitory functional switch of γ-aminobutyric acid (GABA; GABA switch), which normally occurs in the first to the second postnatal week in the hippocampus, is necessary for the development of appropriate central nervous system function. A deficit in GABAergic inhibitory function could cause excitatory/inhibitory (E/I) neuron imbalance that is found in many neurodegenerative disorders. In the present study, we examined whether neonatal stress can affect the timing of the GABA functional switch and cause disorders during adolescence. Neonatal stress was induced in C57BL/6J male mouse pups by maternal separation (MS) on postnatal days (PND) 1-21. Histological quantification of K + -Cl - co-transporter (KCC2) and Ca 2+ imaging were performed to examine the timing of the GABA switch during the MS period. To evaluate the influence of neonatal MS on adolescent hippocampal function, we quantified KCC2 expression and evaluated hippocampal-related behavioral tasks at PND35-38. We showed that MS delayed the timing of the GABA switch in the hippocampus and inhibited the increase in membrane KCC2 expression, with KCC2 expression inhibition persisting until adolescence. Behavioral tests showed impaired cognition, declined attention, hyperlocomotion, and aggressive character in maternally separated mice. Taken together, our results show that neonatal stress delayed the timing of the GABA switch, which could change the E/I balance and cause neurodegenerative disorders in later life. Copyright © 2017 Elsevier Inc. All rights reserved.

Fiat lux! Phylogeny and bioinformatics shed light on GABA functions in plants.

PubMed

Renault, Hugues

2013-06-01

The non-protein amino acid γ-aminobutyric acid (GABA) accumulates in plants in response to a wide variety of environmental cues. Recent data point toward an involvement of GABA in tricarboxylic acid (TCA) cycle activity and respiration, especially in stressed roots. To gain further insights into potential GABA functions in plants, phylogenetic and bioinformatic approaches were undertaken. Phylogenetic reconstruction of the GABA transaminase (GABA-T) protein family revealed the monophyletic nature of plant GABA-Ts. However, this analysis also pointed to the common origin of several plant aminotransferases families, which were found more similar to plant GABA-Ts than yeast and human GABA-Ts. A computational analysis of AtGABA-T co-expressed genes was performed in roots and in stress conditions. This second approach uncovered a strong connection between GABA metabolism and glyoxylate cycle during stress. Both in silico analyses open new perspectives and hypotheses for GABA metabolic functions in plants.

GABA stimulates human hepatocellular carcinoma growth through overexpressed GABAA receptor theta subunit

PubMed Central

Li, Yue-Hui; Liu, Yan; Li, Yan-Dong; Liu, Yan-Hong; Li, Feng; Ju, Qiang; Xie, Ping-Li; Li, Guan-Cheng

2012-01-01

AIM: To investigate the function of gamma-aminobutyric acid (GABA) and gamma-aminobutyric acid A receptor θ subunit (GABRQ) in hepatocellular carcinoma (HCC). METHODS: Semiquantitative polymerase chain reaction was used for detecting the expression of GABRQ receptor among HCC cell line HepG2, normal liver cell line L-02, non-malignant Chang’s liver cells, 8 samples of HCC tissues and paired non-cancerous tissues. HepG2 cells were treated with GABA at serial concentrations (0, 1, 10, 20, 40 and 60 μmol/L), and their proliferating abilities were analyzed with the methyl thiazolyl tetrazolium assay, cell cycle analysis and tumor implanted in nude mice. Small interfering RNA was used for knocking down the endogenous GABRQ in HepG2. Proliferating abilities of these cells treated with or without GABA were analyzed. RESULTS: We identified the overexpression of GABRQ in HCC cell lines and half of the tested HCC tissues. Knockdown of endogenous GABRQ expression in HepG2 attenuated HCC cell growth, suggesting its role in HCC cell viability. We studied the effect of GABA in the proliferation of GABRQ-positive cell lines in vitro and in vivo, and found that GABA increased HCC growth in a dose-dependent manner. Notably, the addition of GABA into the cell culture medium promoted the proliferation of GABRQ-expressing HepG2 cells, but not GABRQ-knockdown HepG2 cells, which means that GABA stimulates HepG2 cell growth through GABRQ. CONCLUSION: GABRQ play important roles in HCC development and progression and could be a promising molecular target for the development of new diagnostic and therapeutic strategies of HCC. PMID:22690081

Sodium p-Aminosalicylic Acid Reverses Sub-Chronic Manganese-Induced Impairments of Spatial Learning and Memory Abilities in Rats, but Fails to Restore γ-Aminobutyric Acid Levels

PubMed Central

Li, Shao-Jun; Ou, Chao-Yan; He, Sheng-Nan; Huang, Xiao-Wei; Luo, Hai-Lan; Meng, Hao-Yang; Lu, Guo-Dong; Jiang, Yue-Ming; Vieira Peres, Tanara; Luo, Yi-Ni; Deng, Xiang-Fa

2017-01-01

Excessive manganese (Mn) exposure is not only a health risk for occupational workers, but also for the general population. Sodium para-aminosalicylic acid (PAS-Na) has been successfully used in the treatment of manganism, but the involved molecular mechanisms have yet to be determined. The present study aimed to investigate the effects of PAS-Na on sub-chronic Mn exposure-induced impairments of spatial learning and memory, and determine the possible involvements of γ-aminobutyric acid (GABA) metabolism in vivo. Sprague-Dawley male rats received daily intraperitoneal injections MnCl2 (as 6.55 mg/kg Mn body weight, five days per week for 12 weeks), followed by daily subcutaneous injections of 100, 200, or 300 mg/kg PAS-Na for an additional six weeks. Mn exposure significantly impaired spatial learning and memory ability, as noted in the Morris water maze test, and the following PAS-Na treatment successfully restored these adverse effects to levels indistinguishable from controls. Unexpectedly, PAS-Na failed to recover the Mn-induced decrease in the overall GABA levels, although PAS-Na treatment reversed Mn-induced alterations in the enzyme activities directly responsible for the synthesis and degradation of GABA (glutamate decarboxylase and GABA-transaminase, respectively). Moreover, Mn exposure caused an increase of GABA transporter 1 (GAT-1) and decrease of GABA A receptor (GABAA) in transcriptional levels, which could be reverted by the highest dose of 300 mg/kg PAS-Na treatment. In conclusion, the GABA metabolism was interrupted by sub-chronic Mn exposure. However, the PAS-Na treatment mediated protection from sub-chronic Mn exposure-induced neurotoxicity, which may not be dependent on the GABA metabolism. PMID:28394286

Distribution of 3H-GABA uptake sites in the nematode Ascaris

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guastella, J.; Stretton, A.O.

1991-05-22

The distribution of uptake sites for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the nematode Ascaris suum was examined by autoradiography of 3H-GABA uptake. Single neural processes in both the ventral and dorsal nerve cords were labeled with 3H-GABA. Serial section analysis identified the cells of origin of these processes as the RMEV-like and RMED-like neurons. These cells belong to a set of four neurons in the nerve ring, all of which are labeled by 3H-GABA. 3H-GABA labeling of at least two other sets of cephalic neurons was seen. One of these pairs consists of medium-sized lateral ganglia neurons, locatedmore » at the level of the amphid commissure bundle. A second pair is located in the lateral ganglia at the level of the deirid commissure bundle. The position and size of these lateral ganglia cells suggest that they are the GABA-immunoreactive lateral ganglia cells frequently seen in whole-mount immunocytochemical preparations. Four neuronal cell bodies located in the retrovesicular ganglion were also labeled with 3H-GABA. These cells, which are probably cholinergic excitatory motor neurons, do not contain detectable GABA-like immunoreactivity. Heavy labeling of muscle cells was also observed. The ventral and dorsal nerve cord inhibitory motor neurons, which are known to contain GABA-like immunoreactivity, were not labeled above background with 3H-GABA. Together with the experiments reported previously, these results define three classes of GABA-associated neurons in Ascaris: (1) neurons that contain endogenous GABA and possess a GABA uptake system; (2) neurons that contain endogenous GABA, but that either lack a GABA uptake system or possess a GABA uptake system of low activity; (3) neurons that possess a GABA uptake system, but that lack endogenous GABA.« less

Clarified Açaí (Euterpe oleracea) Juice as an Anticonvulsant Agent: In Vitro Mechanistic Study of GABAergic Targets

PubMed Central

Arrifano, Gabriela P. F.; Lichtenstein, Mathieu P.; Souza-Monteiro, José Rogério; Rogez, Hervé

2018-01-01

Seizures affect about 50 million people around the world. Approximately 30% of seizures are refractory to the current pharmacological arsenal, so, the pursuit of new therapeutic alternatives is essential. Clarified Euterpe oleracea (EO) juice showed anticonvulsant properties similar to diazepam in an in vivo model with pentylenetetrazol, a GABAA receptor blocker. This study investigated the effects of EO on the main GABAergic targets for anticonvulsant drugs, analyzing the effect on the GABA receptor's benzodiazepine and picrotoxinin binding sites and the GABA uptake. Primary cultures of cortical neurons and astrocytes were treated with EO (0–25%) for up to 90 min. [3H]Flunitrazepam and [3H]TBOB binding, [3H]GABA uptake, cell viability, and morphology were assayed. Nonlethal concentrations of EO increased agonist binding and decreased antagonist binding in cortical neurons. Low concentrations significantly inhibited GABA uptake, especially in astrocytes, suggesting an accumulation of endogenous GABA in the synaptic cleft. The results demonstrate, for the first time, that EO can improve GABAergic neurotransmission via interactions with GABAA receptor and modulation of GABA uptake. Understanding these molecular mechanisms will help in the treatment of seizures and epilepsy, especially in developing countries where geographic isolation and low purchasing power are the main barriers to access to adequate treatment. PMID:29743978

Ichnocarpus frutescens Ameliorates Experimentally Induced Convulsion in Rats

PubMed Central

Singh, Narendra Kumar; Laloo, Damiki; Garabadu, Debapriya; Singh, Tryambak Deo; Singh, Virendra Pratap

2014-01-01

The present study was carried out to evaluate the anticonvulsant activity and probable mechanism of action of the methanol root extract from I. frutescens (MEIF) using different experimental animal models. Anticonvulsant activity of the single dose of MEIF (100, 200, and 400 mg/kg, p.o.) was evaluated in maximal electroshock- (MES-), pentylenetetrazole- (PTZ-), and isoniazid- (INH-) induced convulsions models in rats. The levels of γ-amino butyric acid (GABA), glutamate, GABA-transaminase (GABA-T) activity and oxidative stress markers were measured in pretreated rat's brain homogenate to corroborate the mechanism of observed anticonvulsant activity. MEIF (200–400 mg/kg, p.o.) protected the animals in all the behavioral models used. Pretreatment of MEIF (200–400 mg/kg, p.o.) and diazepam (1.0 mg/kg, i.p.) to the animals in INH-induced convulsion model showed 100% and 80% protection, respectively, as well as significant restoration of GABA and glutamate level in the rat's brain. MEIF and vigabatrin (50 mg/kg, i.p.) reduced the PTZ-induced increase in the activity of GABA-T (46%) in the brain. Further, MEIF reversed the PTZ-induced increase in lipid peroxidase (LPO) and decrease in reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) activities. The findings of this study validate the anticonvulsant activity of I. frutescens. PMID:27379268

Amphetamine regulation of acetylcholine and gamma-aminobutyric acid in nucleus accumbens.

PubMed

Lindefors, N; Hurd, Y L; O'Connor, W T; Brené, S; Persson, H; Ungerstedt, U

1992-01-01

In situ hybridization histochemistry and in vivo microdialysis were combined to study the effect of amphetamine on the expression of choline acetyltransferase and glutamate decarboxylase67 mRNA and in vivo release of acetylcholine and GABA in rat medial nucleus accumbens. Differential effects on acetylcholine and GABA neurons by a single challenge injection of amphetamine (1.5 mg/kg, s.c.) were apparent in saline-pretreated and amphetamine-pretreated (same dose, twice daily for the previous seven days) rats. Extracellular acetylcholine levels were increased up to 50% over a prolonged period following both single and repeated amphetamine. In contrast, extracellular concentrations of GABA were gradually decreased to half the control values, but only in rats receiving repeated amphetamine. Although the increase of acetylcholine release was not associated with any change in choline acetyltransferase mRNA levels, the number of neurons expressing high levels of glutamate decarboxylase67 mRNA was decreased (28%) following repeated injections. Thus we suggest that amphetamine decreases extracellular GABA levels by a slow mechanism, associated with the decreased expression of glutamate decarboxylase67 mRNA in a subpopulation of densely labeled neurons in the medial nucleus accumbens. The delayed response by GABA to amphetamine may reflect supersensitivity in the activity of postsynaptic gamma-aminobutyric acid-containing neurons in nucleus accumbens as a consequence of the repeated amphetamine treatment.

EFFECTS OF MEDIAL SEPTAL LESION ON HIPPOCAMPAL EXTRACELLULAR GLUTAMATE AND GABA LEVELS DURING SPATIAL ALTERNATION TESTING.

PubMed

Mataradze, S; Naneishvili, T; Sephashvili, M; Mikeladze, D; Dashniani, M

2016-10-01

The present study investigated spatial working memory assessed in spontaneous alternation (SA) task and hippocampal glutamate and GABA release prior to, during, and after SA test in sham-operated and electrolytic medial septal (MS) lesioned rats. Also, have been investigated the effects of MS lesion on KCl-stimulated release of glutamate and GABA in the hippocampus. Behavioral study showed that electrolytic lesion of MS significantly impaired SA performance. Although both groups of animals had an insignificant rise in their respective hippocampal glutamate efflux during the SA, the rise of MS lesioned animals was blunted when compared with control animals. Hippocampal GABA levels did not change during behavioral testing in both groups. Most of control animals showed increase in KCl-stimulated glutamate release. By contrast, only one MS lesioned rat showed increase in glutamate release in response to KCl stimulation. Most of control and MS lesioned rats were non-responders in GABA release in response to KCl stimulation. Decreased glutamate release (upon stimulation) in the MS lesioned rats may contribute to spatial working memory impairment in these animals. We propose that SA testing coupled with in vivo microdialysis sampling represents a suitable approach to revealing the neurochemical correlates of hippocampal-dependent memory function, and thus could be a useful tool for better understanding of the neurochemical basis of cognitive decline associated with various disorders and neurodegenerative diseases.

Exploring the relationship between cortical GABA concentrations, auditory gamma-band responses and development in ASD: Evidence for an altered maturational trajectory in ASD.

PubMed

Port, Russell G; Gaetz, William; Bloy, Luke; Wang, Dah-Jyuu; Blaskey, Lisa; Kuschner, Emily S; Levy, Susan E; Brodkin, Edward S; Roberts, Timothy P L

2017-04-01

Autism spectrum disorder (ASD) is hypothesized to arise from imbalances between excitatory and inhibitory neurotransmission (E/I imbalance). Studies have demonstrated E/I imbalance in individuals with ASD and also corresponding rodent models. One neural process thought to be reliant on E/I balance is gamma-band activity (Gamma), with support arising from observed correlations between motor, as well as visual, Gamma and underlying GABA concentrations in healthy adults. Additionally, decreased Gamma has been observed in ASD individuals and relevant animal models, though the direct relationship between Gamma and GABA concentrations in ASD remains unexplored. This study combined magnetoencephalography (MEG) and edited magnetic resonance spectroscopy (MRS) in 27 typically developing individuals (TD) and 30 individuals with ASD. Auditory cortex localized phase-locked Gamma was compared to resting Superior Temporal Gyrus relative cortical GABA concentrations for both children/adolescents and adults. Children/adolescents with ASD exhibited significantly decreased GABA+/Creatine (Cr) levels, though typical Gamma. Additionally, these children/adolescents lacked the typical maturation of GABA+/Cr concentrations and gamma-band coherence. Furthermore, children/adolescents with ASD additionally failed to exhibit the typical GABA+/Cr to gamma-band coherence association. This altered coupling during childhood/adolescence may result in Gamma decreases observed in the adults with ASD. Therefore, individuals with ASD exhibit improper local neuronal circuitry maturation during a childhood/adolescence critical period, when GABA is involved in configuring of such circuit functioning. Provocatively a novel line of treatment is suggested (with a critical time window); by increasing neural GABA levels in children/adolescents with ASD, proper local circuitry maturation may be restored resulting in typical Gamma in adulthood. Autism Res 2017, 10: 593-607. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Excitatory action of GABA on immature neurons is not due to absence of ketone bodies metabolites or other energy substrates.

PubMed

Ben-Ari, Yehezkel; Tyzio, Roman; Nehlig, Astrid

2011-09-01

Brain slices incubated with glucose have provided most of our knowledge on cellular, synaptic, and network driven mechanisms. It has been recently suggested that γ-aminobutyric acid (GABA) excites neonatal neurons in conventional glucose-perfused slices but not when ketone bodies metabolites, pyruvate, and/or lactate are added, suggesting that the excitatory actions of GABA are due to energy deprivation when glucose is the sole energy source. In this article, we review the vast number of studies that show that slices are not energy deprived in glucose-containing medium, and that addition of other energy substrates at physiologic concentrations does not alter the excitatory actions of GABA on neonatal neurons. In contrast, lactate, like other weak acids, can produce an intracellular acidification that will cause a reduction of intracellular chloride and a shift of GABA actions. The effects of high concentrations of lactate, and particularly of pyruvate (4-5 mm), as used are relevant primarily to pathologic conditions; these concentrations not being found in the brain in normal "control" conditions. Slices in glucose-containing medium may not be ideal, but additional energy substrates neither correspond to physiologic conditions nor alter GABA actions. In keeping with extensive observations in a wide range of animal species and brain structures, GABA depolarizes immature neurons and the reduction of the intracellular concentration of chloride ([Cl(-)](i)) is a basic property of brain maturation that has been preserved throughout evolution. In addition, this developmental sequence has important clinical implications, notably concerning the higher incidence of seizures early in life and their long-lasting deleterious sequels. Immature neurons have difficulties exporting chloride that accumulates during seizures, leading to permanent increase of [Cl(-)](i) that converts the inhibitory actions of GABA to excitatory and hampers the efficacy of GABA-acting antiepileptic drugs. Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.

A Negative Allosteric Modulator for α5 Subunit-Containing GABA Receptors Exerts a Rapid and Persistent Antidepressant-Like Action without the Side Effects of the NMDA Receptor Antagonist Ketamine in Mice

PubMed Central

Nelson, Mackenzie E.; Krimmel, Samuel R.; Georgiou, Polymnia; Gould, Todd D.

2017-01-01

Abstract New antidepressant pharmacotherapies that provide rapid relief of depressive symptoms are needed. The NMDA receptor antagonist ketamine exerts rapid antidepressant actions in depressed patients but also side effects that complicate its clinical utility. Ketamine promotes excitatory synaptic strength, likely by producing high-frequency correlated activity in mood-relevant regions of the forebrain. Negative allosteric modulators of GABA-A receptors containing α5 subunits (α5 GABA-NAMs) should also promote high-frequency correlated electroencephalogram (EEG) activity and should therefore exert rapid antidepressant responses. Because α5 subunits display a restricted expression in the forebrain, we predicted that α5 GABA-NAMs would produce activation of principle neurons but exert fewer side effects than ketamine. We tested this hypothesis in male mice and observed that the α5 GABA-NAM MRK-016 exerted an antidepressant-like response in the forced swim test at 1 and 24 h after administration and an anti-anhedonic response after chronic stress in the female urine sniffing test (FUST). Like ketamine, MRK-016 produced a transient increase in EEG γ power, and both the increase in γ power and its antidepressant effects in the forced swim test were blocked by prior administration of the AMPA-type glutamate receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX). Unlike ketamine, however, MRK-016 produced no impairment of rota-rod performance, no reduction of prepulse inhibition (PPI), no conditioned-place preference (CPP), and no change in locomotion. α5 GABA-NAMs, thus reproduce the rapid antidepressant-like actions of ketamine, perhaps via an AMPA receptor (AMPAR)-dependent increase in coherent neuronal activity, but display fewer potential negative side effects. These compounds thus demonstrate promise as clinically useful fast-acting antidepressants. PMID:28275719

p-Coumaric acid activates the GABA-A receptor in vitro and is orally anxiolytic in vivo.

PubMed

Scheepens, Arjan; Bisson, Jean-Francois; Skinner, Margot

2014-02-01

The increasing prevalence and social burden of subclinical anxiety in the western world represents a significant psychosocial and financial cost. Consumers are favouring a more natural and nonpharmacological approach for alleviating the effects of everyday stress and anxiety. The gamma-aminobutyric acid (GABA) receptor is the primary mediator of central inhibitory neurotransmission, and GABA-receptor agonists are well known to convey anxiolytic effects. Using an in vitro screening approach to identify naturally occurring phytochemical GABA agonists, we discovered the plant secondary metabolite p-coumaric acid to have significant GABAergic activity, an effect that could be blocked by co-administration of the specific GABA-receptor antagonist, picrotoxin. Oral administration of p-coumaric acid to rodents induced a significant anxiolytic effect in vivo as measured using the elevated plus paradigm, in line with the effects of oral diazepam. Given that p-coumaric acid is reasonably well absorbed following oral consumption in man and is relatively nontoxic, it may be suitable for the formulation of a safe and effective anxiolytic functional food. Copyright © 2013 John Wiley & Sons, Ltd.

Transcriptome analysis of the key role of GAT2 gene in the hyper-accumulation of copper in the oyster Crassostrea angulata

NASA Astrophysics Data System (ADS)

Shi, Bo; Huang, Zekun; Xiang, Xu; Huang, Miaoqin; Wang, Wen-Xiong; Ke, Caihuan

2015-12-01

One paradigm of oysters as the hyper-accumulators of many toxic metals is the inter-individual variation of metals, but the molecular mechanisms remain very elusive. A comprehensive analysis of the transcriptome of Crassostrea angulata was conducted to reveal the relationship between gene expression and differential Cu body burden in oysters. Gene ontology analysis for the differentially expressed genes showed that the neurotransmitter transporter might affect the oyster behavior, which in turn led to difference in Cu accumulation. The ATP-binding cassette transporters superfamily played an important role in the maintenance of cell Cu homeostasis, vitellogenin and apolipophorin transport, and elimination of excess Cu. Gill and mantle Cu concentrations were significantly reduced after silencing the GABA transporter 2 (GAT2) gene, but increased after the injection of GABA receptor antagonists, suggesting that the function of GABA transporter 2 gene was strongly related to Cu accumulation. These findings demonstrated that GABA transporter can control the action of transmitter GABA in the nervous system, thereby affecting the Cu accumulation in the gills and mantles.

Analgesia and hyperalgesia from GABA-mediated modulation of the cerebral cortex.

PubMed

Jasmin, Luc; Rabkin, Samuel D; Granato, Alberto; Boudah, Abdennacer; Ohara, Peter T

2003-07-17

It is known that pain perception can be altered by mood, attention and cognition, or by direct stimulation of the cerebral cortex, but we know little of the neural mechanisms underlying the cortical modulation of pain. One of the few cortical areas consistently activated by painful stimuli is the rostral agranular insular cortex (RAIC) where, as in other parts of the cortex, the neurotransmitter gamma-aminobutyric acid (GABA) robustly inhibits neuronal activity. Here we show that changes in GABA neurotransmission in the RAIC can raise or lower the pain threshold--producing analgesia or hyperalgesia, respectively--in freely moving rats. Locally increasing GABA, by using an enzyme inhibitor or gene transfer mediated by a viral vector, produces lasting analgesia by enhancing the descending inhibition of spinal nociceptive neurons. Selectively activating GABA(B)-receptor-bearing RAIC neurons produces hyperalgesia through projections to the amygdala, an area involved in pain and fear. Whereas most studies focus on the role of the cerebral cortex as the end point of nociceptive processing, we suggest that cerebral cortex activity can change the set-point of pain threshold in a top-down manner.

Kcnj6(GIRK2) trisomy is not sufficient for conferring the susceptibility to infantile spasms seen in the Ts65Dn mouse model of down syndrome.

PubMed

Joshi, Krutika; Shen, Lily; Cao, Feng; Dong, Susan; Jia, Zhengping; Cortez, Miguel A; Snead, O Carter

2018-06-12

Infantile spasms (IS) is a catastrophic childhood seizure disorder that is characterized by extensor and/or flexor spasms, cognitive deterioration and a characteristic EEG abnormality. The latter consists of a pattern of a spike-wave followed by an electrodecremental response (EDR), which is a flattening of the EEG waveform amplitude. The mechanism/circuitry that underpins IS is unknown. Children with Down Syndrome (DS) are particularly vulnerable to IS. The standard mouse model of DS is the Ts65Dn mutant mouse (Ts). Using the Ts mouse, we have created an animal model of IS in DS. This model entails the treatment of Ts mice with a GABA B R agonist with a resultant recapitulation of the semiological, electrographic, and pharmacological phenotype of IS. One of the genes triplicated in Ts mice is the kcnj6 gene which codes for the G-protein inwardly rectifying potassium channel 2 (GIRK2) protein. We have shown that over expression of GIRK2 in Ts brain is necessary for the production of the GABA B R agonist induced IS phenotype in the Ts mouse. Here, we ask the question whether the excess GIRK2 is sufficient for the production of the GABA B R agonist induced IS phenotype. To address this question, we used kcnj6 triploid mice, and compared the number of spasms via video analysis and EDR events via EEG to that of the WT mice. We now show that GABA R R agonist-treated kcnj6 triploid mice failed to show susceptibility to the IS phenotype. Therefore, over expression of GIRK2 in the brain is necessary, but not sufficient to confer susceptibility to the GABA B R agonist-induced IS phenotype in the Ts model of DS. It is therefore likely that GIRK2 is working in concert with another factor or factors that are altered in the Ts brain in the production of the GABA B R agonist-induced IS phenotype. Copyright © 2018. Published by Elsevier B.V.

Vortioxetine Treatment Reverses Subchronic PCP Treatment-Induced Cognitive Impairments: A Potential Role for Serotonin Receptor-Mediated Regulation of GABA Neurotransmission

PubMed Central

Pehrson, Alan L.; Pedersen, Christian S.; Tølbøl, Kirstine Sloth; Sanchez, Connie

2018-01-01

Major depressive disorder (MDD) is associated with cognitive impairments that may contribute to poor functional outcomes. Clinical data suggests that the multimodal antidepressant vortioxetine attenuates some cognitive impairments in MDD patients, but the mechanistic basis for these improvements is unclear. One theory suggests that vortioxetine improves cognition by suppressing γ-amino butyric acid (GABA)ergic neurotransmission, thereby increasing glutamatergic activation. Vortioxetine’s effects on cognition, GABA and glutamate neurotransmission have been supported in separate experiments, but no empirical work has directly connected vortioxetine’s cognitive effects to those on GABA and glutamate neurotransmission. In this paper, we attempt to bridge this gap by evaluating vortioxetine’s effects in the subchronic PCP (subPCP) model, which induces impaired cognitive function and altered GABA and glutamate neurotransmission. We demonstrate that acute or subchronic vortioxetine treatment attenuated subPCP-induced deficits in attentional set shifting (AST) performance, and that the selective 5-HT3 receptor antagonist ondansetron or the 5-HT reuptake inhibitor escitalopram could mimic this effect. Furthermore, acute vortioxetine treatment reversed subPCP-induced object recognition (OR) deficits in rats, while subchronic vortioxetine reversed subPCP-induced Object Recognition and object placement impairments in mice. Finally, subPCP treatment reduced GABAB receptor expression in a manner that was insensitive to vortioxetine treatment, and subchronic vortioxetine treatment alone, but not in combination with subPCP, significantly increased GABA’s affinity for the GABAA receptor. These data suggest that vortioxetine reverses cognitive impairments in a model associated with altered GABA and glutamate neurotransmission, further supporting the hypothesis that vortioxetine’s GABAergic and glutamatergic effects are relevant for cognitive function. PMID:29559911

Prefrontal cortical GABA modulation of spatial reference and working memory.

PubMed

Auger, Meagan L; Floresco, Stan B

2014-10-31

Dysfunction in prefrontal cortex (PFC) GABA transmission has been proposed to contribute to cognitive dysfunction in schizophrenia, yet how this system regulates different cognitive and mnemonic functions remains unclear. We assessed the effects of pharmacological reduction of GABAA signaling in the medial PFC of rats on spatial reference/working memory using different versions of the radial-arm maze task. We used a massed-trials procedure to probe how PFC GABA regulates susceptibility to proactive interference. Male rats were well-trained to retrieve food from the same 4 arms of an 8-arm maze, receiving 5 trials/day (1-2 min intervals). Infusions of the GABAA receptor antagonist bicuculline (12.5-50 ng) markedly increased working and reference memory errors and response latencies. Similar treatments also impaired short-term memory on an 8-baited arm task. These effects did not appear to be due to increased susceptibility to proactive interference. In contrast, PFC inactivation via infusion of GABA agonists baclofen/muscimol did not affect reference/working memory. In comparison to the pronounced effects on the 8-arm maze tasks, PFC GABAA antagonism only causes a slight and transient decrease in accuracy on a 2-arm spatial discrimination. These findings demonstrate that prefrontal GABA hypofunction severely disrupts spatial reference and short-term memory and that disinhibition of the PFC can, in some instances, perturb memory processes not normally dependent on the frontal lobes. Moreover, these impairments closely resemble those observed in schizophrenic patients, suggesting that perturbation in PFC GABA signaling may contribute to these types of cognitive deficits associated with the disorder. © The Author 2014. Published by Oxford University Press on behalf of CINP.

Neonatal blockade of GABA-A receptors alters behavioral and physiological phenotypes in adult mice.

PubMed

Salari, Ali-Akbar; Amani, Mohammad

2017-04-01

Gamma-aminobutyric acid (GABA) plays an inhibitory role in the mature brain, and has a complex and bidirectional effect in different parts of the immature brain which affects proliferation, migration and differentiation of neurons during development. There is also increasing evidence suggesting that activation or blockade of the GABA-A receptors during early life can induce brain and behavioral abnormalities in adulthood. We investigated whether neonatal blockade of the GABA-A receptors by bicuculline can alter anxiety- and depression-like behaviors, body weight, food intake, corticosterone and testosterone levels in adult mice (postnatal days 80-95). To this end, neonatal mice were treated with either DMSO or bicuculline (70, 150 and 300μg/kg) during postnatal days 7, 9 and 11. When grown to adulthood, mice were exposed to behavioral tests to measure anxiety- (elevated plus-maze and light-dark box) and depression-like behaviors (tail suspension test and forced swim test). Stress-induced serum corticosterone and testosterone levels, body weight and food intake were also evaluated. Neonatal bicuculline exposure at dose of 300μg/kg decreased anxiety-like behavior, stress-induced corticosterone levels and increased testosterone levels, body weight and food intake, without significantly influencing depression-like behavior in adult male mice. However, no significant changes in these parameters were observed in adult females. These findings suggest that neonatal blockade of GABA-A receptors affects anxiety-like behavior, physiological and hormonal parameters in a sex-dependent manner in mice. Taken together, these data corroborate the concept that GABA-A receptors during early life have an important role in programming neurobehavioral phenotypes in adulthood. Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.

Activation of endogenous GABAA channels on airway smooth muscle potentiates isoproterenol-mediated relaxation.

PubMed

Gallos, George; Gleason, Neil R; Zhang, Yi; Pak, Sang-Woo; Sonett, J R; Yang, Jay; Emala, Charles W

2008-12-01

Reactive airway disease predisposes patients to episodes of acute smooth muscle mediated bronchoconstriction. We have for the first time recently demonstrated the expression and function of endogenous ionotropic GABA(A) channels on airway smooth muscle cells. We questioned whether endogenous GABA(A) channels on airway smooth muscle could augment beta-agonist-mediated relaxation. Guinea pig tracheal rings or human bronchial airway smooth muscles were equilibrated in organ baths with continuous digital tension recordings. After pretreatment with or without the selective GABA(A) antagonist gabazine (100 muM), airway muscle was contracted with acetylcholine or beta-ala neurokinin A, followed by relaxation induced by cumulatively increasing concentrations of isoproterenol (1 nM to 1 muM) in the absence or presence of the selective GABA(A) agonist muscimol (10-100 muM). In separate experiments, guinea pig tracheal rings were pretreated with the large conductance K(Ca) channel blocker iberiotoxin (100 nM) after an EC(50) contraction with acetylcholine but before cumulatively increasing concentrations of isoproterenol (1 nM to 1 uM) in the absence or presence of muscimol (100 uM). GABA(A) activation potentiated the relaxant effects of isoproterenol after an acetylcholine or tachykinin-induced contraction in guinea pig tracheal rings or an acetylcholine-induced contraction in human endobronchial smooth muscle. This muscimol-induced potentiation of relaxation was abolished by gabazine pretreatment but persisted after blockade of the maxi K(Ca) channel. Selective activation of endogenous GABA(A) receptors significantly augments beta-agonist-mediated relaxation of guinea pig and human airway smooth muscle, which may have important therapeutic implications for patients in severe bronchospasm.

Brain region-selective cellular redistribution of mGlu5 but not GABA(B) receptors following methamphetamine-induced associative learning.

PubMed

Herrold, Amy A; Voigt, Robin M; Napier, T Celeste

2011-12-01

Alterations in receptor expression and distribution between cell surface and cytoplasm are means by which psychostimulants regulate neurotransmission. Metabotropic glutamate receptor group I, subtype 5 (mGluR5) and GABA(B) receptors (GABA(B) R) are critically involved in the development and expression of stimulant-induced behaviors, including conditioned place preference (CPP), an index of drug-seeking. However, it is not known if psychostimulant-induced CPP alters the trafficking of these receptors. To fill this gap, this study used methamphetamine (Meth)-induced CPP in rats to ascertain if receptor changes occur in limbic brain regions that regulate drug-seeking, the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and ventral pallidum (VP). To do so, ex vivo tissue was assessed for changes in expression and surface vs. intracellular distribution of mGluR5 and GABA(B) Rs. There was a decrease in the surface to intracellular ratio of mGluR5 in the mPFC in Meth-conditioned rats, commensurate with an increase in intracellular levels. mGluR5 levels in the NAc or the VP were unaltered. There were no changes for GABA(B) R in any brain region assayed. This ex vivo snapshot of metabotropic glutamate and GABA receptor cellular distribution following induction of Meth-induced CPP is the first report to determine if these receptors are differentially altered after Meth-induced CPP. The results suggest that this Meth treatment paradigm likely induced a compensatory change in mGluR5 surface to intracellular ratio such that the surface remains unaltered while an increase in intracellular protein occurred. Copyright © 2011 Wiley-Liss, Inc.

Dependence-induced ethanol drinking and GABA neurotransmission are altered in Alk deficient mice

PubMed Central

Schweitzer, Paul; Cates-Gatto, Chelsea; Varodayan, Florence P.; Nadav, Tali; Roberto, Marisa; Lasek, Amy W.; Roberts, Amanda J.

2016-01-01

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is expressed in the brain and implicated in alcohol abuse in humans and behavioral responses to ethanol in mice. Previous studies have shown an association of human ALK with acute responses to alcohol and alcohol dependence. In addition, Alk knockout (Alk −/−) mice consume more ethanol in a binge-drinking test and show increased sensitivity to ethanol sedation. However, the function of ALK in excessive drinking following the establishment of ethanol dependence has not been examined. In this study, we tested Alk −/− mice for dependence-induced drinking using the chronic intermittent ethanol-two bottle choice drinking (CIE-2BC) protocol. We found that Alk −/− mice initially consume more ethanol prior to CIE exposure, but do not escalate ethanol consumption after exposure, suggesting that ALK may promote the escalation of drinking after ethanol dependence. To determine the mechanism(s) responsible for this behavioral phenotype we used an electrophysiological approach to examine GABA neurotransmission in the central nucleus of the amygdala (CeA), a brain region that regulates alcohol consumption and shows increased GABA signaling after chronic ethanol exposure. GABA transmission in ethanol-naïve Alk −/− mice was enhanced at baseline and potentiated in response to acute ethanol application when compared to wild-type (Alk +/+) mice. Moreover, basal GABA transmission was not elevated by CIE exposure in Alk −/− mice as it was in Alk +/+ mice. These data suggest that ALK plays a role in dependence-induced drinking and the regulation of presynaptic GABA release in the CeA. PMID:26946429

Characterization of γ-aminobutyric acid metabolism and oxidative damage in wheat (Triticum aestivum L.) seedlings under salt and osmotic stress.

PubMed

Al-Quraan, Nisreen A; Sartawe, Fatima Al-Batool; Qaryouti, Muien M

2013-07-15

The molecular response of plants to abiotic stresses has been considered a process mainly involved in the modulation of transcriptional activity of stress-related genes. Nevertheless, recent findings have suggested new layers of regulation and complexity. Upstream molecular mechanisms are involved in the plant response to abiotic stress. Plants gain resistance to abiotic stress by reprogramming metabolism and gene expression. GABA is proposed to be a signaling molecule involved in nitrogen metabolism, regulating the cytosolic pH, and protection against oxidative damage in response to various abiotic stresses. The aim of our study was to examine the role of the GABA shunt pathway-specific response in five wheat (Triticum aestivum L.) cultivars (Hurani 75, Sham I, Acsad 65, Um Qayes and Nodsieh) to salt and osmotic stress in terms of seed germination, seedling growth, oxidative damage (malondialdehyde (MDA) accumulation), and characterization of the glutamate decarboxylse gene (GAD) m-RNA level were determined using RT-PCR techniques. Our data showed a marked increase in GABA, MDA and GAD m-RNA levels under salt and osmotic stress in the five wheat cultivars. Um Qayes cultivar showed the highest germination percentage, GABA accumulation, and MDA level under salt and osmotic stresses. The marked increase in GAD gene expression explains the high accumulation of the GABA level under both stresses. Our results indicated that the GABA shunt is a key signaling and metabolic pathway that allows wheat to adapt to salt and osmotic stress. Based on our data, the Um Qayes wheat cultivar is the cultivar most recommended to be grown in soil with high salt and osmotic contents. Copyright © 2013 Elsevier GmbH. All rights reserved.

GABA Levels Are Decreased After Stroke and GABA Changes During Rehabilitation Correlate With Motor Improvement

PubMed Central

Blicher, Jakob Udby; Near, Jamie; Næss-Schmidt, Erhard; Stagg, Charlotte J.; Johansen-Berg, Heidi; Nielsen, Jørgen Feldbæk; Østergaard, Leif; Ho, Yi-Ching Lynn

2017-01-01

Background and Objective γ-Aminobutyric acid (GABA) is the dominant inhibitory neurotransmitter in the brain and is important in motor learning. We aimed to measure GABA content in primary motor cortex poststroke (using GABA-edited magnetic resonance spectroscopy [MRS]) and in relation to motor recovery during 2 weeks of constraint-induced movement therapy (CIMT). Methods Twenty-one patients (3-12 months poststroke) and 20 healthy subjects were recruited. Magnetic resonance imaging structural T1 and GABA-edited MRS were performed at baseline and after CIMT, and once in healthy subjects. GABA:creatine (GABA:Cr) ratio was measured by GABA-edited MRS. Motor function was measured using Wolf Motor Function Test (WMFT). Results Baseline comparison between stroke patients (n = 19) and healthy subjects showed a significantly lower GABA:Cr ratio in stroke patients (P < .001) even after correcting for gray matter content in the voxel (P < .01) and when expressing GABA relative to N-acetylaspartic acid (NAA; P = .03). After 2 weeks of CIMT patients improved significantly on WMFT, but no consistent change across the group was observed for the GABA:Cr ratio (n = 17). However, the extent of improvement on WMFT correlated significantly with the magnitude of GABA:Cr changes (P < .01), with decreases in GABA:Cr ratio being associated with better improvements in motor function. Conclusions In patients 3 to 12 months poststroke, GABA levels are lower in the primary motor cortex than in healthy subjects. The observed association between GABA and recovery warrants further studies on the potential use of GABA MRS as a biomarker in poststroke recovery. PMID:25055837

Frequency-dependent actions of benzodiazepines on GABAA receptors in cultured murine cerebellar granule cells.

PubMed Central

Mellor, J R; Randall, A D

1997-01-01

1. Miniature IPSCs recorded from cultured murine cerebellar granule cells increased in half-width and amplitude following application of the benzodiazepine (BDZ) Flunitrazepam (Flu, 1 microM). The increase in the half-width was much greater than that in the amplitude. 2. Five-millisecond applications of 1 mM GABA to nucleated outside-out patches elicited rapidly rising biexponentially decaying responses that resembled IPSCs. Flu had no effect on the amplitude of such responses, but consistently slowed their deactivation by approximately 50%. This effect was reversed by Flu washout or application of the BDZ antagonist Ro15-1788. The partial inverse agonist. Ro15-4513 speeded deactivation and depressed peak current amplitude by 23 +/- 12%. 3. The EC50 for GABA was between 45 and 50 microM. At submaximally effective agonist concentrations, Flu increased response amplitude and slowed response deactivation. Both effects were present in all cells taken from young cultures (4-7 days in vitro) but the latter was absent in 55% of the neurones obtained from older cultures (14-27 days in vitro). 4. With 120 ms applications of 20 microM GABA, responses activated monoexponentially (time constant, 39.8 +/- 2.8 ms) and deactivated biexponentially (time constants, 40.4 +/- 2.1 and 251 +/- 15 ms). Application of Flu slowed both activation and deactivation. The latter effect arose from an increased contribution of the slower component of decay. 5. Desensitization of responses to 1 mM GABA was biexponential, with time constants of 47 +/- 11 and 479 +/- 49 ms. Flu speeded desensitization by decreasing both fast and slow time constants. GABAA receptor desensitization consistently slowed subsequent deactivation. No significant relationship between the level of desensitization and the amount of slowing of deactivation produced by Flu was found. 6. Responses to paired 5 ms applications of 1 mM GABA indicated that the slowing of deactivation and the speeding of desensitization produced by Flu combine to generate a marked frequency dependence in the actions of this BDZ. Thus when compared with control responses, GABA-induced charge transfer was only enhanced by Flu during the first of two successive agonist applications. PMID:9306278

Aluminum-Activated Malate Transporters Can Facilitate GABA Transport.

PubMed

Ramesh, Sunita A; Kamran, Muhammad; Sullivan, Wendy; Chirkova, Larissa; Okamoto, Mamoru; Degryse, Fien; McLaughlin, Michael; Gilliham, Matthew; Tyerman, Stephen D

2018-05-01

Plant aluminum-activated malate transporters (ALMTs) are currently classified as anion channels; they are also known to be regulated by diverse signals, leading to a range of physiological responses. Gamma-aminobutyric acid (GABA) regulation of anion flux through ALMT proteins requires a specific amino acid motif in ALMTs that shares similarity with a GABA binding site in mammalian GABA A receptors. Here, we explore why TaALMT1 activation leads to a negative correlation between malate efflux and endogenous GABA concentrations ([GABA] i ) in both wheat ( Triticum aestivum ) root tips and in heterologous expression systems. We show that TaALMT1 activation reduces [GABA] i because TaALMT1 facilitates GABA efflux but GABA does not complex Al 3+ TaALMT1 also leads to GABA transport into cells, demonstrated by a yeast complementation assay and via 14 C-GABA uptake into TaALMT1 -expressing Xenopus laevis oocytes; this was found to be a general feature of all ALMTs we examined. Mutation of the GABA motif (TaALMT1 F213C ) prevented both GABA influx and efflux, and resulted in no correlation between malate efflux and [GABA] i We conclude that ALMTs are likely to act as both GABA and anion transporters in planta. GABA and malate appear to interact with ALMTs in a complex manner to regulate each other's transport, suggestive of a role for ALMTs in communicating metabolic status. © 2018 American Society of Plant Biologists. All rights reserved.

Evidence of a role for GABA in benzodiazepine effects on food preference in rats.

PubMed

Hodges, H M; Green, S E

1981-01-01

It has previously been shown that chronic treatment with the GABA-transaminase inhibitor ethanolamine-O-sulphate (EOS), which elevates brain GABA levels by around 200%, selectivity enhances novel food consumption in rats treated with chlordiazepoxide (CDP) and given a food preference test. To replicate and extend these findings, the effects of two doses of CDP with and without EOS pretreatment were compared with those of EOS or saline alone. EOS alone had no significant effects except to decrease eating rate but, in combination with 2.5 mg/kg CDP, it antagonised the increase in weight of familiar food eaten found with CDP alone and marginally increased weight eaten and duration of novel foot eating episodes. EOS magnified the effects of 5.0 mg/kg CDP to increase markedly the weight eaten and duration of episodes for novel chocolate drops. As no additive effects of EOS and CDP on rate of eating were found, the results are consistent with a facilitation of novel food consumption by an anxiolytic action of the two drugs, rather than by a rate-retarding action which might bias animals toward novel food. Finally, that EOS alone did not mimic the effects of CDP suggests that the role of GABA in the anxiolytic action of CDP may be indirect.

Fiat lux!

PubMed Central

Renault, Hugues

2013-01-01

The non-protein amino acid γ-aminobutyric acid (GABA) accumulates in plants in response to a wide variety of environmental cues. Recent data point toward an involvement of GABA in tricarboxylic acid (TCA) cycle activity and respiration, especially in stressed roots. To gain further insights into potential GABA functions in plants, phylogenetic and bioinformatic approaches were undertaken. Phylogenetic reconstruction of the GABA transaminase (GABA-T) protein family revealed the monophyletic nature of plant GABA-Ts. However, this analysis also pointed to the common origin of several plant aminotransferases families, which were found more similar to plant GABA-Ts than yeast and human GABA-Ts. A computational analysis of AtGABA-T co-expressed genes was performed in roots and in stress conditions. This second approach uncovered a strong connection between GABA metabolism and glyoxylate cycle during stress. Both in silico analyses open new perspectives and hypotheses for GABA metabolic functions in plants. PMID:23518583

SYSTEMIC ADMINISTRATION OF KAINIC ACID INCREASES GABA LEVELS IN PERFUSATE FROM THE HIPPOCAMPUS OF RATS IN VIVO

EPA Science Inventory

The ventral hippocampi of male, Fischer-344 rats were implanted with microdialysis probes and the effects of systemically administered kainic acid (KA) (8 mg/kg, s.c.) on the in vivo release of amino acids were measured for four hours after administration. n order to measure GABA...

[Effect of GABA, sodium glutamate and glycine on evoked potentials in the dental zones of the cerebral cortex].

PubMed

Degtiarev, V P

1979-01-01

Intraventricular administration of gamma-aminobutyric acid (GABA) and glycine decreased, whereas sodium glutamate increased the amplitude of primary responses of dental zones of the somatosensory cortex, which arose during electric stimulation of the pulp of the rabbit upper incisors. No changes in the latent periods were recorded.

Modulation of the release of norepinephrine by gamma-aminobutyric acid and morphine in the frontal cerebral cortex of the rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peoples, R.W.

1989-01-01

Agents that enhance gamma-aminobutyric acid, or GABA, neurotransmission modulate certain effects of opioids, such as analgesia. Opioid analgesia is mediated in part by norepinephrine in the forebrain. In this study, the interactions between morphine and GABAergic agents on release of ({sup 3}H) norepinephrine from rat frontal cerebral cortical slices were examined. GABA, 5 {times} 10{sup {minus}5}-10{sup {minus}3} M, enhanced potassium stimulated ({sup 3}H) norepinephrine release and reversed the inhibitory effect of morphine in a noncompetitive manner. GABA did not enhance release of ({sup 3}H) norepinephrine stimulated by the calcium ionophore A23187. The effect of GABA was reduced by the GABA{submore » A} receptor antagonists bicuculline methiodide or picrotoxin, and by the selective inhibitor of GABA uptake SKF 89976A, but was blocked completely only when bicuculline methiodide and SKF 89976A were used in combination. The GABA{sub A} agonist muscimol, 10{sup {minus}4} M, mimicked the effect of GABA, but the GABA{sub B} agonist ({plus minus})baclofen, 10{sup {minus}4} M, did not affect the release of ({sup 3}H) norepinephrine in the absence or the presence of morphine. Thus GABA appears to produce this effect by stimulating GABA uptake and GABA{sub A}, but not GABA{sub B}, receptors. In contrast to the results that would be predicted for an event involving GABA{sub A} receptors, however, the effect of GABA did not desensitize, and benzodiazepine agonists did not enhance the effect of GABA at any concentration tested between 10{sup {minus}8} and 10{sup {minus}4} M. Thus these receptors may constitute a subclass of GABA{sub A} receptors. These results support a role of GABA uptake and GABA{sub A} receptors in enhancing the release of norepinephrine and modulating its inhibition by opioids in the frontal cortex of the rat.« less

Role of glutamic acid decarboxylase 67 in regulating cortical parvalbumin and GABA membrane transporter 1 expression: implications for schizophrenia.

PubMed

Curley, Allison A; Eggan, Stephen M; Lazarus, Matt S; Huang, Z Josh; Volk, David W; Lewis, David A

2013-02-01

Markers of GABA neurotransmission are altered in multiple regions of the neocortex in individuals with schizophrenia. Lower levels of glutamic acid decarboxylase 67 (GAD67) mRNA and protein, which is responsible for most cortical GABA synthesis, are accompanied by lower levels of GABA membrane transporter 1 (GAT1) mRNA. These alterations are thought to be most prominent in the parvalbumin (PV)-containing subclass of interneurons, which also contain lower levels of PV mRNA. Since GAT1 and PV each reduce the availability of GABA at postsynaptic receptors, lower levels of GAT1 and PV mRNAs have been hypothesized to represent compensatory responses to an upstream reduction in cortical GABA synthesis in schizophrenia. However, such cause-and-effect hypotheses cannot be directly tested in a human illness. Consequently, we used two mouse models with reduced GAD67 expression specifically in PV neurons (PV(GAD67+/-)) or in all interneurons (GABA(GAD67+/-)) and quantified GAD67, GAT1 and PV mRNA levels using methods identical to those employed in studies of schizophrenia. Cortical levels of PV or GAT1 mRNAs were not altered in PV(GAD67+/-) mice during postnatal development or in adulthood. Furthermore, cellular analyses confirmed the predicted reduction in GAD67 mRNA, but failed to show a deficit in PV mRNA in these animals. Levels of PV and GAT1 mRNAs were also unaltered in GABA(GAD67+/-) mice. Thus, mouse lines with cortical reductions in GAD67 mRNA that match or exceed those present in schizophrenia, and that differ in the developmental timing and cell type-specificity of the GAD67 deficit, failed to provide proof-of-concept evidence that lower PV and GAT1 expression in schizophrenia are a consequence of lower GAD67 expression. Together, these findings suggest that the correlated decrements in cortical GAD67, PV and GAT1 mRNAs in schizophrenia may be a common consequence of some other upstream factor. Copyright © 2012 Elsevier Inc. All rights reserved.

GABAergic neurons in cerebellar interposed nucleus modulate cellular and humoral immunity via hypothalamic and sympathetic pathways.

PubMed

Lu, Jian-Hua; Wang, Xiao-Qin; Huang, Yan; Qiu, Yi-Hua; Peng, Yu-Ping

2015-06-15

Our previous work has shown that cerebellar interposed nucleus (IN) modulates immune function. Herein, we reveal mechanism underlying the immunomodulation. Treatment of bilateral cerebellar IN of rats with 3-mercaptopropionic acid (3-MP), a glutamic acid decarboxylase antagonist that reduces γ-aminobutyric acid (GABA) synthesis, enhanced cellular and humoral immune responses to bovine serum albumin, whereas injection of vigabatrin, a GABA-transaminase inhibitor that inhibits GABA degradation, in bilateral cerebellar IN attenuated the immune responses. The 3-MP or vigabatrin administrations in the cerebellar IN decreased or increased hypothalamic GABA content and lymphoid tissues' norepinephrine content, respectively, but did not alter adrenocortical or thyroid hormone levels in serum. In addition, a direct GABAergic projection from cerebellar IN to hypothalamus was found. These findings suggest that GABAergic neurons in cerebellar IN regulate immune system via hypothalamic and sympathetic pathways. Copyright © 2015 Elsevier B.V. All rights reserved.

GABA as a rising gliotransmitter

PubMed Central

Yoon, Bo-Eun; Lee, C. Justin

2014-01-01

Gamma-amino butyric acid (GABA) is the major inhibitory neurotransmitter that is known to be synthesized and released from GABAergic neurons in the brain. However, recent studies have shown that not only neurons but also astrocytes contain a considerable amount of GABA that can be released and activate GABA receptors in neighboring neurons. These exciting new findings for glial GABA raise further interesting questions about the source of GABA, its mechanism of release and regulation and the functional role of glial GABA. In this review, we highlight recent studies that identify the presence and release of GABA in glial cells, we show several proposed potential pathways for accumulation and modulation of glial intracellular and extracellular GABA content, and finally we discuss functional roles for glial GABA in the brain. PMID:25565970

Glutamate and GABA receptors and transporters in the basal ganglia: What does their subsynaptic localization reveal about their function?

PubMed Central

Galvan, Adriana; Kuwajima, Masaaki; Smith, Yoland

2006-01-01

GABA and glutamate, the main transmitters in the basal ganglia, exert their effects through ionotropic and metabotropic receptors. The dynamic activation of these receptors in response to released neurotransmitter depends, among other factors, on their precise localization in relation to corresponding synapses. The use of high resolution quantitative electron microscope immunocytochemical techniques has provided in-depth description of the subcellular and subsynaptic localization of these receptors in the CNS. In this article, we review recent findings on the ultrastructural localization of GABA and glutamate receptors and transporters in the basal ganglia, at synaptic, extrasynaptic and presynaptic sites. The anatomical evidence supports numerous potential locations for receptor-neurotransmitter interactions, and raises important questions regarding mechanisms of activation and function of synaptic versus extrasynaptic receptors in the basal ganglia. PMID:17059868

Development and regulation of chloride homeostasis in the central nervous system.

PubMed

Watanabe, Miho; Fukuda, Atsuo

2015-01-01

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter of the mature central nervous system (CNS). The developmental switch of GABAergic transmission from excitation to inhibition is induced by changes in Cl(-) gradients, which are generated by cation-Cl(-) co-transporters. An accumulation of Cl(-) by the Na(+)-K(+)-2Cl(-) co-transporter (NKCC1) increases the intracellular Cl(-) concentration ([Cl(-)]i) such that GABA depolarizes neuronal precursors and immature neurons. The subsequent ontogenetic switch, i.e., upregulation of the Cl(-)-extruder KCC2, which is a neuron-specific K(+)-Cl(-) co-transporter, with or without downregulation of NKCC1, results in low [Cl(-)]i levels and the hyperpolarizing action of GABA in mature neurons. Development of Cl(-) homeostasis depends on developmental changes in NKCC1 and KCC2 expression. Generally, developmental shifts (decreases) in [Cl(-)]i parallel the maturation of the nervous system, e.g., early in the spinal cord, hypothalamus and thalamus, followed by the limbic system, and last in the neocortex. There are several regulators of KCC2 and/or NKCC1 expression, including brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF), and cystic fibrosis transmembrane conductance regulator (CFTR). Therefore, regionally different expression of these regulators may also contribute to the regional developmental shifts of Cl(-) homeostasis. KCC2 and NKCC1 functions are also regulated by phosphorylation by enzymes such as PKC, Src-family tyrosine kinases, and WNK1-4 and their downstream effectors STE20/SPS1-related proline/alanine-rich kinase (SPAK)-oxidative stress responsive kinase-1 (OSR1). In addition, activation of these kinases is modulated by humoral factors such as estrogen and taurine. Because these transporters use the electrochemical driving force of Na(+) and K(+) ions, topographical interaction with the Na(+)-K(+) ATPase and its modulators such as creatine kinase (CK) should modulate functions of Cl(-) transporters. Therefore, regional developmental regulation of these regulators and modulators of Cl(-) transporters may also play a pivotal role in the development of Cl(-) homeostasis.

Abnormal relationship between GABA, neurophysiology and impulsive behavior in neurofibromatosis type 1.

PubMed

Ribeiro, Maria J; Violante, Inês R; Bernardino, Inês; Edden, Richard A E; Castelo-Branco, Miguel

2015-03-01

Neurofibromatosis type 1 (NF1) is a neurodevelopmental disorder characterized by a broad spectrum of cognitive deficits. In particular, executive dysfunction is recognized as a core deficit of NF1, including impairments in executive attention and inhibitory control. Yet, the neural mechanisms behind these important deficits are still unknown. Here, we studied inhibitory control in a visual go/no-go task in children and adolescents with NF1 and age- and gender-matched controls (n = 16 per group). We applied a multimodal approach using high-density electroencephalography (EEG), to study the evoked brain responses, and magnetic resonance spectroscopy (MRS) to measure the levels of GABA and glutamate + glutamine in the medial frontal cortex, a brain region that plays a pivotal role in inhibitory control, and also in a control region, the occipital cortex. Finally, we run correlation analyses to identify the relationship between inhibitory control, levels of neurotransmitters, and EEG markers of neural function. Individuals with NF1 showed impaired impulse control and reduced EEG correlates of early visual processing (parieto-occipital P1) and inhibitory control (frontal P3). MRS data revealed a reduction in medial frontal GABA+/tCr (total Creatine) levels in the NF1 group, in parallel with the already reported reduced occipital GABA levels. In contrast, glutamate + glutamine/tCr levels were normal, suggesting the existence of abnormal inhibition/excitation balance in this disorder. Notably, medial frontal but not occipital GABA levels correlated with general intellectual abilities (IQ) in NF1, and inhibitory control in both groups. Surprisingly, the relationship between inhibitory control and medial frontal GABA was reversed in NF1: higher GABA was associated with a faster response style whereas in controls it was related to a cautious strategy. Abnormal GABAergic physiology appears, thus, as an important factor underlying impaired cognition in NF1, in a level and region dependent manner. Copyright © 2014 Elsevier Ltd. All rights reserved.

Neuropeptide glutamic acid-isoleucine (NEI)-induced paradoxical sleep in rats.

PubMed

Fujimoto, Moe; Fukuda, Satoru; Sakamoto, Hidetoshi; Takata, Junko; Sawamura, Shigehito

2017-01-01

Neuropeptideglutamic acid-isoleucine (NEI) as well as melanin concentrating hormone (MCH) is cleaved from the 165 amino acid protein, prepro-melanin concentrating hormone (prepro-MCH). Among many physiological roles of MCH, we demonstrated that intracerebroventricular (icv) injection of MCH induced increases in REM sleep episodes as well as in non REM sleep episodes. However, there are no studies on the effect of NEI on the sleep-wake cycle. As for the sites of action of MCH for induction of REM sleep, the ventrolateral periaqueductal gray (vlPAG) has been reported to be one of its site of action. Although MCH neurons contain NEI, GABA, MCH, and other neuropeptides, we do not know which transmitter(s) might induce REM sleep by acting on the vlPAG. Thus, we first examined the effect of icv injection of NEI on the sleep-wake cycle, and investigated how microinjection of either NEI, MCH, or GABA into the vlPAG affected REM sleep in rats. Icv injection of NEI (0.61μg/5μl: n=7) significantly increased the time spent in REM episodes compared to control (saline: 5μl; n=6). Microinjection of either NEI (61ng/0.2μl: n=7), MCH (100ng/0.2μl: n=6) or GABA (250mM/0.2μl: n=7) into the vlPAG significantly increased the time spent in REM episodes and the AUC. Precise hourly analysis of REM sleep also revealed that after those microinjections, NEI and MCH increased REM episodes at the latter phase, compared to GABA which increased REM episodes at the earlier phase. This result suggests that NEI and MCH may induce sustained REM sleep, while GABA may initiate REM sleep. In conclusion, our findings demonstrate that NEI, a cleaved peptide from the same precursor, prepro-MCH, as MCH, induce REM sleep at least in part through acting on the vlPAG. Copyright © 2016 Elsevier Inc. All rights reserved.

Effect of the non-NMDA receptor antagonist GYKI 52466 on the microdialysate and tissue concentrations of amino acids following transient forebrain ischaemia.

PubMed

Arvin, B; Lekieffre, D; Graham, J L; Moncada, C; Chapman, A G; Meldrum, B S

1994-04-01

The effect of the non-N-methyl-D-aspartate (non-NMDA) receptor antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466) on ischaemia-induced changes in the microdialysate and tissue concentrations of glutamate, aspartate, and gamma-aminobutyric acid (GABA) was studied in rats. Twenty minutes of four-vessel occlusion resulted in a transient increase in microdialysate levels of glutamate, aspartate, and GABA in striatum, cortex, and hippocampus. Administration of GYKI 52466 (10 mg/kg bolus + 10 mg/kg/60 min intravenously starting 20 min before onset of ischaemia) inhibited ischaemia-induced increases in microdialysate glutamate and GABA in striatum without affecting the increases in hippocampus or cortex. Twenty minutes of four-vessel occlusion resulted in immediate small decreases and larger delayed (72 h) decreases in tissue levels of glutamate and aspartate. Transient increases in tissue levels of GABA were shown in all three structures at the end of the ischaemic period. At 72 h, after the ischaemic period, significantly reduced GABA levels were observed in striatum and hippocampus. GYKI 52466, given under identical conditions as above, augmented the ischaemia-induced decrease in striatal tissue levels of glutamate and aspartate, without significantly affecting the decreases in hippocampus and cortex. Twenty minutes of ischaemia resulted in a large increase in microdialysate dopamine in striatum. GYKI 52466 failed to inhibit this increase. Kainic acid (500 microM infused through the probe for 20 min) caused increases in microdialysate glutamate and aspartate in the striatum. GYKI 52466 (10 mg/kg bolus + 10 mg/kg/60 min) completely inhibited the kainic acid-induced glutamate release. In conclusion, the action of the non-NMDA antagonist, GYKI 52466, in the striatum is different from that in the cortex and hippocampus. The inhibition by GYKI 52466 of ischaemia-induced and kainate-induced increases in microdialysate glutamate concentration in the striatum may be related to the neuroprotection provided by GYKI 52466 in this region.

Prenatal cocaine exposure decreases parvalbumin-immunoreactive neurons and GABA-to-projection neuron ratio in the medial prefrontal cortex.

PubMed

McCarthy, Deirdre M; Bhide, Pradeep G

2012-01-01

Cocaine abuse during pregnancy produces harmful effects not only on the mother but also on the unborn child. The neurotransmitters dopamine and serotonin are known as the principal targets of the action of cocaine in the fetal and postnatal brain. However, recent evidence suggests that cocaine can impair cerebral cortical GABA neuron development and function. We sought to analyze the effects of prenatal cocaine exposure on the number and distribution of GABA and projection neurons (inhibitory interneurons and excitatory output neurons, respectively) in the mouse cerebral cortex. We found that the prenatal cocaine exposure decreased GABA neuron numbers and GABA-to-projection neuron ratio in the medial prefrontal cortex of 60-day-old mice. The neighboring prefrontal cortex did not show significant changes in either of these measures. However, there was a significant increase in projection neuron numbers in the prefrontal cortex but not in the medial prefrontal cortex. Thus, the effects of cocaine on GABA and projection neurons appear to be cortical region specific. The population of parvalbumin-immunoreactive GABA neurons was decreased in the medial prefrontal cortex following the prenatal cocaine exposure. The cocaine exposure also delayed the developmental decline in the volume of the medial prefrontal cortex. Thus, prenatal cocaine exposure produced persisting and region-specific effects on cortical cytoarchitecture and impaired the physiological balance between excitatory and inhibitory neurotransmission. These structural changes may underlie the electrophysiological and behavioral effects of prenatal cocaine exposure observed in animal models and human subjects. Copyright © 2012 S. Karger AG, Basel.

A therapeutic dose of zolpidem reduces thalamic GABA in healthy volunteers: a proton MRS study at 4 T.

PubMed

Licata, Stephanie C; Jensen, J Eric; Penetar, David M; Prescot, Andrew P; Lukas, Scott E; Renshaw, Perry F

2009-05-01

Zolpidem is a nonbenzodiazepine sedative/hypnotic that acts at GABA(A) receptors to influence inhibitory neurotransmission throughout the central nervous system. A great deal is known about the behavioral effects of this drug in humans and laboratory animals, but little is known about zolpidem's specific effects on neurochemistry in vivo. We evaluated how acute administration of zolpidem affected levels of GABA, glutamate, glutamine, and other brain metabolites. Proton magnetic resonance spectroscopy ((1)H MRS) at 4 T was employed to measure the effects of zolpidem on brain chemistry in 19 healthy volunteers. Participants underwent scanning following acute oral administration of a therapeutic dose of zolpidem (10 mg) in a within-subject, single-blind, placebo-controlled, single-visit study. In addition to neurochemical measurements from single voxels within the anterior cingulate (ACC) and thalamus, a series of questionnaires were administered periodically throughout the experimental session to assess subjective mood states. Zolpidem reduced GABA levels in the thalamus, but not the ACC. There were no treatment effects with respect to other metabolite levels. Self-reported ratings of "dizzy," "nauseous," "confused," and "bad effects" were increased relative to placebo, as were ratings on the sedation/intoxication (PCAG) and psychotomimetic/dysphoria (LSD) scales of the Addiction Research Center Inventory. Moreover, there was a significant correlation between the decrease in GABA and "dizzy." Zolpidem engendered primarily dysphoric-like effects and the correlation between reduced thalamic GABA and "dizzy" may be a function of zolpidem's interaction with alpha1GABA(A) receptors in the cerebellum, projecting through the vestibular system to the thalamus.

Decreased GABA receptor in the striatum and spatial recognition memory deficit in epileptic rats: effect of Bacopa monnieri and bacoside-A.

PubMed

Mathew, Jobin; Soman, Smijin; Sadanandan, Jayanarayanan; Paulose, Cheramadathikudyil Skaria

2010-07-20

Gamma-aminobutyric acid A receptors are the principal mediators of synaptic inhibition in striatal neurons and play an important role in preventing the spreading of seizures through the striatum. In the present study, effect of Bacopa monnieri (L.) Pennel and its active component bacoside-A on spatial recognition memory deficit and alterations of GABA receptor in the striatum of epileptic rats were investigated. Total GABA and GABA(A) receptor numbers in the control and epileptic rats were evaluated using [(3)H]GABA and [(3)H]bicuculline binding. GABA(Aalpha1,) GABA(Aalpha5,) GABA(Agamma3) and GABA(Adelta) gene expressions were studied. Behavioral performance was assed using Y-maze. Scatchard analysis of [(3)H]GABA and [(3)H]bicuculline in the striatum of epileptic rats showed significant decrease in B(max) compared to control. Real-Time PCR amplification of GABA(A) receptor subunits such as GABA(Aalpha1,) GABA(Aalpha5) and GABA(Adelta), were down regulated (p<0.001) in the striatum of epileptic rats compared to control. Epileptic rats have deficit in Y-maze performance. Bacopa monnieri and bacoside-A treatment reversed these changes to near control. Our results suggest that decreased GABA receptors in the striatum have an important role in epilepsy associated motor learning deficits and Bacopa monnieri and bacoside-A has a beneficial effect in the management of epilepsy. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

PKC/CREB pathway mediates the expressions of GABAA receptor subunits in cultured hippocampal neurons after low-Mg2+ solution treatment.

PubMed

Wu, Guofeng; Yu, Jinpeng; Wang, Likun; Ren, Siying; Zhang, Yixia

2018-02-01

To investigate the potential effects of the PKC/CREB pathway on the expressions of GABA A receptor subunits α1, γ2, and δ in cultured hippocampal neurons using a model of epilepsy that employed conditions of low magnesium (Mg 2+ ). A total of 108 embryonic rats at the age of 18 embryonic days (E18)prepared from adult female SD rats were used as experimental subjects. Primary rat hippocampal cultures were prepared from the embryonic 18 days rats. The cultured hippocampal neurons were then treated with artificial cerebrospinal fluid containing low Mg 2+ solutions to generate a low Mg 2+ model of epilepsy. The low Mg 2+ stimulation lasted for 3 h and then returned to in maintenance medium for 20 h. The changes of the GABA A receptor subunit α1, γ2, δ were observed by blocking or activating the function of the CREB. The quantification of the GABA A receptor subunit α1, γ2, δ and the CREB were determined by a qRT-PCR and a Western blot method. After the neurons were exposed to a low-Mg 2+ solution for 3 h, GABA A receptor mRNA expression markedly increased compared to the control, and then gradually decreased. In contrast, CREB mRNA levels exhibited a dramatic down-regulation 3 h after terminating low-Mg 2+ treatment, and then peaked at 9 h. Western blot analyses verified that staurosporine suppressed CREB phosphorylation (p-CREB). The mRNA expression of GABA A receptor subunit α1 increased only in the presence of staurosporine, whereas the expressions of subunits γ2 and δ significantly increased in the presence of either KG-501 or staurosporine. Furthermore, phorbol 12-myristate 13-acetate (PMA) decreased the expressions of GABA A subunits α1, γ2, and δ when administered alone. However, the administration of either KG-501 or staurosporine reversed the inhibitory effects of PMA. The PKC/CREB pathway may negatively regulate the expressions of GABA A receptor subunits α1, γ2, and δ in cultured hippocampal neurons in low Mg 2+ model of epilepsy. Copyright © 2017. Published by Elsevier B.V.

In Vivo Hypocholesterolemic Effect of MARDI Fermented Red Yeast Rice Water Extract in High Cholesterol Diet Fed Mice

PubMed Central

Beh, Boon Kee; Kong, Joan; Ho, Wan Yong; Mohd Yusof, Hamidah; Hussin, Aminuddin bin; Jaganath, Indu Bala; Alitheen, Noorjahan Banu; Jamaluddin, Anisah

2014-01-01

Fermented red yeast rice has been traditionally consumed as medication in Asian cuisine. This study aimed to determine the in vivo hypocholesterolemic and antioxidant effects of fermented red yeast rice water extract produced using Malaysian Agricultural Research and Development Institute (MARDI) Monascus purpureus strains in mice fed with high cholesterol diet. Absence of monacolin-k, lower level of γ-aminobutyric acid (GABA), higher content of total amino acids, and antioxidant activities were detected in MARDI fermented red yeast rice water extract (MFRYR). In vivo MFRYR treatment on hypercholesterolemic mice recorded similar lipid lowering effect as commercial red yeast rice extract (CRYR) as it helps to reduce the elevated serum liver enzyme and increased the antioxidant levels in liver. This effect was also associated with the upregulation of apolipoproteins-E and inhibition of Von Willebrand factor expression. In summary, MFRYR enriched in antioxidant and amino acid without monacolin-k showed similar hypocholesterolemic effect as CRYR that was rich in monacolin-k and GABA. PMID:25031606

Effects of GABA receptor antagonists on thresholds of P23H rat retinal ganglion cells to electrical stimulation of the retina

NASA Astrophysics Data System (ADS)

Jensen, Ralph J.; Rizzo, Joseph F., III

2011-06-01

An electronic retinal prosthesis may provide useful vision for patients suffering from retinitis pigmentosa (RP). In animal models of RP, the amount of current needed to activate retinal ganglion cells (RGCs) is higher than in normal, healthy retinas. In this study, we sought to reduce the stimulation thresholds of RGCs in a degenerate rat model (P23H-line 1) by blocking GABA receptor mediated inhibition in the retina. We examined the effects of TPMPA, a GABAC receptor antagonist, and SR95531, a GABAA receptor antagonist, on the electrically evoked responses of RGCs to biphasic current pulses delivered to the subretinal surface through a 400 µm diameter electrode. Both TPMPA and SR95531 reduced the stimulation thresholds of ON-center RGCs on average by 15% and 20% respectively. Co-application of the two GABA receptor antagonists had the greatest effect, on average reducing stimulation thresholds by 32%. In addition, co-application of the two GABA receptor antagonists increased the magnitude of the electrically evoked responses on average three-fold. Neither TPMPA nor SR95531, applied alone or in combination, had consistent effects on the stimulation thresholds of OFF-center RGCs. We suggest that the effects of the GABA receptor antagonists on ON-center RGCs may be attributable to blockage of GABA receptors on the axon terminals of ON bipolar cells.

The association of plasma gamma-aminobutyric acid concentration with postoperative delirium in critically ill patients.

PubMed

Yoshitaka, Shiho; Egi, Moritoki; Kanazawa, Tomoyuki; Toda, Yuichiro; Morita, Kiyoshi

2014-12-01

Delirium is a common complication in postoperative, critically ill patients. The mechanism of postoperative delirium is not well understood but many studies have shown significant associations between benzodiazepine use, alcohol withdrawal and cirrhosis, and an increased risk of delirium. We aimed to investigate a possible link with alterations of gamma-aminobutyric acid (GABA) activity. A prospective observational investigation of 40 patients > 20 years old who had undergone elective surgery with general anaesthesia and were expected to need postoperative intensive care for more than 48 hours. We assessed postoperative delirium using the confusion assessment method in the intensive care unit at 1 hour after the operation and on postoperative Day (POD) 1 and POD 2. We collected blood samples for measurement of plasma GABA concentrations before the operation and on POD 1 and 2. Postoperative delirium and perioperative plasma GABA concentrations in patients with and without delirium. Postoperative delirium occurred in 13 of the patients. Patients with delirium had significantly higher Acute Physiology and Chronic Health Evaluation II scores than patients without delirium. The mean plasma GABA concentration on POD 2 was significantly lower in patients with delirium than in those without delirium. After adjustment of relevant variables, plasma GABA concentration on POD 2 was independently associated with postoperative delirium. Plasma GABA level on POD 2 has a significant independent association with postoperative delirium.

Molecular Mechanisms Underlying γ-Aminobutyric Acid (GABA) Accumulation in Giant Embryo Rice Seeds.

PubMed

Zhao, Guo-Chao; Xie, Mi-Xue; Wang, Ying-Cun; Li, Jian-Yue

2017-06-21

To uncover the molecular mechanisms underlying GABA accumulation in giant embryo rice seeds, we analyzed the expression levels of GABA metabolism genes and contents of GABA and GABA metabolic intermediates in developing grains and germinated brown rice of giant embryo rice 'Shangshida No. 5' and normal embryo rice 'Chao2-10' respectively. In developing grains, the higher GABA contents in 'Shangshida No. 5' were accompanied with upregulation of gene transcripts and intermediate contents in the polyamine pathway and downregulation of GABA catabolic gene transcripts, as compared with those in 'Chao2-10'. In germinated brown rice, the higher GABA contents in 'Shangshida No. 5' were parallel with upregulation of OsGAD and polyamine pathway gene transcripts and Glu and polyamine pathway intermediate contents and downregulation of GABA catabolic gene transcripts. These results are the first to indicate that polyamine pathway and GABA catabolic genes play a crucial role in GABA accumulation in giant embryo rice seeds.

Initial characterization of receptors for molecules that induce the settlement and metamorphosis of Haliotis rufescens larvae

DOE Office of Scientific and Technical Information (OSTI.GOV)

Trapido-Rosenthal, H.G.

1985-01-01

Larvae of the marine gastropod mollusc Haliotis refescens are induced to undergo metamorphosis by ..gamma..-aminobutyric acid (GABA) and stereochemically related compounds. The most potent of these inducers is (-)-..beta..-(parachlorophenyl)-GABA (baclofen). The inductive response exhibits positive cooperatively, and is subject to both facilitation (up-regulation) and habituation (down-regulation). Facilitation is brought about by diamino acids such as L-diaminopropionic acid (L-DAPA), and is characterized by decreased Hill coefficients (n/sub H/) and concentration requirements (EC/sub 50/) for inducers. Facilitation does not require the simultaneous presence of facilitating and inducing compounds, and the facilitated state is persistent. Larvae are capable of being up-regulated 2 daysmore » before they are capable of undergoing settlement and metamorphosis. Habituation can be brought about by exposure of pre-competent larvae to GABA 4 days prior to the attainment of competence; it is then slowly reversible. Larvae specifically bind tritiated (-)-baclofen in a manner that is saturable with both increasing time of exposure of larvae to, and with increasing concentration of, this compound. Specific binding can be competed for by unlabeled GABA-mimetic inducing molecules; the order of effectiveness of these molecules as competitors for specific binding correlates well with their effectiveness as inducers of metamorphosis. Facilitation of larvae by exposure to diamino acids does not alter their specific binding of tritiated (-)-baclofen. It is concluded from these findings that Haliotis larvae possess receptors for GABA-mimetic compounds.« less

Brain dynamic neurochemical changes in dystonic patients: a magnetic resonance spectroscopy study.

PubMed

Marjańska, Malgorzata; Lehéricy, Stéphane; Valabrègue, Romain; Popa, Traian; Worbe, Yulia; Russo, Margherita; Auerbach, Edward J; Grabli, David; Bonnet, Cecilia; Gallea, Cécile; Coudert, Mathieu; Yahia-Cherif, Lydia; Vidailhet, Marie; Meunier, Sabine

2013-02-01

Measurements of the concentrations of γ-aminobutyric acid (GABA) and glutamate in the motor cortices and lentiform nuclei of dystonic patients using single-voxel (1)H magnetic resonance spectroscopy (MRS) have yielded conflicting results so far. This study aimed to investigate dynamic changes in metabolite concentrations after stimulation of the motor cortices in patients with upper limb dystonia. Using single-voxel MRS at 3 T, the concentrations of GABA, glutamate plus glutamine, and N-acetylaspartate were measured bilaterally in the primary sensorimotor cortex, lentiform nucleus, and occipital region before and after 5-Hz transcranial magnetic stimulation (TMS) over the dominant motor cortex. Data obtained from 15 patients with upper limb primary dystonia were compared with data obtained from 14 healthy volunteers. At baseline, there was no group difference in concentration of metabolites in any region. rTMS induced a local (in the stimulated motor cortex) decrease of N-acetylaspartate (P < .006) to the same extent in healthy volunteers and patients. GABA concentrations were modulated differently, however, decreasing mildly in patients and increasing mildly in healthy volunteers (P = .05). There were no remote effects in the lentiform nucleus in either group. The stimulation-induced changes in metabolite concentrations have been interpreted in view of the increased energy demand induced by rTMS. The dynamics of the GABA concentration were specifically impaired in dystonic patients. Whether these changes reflect changes in the extrasynaptic or synaptic GABA component is discussed. Copyright © 2012 Movement Disorders Society.

Food hoarding, but not food intake, is attenuated by acute diazepam treatment in female Mongolian gerbils (Meriones unguiculatus).

PubMed

Yang, Hui-Di; Wang, Qian; Wang, De-Hua

2014-06-01

This article is part of a Special Issue "Energy Balance". Effects of γ-aminobutyric acid (GABA) on food hoarding are unknown in rodents, and the effects of energy balance and GABA have not been evaluated in females. To evaluate the role of food deprivation and GABA on food hoarding, female Mongolian gerbils were given i.p. injection of diazepam (1mg/kg and 3mg/kg, respectively), a GABAA receptor agonist. Among food-deprived females, there was a bimodal pattern in the frequency of gerbils with different levels of food hoarding. High food hoarding (HFH) and low food hoarding (LFH) gerbils were analyzed. Diazepam blocked food deprivation-induced food hoarding in HFH gerbils, but not in LFH gerbils. This blockade was associated with increased cellular activation in selected brain areas, such as the nucleus accumbens (NAcc), caudate putamen (CP) and ventral tegmental area (VTA), which suggested that direct activation of GABA in the brain reward circuitry decreased food hoarding in HFH females. Moreover, diazepam increased Fos expression in field CA2 and CA3 of the hippocampus, but had no significant effect on Fos expression in field CA1 and dentate gyrus (DG) of the hippocampus, indicating that the hippocampus has area-specific effects on food hoarding in HFH gerbils. Diazepam did not alter food intake in both HFH and LFH gerbils. In addition, serum corticosterone concentrations were higher in the HFH than in the LFH ones. Together, these data indicated that food deprivation increased food hoarding in female gerbils, diazepam reduced food deprivation-induced food hoarding in HFH gerbils, and that GABA might influence food hoarding via classical reward circuitry via the mesolimbic dopamine system and specific hippocampal areas. Copyright © 2014 Elsevier Inc. All rights reserved.

Diphenyl diselenide ameliorates monosodium glutamate induced anxiety-like behavior in rats by modulating hippocampal BDNF-Akt pathway and uptake of GABA and serotonin neurotransmitters.

PubMed

Rosa, Suzan Gonçalves; Quines, Caroline Brandão; Stangherlin, Eluza Curte; Nogueira, Cristina Wayne

2016-03-01

Monosodium glutamate (MSG), a flavor enhancer used in food, administered to neonatal rats causes neuronal lesions and leads to anxiety when adulthood. We investigated the anxiolytic-like effect of diphenyl diselenide (PhSe)2 and its mechanisms on anxiety induced by MSG. Neonatal male and female Wistar rats received a subcutaneous injection of saline (0.9%) or MSG (4 g/kg/day) from the 1st to 10th postnatal day. At 60 days of life, the rats received (PhSe)2 (1mg/kg/day) or vehicle by the intragastric route for 7 days. The spontaneous locomotor activity (LAM), elevated plus maze test (EPM) and contextual fear conditioning test (CFC) as well as neurochemical ([(3)H]GABA and [(3)H]5-HT uptake) and molecular analyses (Akt and p-Akt and BDNF levels) were carried out after treatment with (PhSe)2. Neonatal exposure to MSG increased all anxiogenic parameters in LAM, EPM and CFC tests. MSG increased GABA and 5-HT uptake in hippocampus of rats, without changing uptake in cerebral cortex. The levels of BDNF and p-Akt were reduced in hippocampus of rats treated with MSG. The administration of (PhSe)2 to rats reversed all behavioral anxiogenic parameters altered by MSG. The increase in hippocampal GABA and 5-HT uptake induced by MSG was reversed by (PhSe)2. (PhSe)2 reversed the reduction in hippocampal BDNF and p-Akt levels induced by MSG. In conclusion, the anxiolytic-like action of (PhSe)2 in rats exposed to MSG during their neonatal period is related to its modulation of hippocampal GABA and 5-HT uptake as well as the BDNF-Akt pathway. Copyright © 2015 Elsevier Inc. All rights reserved.

Acute sleep deprivation preconditions the heart against ischemia/ reperfusion injury: the role of central GABA-A receptors

PubMed Central

Parsa, Hoda; Imani, Alireza; Faghihi, Mahdieh; Riahi, Esmail; Badavi, Mohammad; Shakoori, Abbas; Rastegar, Tayebeh; Aghajani, Marjan; Rajani, Sulail Fatima

2017-01-01

Objective(s): Central γ-aminobutyric acid (GABA) neurotransmission modulates cardiovascular functions and sleep. Acute sleep deprivation (ASD) affects functions of various body organs via different mechanisms. Here, we evaluated the effect of ASD on cardiac ischemia/reperfusion injury (IRI), and studied the role of GABA-A receptor inhibition in central nucleus of amygdala (CeA) by assessing nitric oxide (NO) and oxidative stress. Materials and Methods: The CeA in sixty male Wistar rats was cannulated for saline or bicuculline (GABA-A receptor antagonist) administration. All animals underwent 30 min of coronary occlusion (ischemia), followed by 2 hr reperfusion (IR). The five experimental groups (n=12) included are as follows: IR: received saline; BIC+IR: received Bicuculline; MLP+IR: received saline, followed by the placement of animals in an aquarium with multiple large platforms; ASD+IR: underwent ASD in an aquarium with multiple small platforms; and BIC+ASD+IR: received bicuculline prior to ASD. Results: Bicuculline administration increased the malondialdehyde levels and infarct size, and decreased the NO metabolites levels and endothelial nitric oxide synthase (eNOS) gene expression in infarcted and non-infarcted areas in comparison to IR group. ASD reduced malondialdehyde levels and infarct size and increased NO metabolites, corticosterone levels and eNOS expression in infarcted and non-infarcted areas as compared to the IR group. Levels of malondialdehyde were increased while levels of NO metabolites, corticosterone and eNOS expression in infarcted and non-infarcted areas were reduced in the BIC+ASD+IR as compared to the ASD+IR group. Conclusion: Blockade of GABA-A receptors in the CeA abolishes ASD-induced cardioprotection by suppressing oxidative stress and NO production. PMID:29299201

Acute sleep deprivation preconditions the heart against ischemia/ reperfusion injury: the role of central GABA-A receptors.

PubMed

Parsa, Hoda; Imani, Alireza; Faghihi, Mahdieh; Riahi, Esmail; Badavi, Mohammad; Shakoori, Abbas; Rastegar, Tayebeh; Aghajani, Marjan; Rajani, Sulail Fatima

2017-11-01

Central γ-aminobutyric acid (GABA) neurotransmission modulates cardiovascular functions and sleep. Acute sleep deprivation (ASD) affects functions of various body organs via different mechanisms. Here, we evaluated the effect of ASD on cardiac ischemia/reperfusion injury (IRI), and studied the role of GABA-A receptor inhibition in central nucleus of amygdala (CeA) by assessing nitric oxide (NO) and oxidative stress. The CeA in sixty male Wistar rats was cannulated for saline or bicuculline (GABA-A receptor antagonist) administration. All animals underwent 30 min of coronary occlusion (ischemia), followed by 2 hr reperfusion (IR). The five experimental groups (n=12) included are as follows: IR: received saline; BIC+IR: received Bicuculline; MLP+IR: received saline, followed by the placement of animals in an aquarium with multiple large platforms; ASD+IR: underwent ASD in an aquarium with multiple small platforms; and BIC+ASD+IR: received bicuculline prior to ASD. Bicuculline administration increased the malondialdehyde levels and infarct size, and decreased the NO metabolites levels and endothelial nitric oxide synthase (eNOS) gene expression in infarcted and non-infarcted areas in comparison to IR group. ASD reduced malondialdehyde levels and infarct size and increased NO metabolites, corticosterone levels and eNOS expression in infarcted and non-infarcted areas as compared to the IR group. Levels of malondialdehyde were increased while levels of NO metabolites, corticosterone and eNOS expression in infarcted and non-infarcted areas were reduced in the BIC+ASD+IR as compared to the ASD+IR group. Blockade of GABA-A receptors in the CeA abolishes ASD-induced cardioprotection by suppressing oxidative stress and NO production.

Impact of exogenous GABA treatments on endogenous GABA metabolism in anthurium cut flowers in response to postharvest chilling temperature.

PubMed

Aghdam, Morteza Soleimani; Naderi, Roohangiz; Jannatizadeh, Abbasali; Babalar, Mesbah; Sarcheshmeh, Mohammad Ali Askari; Faradonbe, Mojtaba Zamani

2016-09-01

Anthurium flowers are susceptible to chilling injury, and the optimum storage temperature is 12.5-20 °C. The γ-aminobutyric acid (GABA) shunt pathway may alleviate chilling stress in horticultural commodities by providing energy (ATP), reducing molecules (NADH), and minimizing accumulation of reactive oxygen species (ROS). In this experiment, the impact of a preharvest spray treatment with 1 mM GABA and postharvest treatment of 5 mM GABA stem-end dipping on GABA shunt pathway activity of anthurium cut flowers (cv. Sirion) in response to cold storage (4 °C for 21 days) was investigated. GABA treatments resulted in lower glutamate decarboxylase (GAD) and higher GABA transaminase (GABA-T) activities in flowers during cold storage, which was associated with lower GABA content and coincided with higher ATP content. GABA treatments also enhanced accumulation of endogenous glycine betaine (GB) in flowers during cold storage, as well as higher spathe relative water content (RWC). These findings suggest that GABA treatments may alleviate chilling injury of anthurium cut flowers by enhancing GABA shunt pathway activity leading to provide sufficient ATP and promoting endogenous GB accumulation. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

GABA, its receptors, and GABAergic inhibition in mouse taste buds

PubMed Central

Dvoryanchikov, Gennady; Huang, Yijen A; Barro-Soria, Rene; Chaudhari, Nirupa; Roper, Stephen D.

2012-01-01

Taste buds consist of at least three principal cell types that have different functions in processing gustatory signals — glial-like Type I cells, Receptor (Type II) cells, and Presynaptic (Type III) cells. Using a combination of Ca2+ imaging, single cell RT-PCR, and immunostaining, we show that γ-amino butyric acid (GABA) is an inhibitory transmitter in mouse taste buds, acting on GABA-A and GABA-B receptors to suppress transmitter (ATP) secretion from Receptor cells during taste stimulation. Specifically, Receptor cells express GABA-A receptor subunits β2, δ, π, as well as GABA-B receptors. In contrast, Presynaptic cells express the GABA-Aβ3 subunit and only occasionally GABA-B receptors. In keeping with the distinct expression pattern of GABA receptors in Presynaptic cells, we detected no GABAergic suppression of transmitter release from Presynaptic cells. We suggest that GABA may serve function(s) in taste buds in addition to synaptic inhibition. Finally, we also defined the source of GABA in taste buds: GABA is synthesized by GAD65 in Type I taste cells as well as by GAD67 in Presynaptic (Type III) taste cells and is stored in both those two cell types. We conclude that GABA is released during taste stimulation and possibly also during growth and differentiation of taste buds. PMID:21490220

GABA, its receptors, and GABAergic inhibition in mouse taste buds.

PubMed

Dvoryanchikov, Gennady; Huang, Yijen A; Barro-Soria, Rene; Chaudhari, Nirupa; Roper, Stephen D

2011-04-13

Taste buds consist of at least three principal cell types that have different functions in processing gustatory signals: glial-like (type I) cells, receptor (type II) cells, and presynaptic (type III) cells. Using a combination of Ca2+ imaging, single-cell reverse transcriptase-PCR and immunostaining, we show that GABA is an inhibitory transmitter in mouse taste buds, acting on GABA(A) and GABA(B) receptors to suppress transmitter (ATP) secretion from receptor cells during taste stimulation. Specifically, receptor cells express GABA(A) receptor subunits β2, δ, and π, as well as GABA(B) receptors. In contrast, presynaptic cells express the GABA(A) β3 subunit and only occasionally GABA(B) receptors. In keeping with the distinct expression pattern of GABA receptors in presynaptic cells, we detected no GABAergic suppression of transmitter release from presynaptic cells. We suggest that GABA may serve function(s) in taste buds in addition to synaptic inhibition. Finally, we also defined the source of GABA in taste buds: GABA is synthesized by GAD65 in type I taste cells as well as by GAD67 in presynaptic (type III) taste cells and is stored in both those two cell types. We conclude that GABA is an inhibitory transmitter released during taste stimulation and possibly also during growth and differentiation of taste buds.

The vigilance promoting drug modafinil increases extracellular glutamate levels in the medial preoptic area and the posterior hypothalamus of the conscious rat: prevention by local GABAA receptor blockade.

PubMed

Ferraro, L; Antonelli, T; Tanganelli, S; O'Connor, W T; Perez de la Mora, M; Mendez-Franco, J; Rambert, F A; Fuxe, K

1999-04-01

The effects of modafinil on glutamatergic and GABAergic transmission in the rat medial preoptic area (MPA) and posterior hypothalamus (PH), are analysed. Modafinil (30-300 mg/kg) increased glutamate and decreased GABA levels in the MPA and PH. Local perfusion with the GABAA agonist muscimol (10 microM), reduced, while the GABAA antagonist bicuculline (1 microM and 10 microM) increased glutamate levels. The modafinil (100 mg/kg)-induced increase of glutamate levels was antagonized by local perfusion with bicuculline (1 microM). When glutamate levels were increased by the local perfusion with the glutamate uptake inhibitor L-trans-PDC (0.5 mM), modafinil produced an additional enhancement of glutamate levels. Modafinil (1-33 microM) failed to affect [3H]glutamate uptake in hypothalamic synaptosomes and slices. These findings show that modafinil increases glutamate and decreases GABA levels in MPA and PH. The evidence that bicuculline counteracts the modafinil-induced increase of glutamate levels strengthens the evidence for an inhibitory GABA/glutamate interaction in the above regions controlling the sleep-wakefulness cycle.

GABA release in the zona incerta of the sheep in response to the sight and ingestion of food and salt.

PubMed

Kendrick, K M; Hinton, M R; Baldwin, B A

1991-05-31

In order to establish which neurotransmitters may influence the activity of zona incerta neurones in the sheep which respond selectively to the sight or ingestion of food, we have measured the release of amino acid and monoamine neurotransmitters from this region using microdialysis sampling. Co-ordinates for the placement of microdialysis probes in regions of the zona incerta where cells respond to the sight or ingestion of food were first established by making single-unit extracellular recordings. When animals were food-deprived results showed that release of gamma-aminobutyric acid (GABA) was increased in response to the sight and ingestion of food but not of aspartate, glutamate, taurine, noradrenaline, dopamine or serotonin. This release of GABA was absent when the animals were shown non-food objects or saw or ingested salt solutions. When the same animals were physiologically sodium-depleted GABA release was evoked by the sight and ingestion of salt solutions and release following the sight and ingestion of food was significantly reduced. These results provide further evidence that GABA is an important neurotransmitter in neural circuits controlling the regulation of food intake.

GABA/sub B/ receptor activation inhibits Ca/sup 2 +/-activated potassium channels in synaptosomes: involvement of G-proteins

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ticku, M.K.; Delgado, A.

1989-01-01

/sup 86/Rb-efflux assay from preloaded synaptosomes of rat cerebral cortex was developed to study the effect of GABA/sub B/ receptor agonist baclofen on Ca/sup 2 +/-activated K/sup +/-channels. Depolarization of /sup 86/Rb-loaded synaptosomes in physiological buffer increased Ca/sup 2 +/-activated /sup 86/Rb-efflux by 400%. The /sup 86/Rb-efflux was blocked by quinine sulfate, tetraethylammonium, and La/sup 3 +/ indicating the involvement of Ca/sup 2 +/-activated K/sup +/-channels. (-)Baclofen inhibited Ca/sup 2 +/-activated /sup 86/Rb-efflux in a stereospecific manner. The inhibitory effect of (-)baclofen was mediated by GABA/sub B/ receptor activation, since it was blocked by GABA/sub B/ antagonist phaclofen, but notmore » by bicuculline. Further, pertussis toxin also blocked the ability of baclofen or depolarizing action to affect Ca/sup 2 +/-activated K/sup +/-channels. These results suggest that baclofen inhibits Ca/sup 2 +/-activated K/sup +/-channels in synaptosomes and these channels are regulated by G-proteins. This assay may provide an ideal in vitro model to study GABA/sub B/ receptor pharmacology.« less

Polyamine metabolism in ripening tomato fruit. I. Identification of metabolites of putrescine and spermidine. [Lycopersicon esculentum Mill

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rastogi, R.; Davies, P.J.

The metabolism of (1,4-{sup 14}C)putrescine and (terminal methylene-{sup 3}H)spermidine was studied in the fruit pericarp (breaker stage) discs of tomato (Lycopersicon esculentum Mill.) cv Rutgers, and the metabolites identified by high performance liquid chromatography and gas chromatography-mass spectrometry. The metabolism of both putrescine and spermidine was relatively slow; in 24 hours about 15% of each amine was metabolized. The {sup 14}C label from putrescine was incorporated into spermidine, {gamma}-aminobutyric acid (GABA), glutamic acid, and a polar fraction eluting with sugars and organic acids. In the presence of gabaculine, a specific inhibitor of GABA:pyruvate transminase, the label going into glutamic acid,more » sugars and organic acids decreased by 80% while that in GABA increased about twofold, indicating that the transamination reaction is probably a major fate of GABA produced from putrescine in vivo. ({sup 3}H)Spermidine was catabolized into putrescine and {beta}-alanine. The conversion of putrescine into GABA, and that of spermidine into putrescine, suggests the presence of polyamine oxidizing enzymes in tomato pericarp tissues. The possible pathways of putrescine and spermidine metabolism are discussed.« less

[Effects of extracts from ziziphi spinosae semen and schisandrae chinensis fructus on amino acid neurotransmitter in rats with insomnia induced by PCPA].

PubMed

Gao, Jia-Rong; Ji, Wen-Bo; Jiang, Hui; Chen, Jin-Feng

2013-10-01

To observe the effects of extract from Ziziphus Spinosa Semen and Schisandrae Chinensis Fructus on the content of amino acid neurotransmitter in the hypothalamus of insomnia rats induced by P-Chlorophenylalanine (PCPA) and its mechanism. The model of insomnia rats were established by PCPA intraperitoneal injection, after the modeling, all the therapeutic group were treated with corresponding drug for one week. The hypothalamus pathological changes of the rats were observed. The contents of GABA, Glu in the hypothalamus were detected by Elisa. The GABA, Glu protein expression were detected by immunohistochemical. GABA(A), R(alpha1) and GABA(A)R(gamma2) mRNA expressions were detected by RT-PCR. Compared with model group, the content of GABA in the hypothalamus of rats increased obviously in the alcohol-water group (P < 0.05 or P < 0.01), while the content of Glu decreased obviously (P < 0.05 or P < 0.01). The extract from Ziziphus Spinosae Semen and Schisandrae Chinensis Fructus has obviously Sedative-hypnotic effect. Its mechanism may be related to regulating the content of amino acid neurotransmitter in the hypothalamus of rats.

Enhanced GABAergic transmission in the central nucleus of the amygdala of genetically selected Marchigian Sardinian rats: alcohol and CRF effects

PubMed Central

Herman, Melissa; Kallupi, Marsida; Luu, George; Oleata, Christopher; Heilig, Markus; Koob, George F.; Ciccocioppo, Roberto; Roberto, Marisa

2012-01-01

The GABAergic system in the central amygdala (CeA) plays a major role in ethanol dependence and the anxiogenic-like response to ethanol withdrawal. Alcohol dependence is associated with increased corticotropin releasing factor (CRF) influence on CeA GABA release and CRF type 1 receptor (CRF1) antagonists prevent the excessive alcohol consumption associated with dependence. Genetically-selected Marchigian Sardinian (msP) rats have an overactive extrahypothalamic CRF1 system, are highly sensitive to stress, and display an innate preference for alcohol. The present study examined differences in CeA GABAergic transmission and the effects of ethanol, CRF and a CRF1 antagonist in msP, Sprague-Dawley, and Wistar rats using an electrophysiological approach. We found no significant differences in membrane properties or mean amplitude of evoked GABAA-inhibitory postsynaptic potentials (IPSPs). However, paired-pulse facilitation (PPF) ratios of evoked IPSPs were significantly lower and spontaneous miniature inhibitory postsynaptic current (mIPSC) frequencies were higher in msP rats, suggesting increased CeA GABA release in msP as compared to Sprague-Dawley and Wistar rats. The sensitivity of spontaneous GABAergic transmission to ethanol (44 mM), CRF (200 nM) and CRF1 antagonist (R121919, 1 μM) was comparable in msP, Sprague Dawley, and Wistar rats. However, a history of ethanol drinking significantly increased the baseline mIPSC frequency and decreased the effects of a CRF1 antagonist in msP rats, suggesting increased GABA release and decreased CRF1 sensitivity. These results provide electrophysiological evidence that msP rats display distinct CeA GABAergic activity as compared to Sprague Dawley and Wistar rats. The elevated GABAergic transmission observed in naïve mSP rats is consistent with the neuroadaptations reported in Sprague Dawley rats after the development of ethanol dependence. PMID:23220399

GABAA receptor: Positive and negative allosteric modulators.

PubMed

Olsen, Richard W

2018-01-31

gamma-Aminobutyric acid (GABA)-mediated inhibitory neurotransmission and the gene products involved were discovered during the mid-twentieth century. Historically, myriad existing nervous system drugs act as positive and negative allosteric modulators of these proteins, making GABA a major component of modern neuropharmacology, and suggesting that many potential drugs will be found that share these targets. Although some of these drugs act on proteins involved in synthesis, degradation, and membrane transport of GABA, the GABA receptors Type A (GABA A R) and Type B (GABA B R) are the targets of the great majority of GABAergic drugs. This discovery is due in no small part to Professor Norman Bowery. Whereas the topic of GABA B R is appropriately emphasized in this special issue, Norman Bowery also made many insights into GABA A R pharmacology, the topic of this article. GABA A R are members of the ligand-gated ion channel receptor superfamily, a chloride channel family of a dozen or more heteropentameric subtypes containing 19 possible different subunits. These subtypes show different brain regional and subcellular localization, age-dependent expression, and potential for plastic changes with experience including drug exposure. Not only are GABA A R the targets of agonist depressants and antagonist convulsants, but most GABA A R drugs act at other (allosteric) binding sites on the GABA A R proteins. Some anxiolytic and sedative drugs, like benzodiazepine and related drugs, act on GABA A R subtype-dependent extracellular domain sites. General anesthetics including alcohols and neurosteroids act at GABA A R subunit-interface trans-membrane sites. Ethanol at high anesthetic doses acts on GABA A R subtype-dependent trans-membrane domain sites. Ethanol at low intoxicating doses acts at GABA A R subtype-dependent extracellular domain sites. Thus GABA A R subtypes possess pharmacologically specific receptor binding sites for a large group of different chemical classes of clinically important neuropharmacological agents. Copyright © 2018 Elsevier Ltd. All rights reserved.

Postnatal changes in somatic gamma-aminobutyric acid signalling in the rat hippocampus.

PubMed

Tyzio, Roman; Minlebaev, Marat; Rheims, Sylvain; Ivanov, Anton; Jorquera, Isabelle; Holmes, Gregory L; Zilberter, Yuri; Ben-Ari, Yehezkiel; Khazipov, Rustem

2008-05-01

During postnatal development of the rat hippocampus, gamma-aminobutyric acid (GABA) switches its action on CA3 pyramidal cells from excitatory to inhibitory. To characterize the underlying changes in the GABA reversal potential, we used somatic cell-attached recordings of GABA(A) and N-methyl-D-aspartate channels to monitor the GABA driving force and resting membrane potential, respectively. We found that the GABA driving force is strongly depolarizing during the first postnatal week. The strength of this depolarization rapidly declines with age, although GABA remains slightly depolarizing, by a few millivolts, even in adult neurons. Reduction in the depolarizing GABA driving force was due to a progressive negative shift of the reversal potential of GABA currents. Similar postnatal changes in GABA signalling were also observed using the superfused hippocampus preparation in vivo, and in the hippocampal interneurons in vitro. We also found that in adult pyramidal cells, somatic GABA reversal potential is maintained at a slightly depolarizing level by bicarbonate conductance, chloride-extrusion and chloride-loading systems. Thus, the postnatal excitatory-to-inhibitory switch in somatic GABA signalling is associated with a negative shift of the GABA reversal potential but without a hyperpolarizing switch in the polarity of GABA responses. These results also suggest that in adult CA3 pyramidal cells, somatic GABAergic inhibition takes place essentially through shunting rather than hyperpolarization. Apparent hyperpolarizing GABA responses previously reported in the soma of CA3 pyramidal cells are probably due to cell depolarization during intracellular or whole-cell recordings.

Inhibition of GABA-gated chloride channels by 12,14-dichlorodehydroabietic acid in mammalian brain.

PubMed

Nicholson, R A; Lees, G; Zheng, J; Verdon, B

1999-03-01

1. 12,14-dichlorodehydroabietic acid (12,14-Cl2DHA) reduced GABA-stimulated uptake of 36Cl- into mouse brain synaptoneurosomes suggesting inhibition of mammalian GABA(A) receptor function. 2. 12,14-Cl2DHA did not affect the binding of [3H]-muscimol to brain membranes but displaced specifically bound [3H]-EBOB. The inhibitory effect on [3H]-EBOB binding was not reversible. 12,14-Cl2DHA reduced the availability of [3H]-EBOB binding sites (Bmax) without changing the KD of the radioligand for remaining sites. 12,14-Cl2DHA did not affect the rate of association of [3H]-EBOB with its chloride channel receptor, but increased the initial rate of [3H]-EBOB dissociation. 3. 12,14-Cl2DHA enhanced the incidence of EPSCs when rapidly applied to cultured rat cortical neurones. Longer exposures produced block of IPSCs with marked increases in the frequency of EPSCs and min EPSCs. 12,14-Cl2DHA also irreversibly suppressed chloride currents evoked by pulses of exogenous GABA in these cells. 4. Ultimately, 12,14-Cl2DHA inhibited all synaptic traffic and action currents in current clamped cells indicating that, in contrast to picrotoxinin (which causes paroxysmal bursting), it is not fully selective for the GABA(A) receptor-chloride channel complex. 5. The depolarizing block seen with 12,14-Cl2DHA in amphotericin-perforated preparations implicates loss of Ca2+ buffering in the polarity change and this may account for inhibition of spontaneous action potentials. 6. Our investigation demonstrates that 12,14-Cl2DHA blocks GABA-dependent chloride entry in mammalian brain and operates as a non-competitive insurmountable GABA(A) antagonist. The mechanism likely involves either irreversible binding of 12,14-Cl2DHA to the trioxabicyclooctane recognition site or a site that is allosterically coupled to it. We cannot exclude, however, the possibility that 12,14-Cl2DHA causes localized proteolysis or more extensive conformational change within a critical subunit of the chloride channel.

Meroterpenoid Chrodrimanins Are Selective and Potent Blockers of Insect GABA-Gated Chloride Channels

PubMed Central

Ihara, Makoto; Ling, Yun; Yang, Xinling; Kai, Kenji; Hayashi, Hideo; Matsuda, Kazuhiko

2015-01-01

Meroterpenoid chrodrimanins, produced from Talaromyces sp. YO-2, are known to paralyze silkworm (Bombyx mori) larvae, but their target is unknown. We have investigated the actions of chrodrimanin B on ligand-gated ion channels of silkworm larval neurons using patch-clamp electrophysiology. Chrodrimanin B had no effect on membrane currents when tested alone at 1 μM. However, it completely blocked the γ-aminobutyric acid (GABA)-induced current and showed less pronounced actions on acetylcholine- and L-glutamate-induced currents, when delivered at 1 μM for 1 min prior to co-application with transmitter GABA. Thus, chrodrimanins were also tested on a wild-type isoform of the B. mori GABA receptor (GABAR) RDL using two-electrode voltage-clamp electrophysiology. Chrodrimanin B attenuated the peak current amplitude of the GABA response of RDL with an IC50 of 1.66 nM. The order of the GABAR-blocking potency of chrodrimanins B > D > A was in accordance with their reported insecticidal potency. Chrodrimanin B had no open channel blocking action when tested at 3 nM on the GABA response of RDL. Co-application with 3 nM chrodrimanin B shifted the GABA concentration response curve to a higher concentration and further increase of chrodrimanin B concentration to10 nM; it reduced maximum current amplitude of the GABA response, pointing to a high-affinity competitive action and a lower affinity non-competitive action. The A282S;T286V double mutation of RDL, which impairs the actions of fipronil, hardly affected the blocking action of chrodrimanin B, indicating a binding site of chrodrimanin B distinct from that of fipronil. Chrodrimanin B showed approximately 1,000-fold lower blocking action on human α1β2γ2 GABAR compared to RDL and thus is a selective blocker of insect GABARs. PMID:25902139

Enhancement of gamma-aminobutyric acid (GABA) levels using an autochthonous Lactobacillus futsaii CS3 as starter culture in Thai fermented shrimp (Kung-Som).

PubMed

Sanchart, Chatthaphisuth; Rattanaporn, Onnicha; Haltrich, Dietmar; Phukpattaranont, Pimpimol; Maneerat, Suppasil

2017-08-01

Gamma-aminobutyric acid (GABA) is a non-proteinogenic amino acid, which has a variety of well-characterized beneficial physiological functions. In order to improve GABA levels and the fermentation process of Thai fermented shrimp (Kung-Som), autochthonous Lactobacillus futsaii CS3 was inoculated as a starter culture into Kung-Som, and its effects on the quality of Kung-Som were studied. The optimal conditions for GABA production in Kung-Som as obtained by response surface methodology (RSM) using a central composite design (CCD) were an inoculum size of roughly 10 7 CFU/g (X 1 ) of L. futsaii cells together with the addition of 0.5% (w/w) monosodium glutamate (MSG) (X 2 ), resulting in maximum GABA levels of 10,500 mg per kg fresh product. Under these optimized conditions, the experimental GABA content of Kung-Som with an added starter culture was up to four times higher than that of the control (without starter culture) or commercial Kung-Som products (10,120 mg/kg product). Kung-Som produced by inoculation with L. futsaii CS3 but without addition of MSG showed a considerably increased GABA content of 7790 mg/kg compared to the control. Fermentation time was reduced to less than 1 week for these samples compared to the control batches, which took up to 19 days. Polymerase chain reaction denaturing gradient gel electrophoresis (PCR-DGGE) revealed that L. futsaii CS3 remained prominently throughout the Kung-Som fermentation, and that lactic acid bacteria (LAB) rapidly dominated the total microflora because of this inoculation with L. futsaii CS3. Kung-Som samples with starter culture were accepted as well as commercial ones by 30 panelists (p > 0.05). In conclusion, L. futsaii CS3 is a good starter culture for GABA production, resulting in, improved microbiological safety as well as reduced fermentation time.

Brain GABA levels across psychiatric disorders: A systematic literature review and meta-analysis of (1) H-MRS studies.

PubMed

Schür, Remmelt R; Draisma, Luc W R; Wijnen, Jannie P; Boks, Marco P; Koevoets, Martijn G J C; Joëls, Marian; Klomp, Dennis W; Kahn, René S; Vinkers, Christiaan H

2016-09-01

The inhibitory gamma-aminobutyric acid (GABA) system is involved in the etiology of most psychiatric disorders, including schizophrenia, autism spectrum disorder (ASD) and major depressive disorder (MDD). It is therefore not surprising that proton magnetic resonance spectroscopy ((1) H-MRS) is increasingly used to investigate in vivo brain GABA levels. However, integration of the evidence for altered in vivo GABA levels across psychiatric disorders is lacking. We therefore systematically searched the clinical (1) H-MRS literature and performed a meta-analysis. A total of 40 studies (N = 1,591) in seven different psychiatric disorders were included in the meta-analysis: MDD (N = 437), schizophrenia (N = 517), ASD (N = 150), bipolar disorder (N = 129), panic disorder (N = 81), posttraumatic stress disorder (PTSD) (N = 104), and attention deficit/hyperactivity disorder (ADHD) (N = 173). Brain GABA levels were lower in ASD (standardized mean difference [SMD] = -0.74, P = 0.001) and in depressed MDD patients (SMD = -0.52, P = 0.005), but not in remitted MDD patients (SMD = -0.24, P = 0.310) compared with controls. In schizophrenia this finding did not reach statistical significance (SMD = -0.23, P = 0.089). No significant differences in GABA levels were found in bipolar disorder, panic disorder, PTSD, and ADHD compared with controls. In conclusion, this meta-analysis provided evidence for lower brain GABA levels in ASD and in depressed (but not remitted) MDD patients compared with healthy controls. Findings in schizophrenia were more equivocal. Even though future (1) H-MRS studies could greatly benefit from a longitudinal design and consensus on the preferred analytical approach, it is apparent that (1) H-MRS studies have great potential in advancing our understanding of the role of the GABA system in the pathogenesis of psychiatric disorders. Hum Brain Mapp 37:3337-3352, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Under stressful conditions activation of the ionotropic P2X7 receptor differentially regulates GABA and glutamate release from nerve terminals of the rat cerebral cortex.

PubMed

Barros-Barbosa, Aurora R; Oliveira, Ângela; Lobo, M Graça; Cordeiro, J Miguel; Correia-de-Sá, Paulo

2018-01-01

γ-Aminobutyric acid (GABA) and glutamate (Glu) are the main inhibitory and excitatory neurotransmitters in the central nervous system (CNS), respectively. Fine tuning regulation of extracellular levels of these amino acids is essential for normal brain activity. Recently, we showed that neocortical nerve terminals from patients with epilepsy express higher amounts of the non-desensitizing ionotropic P2X7 receptor. Once activated by ATP released from neuronal cells, the P2X7 receptor unbalances GABAergic vs. glutamatergic neurotransmission by differentially interfering with GABA and Glu uptake. Here, we investigated if activation of the P2X7 receptor also affects [ 3 H]GABA and [ 14 C]Glu release measured synchronously from isolated nerve terminals (synaptosomes) of the rat cerebral cortex. Data show that activation of the P2X7 receptor consistently increases [ 14 C]Glu over [ 3 H]GABA release from cortical nerve terminals, but the GABA/Glu ratio depends on extracellular Ca 2+ concentrations. While the P2X7-induced [ 3 H]GABA release is operated by a Ca 2+ -dependent pathway when external Ca 2+ is available, this mechanism shifts towards the reversal of the GAT1 transporter in low Ca 2+ conditions. A different scenario is verified regarding [ 14 C]Glu outflow triggered by the P2X7 receptor, since the amino acid seems to be consistently released through the recruitment of connexin-containing hemichannels upon P2X7 activation, both in the absence and in the presence of external Ca 2+ . Data from this study add valuable information suggesting that ATP, via P2X7 activation, not only interferes with the high-affinity uptake of GABA and Glu but actually favors the release of these amino acids through distinct molecular mechanisms amenable to differential therapeutic control. Copyright © 2017 Elsevier Ltd. All rights reserved.

GABA+ levels in postmenopausal women with mild-to-moderate depression

PubMed Central

Wang, Zhensong; Zhang, Aiying; Zhao, Bin; Gan, Jie; Wang, Guangbin; Gao, Fei; Liu, Bo; Gong, Tao; Liu, Wen; Edden, Richard A.E.

2016-01-01

Abstract Background: It is increasingly being recognized that alterations of the GABAergic system are implicated in the pathophysiology of depression. This study aimed to explore in vivo gamma-aminobutyric acid (GABA) levels in the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) and posterior-cingulate cortex (PCC) of postmenopausal women with depression using magnetic resonance spectroscopy (1H-MRS). Methods: Nineteen postmenopausal women with depression and thirteen healthy controls were enrolled in the study. All subjects underwent 1H-MRS of the ACC/mPFC and PCC using the “MEGA Point Resolved Spectroscopy Sequence” (MEGA-PRESS) technique. The severity of depression was assessed by 17-item Hamilton Depression Scale (HAMD). Quantification of MRS data was performed using Gannet program. Differences of GABA+ levels from patients and controls were tested using one-way analysis of variance. Spearman correlation coefficients were used to evaluate the linear associations between GABA+ levels and HAMD scores, as well as estrogen levels. Results: Significantly lower GABA+ levels were detected in the ACC/mPFC of postmenopausal women with depression compared to healthy controls (P = 0.002). No significant correlations were found between 17-HAMD/14-HAMA and GABA+ levels, either in ACC/mPFC (P = 0.486; r = 0.170/P = 0.814; r = −0.058) or PCC (P = 0.887; r = 0.035/ P = 0.987; r = −0.004) in the patients; there is also no significant correlation between GABA+ levels and estrogen levels in patients group (ACC/mPFC: P = 0.629, r = −0.018; PCC: P = 0.861, r = 0.043). Conclusion: Significantly lower GABA+ levels were found in the ACC/mPFC of postmenopausal women with depression, suggesting that the dysfunction of the GABAergic system may also be involved in the pathogenesis of depression in postmenopausal women. PMID:27684829

Human Occipital and Parietal GABA Selectively Influence Visual Perception of Orientation and Size.

PubMed

Song, Chen; Sandberg, Kristian; Andersen, Lau Møller; Blicher, Jakob Udby; Rees, Geraint

2017-09-13

GABA is the primary inhibitory neurotransmitter in human brain. The level of GABA varies substantially across individuals, and this variability is associated with interindividual differences in visual perception. However, it remains unclear whether the association between GABA level and visual perception reflects a general influence of visual inhibition or whether the GABA levels of different cortical regions selectively influence perception of different visual features. To address this, we studied how the GABA levels of parietal and occipital cortices related to interindividual differences in size, orientation, and brightness perception. We used visual contextual illusion as a perceptual assay since the illusion dissociates perceptual content from stimulus content and the magnitude of the illusion reflects the effect of visual inhibition. Across individuals, we observed selective correlations between the level of GABA and the magnitude of contextual illusion. Specifically, parietal GABA level correlated with size illusion magnitude but not with orientation or brightness illusion magnitude; in contrast, occipital GABA level correlated with orientation illusion magnitude but not with size or brightness illusion magnitude. Our findings reveal a region- and feature-dependent influence of GABA level on human visual perception. Parietal and occipital cortices contain, respectively, topographic maps of size and orientation preference in which neural responses to stimulus sizes and stimulus orientations are modulated by intraregional lateral connections. We propose that these lateral connections may underlie the selective influence of GABA on visual perception. SIGNIFICANCE STATEMENT GABA, the primary inhibitory neurotransmitter in human visual system, varies substantially across individuals. This interindividual variability in GABA level is linked to interindividual differences in many aspects of visual perception. However, the widespread influence of GABA raises the question of whether interindividual variability in GABA reflects an overall variability in visual inhibition and has a general influence on visual perception or whether the GABA levels of different cortical regions have selective influence on perception of different visual features. Here we report a region- and feature-dependent influence of GABA level on human visual perception. Our findings suggest that GABA level of a cortical region selectively influences perception of visual features that are topographically mapped in this region through intraregional lateral connections. Copyright © 2017 Song, Sandberg et al.

Are the effects of benzodiazepines on discrimination and punishment dissociable?

PubMed

Hodges, H; Green, S

1987-01-01

Studies have shown that benzodiazepines (BZs) both disrupt discrimination and increase resistance to punishment. Using a delayed response task, we provide evidence that effects of BZs on discrimination cannot be fully explained by deficits in either short or long term memory, or by intolerance for delay of reward. A schedule with rewarded, nonrewarded (Time out: TO) and conflict components was used to investigate effects in rats of compounds active at the BZ receptor on successive discrimination and punished responding in parallel. The GABA transaminase inhibitor ethanolamine-O-sulphate exerted additive effects with chlordiazepoxide (CDP) on punished but not TO responding. Both GABA and CDP injected into the amygdala selectively increased conflict rates, but with peripheral treatment CDP also increased TO rates. Two inverse BZ agonists, CGS 8216 and FG 7142 antagonzied the anti-conflict effects of GABA and CDP, given within the amygdala or peripherally, but the increase in TO rates induced by systemic CDP was counteracted only by peripheral treatments. These compounds also reduced rates of conflict responding below baseline, consistent with anxiogenic activity. Effects of the BZ antagonist Ro 15-1788 were broadly similar to those of the inverse agonists, except that it did not antagonise the anti-conflict action of intra-amygdaloid GABA, nor significantly reduce punished responding at the single dose used. We conclude from these results that the anti-conflict effects of BZs are mediated by a GABAergic amygdaloid mechanism, but that the same mechanism is not involved in BZ effects on discrimination.

[GABA-NO interaction in the N. Accumbens during danger-induced inhibition of exploratory behavior].

PubMed

Saul'skaia, N V; Terekhova, E A

2013-01-01

In Sprague-Dawley rats by means of in vivo microdialysis combined with HPLC analysis, it was shown that presentation to rats during exploratory activity of a tone previously pared with footshock inhibited the exploration and prevented the exploration-induced increase in extracellular levels of citrulline (an NO co-product) in the medial n. accumbens. Intra-accumbal infusions of 20 μM bicuculline, a GABA(A)-receptor antagonist, firstly, partially restored the exploration-induced increase of extracellular citrulline levels in this brain area, which was inhibited by presentation of the tone, previously paired with foot-shock and, secondly, prevented the inhibition of exploratory behavior produced by this sound signal of danger. The data obtained indicate for the first time that signals of danger inhibit exploratory behavior and exploration-induced activation of the accumbal nitrergic system via GABA(A)-receptor mechanisms.

The ly-6 protein, lynx1, is an endogenous inhibitor of nicotinic signaling in airway epithelium.

PubMed

Fu, Xiao Wen; Rekow, Stephen S; Spindel, Eliot R

2012-10-15

Our laboratory has previously reported that bronchial epithelial cells (BEC) express a regulatory cascade of classic neurotransmitters and receptors that communicate in an almost neuronal-like manner to achieve physiological regulation. In this paper we show that the similarity between neurotransmitter signaling in neurons and BEC extends to the level of transmitter receptor allosteric modulators. Lynx1 is a member of the ly-6/three-finger superfamily of proteins, many of which modulate receptor signaling activity. Lynx1 specifically has been shown to modulate nicotinic acetylcholine receptor (nAChR) function in neurons by altering receptor sensitivity and desensitization. We now report that lynx1 forms a complex with α7 nAChR in BEC and serves to negatively regulate α7 downstream signaling events. Treatment of primary cultures of BEC with nicotine increased levels of nAChR subunits and that increase was potentiated by lynx1 knockdown. Lynx1 knockdown also potentiated the nicotine-induced increase in GABA(A) receptors (GABA(A)R) and MUC5AC mRNA expression, and that effect was blocked by α7 antagonists and α7 knockdown. In parallel with the increases in nAChR, GABA(A)R, and mucin mRNA levels, lynx1 knockdown also increased levels of p-Src. Consistent with this, inhibition of Src signaling blocked the ability of the lynx1 knockdown to increase basal and nicotine-stimulated GABA(A)R and mucin mRNA expression. Thus lynx1 appears to act as a negative modulator of α7 nAChR-induced events by inhibiting Src activation. This suggests that lynx1 agonists or mimetics are a potentially important therapeutic target to develop new therapies for smoking-related diseases characterized by increased mucin expression.

GABA homeostasis contributes to the developmental programming of anxiety-related behavior.

PubMed

Depino, Amaicha Mara; Tsetsenis, Theodoros; Gross, Cornelius

2008-05-19

During development, when inhibitory and excitatory synapses are formed and refined, homeostatic mechanisms act to adjust inhibitory input in order to maintain neural activity within a normal range. As the brain matures, synaptogenesis slows and a relatively stable level of inhibition is achieved. Deficits in inhibitory neurotransmission are associated with increased anxiety-related behavior and drugs that potentiate GABA function, the major inhibitory neurotransmitter in the brain, are effective anxiolytics. These observations raise the possibility that transient perturbations in the activity of neural circuits during development might induce compensatory changes in inhibition that could persist into adulthood and contribute to changes in anxiety-related behavior. To test this hypothesis, we treated mice continuously during the major period of forebrain synaptogenesis (P14-28) with the GABA-A receptor positive modulator diazepam and assessed anxiety-related behavior in adulthood. Control experiments confirmed anxiolytic effects of the drug following one day of treatment and the development of tolerance following two weeks of treatment. When tested in adulthood, one month after the end of treatment, diazepam-treated mice exhibited significantly increased behavioral inhibition in the open-field, elevated-plus maze, and novel object behavioral paradigms. Levels of benzodiazepine binding sites in amygdala and frontal cortex were specifically decreased in diazepam-treated mice demonstrating that homeostatic adjustments in GABA function persist into adulthood. Our results show that increased GABAergic activity can affect the developmental programming of anxiety-related behavior.

Alcohol interactions with channel activation and desensitization at 5-HT[sub 3] and GABA[sub A] receptors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lovinger, D.M.; Zhou, O.

1992-01-01

Ethanol (EtOH) and trichloroethanol (TCEt) potentiate 5-HT[sub 3] receptor-mediated ion current in NCB-20 neuroblastoma cells and nodose ganglion neurons. TCEt potentiates GABA[sub A] receptor-mediated current in dorsal root ganglion neurons. Whole-cell patch-clamp recording was used to examine the interactions of alcohols with current activation and receptor desensitization. Alcohols increased the potency of 5-HT, consistent with an increase in channel activation rate. Current decay rate increased in the presence of alcohols such that potentiation decreased with time following in onset of agonist + alcohol treatment. Potentiation of 5-HT-activated current by EtOH was 61 [plus minus] 17% above control at the startmore » of application but was absent 10 sec after current onset. Agonist pretreatment decreased potentiation by subsequent agonist + alcohol application. Potentiation by TCEt of 5-HT-activated current decreased from 96% above control with simultaneous application of 5-HT + TCEt to 44% after a 30 sec 5-HT treatment. This agonist- and time-dependent loss of potentiation was observed prior to the onset of current decay when low agonist concentrations were used. Agonist pretreatment appears to drive the channel into an alcohol-insensitive. Current activated by GABA + TCEt recovers from desensitization produced by GABA alone more slowly than recovery tested in the absence of TCEt.« less

GABA(A) receptor antagonism in the ventrocaudal periaqueductal gray increases anxiety in the anxiety-resistant postpartum rat.

PubMed

Miller, Stephanie M; Piasecki, Christopher C; Peabody, Mitchell F; Lonstein, Joseph S

2010-06-01

Postpartum mammals show suppressed anxiety, which is necessary for their ability to appropriately care for offspring. It is parsimonious to suggest that the neurobiological basis of this reduced anxiety is similar to that of non-parturient animals, involving GABA(A) receptor activity in sites including the midbrain periaqueductal gray (PAG). In Experiment 1, postpartum and diestrous virgin female rats received an intraperitoneal injection of the GABA(A) receptor antagonist (+)-bicuculline (0, 2 and 4 mg/kg) and anxiety-related behavior was assessed with an elevated plus maze. The 4 mg/kg dose of (+)-bicuculline significantly increased anxiety-related behavior, particularly in the postpartum females. Experiment 2 revealed that bicuculline's action was within the central nervous system, because anxiety in neither dams nor virgins was significantly affected by intraperitoneal injection of bicuculline methiodide (0, 2 and 6 mg/kg), which does not readily cross the blood-brain-barrier. In Experiment 3, bicuculline methiodide (2.5 ng/side) was directly infused into the ventrocaudal PAG (cPAGv) and significantly increased dams' anxiety compared to saline-infused controls. These studies expand our knowledge of how GABA(A) receptor modulators affect anxiety behaviors in postpartum rats to the widely-used elevated plus maze, and indicate that the postpartum suppression of anxiety is in part a consequence of elevated GABAergic neurotransmission in the cPAGv. Copyright 2010 Elsevier Inc. All rights reserved.

Effect of dietary γ-aminobutyric acid on laying performance, egg quality, immune activity and endocrine hormone in heat-stressed Roman hens.

PubMed

Zhang, Min; Zou, Xiao-Ting; Li, Hui; Dong, Xin-Yang; Zhao, Wenjing

2012-02-01

This study was conducted to evaluate the effect of γ-aminobutyric acid (GABA) on laying performance, egg quality, digestive enzyme activity, hormone level and immune activities in Roman hens under heat stress. Roman hens (320 days old) were fed with 0, 25, 50, 75 and 100 mg/kg GABA, respectively during a 60-day experiment. Compared with control, supplementation of 50 mg/kg GABA improved the laying performance and egg quality by significantly increasing egg production, average egg weight and shell strength (P < 0.05), while decreasing the feed-egg ratio and cholesterol level. Anti-oxidation activity was improved by significantly increasing the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), but decreasing malondialdehyde level in serum (P < 0.05), while significantly increasing the glucose and total protein (TP) level, follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E(2) ), insulin, triiodothyronine (T(3) ) and free triiodothyronine (FT(3) ) levels, and IgG, IgA and complement (C3)activity in serum (P < 0.05). The results indicated that oral GABA improved laying performance and physical condition mainly by modulating hormone secretion, enhancing anti-oxidation and immune activity, and maintaining electrolyte balance. Fifty mg/kg was the optimum level for laying hens under heat stress in the present study. © 2011 The Authors. Animal Science Journal © 2011 Japanese Society of Animal Science.

Effects of disrupting medial prefrontal cortex GABA transmission on decision-making in a rodent gambling task.

PubMed

Paine, T A; O'Hara, A; Plaut, B; Lowes, D C

2015-05-01

Decision-making is a complex cognitive process that is mediated, in part, by subregions of the medial prefrontal cortex (PFC). Decision-making is impaired in a number of psychiatric conditions including schizophrenia. Notably, people with schizophrenia exhibit reductions in GABA function in the same PFC areas that are implicated in decision-making. For example, expression of the GABA-synthesizing enzyme GAD67 is reduced in the dorsolateral PFC of people with schizophrenia. The goal of this experiment was to determine whether disrupting cortical GABA transmission impairs decision-making using a rodent gambling task (rGT). Rats were trained on the rGT until they reached stable performance and then were implanted with guide cannulae aimed at the medial PFC. Following recovery, the effects of intra-PFC infusions of the GABAA receptor antagonist bicuculline methiodide (BMI) or the GABA synthesis inhibitor L-allylglycine (LAG) on performance on the rGT were assessed. Intracortical infusions of BMI (25 ng/μl/side), but not LAG (10 μg/μl/side), altered decision-making. Following BMI infusions, rats made fewer advantageous choices. Follow-up experiments suggested that the change in decision-making was due to a change in the sensitivity to the punishments, rather than a change in the sensitivity to reward magnitudes, associated with each outcome. LAG infusions increased premature responding, a measure of response inhibition, but did not affect decision-making. Blocking GABAA receptors, but not inhibiting cortical GABA synthesis, within the medial PFC affects decision-making in the rGT. These data provide proof-of-concept evidence that disruptions in GABA transmission can contribute to the decision-making deficits in schizophrenia.

Furosemide suppresses ileal and colonic contractility via interactions with GABA-A receptor in mice.

PubMed

Kaewsaro, Kannaree; Nualplub, Suparp; Bumrungsri, Sara; Khuituan, Pissared

2017-11-01

The loop diuretic furosemide has an action to inhibit Na + -K + -2Cl - co-transporter at the thick ascending limb of Henle's loop resulting in diuresis. Furosemide also has the non-diuretic effects by binding to GABA-A receptor which may involve the gastrointestinal tract. The aim of this study was to investigate the effects of furosemide on smooth muscle contractions in mice ileum and proximal colon. Each intestinal segment suspended in an organ bath was connected to a force transducer. Signal output of mechanical activity was amplified and recorded for analysis using PowerLab System. After equilibration, the intestine was directly exposed to furosemide, GABA, GABA-A receptor agonist (muscimol), or muscarinic receptor antagonist (atropine). Furosemide (50, 100 and 500 μmol L -1 ) acutely reduced the amplitude of ileal and colonic contraction. In the ileum, 1 mmol L -1 GABA and 10-60 μmol L -1 muscimol significantly increased the amplitude, whereas in the colon, 50-100 mmol L -1 GABA and 60 μmol L -1 muscimol decreased the contractions. The contractions were also significantly suppressed by atropine. To investigate the mechanisms underlying the inhibiting effect of furosemide, furosemide was added to the organ bath prior to the addition of muscimol or atropine. A comparison of furosemide combined with muscimol or atropine group and furosemide group showed no significant difference of the ileal contraction, but the amplitude of colonic contraction significantly decreased when compared to adding furosemide alone. These results suggest that furosemide can reduce the ileal and proximal colonic contraction mediated by blocking and supporting of GABA-A receptor, respectively, resulting in decreased acetylcholine release. © 2017 John Wiley & Sons Australia, Ltd.

Ionic plasticity and pain: The loss of descending serotonergic fibers after spinal cord injury transforms how GABA affects pain.

PubMed

Huang, Yung-Jen; Grau, James W

2018-05-02

Activation of pain (nociceptive) fibers can sensitize neural circuits within the spinal cord, inducing an increase in excitability (central sensitization) that can foster chronic pain. The development of spinally-mediated central sensitization is regulated by descending fibers and GABAergic interneurons. In adult animals, the co-transporter KCC2 maintains a low intracellular concentration of the anion Cl - . As a result, when the GABA-A receptor is engaged, Cl - flows in the neuron which has a hyperpolarizing (inhibitory) effect. Spinal cord injury (SCI) can down-regulate KCC2 and reverse the flow of Cl - . Under these conditions, engaging the GABA-A receptor can have a depolarizing (excitatory) effect that fosters the development of nociceptive sensitization. The present paper explores how SCI alters GABA function and provides evidence that the loss of descending fibers alters pain transmission to the brain. Prior work has shown that, after SCI, administration of a GABA-A antagonist blocks the development of capsaicin-induced nociceptive sensitization, implying that GABA release plays an essential role. This excitatory effect is linked to serotonergic (5HT) fibers that descend through the dorsolateral funiculus (DLF) and impact spinal function via the 5HT-1A receptor. Supporting this, blocking the 5HT-1A receptor, or lesioning the DLF, emulated the effect of SCI. Conversely, spinal application of a 5HT-1A agonist up-regulated KCC2 and reversed the effect of bicuculline treatment. Finally, lesioning the DLF reversed how a GABA-A antagonist affects a capsaicin-induced aversion in a place conditioning task; in sham operated animals, bicuculline enhanced aversion whereas in DLF-lesioned rats biciculline had an antinociceptive effect. Copyright © 2018 Elsevier Inc. All rights reserved.

CB1-Dependent Long-Term Depression in Ventral Tegmental Area GABA Neurons: A Novel Target for Marijuana

PubMed Central

Friend, Lindsey; Sandoval, Philip; Nufer, Teresa; Ostlund, Isaac

2017-01-01

The VTA is necessary for reward behavior with dopamine cells critically involved in reward signaling. Dopamine cells in turn are innervated and regulated by neighboring inhibitory GABA cells. Using whole-cell electrophysiology in juvenile-adolescent GAD67-GFP male mice, we examined excitatory plasticity in fluorescent VTA GABA cells. A novel CB1-dependent LTD was induced in GABA cells that was dependent on metabotropic glutamate receptor 5, and cannabinoid receptor 1 (CB1). LTD was absent in CB1 knock-out mice but preserved in heterozygous littermates. Bath applied Δ9-tetrahydrocannabinol depressed GABA cell activity, therefore downstream dopamine cells will be disinhibited; and thus, this could potentially result in increased reward. Chronic injections of Δ9-tetrahydrocannabinol occluded LTD compared with vehicle injections; however, a single exposure was insufficient to do so. As synaptic modifications by drugs of abuse are often tied to addiction, these data suggest a possible mechanism for the addictive effects of Δ9-tetrahydrocannabinol in juvenile-adolescents, by potentially altering reward behavioral outcomes. SIGNIFICANCE STATEMENT The present study identifies a novel form of glutamatergic synaptic plasticity in VTA GABA neurons, a currently understudied cell type that is critical for the brain's reward circuit, and how Δ9-tetrahydrocannabinol occludes this plasticity. This study specifically addresses a potential unifying mechanism whereby marijuana could exert rewarding and addictive/withdrawal effects. Marijuana use and legalization are a pressing issue for many states in the United States. Although marijuana is the most commonly abused illicit drug, the implications of legalized, widespread, or continued usage are speculative. This study in juvenile-adolescent aged mice identifies a novel form of synaptic plasticity in VTA GABA cells, and the synaptic remodeling that can occur after Δ9-tetrahydrocannabinol use. PMID:29038246

Overexpression of ppc or deletion of mdh for improving production of γ-aminobutyric acid in recombinant Corynebacterium glutamicum.

PubMed

Shi, Feng; Zhang, Ming; Li, Yongfu

2017-06-01

L-Glutamate decarboxylase (GAD) transforms L-glutamate into γ-aminobutyric acid (GABA). Corynebacterium glutamicum that expresses exogenous GAD gene(s) can synthesize GABA from its own produced L-glutamate. To enhance GABA production in recombinant C. glutamicum strain SH, metabolic engineering strategies were used to improve the supply of the GABA precursor, L-glutamate. Five new strains were constructed here. First, the ppc gene was coexpressed with two GAD genes (gadB1 and gadB2). Then, the mdh gene was deleted in C. glutamicum SH. Next, gadB1-gadB2 and gadB1-gadB2-ppc co-expression plasmids were transformed into C. glutamicum strains SH and Δmdh, resulting in four recombinant GAD strains SE1, SE2, SDE1, and SDE2, respectively. Finally, the mdh gene was overexpressed in mdh-deleted SDE1, generating the mdh-complemented GAD strain SDE3. After fermenting for 72 h, GABA production increased to 26.3 ± 3.4, 24.8 ± 0.7, and 25.5 ± 3.3 g/L in ppc-overexpressed SE2, mdh-deleted SDE1, and mdh-deleted ppc-overexpressed SDE2, respectively, which was higher than that in the control GAD strain SE1 (22.7 ± 0.5 g/L). While in the mdh-complemented SDE3, GABA production decreased to 20.0 ± 0.6 g/L. This study demonstrates that the recombinant strains SE2, SDE1, and SDE2 can be used as candidates for GABA production.

Impact of single-site axonal GABAergic synaptic events on cerebellar interneuron activity.

PubMed

de San Martin, Javier Zorrilla; Jalil, Abdelali; Trigo, Federico F

2015-12-01

Axonal ionotropic receptors are present in a variety of neuronal types, and their function has largely been associated with the modulation of axonal activity and synaptic release. It is usually assumed that activation of axonal GABA(A)Rs comes from spillover, but in cerebellar molecular layer interneurons (MLIs) the GABA source is different: in these cells, GABA release activates presynaptic GABA(A) autoreceptors (autoRs) together with postsynaptic targets, producing an autoR-mediated synaptic event. The frequency of presynaptic, autoR-mediated miniature currents is twice that of their somatodendritic counterparts, suggesting that autoR-mediated responses have an important effect on interneuron activity. Here, we used local Ca(2+) photolysis in MLI axons of juvenile rats to evoke GABA release from individual varicosities to study the activation of axonal autoRs in single release sites. Our data show that single-site autoR conductances are similar to postsynaptic dendritic conductances. In conditions of high [Cl(-)](i), autoR-mediated conductances range from 1 to 5 nS; this corresponds to ∼30-150 GABA(A) channels per presynaptic varicosity, a value close to the number of channels in postsynaptic densities. Voltage responses produced by the activation of autoRs in single varicosities are amplified by a Na(v)-dependent mechanism and propagate along the axon with a length constant of 91 µm. Immunolabeling determination of synapse location shows that on average, one third of the synapses produce autoR-mediated signals that are large enough to reach the axon initial segment. Finally, we show that single-site activation of presynaptic GABA(A) autoRs leads to an increase in MLI excitability and thus conveys a strong feedback signal that contributes to spiking activity. © 2015 Zorrilla de San Martin et al.

Evidence for respiratory neuromodulator interdependence after cholinergic disruption in the ventral respiratory column.

PubMed

Muere, Clarissa; Neumueller, Suzanne; Miller, Justin; Olesiak, Samantha; Hodges, Matthew R; Pan, Lawrence; Forster, Hubert V

2015-01-01

Reverse dialysis of the muscarinic receptor antagonist, atropine (ATR, 50 mM), into the pre-Bötzinger Complex region of the ventral respiratory column (VRC) of awake and sleeping goats increases breathing frequency and serotonin (5-HT), substance P (SP), glycine, and GABA concentrations in the effluent dialysate. Herein, we report data from goats in which we reverse dialyzed 5 mM ATR or specific antagonists of M2 or M3 muscarinic receptors into the VRC. The effects on frequency of all three antagonists were not significantly different from time control studies. 5 mM ATR and the M3 antagonist increased SP sevenfold less than 50 mM ATR. The antagonists had no effect on 5-HT, glycine, and/or GABA, suggesting that the increases in glycine and GABA with 50 mM ATR were secondary to the larger increases in 5-HT and/or SP. These data are suggestive of neuromodulator interdependence, whereby attenuation of one neuromodulator is compensated for by local changes in other neuromodulators to stabilize breathing. Copyright © 2014. Published by Elsevier B.V.

Evidence for respiratory neuromodulator interdependence after cholinergic disruption in the ventral respiratory column

PubMed Central

Muere, Clarissa; Neumueller, Suzanne; Miller, Justin; Olesiak, Samantha; Hodges, Matthew R.; Pan, Lawrence; Forster, Hubert V.

2015-01-01

Reverse dialysis of the muscarinic receptor antagonist, atropine (ATR, 50 mM), into the pre-Bötzinger Complex region of the ventral respiratory column (VRC) of awake and sleeping goats increases breathing frequency and serotonin (5-HT), substance P (SP), glycine, and GABA concentrations in the effluent dialysate. Herein, we report data from goats in which we reverse dialyzed 5 mM ATR or specific antagonists of M2 or M3 muscarinic receptors into the VRC. The effects on frequency of all three antagonists were not significantly different from time control studies. 5 mM ATR and the M3 antagonist increased SP seven-fold less than 50 mM ATR. The antagonists had no effect on 5-HT, glycine, and/or GABA, suggesting that the increases in glycine and GABA with 50 mM ATR were secondary to the larger increases in 5-HT and/or SP. These data are suggestive of neuromodulator interdependence, whereby attenuation of one neuromodulator is compensated for by local changes in other neuromodulators to stabilize breathing. PMID:25262584

The effects of intraperitoneal administration of the GABA(B) receptor agonist baclofen on food intake in CFLP and C57BL/6 mice.

PubMed

Ebenezer, Ivor S; Prabhaker, Monika

2007-08-13

The effects of the GABA(B) receptor agonist baclofen were investigated on food intake in non-deprived CFLP and C57BL/6 mice. In Experiment 1, baclofen (1-8 mg /kg) administered i.p. to CFLP mice, produced a dose-related increase in food intake. The 4 and 8 mg/kg doses produced significant increases in cumulative feeding when measure 120 min after administration (at least P < 0.05, in each case). In Experiment 2, baclofen (1-10 mg/kg), administered intraperitoneally (i.p.) to C57BL/6 mice, also produced a dose-related increase in food intake. The 4 mg/kg dose of baclofen significantly increased cumulative food intake at 60 min (P < 0.05), while the 2 and 4 mg/kg doses significantly increased cumulative food intake at 120 min (P < 0.01, in each case). The 10mg/kg dose was without effect. These data show that systemic administration of the GABA(B) agonist baclofen produces an increase in food consumption in two different strains of mice and extend previous observations made in rat to another rodent species.

Changes in the GABA and polyphenols contents of foxtail millet on germination and their relationship with in vitro antioxidant activity.

PubMed

Sharma, Seema; Saxena, Dharmesh C; Riar, Charanjit S

2018-04-15

Germination along with ultrasonic assisted extraction induced a significant beneficial effect on the characteristics of polyphenolic components profile, GABA contents and in vitro antioxidant capacity of the foxtail millet flour extracts. The total antioxidant activity (29.0-45.23 mgAAE/g) and reducing power (0.53-0.76 µg/ml) increase during germination were due to quantitative increase in phthalicacid; hex-3yl-ester; hexadecanoicacid methylester etc. whereas, increase in DPPH (48.32-59.62%) and hydrogen peroxide scavenging activities (35.44-63.07 mM-Trolox/g) were attributed to increase in hexadecanoic acid methylester; 9,12-Octadecadienoicacid ethylester and synthesis of new compounds like pentadecanoicacid; 14-methyl-methylester etc. The metal chelating abilities (34.92-57.38 mgEDTA/g) and in vitro antioxidant activity increase due to overall increase in phenolics, flavonoids along with GABA contents. Synthesis of additional polyphenolic components viz. astaxanthin, propanoicacid, 1-monolinoleoylglycerol trimethylsilylether, 9,12,15-octadecatrienoicacid etc. as a result of germinated explored the possible potential utilization of germinated foxtail millet grains in various functional and convenience food formulations. Copyright © 2017 Elsevier Ltd. All rights reserved.

Polygonatum sibiricum rhizome promotes sleep by regulating non-rapid eye movement and GABAergic/serotonergic receptors in rodent models.

PubMed

Jo, Kyungae; Suh, Hyung Joo; Choi, Hyeon-Son

2018-05-29

The aim of this study is to investigate the sleep-promoting effect of a water extract of the Polygonatum sibiricum rhizome (PSE) in rodent models. PSE contained oleamide (0.10 mg/g extract) and glyceryl monolinoleate (0.17 mg/g extract), which are recognized as sleep-promoting substances. In pentobarbital-induced sleep model at hypnotic level, PSE (160 mg/kg) administration significantly decreased sleep latency time by 29% (2.7 min) and increased sleep duration time by 70% (68.4 min) compared with the normal control (3.8 min and 40.7 min, respectively). In the electroencephalography (EEG) analysis of rats, PSE-mediated sleep promotion accompanied the change of sleep architecture including increase of non-rapid eye movement (NREM) and decrease of REM. This sleep promoting effect was more obvious in caffeine-induced awakening model; total sleep time was increased by 40% along with increased NREM by PSE treatment at 160 mg/kg. In addition, PSE significantly increased the protein and mRNA levels of GABA A -R2 and 5-HT1A receptor, the major sleep-related neurotransmitter receptors. Furthermore, glyceryl monolinoleate and oleamide effectively bound to GABA A receptor in a competitive binding assay. These results indicate that PSE-mediated sleep-promoting effect is associated with the extension of NREM and upregulation of GABA A -R2 and 5-HT1A, and is mediated by binding to the GABA A receptor in vertebrate models. Copyright © 2018. Published by Elsevier Masson SAS.

GABA signaling stimulates α-cell-mediated β-like cell neogenesis.

PubMed

Napolitano, Tiziana; Avolio, Fabio; Vieira, Andhira; Ben-Othman, Nouha; Courtney, Monica; Gjernes, Elisabet; Hadzic, Biljana; Druelle, Noémie; Navarro Sanz, Sergi; Silvano, Serena; Mansouri, Ahmed; Collombat, Patrick

2017-01-01

Diabetes is a chronic and progressing disease, the number of patients increasing exponentially, especially in industrialized countries. Regenerating lost insulin-producing cells would represent a promising therapeutic alternative for most diabetic patients. To this end, using the mouse as a model, we reported that GABA, a food supplement, could induce insulin-producing beta-like cell neogenesis offering an attractive and innovative approach for diabetes therapeutics.

Elevated striatal γ-aminobutyric acid in youth with major depressive disorder.

PubMed

Bradley, Kailyn A; Alonso, Carmen M; Mehra, Lushna M; Xu, Junqian; Gabbay, Vilma

2018-06-08

Alterations in γ-aminobutyric acid (GABA) have been hypothesized to play a role in the pathogenesis of psychiatric illness. Our previous work has specifically linked anterior cingulate cortex (ACC) GABA deficits with anhedonia in youth with major depressive disorder (MDD). As anhedonia reflects alterations within the reward circuitry, we sought to extend this investigation and examine GABA levels in another key reward-related region, the striatum, in the same adolescent population. Thirty-six youth [20 with MDD and 16 healthy controls; (HC)], ages 12 to 21 years old, underwent J-edited proton magnetic resonance spectroscopy ( 1 H MRS) whereby GABA levels were measured in striatal and ACC voxels. GABA levels were compared between groups and between voxel positions and were examined in relation to clinical symptomatology, such as depression severity, anhedonia, anxiety, and suicidality. Depressed youth had unexpectedly higher GABA levels in the striatum compared to HC. In both depressed and healthy youth, GABA levels were higher in the striatum than in the ACC, while the differences in depressed youth were greater. Moreover, in depressed youth, higher striatal GABA above the mean of HCs was correlated with lower ACC GABA below the mean of HCs. Striatal GABA was not correlated with clinical symptomatology in this small sample. Together, these findings suggest that higher striatal GABA levels may serve some compensatory function as a result of lower ACC GABA in depressed adolescents. It is also possible that, like lower ACC GABA, higher striatal GABA might simply be another pathological feature of adolescent depression. Copyright © 2018 Elsevier Inc. All rights reserved.

Genetic manipulation of the γ-aminobutyric acid (GABA) shunt in rice: overexpression of truncated glutamate decarboxylase (GAD2) and knockdown of γ-aminobutyric acid transaminase (GABA-T) lead to sustained and high levels of GABA accumulation in rice kernels.

PubMed

Shimajiri, Yasuka; Oonishi, Takayuki; Ozaki, Kae; Kainou, Kumiko; Akama, Kazuhito

2013-06-01

Gamma-aminobutyric acid (GABA) is a non-protein amino acid commonly present in all organisms. Because cellular levels of GABA in plants are mainly regulated by synthesis (glutamate decarboxylase, GAD) and catabolism (GABA-transaminase, GABA-T), we attempted seed-specific manipulation of the GABA shunt to achieve stable GABA accumulation in rice. A truncated GAD2 sequence, one of five GAD genes, controlled by the glutelin (GluB-1) or rice embryo globulin promoters (REG) and GABA-T-based trigger sequences in RNA interference (RNAi) cassettes controlled by one of these promoters as well, was introduced into rice (cv. Koshihikari) to establish stable transgenic lines under herbicide selection using pyriminobac. T₁ and T₂ generations of rice lines displayed high GABA concentrations (2-100 mg/100 g grain). In analyses of two selected lines from the T₃ generation, there was a strong correlation between GABA level and the expression of truncated GAD2, whereas the inhibitory effect of GABA-T expression was relatively weak. In these two lines both with two T-DNA copies, their starch, amylose, and protein levels were slightly lower than non-transformed cv. Koshihikari. Free amino acid analysis of mature kernels of these lines demonstrated elevated levels of GABA (75-350 mg/100 g polished rice) and also high levels of several amino acids, such as Ala, Ser, and Val. Because these lines of seeds could sustain their GABA content after harvest (up to 6 months), the strategy in this study could lead to the accumulation GABA and for these to be sustained in the edible parts. © 2013 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.

Expression of GABA signaling molecules KCC2, NKCC1, and GAD1 in cortical development and schizophrenia.

PubMed

Hyde, Thomas M; Lipska, Barbara K; Ali, Towhid; Mathew, Shiny V; Law, Amanda J; Metitiri, Ochuko E; Straub, Richard E; Ye, Tianzhang; Colantuoni, Carlo; Herman, Mary M; Bigelow, Llewellyn B; Weinberger, Daniel R; Kleinman, Joel E

2011-07-27

GABA signaling molecules are critical for both human brain development and the pathophysiology of schizophrenia. We examined the expression of transcripts derived from three genes related to GABA signaling [GAD1 (GAD67 and GAD25), SLC12A2 (NKCC1), and SLC12A5 (KCC2)] in the prefrontal cortex (PFC) and hippocampal formation of a large cohort of nonpsychiatric control human brains (n = 240) across the lifespan (from fetal week 14 to 80 years) and in patients with schizophrenia (n = 30-31), using quantitative RT-PCR. We also examined whether a schizophrenia risk-associated promoter SNP in GAD1 (rs3749034) is related to expression of these transcripts. Our studies revealed that development and maturation of both the PFC and hippocampal formation are characterized by progressive switches in expression from GAD25 to GAD67 and from NKCC1 to KCC2. Previous studies have demonstrated that the former leads to GABA synthesis, and the latter leads to switching from excitatory to inhibitory neurotransmission. In the hippocampal formation, GAD25/GAD67 and NKCC1/KCC2 ratios are increased in patients with schizophrenia, reflecting a potentially immature GABA physiology. Remarkably, GAD25/GAD67 and NKCC1/KCC2 expression ratios are associated with rs3749034 genotype, with risk alleles again predicting a relatively less mature pattern. These findings suggest that abnormalities in GABA signaling critical to brain development contribute to genetic risk for schizophrenia.

The effects of elevated endogenous GABA levels on movement-related network oscillations.

PubMed

Muthukumaraswamy, S D; Myers, J F M; Wilson, S J; Nutt, D J; Lingford-Hughes, A; Singh, K D; Hamandi, K

2013-02-01

The EEG/MEG signal is generated primarily by the summation of the post-synaptic potentials of cortical principal cells. At a microcircuit level, these glutamatergic principal cells are reciprocally connected to GABAergic interneurons and cortical oscillations are thought to be dependent on the balance of excitation and inhibition between these cell types. To investigate the dependence of movement-related cortical oscillations on excitation-inhibition balance, we pharmacologically manipulated the GABA system using tiagabine, which blocks GABA Transporter 1(GAT-1), the GABA uptake transporter and increases endogenous GABA activity. In a blinded, placebo-controlled, crossover design, in 15 healthy participants we administered either 15mg of tiagabine or a placebo. We recorded whole-head magnetoencephalograms, while the participants performed a movement task, prior to, one hour post, three hour post and five hour post tiagabine ingestion. Using time-frequency analysis of beamformer source reconstructions, we quantified the baseline level of beta activity (15-30Hz), the post-movement beta rebound (PMBR), beta event-related desynchronisation (beta-ERD) and movement-related gamma synchronisation (MRGS) (60-90Hz). Our results demonstrated that tiagabine, and hence elevated endogenous GABA levels causes, an elevation of baseline beta power, enhanced beta-ERD and reduced PMBR, but no modulation of MRGS. Comparing our results to recent literature (Hall et al., 2011) we suggest that beta-ERD may be a GABAA receptor mediated process while PMBR may be GABAB receptor mediated. Copyright © 2012 Elsevier Inc. All rights reserved.

GABA-benzodiazepine receptor function in alcohol dependence: a combined 11C-flumazenil PET and pharmacodynamic study.

PubMed

Lingford-Hughes, A R; Wilson, S J; Cunningham, V J; Feeney, A; Stevenson, B; Brooks, D J; Nutt, D J

2005-08-01

Gamma-aminobutyric acid (GABA)-benzodiazepine receptor function is hypothesised to be reduced in alcohol dependence. We used positron emission tomography (PET) with [11C]flumazenil, a non-selective tracer for brain GABA-benzodiazepine (GABA-BDZ) receptor binding, to determine in vivo the relationship between BDZ receptor occupancy by an agonist, midazolam, and its functional effects. Abstinent male alcohol dependent subjects underwent [11C]flumazenil PET to measure occupancy of BDZ receptors by midazolam whilst recording its pharmacodynamic effects on behavioural and physiological measures. Rate constants describing the exchange of [11C]flumazenil between the plasma and brain compartments were derived from time activity curves. A 50% reduction in electroencephalography (EEG)-measured sleep time was seen in the alcohol dependent group despite the same degree of occupancy by midazolam as seen in the control group. The effects of midazolam on other measures of benzodiazepine receptor function, increasing EEG beta1 power and slowing of saccadic eye movements, were similar in the two groups. No differences in midazolam or flumazenil metabolism were found between the groups. In summary, our study suggests that alcohol dependence in man is associated with a reduced EEG sleep response to the benzodiazepine agonist, midazolam, which is not explained by reduced BDZ receptor occupancy, and is consistent with reduced sensitivity in this measure of GABA-BDZ receptor function in alcohol dependence. The lack of change in other functional measures may reflect a differential involvement of particular subtypes of the GABA-BDZ receptor.

A comparative density functional theory study of electronic structure and optical properties of γ-aminobutyric acid and its cocrystals with oxalic and benzoic acid

NASA Astrophysics Data System (ADS)

da Silva Filho, J. G.; Freire, V. N.; Caetano, E. W. S.; Ladeira, L. O.; Fulco, U. L.; Albuquerque, E. L.

2013-11-01

In this letter, we study the electronic structure and optical properties of the active medicinal component γ-aminobutyric acid (GABA) and its cocrystals with oxalic (OXA) and benzoic (BZA) acid by means of the density functional theory formalism. It is shown that the cocrystallization strongly weakens the zwitterionic character of the GABA molecule leading to striking differences among the electronic band structures and optical absorption spectra of the GABA crystal and GABA:OXA, GABA:BZA cocrystals, originating from distinct sets of hydrogen bonds. Calculated band widths and Δ-sol band gap estimates indicate that both GABA and GABA:OXA, GABA:BZA cocrystals are indirect gap insulators.

Neurochemical correlates of. gamma. -aminobutyrate (GABA) inhibition in cat visual cortex

DOE Office of Scientific and Technical Information (OSTI.GOV)

Balcar, V.J.; Dreher, B.

1990-01-01

High affinity binding of ({sup 3}H){gamma}-aminobutyric acid (GABA) to neuronal membranes from different parts of cat visual cortex was tested for sensitivity to GABA{sub A} agonists isoguvacine and THIP, GABA{sub A} antagonist SR95531 and GABA{sub B} agonist baclofen. Some of the GABA{sub A}-binding sites were found to have a very low affinity for THIP, suggesting the presence and, possibly, uneven distribution of non-synaptic GABA{sub A} receptors in cat visual cortex. There were no differences in K{sub m} and V{sub max} values of high affinity uptake of GABA and in the potency of K{sup +}-stimulated release of GABA, between primary andmore » association cortices. Consequently, the present results indicate that despite the anatomical and physiological differences between the primary and association feline visual cortices the neurochemical characteristics of GABAergic inhibition are very similar in the two regions.« less

Mechanism of Inactivation of GABA Aminotransferase by (E)- and (Z)-(1S,3S)-3-Amino-4-fluoromethylenyl-1-cyclopentanoic Acid

PubMed Central

Lee, Hyunbeom; Le, Hoang V.; Wu, Rui; Doud, Emma; Sanishvili, Ruslan; Kellie, John F.; Compton, Phillip D.; Pachaiyappan, Boobalan; Liu, Dali; Kelleher, Neil L.

2015-01-01

When γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, falls below a threshold level, seizures occur. One approach to raise GABA concentrations is to inhibit GABA aminotransferase (GABA-AT), a pyridoxal 5’-phosphate-dependent enzyme that degrades GABA. We have previously developed (1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid (CPP-115), which is 186 times more efficient in inactivating GABA-AT than vigabatrin, the only FDA-approved inactivator of GABA-AT. We also developed (E)- and (Z)-(1S,3S)-3-amino-4-fluoromethylenyl-1-cyclopentanoic acid (1 and 2, respectively), monofluorinated analogs of CPP-115, which are comparable to vigabatrin in inactivating GABA-AT. Here we report the mechanism of inactivation of GABA-AT by 1 and 2. Both produce a metabolite that induces disruption of the Glu270-Arg445 salt bridge to accommodate interaction between the metabolite formyl group and Arg445. This is the second time that Arg445 has interacted with a ligand and is involved in GABA-AT inactivation, thereby confirming the importance of Arg445 in future inactivator design. PMID:26110556

Design and Mechanism of Tetrahydrothiophene-based GABA Aminotransferase Inactivators

PubMed Central

Le, Hoang V.; Hawker, Dustin D.; Wu, Rui; Doud, Emma; Widom, Julia; Sanishvili, Ruslan; Liu, Dali; Kelleher, Neil L.; Silverman, Richard B.

2015-01-01

Low levels of γ-aminobutyric acid (GABA), one of two major neurotransmitters that regulate brain neuronal activity, are associated with many neurological disorders, such as epilepsy, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and cocaine addiction. One of the main methods to raise the GABA level in human brain is to use small molecules that cross the blood-brain barrier and inhibit the activity of γ-aminobutyric acid aminotransferase (GABA-AT), the enzyme that degrades GABA. We have designed a series of conformationally-restricted, tetrahydrothiophene-based GABA analogs with a properly-positioned leaving group that could facilitate a ring-opening mechanism, leading to inactivation of GABA-AT. One compound in the series is eight times more efficient an inactivator of GABA-AT than vigabatrin, the only FDA-approved inactivator of GABA-AT. Our mechanistic studies show that the compound inactivates GABA-AT by a new mechanism. The metabolite resulting from inactivation does not covalently bind to amino acid residues of GABA-AT but stays in the active site via H-bond interactions with Arg-192, a π-π interaction with Phe-189, and a weak nonbonded S···O=C interaction with Glu-270, thereby inactivating the enzyme. PMID:25781189

GABA(C) receptors: a molecular view.

PubMed

Enz, R

2001-08-01

In the central nervous system inhibitory neurotransmission is primarily achieved through activation of receptors for gamma-aminobutyric acid (GABA). Three types of GABA receptors have been identified on the basis of their pharmacological and electrophysiological properties. The predominant type, termed GABA(A), and a recently identified GABA(C) type, form ligand-gated chloride channels, whereas GABA(B) receptors activate separate cation channels via G proteins. Based on their homology to nicotinic acetylcholine receptors, GABA(C) receptors are believed to be oligomeric protein complexes composed of five subunits in a pentameric arrangement. To date up to five different GABA(C) receptors subunits have been identified in various species. Recent studies have shed new light on the biological characteristics of GABA(C) receptors, including the chromosomal localization of its subunit genes and resulting links to deseases, the cloning of new splice variants, the identification of GABA(C) receptor-associated proteins, the identification of domains involved in subunit assembly, and finally structure/function studies examining functional consequences of introduced mutations. This review summarizes recent data in view of the molecular structure of GABA(C) receptors and presents new insights into the biological function of this protein in the retina.

Gas release-based prescreening combined with reversed-phase HPLC quantitation for efficient selection of high-γ-aminobutyric acid (GABA)-producing lactic acid bacteria.

PubMed

Wu, Qinglong; Shah, Nagendra P

2015-02-01

High γ-aminobutyric acid (GABA)-producing lactobacilli are promising for the manufacture of GABA-rich foods and to synthesize GRAS (generally recognized as safe)-grade GABA. However, common chromatography-based screening is time-consuming and inefficient. In the present study, Korean kimchi was used as a model of lactic acid-based fermented foods, and a gas release-based prescreening of potential GABA producers was developed. The ability to produce GABA by potential GABA producers in de Man, Rogosa, and Sharpe medium supplemented with or without monosodium glutamate was further determined by HPLC. Based on the results, 9 isolates were regarded as high GABA producers, and were further genetically identified as Lactobacillus brevis based on the sequences of 16S rRNA gene. Gas release-based prescreening combined with reversed-phase HPLC confirmation was an efficient and cost-effective method to identify high-GABA-producing LAB, which could be good candidates for probiotics. The GABA that is naturally produced by these high-GABA-producing LAB could be used as a food additive. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Mechanism of Inactivation of GABA Aminotransferase by (E)- and (Z)-(1S,3S)-3-Amino-4-fluoromethylenyl-1-cyclopentanoic Acid.

PubMed

Lee, Hyunbeom; Le, Hoang V; Wu, Rui; Doud, Emma; Sanishvili, Ruslan; Kellie, John F; Compton, Phillip D; Pachaiyappan, Boobalan; Liu, Dali; Kelleher, Neil L; Silverman, Richard B

2015-09-18

When γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, falls below a threshold level, seizures occur. One approach to raise GABA concentrations is to inhibit GABA aminotransferase (GABA-AT), a pyridoxal 5'-phosphate-dependent enzyme that degrades GABA. We have previously developed (1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid (CPP-115), which is 186 times more efficient in inactivating GABA-AT than vigabatrin, the only FDA-approved inactivator of GABA-AT. We also developed (E)- and (Z)-(1S,3S)-3-amino-4-fluoromethylenyl-1-cyclopentanoic acid (1 and 2, respectively), monofluorinated analogs of CPP-115, which are comparable to vigabatrin in inactivating GABA-AT. Here, we report the mechanism of inactivation of GABA-AT by 1 and 2. Both produce a metabolite that induces disruption of the Glu270-Arg445 salt bridge to accommodate interaction between the metabolite formyl group and Arg445. This is the second time that Arg445 has interacted with a ligand and is involved in GABA-AT inactivation, thereby confirming the importance of Arg445 in future inactivator design.

Brain gamma-aminobutyric acid (GABA) abnormalities in bipolar disorder

PubMed Central

Brady, Roscoe O; McCarthy, Julie M; Prescot, Andrew P; Jensen, J Eric; Cooper, Alissa J; Cohen, Bruce M; Renshaw, Perry F; Ongür, Dost

2017-01-01

Objectives Gamma-aminobutyric acid (GABA) abnormalities have been implicated in bipolar disorder. However, due to discrepant studies measuring postmortem, cerebrospinal fluid, plasma, and in vivo brain levels of GABA, the nature of these abnormalities is unclear. Using proton magnetic resonance spectroscopy, we investigated tissue levels of GABA in the anterior cingulate cortex and parieto-occipital cortex of participants with bipolar disorder and healthy controls. Methods Fourteen stably medicated euthymic outpatients with bipolar disorder type I (mean age 32.6 years, eight male) and 14 healthy control participants (mean age 36.9 years, 10 male) completed a proton magnetic resonance spectroscopy scan at 4-Tesla after providing informed consent. We collected data from two 16.7-mL voxels using MEGAPRESS, and they were analyzed using LCModel. Results GABA/creatine ratios were elevated in bipolar disorder participants compared to healthy controls [F(1,21) = 4.4, p = 0.048] in the anterior cingulate cortex (25.1% elevation) and the parieto-occipital cortex (14.6% elevation). Bipolar disorder participants not taking GABA-modulating medications demonstrated greater GABA/creatine elevations than patients taking GABA-modulating medications. Conclusions We found higher GABA/creatine levels in euthymic bipolar disorder outpatients compared to healthy controls, and the extent of this elevation may be affected by the use of GABA-modulating medications. Our findings suggest that elevated brain GABA levels in bipolar disorder may be associated with GABAergic dysfunction and that GABA-modulating medications reduce GABA levels in this condition. PMID:23634979

Growth Hormone–Releasing Hormone Effects on Brain γ-Aminobutyric Acid Levels in Mild Cognitive Impairment and Healthy Aging

PubMed Central

Friedman, Seth D.; Baker, Laura D.; Borson, Soo; Jensen, J. Eric; Barsness, Suzanne M.; Craft, Suzanne; Merriam, George R.; Otto, Randolph K.; Novotny, Edward J.; Vitiello, Michael V.

2013-01-01

Importance Growth hormone–releasing hormone (GHRH) has been previously shown to have cognition-enhancing effects. The role of neurotransmitter changes, measured by proton magnetic resonance spectroscopy, may inform the mechanisms for this response. Objective To examine the neurochemical effects of GHRH in a subset of participants from the parent trial. Design Randomized, double-blind, placebo-controlled substudy of a larger trial. Setting Clinical research unit at the University of Washington School of Medicine. Participants Thirty adults (17 with mild cognitive impairment [MCI]), ranging in age from 55 to 87 years, were enrolled and successfully completed the study. Interventions Participants self-administered daily subcutaneous injections of tesamorelin (Theratechnologies Inc), a stabilized analogue of human GHRH (1 mg/d), or placebo 30 minutes before bedtime for 20 weeks. At baseline and weeks 10 and 20, participants underwent brain magnetic resonance imaging and spectroscopy protocols and cognitive testing and provided blood samples after fasting. Participants also underwent glucose tolerance tests before and after intervention. Main Outcomes and Measures Brain levels of glutamate, inhibitory transmitters γ-aminobutyric acid (GABA) and N-acetylaspartylglutamate (NAAG), and myo-inositol (MI), an osmolyte linked to Alzheimer disease in humans, were measured in three 2×2×2-cm3 left-sided brain regions (dorsolateral frontal, posterior cingulate, and posterior parietal). Glutamate, GABA, and MI levels were expressed as ratios to creatine plus phospho-creatine, and NAAG was expressed as a ratio to N-acetylaspartate. Results After 20 weeks of GHRH administration, GABA levels were increased in all brain regions (P<.04), NAAG levels were increased (P=.03) in the dorsolateral frontal cortex, and MI levels were decreased in the posterior cingulate (P=.002). These effects were similar in adults with MCI and older adults with normal cognitive function. No changes in the brain levels of glutamate were observed. In the posterior cingulate, treatment-related changes in serum insulin-like growth factor 1 were positively correlated with changes in GABA (r=0.47; P=.001) and tended to be negatively correlated with MI (r=−0.34; P=.06). Consistent with the results of the parent trial, a favorable treatment effect on cognition was observed in substudy participants (P=.03). No significant associations were observed between treatment-related changes in neurochemical and cognitive outcomes. Glucose homeostasis in the periphery was not reliably affected by GHRH administration and did not account for treatment neurochemical effects. Conclusions Twenty weeks of GHRH administration increased GABA levels in all 3 brain regions, increased NAAG levels in the frontal cortex, and decreased MI levels in the posterior cingulate. To our knowledge, this is the first evidence that 20 weeks of somatotropic supplementation modulates inhibitory neurotransmitter and brain metabolite levels in a clinical trial, and it provides preliminary support for one possible mechanism to explain favorable GHRH effects on cognition in adults with MCI and in healthy older adults. Trial Registration clinicaltrials.gov Identifier: NCT00257712 PMID:23689947

Alteration of glutamate/GABA balance during acute alcohol intoxication in rats: effect of Xingnaojing injection.

PubMed

Wei, Jingjing; Yao, Limei; Yang, Lei; Zhao, Wei; Shi, Si; Cai, Qingyan; Chen, Dingsheng; Li, Weirong; Wang, Qi

2015-05-26

Xingnaojing Injection (XNJI) is a modern Chinese formula came from famous Chinese medicine An Gong Niu Huang Pill. XNJI has been used for treatment of cerebral diseases and stroke in China, and is approved by the State Food and Drug Administration of China for the treatment of acute alcohol intoxication (AAI). XNJI belongs to the ethnopharmacological family of medicines. In this study, we investigated the mechanisms of the XNJI effect on AAI. To investigate the effects of XNJI on glutamate, gamma-aminobutyric acid (GABA) and related receptor in lateral hypothalamic area (LHA) of AAI rat. Adult male Sprague-Dawley rats were implanted with microdialysis probes in LHA. Rats were randomly divided into control, model, 1.36mg/kg XNJI, 0.68mg/kg XNJI and 0.34mg/kg XNJI groups. During microdialysis, baseline samples were collected from 1h to 2.5h; thereafter, the rats were given an intraperitoneal injection of 52% ethanol, 5.2g/kg, or saline for control group. Twenty minutes later, three doses of XNJI was given by unilateral injection respectively, while saline for control and model groups, and samples were collected for the next 4h. The extracellular glutamate and GABA levels were measured in the LHA by a high performance liquid chromatography coupled with fluorescence detector (HPLC-FLU). The expression levels of related receptors N-methyl-d-aspartate receptor (NR) subunit NR2A, NR2B and GABAA were analyzed by reverse transcription polymerase chain reaction (RT-PCR). Ethanol (5.2g/kg) significantly decreased the extracellular levels of glutamate and increased extracellular GABA in LHA. On the other hand ethanol significantly decreased NR2A and NR2B mRNAs expression, and increase GABAA mRNA expression. XNJI could increase the extracellular level of glutamate and decrease that of GABA; moreover, induced an increase in NR2A and NR2B mRNA expression, and a decrease in GABAA mRNA expression in LHA. The current changes in glutamate, GABA and mRNA expressions of related receptors in LHA after injection of XNJI suggest that changes in these neurotransmitters and receptors as a potential mechanism of action for AAI. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Treatment of addiction and addiction-related behavior

DOEpatents

Dewey, Stephen L.; Brodie, Jonathan D.; Ashby, Jr., Charles R.

2003-01-01

The present invention provides a highly efficient method for treating substance addiction and for changing addiction-related behavior of a mammal suffering from substance addiction. The method includes administering to a mammal an effective amount of gamma vinylGABA or a pharmaceutically acceptable salt thereof. The present invention also provides a method of treatment of cocaine, morphine, heroin, nicotine, amphetamine, methamphetamine, or ethanol addiction by treating a mammal with an effective amount of gamma vinylGABA or a pharmaceutically acceptable salt thereof. In one embodiment, the method of the present invention includes administering to the mammal an effective amount of a composition which increases central nervous system GABA levels wherein the effective amount is sufficient to diminish, inhibit or eliminate behavior associated with craving or use of drugs of abuse. The composition includes GVG, gabapentin, valproic acid, progabide, gamma-hydroxybutyric acid, fengabine, cetylGABA, topiramate or tiagabine or a pharmaceutically acceptable salt thereof, or an enantiomer or a racemic mixture thereof.

Wnt signaling pathway improves central inhibitory synaptic transmission in a mouse model of Duchenne muscular dystrophy.

PubMed

Fuenzalida, Marco; Espinoza, Claudia; Pérez, Miguel Ángel; Tapia-Rojas, Cheril; Cuitino, Loreto; Brandan, Enrique; Inestrosa, Nibaldo C

2016-02-01

The dystrophin-associated glycoprotein complex (DGC) that connects the cytoskeleton, plasma membrane and the extracellular matrix has been related to the maintenance and stabilization of channels and synaptic receptors, which are both essential for synaptogenesis and synaptic transmission. The dystrophin-deficient (mdx) mouse model of Duchenne muscular dystrophy (DMD) exhibits a significant reduction in hippocampal GABA efficacy, which may underlie the altered synaptic function and abnormal hippocampal long-term plasticity exhibited by mdx mice. Emerging studies have implicated Wnt signaling in the modulation of synaptic efficacy, neuronal plasticity and cognitive function. We report here that the activation of the non-canonical Wnt-5a pathway and Andrographolide, improves hippocampal mdx GABAergic efficacy by increasing the number of inhibitory synapses and GABA(A) receptors or GABA release. These results indicate that Wnt signaling modulates GABA synaptic efficacy and could be a promising novel target for DMD cognitive therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

A hypothalamic circuit for the circadian control of aggression.

PubMed

Todd, William D; Fenselau, Henning; Wang, Joshua L; Zhang, Rong; Machado, Natalia L; Venner, Anne; Broadhurst, Rebecca Y; Kaur, Satvinder; Lynagh, Timothy; Olson, David P; Lowell, Bradford B; Fuller, Patrick M; Saper, Clifford B

2018-05-01

'Sundowning' in dementia and Alzheimer's disease is characterized by early-evening agitation and aggression. While such periodicity suggests a circadian origin, whether the circadian clock directly regulates aggressive behavior is unknown. We demonstrate that a daily rhythm in aggression propensity in male mice is gated by GABAergic subparaventricular zone (SPZ GABA ) neurons, the major postsynaptic targets of the central circadian clock, the suprachiasmatic nucleus. Optogenetic mapping revealed that SPZ GABA neurons receive input from vasoactive intestinal polypeptide suprachiasmatic nucleus neurons and innervate neurons in the ventrolateral part of the ventromedial hypothalamus (VMH), which is known to regulate aggression. Additionally, VMH-projecting dorsal SPZ neurons are more active during early day than early night, and acute chemogenetic inhibition of SPZ GABA transmission phase-dependently increases aggression. Finally, SPZ GABA -recipient central VMH neurons directly innervate ventrolateral VMH neurons, and activation of this intra-VMH circuit drove attack behavior. Altogether, we reveal a functional polysynaptic circuit by which the suprachiasmatic nucleus clock regulates aggression.

Endogenous GABA and glutamate finely tune the bursting of olfactory bulb external tufted cells.

PubMed

Hayar, Abdallah; Ennis, Matthew

2007-08-01

In rat olfactory bulb slices, external tufted (ET) cells spontaneously generate spike bursts. Although ET cell bursting is intrinsically generated, its strength and precise timing may be regulated by synaptic input. We tested this hypothesis by analyzing whether the burst properties are modulated by activation of ionotropic gamma-aminobutyric acid (GABA) and glutamate receptors. Blocking GABA(A) receptors increased--whereas blocking ionotropic glutamate receptors decreased--the number of spikes/burst without changing the interburst frequency. The GABA(A) agonist (isoguvacine, 10 microM) completely inhibited bursting or reduced the number of spikes/burst, suggesting a shunting effect. These findings indicate that the properties of ET cell spontaneous bursting are differentially controlled by GABAergic and glutamatergic fast synaptic transmission. We suggest that ET cell excitatory and inhibitory inputs may be encoded as a change in the pattern of spike bursting in ET cells, which together with mitral/tufted cells constitute the output circuit of the olfactory bulb.

The Timing of the Excitatory-to-Inhibitory GABA Switch Is Regulated by the Oxytocin Receptor via KCC2

PubMed Central

Leonzino, Marianna; Busnelli, Marta; Antonucci, Flavia; Verderio, Claudia; Mazzanti, Michele; Chini, Bice

2016-01-01

Summary Oxytocin and its receptor (Oxtr) play a crucial role in the postnatal transition of neuronal GABA neurotransmission from excitatory to inhibitory, a developmental process known as the GABA switch. Using hippocampal neurons from Oxtr-null mice, we show that (1) Oxtr is necessary for the correct timing of the GABA switch by upregulating activity of the chloride cotransporter KCC2, (2) Oxtr, in a very early and narrow time window, directly modulates the functional activity of KCC2 by promoting its phosphorylation and insertion/stabilization at the neuronal surface, and (3) in the absence of Oxtr, electrophysiological alterations are recorded in mature neurons, a finding consistent with a reduced level of KCC2 and increased susceptibility to seizures observed in adult Oxtr-null mice. These data identify KCC2 as a key target of oxytocin in postnatal events that may be linked to pathogenesis of neurodevelopmental disorders. PMID:27052180

Gamma-aminobutyric acid fermentation with date residue by a lactic acid bacterium, Lactobacillus brevis.

PubMed

Hasegawa, Momoko; Yamane, Daisuke; Funato, Kouichi; Yoshida, Atsushi; Sambongi, Yoshihiro

2018-03-01

Dates are commercially consumed as semi-dried fruit or processed into juice and puree for further food production. However, the date residue after juice and puree production is not used, although it appears to be nutrient enriched. Here, date residue was fermented by a lactic acid bacterium, Lactobacillus brevis, which has been generally recognized as safe. Through degradation of sodium glutamate added to the residue during the fermentation, γ-aminobutyric acid (GABA), which reduces neuronal excitability, was produced at the conversion rate of 80-90% from glutamate. In order to achieve this GABA production level, pretreatment of the date residue with carbohydrate-degrading enzymes, i.e., cellulase and pectinase, was necessary. All ingredients used for this GABA fermentation were known as being edible. These results provide us with a solution for the increasing commercial demand for GABA in food industry with the use of date residue that has been often discarded. Copyright © 2017 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

β-Hydroxybutyrate Boosts Mitochondrial and Neuronal Metabolism but is not Preferred Over Glucose Under Activated Conditions.

PubMed

Achanta, Lavanya B; Rowlands, Benjamin D; Thomas, Donald S; Housley, Gary D; Rae, Caroline D

2017-06-01

The ketone body, β-hydroxybutyrate (βOHB), is metabolised by the brain alongside the mandatory brain fuel glucose. To examine the extent and circumstances by which βOHB can supplement glucose metabolism, we studied guinea pig cortical brain slices using increasing concentrations of [U- 13 C]D-βOHB in conjunction with [1- 13 C]D-glucose under conditions of normo- and hypoglycaemia, as well as under high potassium (40 mmol/L K + ) depolarization in normo- and hypoglycaemic conditions. The contribution of βOHB to synthesis of GABA was also probed by inhibiting the synthesis of glutamine, a GABA precursor, with methionine sulfoximine (MSO). [U- 13 C]D-βOHB at lower concentrations (0.25 and 1.25 mmol/L) stimulated mitochondrial metabolism, producing greater total incorporation of label into glutamate and GABA but did not have a similar effect in the cytosolic compartment where labelling of glutamine was reduced at 1.25 mmol/L [U- 13 C]D-βOHB. At higher concentrations (2.5 mmol/L) [U- 13 C]D-βOHB inhibited metabolism of [1- 13 C]D-glucose, and reduced total label incorporation and total metabolite pools. When glucose levels were reduced, βOHB was able to partially restore the loss of glutamate and GABA caused by hypoglycaemia, but was not able to supplement levels of lactate, glutamine or alanine or to prevent the increase in aspartate. Under depolarizing conditions glucose was the preferred substrate over βOHB, even in hypoglycaemic conditions where comparatively less βOHB was incorporated except into aspartate isotopomers. Inhibition of glutamine synthesis with MSO had no significant effect on incorporation of label from [U- 13 C]D-βOHB into GABA C2,1 indicating that the majority of this GABA was synthesized in GABAergic neurons from [U- 13 C]D-βOHB rather than from Gln C4,5 imported from astrocytes.

Insights into the binding of GABA to the insect RDL receptor from atomistic simulations: a comparison of models

NASA Astrophysics Data System (ADS)

Comitani, Federico; Cohen, Netta; Ashby, Jamie; Botten, Dominic; Lummis, Sarah C. R.; Molteni, Carla

2014-01-01

The resistance to dieldrin (RDL) receptor is an insect pentameric ligand-gated ion channel (pLGIC). It is activated by the neurotransmitter γ-aminobutyric acid (GABA) binding to its extracellular domain; hence elucidating the atomistic details of this interaction is important for understanding how the RDL receptor functions. As no high resolution structures are currently available, we built homology models of the extracellular domain of the RDL receptor using different templates, including the widely used acetylcholine binding protein and two pLGICs, the Erwinia Chrysanthemi ligand-gated ion channel (ELIC) and the more recently resolved GluCl. We then docked GABA into the selected three dimensional structures, which we used as starting points for classical molecular dynamics simulations. This allowed us to analyze in detail the behavior of GABA in the binding sites, including the hydrogen bond and cation-π interaction networks it formed, the conformers it visited and the possible role of water molecules in mediating the interactions; we also estimated the binding free energies. The models were all stable and showed common features, including interactions consistent with experimental data and similar to other pLGICs; differences could be attributed to the quality of the models, which increases with increasing sequence identity, and the use of a pLGIC template. We supplemented the molecular dynamics information with metadynamics, a rare event method, by exploring the free energy landscape of GABA binding to the RDL receptor. Overall, we show that the GluCl template provided the best models. GABA forming direct salt-bridges with Arg211 and Glu204, and cation-π interactions with an aromatic cage including Tyr109, Phe206 and Tyr254, represents a favorable binding arrangement, and the interaction with Glu204 can also be mediated by a water molecule.

Magnolol, a major bioactive constituent of the bark of Magnolia officinalis, induces sleep via the benzodiazepine site of GABA(A) receptor in mice.

PubMed

Chen, Chang-Rui; Zhou, Xu-Zhao; Luo, Yan-Jia; Huang, Zhi-Li; Urade, Yoshihiro; Qu, Wei-Min

2012-11-01

Magnolol (6,6',7,12-tetramethoxy-2,2'-dimethyl-1-beta-berbaman, C(18)H(18)O(2)), an active ingredient of the bark of Magnolia officinalis, has been reported to exert potent anti-epileptic effects via the GABA(A) receptor. The receptor also mediates sleep in humans and animals. The aim of this study was to determine whether magnolol could modulate sleep behaviors by recording EEG and electromyogram in mice. The results showed that magnolol administered i.p. at a dose of 5 or 25 mg/kg could significantly shorten the sleep latency, increase the amount of non-rapid eye movement (non-REM, NREM) and rapid eye movement (REM) sleep for 3 h after administration with an increase in the number of NREM and REM sleep episodes. Magnolol at doses of 5 and 25 mg/kg increased the number of bouts of wakefulness but decreased their duration. On the other hand, magnolol increased the number of state transitions from wakefulness to NREM sleep and subsequently from NREM sleep to wakefulness. Immunohistochemical study showed that magnolol increased c-Fos expression in the neurons of ventrolateral preoptic area, a sleep center in the anterior hypothalamus, and decreased c-Fos expression in the arousal tuberomammillary nucleus, which was located in the caudolateral hypothalamus. The sleep-promoting effects and changes in c-Fos induced by magnolol were reversed by flumazenil, an antagonist at the benzodiazepine site of the GABA(A) receptor. These results indicate that magnolol increased NREM and REM sleep via the GABA(A) receptor. Copyright © 2012 Elsevier Ltd. All rights reserved.

4,5-Dichloro-2-octyl-4-isothiazolin-3-one (DCOIT) modifies synaptic transmission in hippocampal CA3 neurons of rats.

PubMed

Wakita, Masahito; Shoudai, Kiyomitsu; Oyama, Yasuo; Akaike, Norio

2017-10-01

4,5-Dichloro-2-octyl-4-isothiazolin-3-one (DCOIT) is an alternative to organotin antifoulants, such as tributyltin and triphenyltin. Since DCOIT is found in harbors, bays, and coastal areas worldwide, this chemical compound may have some impacts on ecosystems. To determine whether DCOIT possesses neurotoxic activity by modifying synaptic transmission, we examined the effects of DCOIT on synaptic transmission in a 'synaptic bouton' preparation of rat brain. DCOIT at concentrations of 0.03-1 μM increased the amplitudes of evoked synaptic currents mediated by GABA and glutamate, while it reduced the amplitudes of these currents at 3-10 μM. However, the currents elicited by exogenous applications of GABA and glutamate were not affected by DCOIT. DCOIT at 1-10 μM increased the frequency of spontaneous synaptic currents mediated by GABA. It also increased the frequency of glutamate-mediated spontaneous currents at0.3-10 μM. The frequencies of miniature synaptic currents mediated by GABA and glutamate, observed in the presence of tetrodotoxin under external Ca 2+ -free conditions, were increased by 10 μM DCOIT. With the repetitive applications of DCOIT, the frequency of miniature synaptic currents mediated by glutamate was not increased by the second and third applications of DCOIT. Voltage-dependent Ca 2+ channels were not affected by DCOIT, but DCOIT slowed the inactivation of voltage-dependent Na + channels. These results suggest that DCOIT increases Ca 2+ release from intracellular Ca 2+ stores, resulting in the facilitation of both action potential-dependent and spontaneous neurotransmission, possibly leading to neurotoxicity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Glucose sensing by GABAergic neurons in the mouse nucleus tractus solitarii

PubMed Central

Boychuk, Carie R.; Gyarmati, Peter; Xu, Hong

2015-01-01

Changes in blood glucose concentration alter autonomic function in a manner consistent with altered neural activity in brain regions controlling digestive processes, including neurons in the brain stem nucleus tractus solitarii (NTS), which process viscerosensory information. With whole cell or on-cell patch-clamp recordings, responses to elevating glucose concentration from 2.5 to 15 mM were assessed in identified GABAergic NTS neurons in slices from transgenic mice that express EGFP in a subset of GABA neurons. Single-cell real-time RT-PCR was also performed to detect glutamic acid decarboxylase (GAD67) in recorded neurons. In most identified GABA neurons (73%), elevating glucose concentration from 2.5 to 15 mM resulted in either increased (40%) or decreased (33%) neuronal excitability, reflected by altered membrane potential and/or action potential firing. Effects on membrane potential were maintained when action potentials or fast synaptic inputs were blocked, suggesting direct glucose sensing by GABA neurons. Glucose-inhibited GABA neurons were found predominantly in the lateral NTS, whereas glucose-excited cells were mainly in the medial NTS, suggesting regional segregation of responses. Responses were prevented in the presence of glucosamine, a glucokinase (GCK) inhibitor. Depolarizing responses were prevented when KATP channel activity was blocked with tolbutamide. Whereas effects on synaptic input to identified GABAergic neurons were variable in GABA neurons, elevating glucose increased glutamate release subsequent to stimulation of tractus solitarius in unlabeled, unidentified neurons. These results indicate that GABAergic NTS neurons act as GCK-dependent glucose sensors in the vagal complex, providing a means of modulating central autonomic signals when glucose is elevated. PMID:26084907

Reduced Chrna7 expression in mice is associated with decreases in hippocampal markers of inhibitory function: implications for neuropsychiatric diseases

PubMed Central

Adams, Catherine E.; Yonchek, Joan C.; Schulz, Kalynn M.; Graw, Sharon L.; Stitzel, Jerry; Teschke, Patricia U.; Stevens, Karen E.

2012-01-01

The α7* nicotinic acetylcholine receptor encoded by CHRNA7 (human)/Chrna7 (mice) regulates the release of both the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and the excitatory neurotransmitter glutamate in the hippocampal formation. A heterozygous deletion at 15q13.3 containing CHRNA7 is associated with increased risk for schizophrenia, autism and epilepsy. Each of these diseases is characterized by abnormalities in excitatory and inhibitory hippocampal circuit function. Reduced Chrna7 expression results in decreased hippocampal α7* receptor density, abnormal hippocampal auditory sensory processing and increased hippocampal CA3 pyramidal neuron activity in C3H mice heterozygous for a null mutation in Chrna7. These abnormalities demonstrate that decreased Chrna7 expression alters hippocampal inhibitory circuit function. The current study examined the specific impact of reduced Chrna7 expression on hippocampal inhibitory circuits by measuring the levels of GABA, GABAA receptors, the GABA synthetic enzyme glutamate decarboxylase-65 (GAD-65) and the vesicular GABA transporter GAT-1 in wild type (Chrna7 +/+) and heterozygous (Chrna7 +/−) C3H α7 mice of both genders. GAD-65 levels were significantly decreased in male and female heterozygous C3H α7 mice while GABAA receptors were significantly reduced only in male heterozygous C3H α7 mice. No changes in GABA and GAT-1 levels were detected. These data suggest that reduced CHRNA7 expression may contribute to the abnormalities in hippocampal inhibitory circuits observed in schizophrenia, autism and/or epilepsy. PMID:22314319

Behavioural endophenotypes in mice lacking the auxiliary GABAB receptor subunit KCTD16.

PubMed

Cathomas, Flurin; Sigrist, Hannes; Schmid, Luca; Seifritz, Erich; Gassmann, Martin; Bettler, Bernhard; Pryce, Christopher R

2017-01-15

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and is implicated in the pathophysiology of a number of neuropsychiatric disorders. The GABA B receptors are G-protein coupled receptors consisting of principle subunits and auxiliary potassium channel tetramerization domain (KCTD) subunits. The KCTD subunits 8, 12, 12b and 16 are cytosolic proteins that determine the kinetics of the GABA B receptor response. Previously, we demonstrated that Kctd12 null mutant mice (Kctd12 -/- ) exhibit increased auditory fear learning and that Kctd12 +/- mice show altered circadian activity, as well as increased intrinsic excitability in hippocampal pyramidal neurons. KCTD16 has been demonstrated to influence neuronal excitability by regulating GABA B receptor-mediated gating of postsynaptic ion channels. In the present study we investigated for behavioural endophenotypes in Kctd16 -/- and Kctd16 +/- mice. Compared with wild-type (WT) littermates, auditory and contextual fear conditioning were normal in both Kctd16 -/- and Kctd16 +/- mice. When fear memory was tested on the following day, Kctd16 -/- mice exhibited less extinction of auditory fear memory relative to WT and Kctd16 +/- mice, as well as more contextual fear memory relative to WT and, in particular, Kctd16 +/- mice. Relative to WT, both Kctd16 +/- and Kctd16 -/- mice exhibited normal circadian activity. This study adds to the evidence that auxillary KCTD subunits of GABA B receptors contribute to the regulation of behaviours that could constitute endophenotypes for hyper-reactivity to aversive stimuli in neuropsychiatric disorders. Copyright © 2016 Elsevier B.V. All rights reserved.

Deficient GABAergic gliotransmission may cause broader sensory tuning in schizophrenia.

PubMed

Hoshino, Osamu

2013-12-01

We examined how the depression of intracortical inhibition due to a reduction in ambient GABA concentration impairs perceptual information processing in schizophrenia. A neural network model with a gliotransmission-mediated ambient GABA regulatory mechanism was simulated. In the network, interneuron-to-glial-cell and principal-cell-to-glial-cell synaptic contacts were made. The former hyperpolarized glial cells and let their transporters import (remove) GABA from the extracellular space, thereby lowering ambient GABA concentration, reducing extrasynaptic GABAa receptor-mediated tonic inhibitory current, and thus exciting principal cells. In contrast, the latter depolarized the glial cells and let the transporters export GABA into the extracellular space, thereby elevating the ambient GABA concentration and thus inhibiting the principal cells. A reduction in ambient GABA concentration was assumed for a schizophrenia network. Multiple dynamic cell assemblies were organized as sensory feature columns. Each cell assembly responded to one specific feature stimulus. The tuning performance of the network to an applied feature stimulus was evaluated in relation to the level of ambient GABA. Transporter-deficient glial cells caused a deficit in GABAergic gliotransmission and reduced ambient GABA concentration, which markedly deteriorated the tuning performance of the network, broadening the sensory tuning. Interestingly, the GABAergic gliotransmission mechanism could regulate local ambient GABA levels: it augmented ambient GABA around stimulus-irrelevant principal cells, while reducing ambient GABA around stimulus-relevant principal cells, thereby ensuring their selective responsiveness to the applied stimulus. We suggest that a deficit in GABAergic gliotransmission may cause a reduction in ambient GABA concentration, leading to a broadening of sensory tuning in schizophrenia. The GABAergic gliotransmission mechanism proposed here may have an important role in the regulation of local ambient GABA levels, thereby improving the sensory tuning performance of the cortex.

GABAB receptor attenuation of GABAA currents in neurons of the mammalian central nervous system.

PubMed

Shen, Wen; Nan, Changlong; Nelson, Peter T; Ripps, Harris; Slaughter, Malcolm M

2017-03-01

Ionotropic receptors are tightly regulated by second messenger systems and are often present along with their metabotropic counterparts on a neuron's plasma membrane. This leads to the hypothesis that the two receptor subtypes can interact, and indeed this has been observed in excitatory glutamate and inhibitory GABA receptors. In both systems the metabotropic pathway augments the ionotropic receptor response. However, we have found that the metabotropic GABA B receptor can suppress the ionotropic GABA A receptor current, in both the in vitro mouse retina and in human amygdala membrane fractions. Expression of amygdala membrane microdomains in Xenopus oocytes by microtransplantation produced functional ionotropic and metabotropic GABA receptors. Most GABA A receptors had properties of α -subunit containing receptors, with ~5% having ρ -subunit properties. Only GABA A receptors with α -subunit-like properties were regulated by GABA B receptors. In mouse retinal ganglion cells, where only α -subunit-containing GABA A receptors are expressed, GABA B receptors suppressed GABA A receptor currents. This suppression was blocked by GABA B receptor antagonists, G-protein inhibitors, and GABA B receptor antibodies. Based on the kinetic differences between metabotropic and ionotropic receptors, their interaction would suppress repeated, rapid GABAergic inhibition. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

GABA[subscript A] Receptor Downregulation in Brains of Subjects with Autism

ERIC Educational Resources Information Center

Fatemi, S. Hossein; Reutiman, Teri J.; Folsom, Timothy D.; Thuras, Paul D.

2009-01-01

Gamma-aminobutyric acid A (GABA[subscript A]) receptors are ligand-gated ion channels responsible for mediation of fast inhibitory action of GABA in the brain. Preliminary reports have demonstrated altered expression of GABA receptors in the brains of subjects with autism suggesting GABA/glutamate system dysregulation. We investigated the…

Glial GABA, synthesized by monoamine oxidase B, mediates tonic inhibition

PubMed Central

Yoon, Bo-Eun; Woo, Junsung; Chun, Ye-Eun; Chun, Heejung; Jo, Seonmi; Bae, Jin Young; An, Heeyoung; Min, Joo Ok; Oh, Soo-Jin; Han, Kyung-Seok; Kim, Hye Yun; Kim, Taekeun; Kim, Young Soo; Bae, Yong Chul; Lee, C Justin

2014-01-01

GABA is the major inhibitory transmitter in the brain and is released not only from a subset of neurons but also from glia. Although neuronal GABA is well known to be synthesized by glutamic acid decarboxylase (GAD), the source of glial GABA is unknown. After estimating the concentration of GABA in Bergmann glia to be around 5–10 mm by immunogold electron microscopy, we demonstrate that GABA production in glia requires MAOB, a key enzyme in the putrescine degradation pathway. In cultured cerebellar glia, both Ca2+-induced and tonic GABA release are significantly reduced by both gene silencing of MAOB and the MAOB inhibitor selegiline. In the cerebellum and striatum of adult mice, general gene silencing, knock out of MAOB or selegiline treatment resulted in elimination of tonic GABA currents recorded from granule neurons and medium spiny neurons. Glial-specific rescue of MAOB resulted in complete rescue of tonic GABA currents. Our results identify MAOB as a key synthesizing enzyme of glial GABA, which is released via bestrophin 1 (Best1) channel to mediate tonic inhibition in the brain. PMID:25239459

Role of GABAA receptors in the physiology and pharmacology of sleep.

PubMed

Winsky-Sommerer, Raphaëlle

2009-05-01

Most sedative-hypnotics used in insomnia treatment target the gamma-aminobutyric acid (GABA)(A) receptors. A vast repertoire of GABA(A) receptor subtypes has been identified and displays specific electrophysiological and functional properties. GABA(A)-mediated inhibition traditionally refers to 'phasic' inhibition, arising from synaptic GABA(A) receptors which transiently inhibit neurons. However, there is growing evidence that peri- or extra-synaptic GABA(A) receptors are continuously activated by low GABA concentrations and mediate a 'tonic' conductance. This slower type of signaling appears to play a key role in controlling cell excitability. This review aims at summarizing recent knowledge on GABA transmission, including the emergence of tonic conductance, and highlighting the importance of GABA(A) receptor heterogeneity. The mechanism of action of sedative-hypnotic drugs and their effects on sleep and the electroencephalogram will be reported. Furthermore, studies using genetically engineered mice will be emphasized, providing insights into the role of GABA(A) receptors in mechanisms underlying physiological and pharmacological sleep. Finally, we will address the potential of GABA(A) receptor pharmacology for the treatment of insomnia.

Cortical GABAergic excitation contributes to epileptic activities around human glioma

PubMed Central

Pallud, Johan; Varlet, Pascale; Cresto, Noemie; Baulac, Michel; Duyckaerts, Charles; Kourdougli, Nazim; Chazal, Geneviève; Devaux, Bertrand; Rivera, Claudio; Miles, Richard; Capelle, Laurent; Huberfeld, Gilles

2015-01-01

Rationale Diffuse brain gliomas induce seizures in a majority of patients. As in most epileptic disorders, excitatory glutamatergic mechanisms are involved in the generation of epileptic activities in the neocortex surrounding gliomas. However, chloride homeostasis is known to be perturbed in glial tumor cells. Thus the contribution of GABAergic mechanisms which depend on intracellular chloride and which are defective or pro-epileptic in other structural epilepsies merits closer study. Objective We studied in neocortical slices from the peritumoral security margin resected around human brain gliomas, the occurrence, networks, cells and signaling basis of epileptic activities. Results Postoperative glioma tissue from 69% of patients spontaneously generated interictal-like discharges. These events were synchronized, with a high frequency oscillation signature, in superficial layers of neocortex around glioma areas with tumor infiltration. Interictal-like events depended on both glutamatergic transmission and on depolarizing GABAergic signaling. About 65% of pyramidal cells were depolarized by GABA released by interneurons. This effect was related to perturbations in Chloride homeostasis, due to changes in expression of chloride co-transporters: KCC2 was reduced and expression of NKCC1 increased. Ictal-like activities were initiated by convulsant stimuli exclusively in these epileptogenic areas. Conclusions Epileptic activities are sustained by excitatory effects of GABA in the peritumoral human neocortex, as in temporal lobe epilepsies. Glutamate and GABA signaling are involved in oncogenesis and chloride homeostasis is perturbed. These same factors, induce an imbalance between synaptic excitatory and inhibition underly epileptic discharges in tumor patients. PMID:25009229

Flooding of the root system in soybean: biochemical and molecular aspects of N metabolism in the nodule during stress and recovery.

PubMed

Souza, Sarah C R; Mazzafera, Paulo; Sodek, Ladaslav

2016-05-01

Nitrogen fixation of the nodule of soybean is highly sensitive to oxygen deficiency such as provoked by waterlogging of the root system. This study aimed to evaluate the effects of flooding on N metabolism in nodules of soybean. Flooding resulted in a marked decrease of asparagine (the most abundant amino acid) and a concomitant accumulation of γ-aminobutyric acid (GABA). Flooding also resulted in a strong reduction of the incorporation of (15)N2 in amino acids. Nodule amino acids labelled before flooding rapidly lost (15)N during flooding, except for GABA, which initially increased and declined slowly thereafter. Both nitrogenase activity and the expression of nifH and nifD genes were strongly decreased on flooding. Expression of the asparagine synthetase genes SAS1 and SAS2 was reduced, especially the former. Expression of genes encoding the enzyme glutamic acid decarboxylase (GAD1, GAD4, GAD5) was also strongly suppressed except for GAD2 which increased. Almost all changes observed during flooding were reversible after draining. Possible changes in asparagine and GABA metabolism that may explain the marked fluctuations of these amino acids during flooding are discussed. It is suggested that the accumulation of GABA has a storage role during flooding stress.

Transcutaneous vagus nerve stimulation (tVNS) enhances divergent thinking.

PubMed

Colzato, Lorenza S; Ritter, Simone M; Steenbergen, Laura

2018-03-01

Creativity is one of the most important cognitive skills in our complex and fast-changing world. Previous correlative evidence showed that gamma-aminobutyric acid (GABA) is involved in divergent but not convergent thinking. In the current study, a placebo/sham-controlled, randomized between-group design was used to test a causal relation between vagus nerve and creativity. We employed transcutaneous vagus nerve stimulation (tVNS), a novel non-invasive brain stimulation technique to stimulate afferent fibers of the vagus nerve and speculated to increase GABA levels, in 80 healthy young volunteers. Creative performance was assessed in terms of divergent thinking (Alternate Uses Task) and convergent thinking tasks (Remote Associates Test, Creative Problem Solving Task, Idea Selection Task). Results demonstrate active tVNS, compared to sham stimulation, enhanced divergent thinking. Bayesian analysis reported the data to be inconclusive regarding a possible effect of tVNS on convergent thinking. Therefore, our findings corroborate the idea that the vagus nerve is causally involved in creative performance. Even thought we did not directly measure GABA levels, our results suggest that GABA (likely to be increased in active tVNS condition) supports the ability to select among competing options in high selection demand (divergent thinking) but not in low selection demand (convergent thinking). Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Gamma-aminobutyric acid and related molecules in the sea fan Eunicella cavolini (Cnidaria: Octocorallia): a biochemical and immunohistochemical approach.

PubMed

Girosi, Laura; Ferrando, Sara; Beltrame, Francesco; Ciarcia, Gaetano; Diaspro, Alberto; Fato, Marco; Magnone, Mirko; Raiteri, Luca; Ramoino, Paola; Tagliafierro, Grazia

2007-07-01

The aim of this study has been the biochemical demonstration of the presence of gamma-aminobutyric acid (GABA) in the Mediterranean sea fan Eunicella cavolini by means of high-performance liquid chromatography, and the description of the distribution pattern of GABA and its related molecules, glutamic acid decarboxylase (GAD), vesicular GABA transporter (VGAT) and one of the GABA receptors (GABA(B) R) by immunohistochemical methods. The interrelationships of GABA, GAD and GABA receptor immunoreactivity have been established by using double-immunohistochemical methods and confocal microscopy. The immunodetection of monoclonal and/or polyclonal antibodies has revealed GABA immunoreactivity throughout the polyp tissue, both in neuronal and non-neuronal elements. GAD immunoreactivity has been mostly localized in the neuronal compartment, contacting epithelial and muscular elements. GABA(B) R immunoreactivity appears particularly intense in the nematocytes and in the oocyte envelope; its presence in GAD-immunoreactive neurons in the tentacles suggests an autocrine type of regulation. Western blot analysis has confirmed that a GABA(B) R, with a molecular weight of 142 kDa, similar to that of rat brain, is present in E. cavolini polyp tissue. The identification of the sites of the synthesis, vesicular transport, storage and reception of GABA strongly suggests the presence of an almost complete set of GABA-related molecules for the functioning of the GABAergic system in this simple nervous system. The distribution of these different immunoreactivities has allowed us to hypothesize GABA involvement in nematocyst discharge, in body wall and enteric muscular contraction, in neuronal integration and in male gametocyte differentiation.

Mechanisms of multiple neurotransmitters in the effects of Lycopene on brain injury induced by Hyperlipidemia.

PubMed

Yang, Weichun; Shen, Ziyi; Wen, Sixian; Wang, Wei; Hu, Minyu

2018-02-07

Lycopene is a kind of carotenoid, with a strong capacity of antioxidation and regulating the bloodlipid. There has been some evidence that lycopene has protective effects on the central nervous system, but few studies have rigorously explored the role of neurotransmitters in it. Therefore, the present study was designed to investigate the effects of several neurotransmitters as lycopene exerts anti-injury effects induced by hyperlipidemia. Eighty adult SD rats, half male and half female, were randomly divided into eight groups on the basis of serum total cholesterol (TC) levels and body weight. There was a control group containing rats fed a standard laboratory rodent chow diet (CD); a hypercholesterolemic diet (rat chow supplemented with 4% cholesterol, 1% cholic acid and 0.5% thiouracil - this is also called a CCT diet) group; a positive group (CCT + F) fed CCT, supplemented with 10 mg·kg·bw - 1 ·d - 1 fluvastatin sodium by gastric perfusion; and lycopene groups at five dose levels (CCT + LYCO) fed with CCT and supplied lycopene at doses of 5, 25, 45, 65, and 85 mg·kg·bw - 1 ·d - 1 . The levels of TC, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-α), oxidized low density lipoprotein (ox-LDL), low-density lipoprotein receptor (LDLR), nerve growth factor (NGF), glutamic acid (Glu), Gamma aminobutyric acid (GABA), dopamine (DA), 5-hydroxytryptamine (5-HT), N-methyl-D-aspartate (NMDA1R), GABA A , 5-HT 1 , D 1 , and apoptosis-related proteins Caspase3, bax, and bcl-2 were measured after the experiment. Nissl staining was adopted to observe the morphological changes in neurons. At the end of the experiment, the levels of TC, TG, LDL-C, IL-1, TNF-α, and ox-LDL in the serum and brain as well as the content of Glu, DA, NMDA, and D 1 in the brain of rats in the CCT group were higher than those in the control group (P<0.05); the levels of LDLR, NGF, GABA, 5-HT, GABA A , 5-HT 1 , and neuron quantities in the hippocampal CA1 and CA3 areas were lower than those in the control group (P<0.05). Compared to the CCT group, levels of TC, TG, LDL-C, IL-1, TNF-α, and ox-LDL in the serum and brain, as well as the content of Glu, DA and the expression of pro-apoptotic Caspase3 in the brain decreased in the rats with lycopene (25 mg to 85 mg) added to the diet (P<0.05); the levels of LDLR, NGF, GABA, 5-HT, GABA A , and 5-HT 1 as well as the expression of anti-apoptotic bcl-2 and the neuron quantity in hippocampal CA1 and CA3 areas increased (P<0.05); further, the hippocampal cells were closely arranged. Lycopene dose was negatively correlated with the levels of TC, TG, and LDL-C in the serum and brain as well as levels of IL-1, TNF-α, ox-LDL, Glu/GABA, NMDA1R, and Caspase3 (P<0.05); it was positively correlated with the levels of LDLR, NGF, 5-HT, 5-HT 1 , GABA A , bcl-2, and the neuron quantity in hippocampal CA1 and CA3 areas (P<0.05). Lycopene exerts anti-injury effects in the brain as-induced by hyperlipidemia. It can inhibit the elevation of serum TC, TG, and LDL-C in rats with hyperlipidemia while indirectly affecting the levels of TC, TG, and LDL-C in the brain, leading to a reduction in ox-LDL, IL-1, and TNF-α in the brain. This inhibits the release of Glu, which weakens nerve toxicity and downregulates pro-apoptotic Caspase3. Lycopene also plays an anti-injury role by promoting the release of the inhibitory neurotransmitter GABA and 5-HT, which enhances the protective effect, and by upregulating the anti-apoptotic bcl-2.

Abnormal Concentration of GABA and Glutamate in The Prefrontal Cortex in Schizophrenia.-An in Vivo 1H-MRS Study.

PubMed

Chen, Tianyi; Wang, Yingchan; Zhang, Jianye; Wang, Zuowei; Xu, Jiale; Li, Yao; Yang, Zhilei; Liu, Dengtang

2017-10-25

The etiology and pathomechanism of schizophrenia are unknown. The traditional dopamine (DA) hypothesis is unable to fully explain its pathology and therapeutics. The glutamate (Glu) and γ-aminobutyric acid (GABA) hypotheses suggest Glu or GABA concentrations are abnormal in the brains of patients with schizophrenia. Magnetic resonance spectroscopy (MRS) show glutamate level increases in the ventromedial prefrontal cortex (vmPFC) including the anterior cingulated cortex (ACC) in those with schizophrenia. To investigate the function of the glutamate system (glutamate and γ-aminobutyric acid) in the etiology and pathomechanism of schizophrenia. 24 drug naïve patients with schizophrenia and 24 healthy volunteers were matched by gender, age, and educational level. The Siemens 3T MRI system was used to collect the magnetic resonance spectroscopy (MRS) data of the subjects. The regions of interest included the left dorsolateral prefrontal cortex (IDLPFC), ventromedial prefrontal cortex (vmPFC), and anterior cingulate cortex (ACC). LCModel software was used to analyze the concentrations of γ-aminobutyric acid (GABA), glutamate (Glu), glutamine (Gln), N-acetylaspartate (NAA), and N-acetylaspartylglutamate (NAAG) in the region of interest. Meanwhile, the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Scale (CGI) were used to assess the mental symptoms and severity of the disease. The median GABA concentrations in the anterior cingulate cortex of the schizophrenia group and the healthy control group were 1.90 (Q1=1.55, Q3=2.09) and 2.16 (Q1=1.87, Q3=2.59) respectively; the mean (sd) Glu concentrations were 6.07 (2.48) and 6.54 (1.99); the median Gln concentrations were 0.36 (Q1=0.00, Q3=0.74) and 0.29 (Q1=0.00, Q3=0.59); the between-group difference of the GABA concentrations was statistically significant ( Z =-2.95, p =0.003); the between-group difference of the GABA/(NAA+NAAG) was statistically significant ( Z =-2.72, p =0.012); the between-group difference of Glu and Gln was not statistically significant. The age of the schizophrenia group was negatively correlated with the GABA concentration in the anterior cingulate ( R =-0.494, p =0.014), and negatively correlated with GABA/ (NAA+NAAG) ( R =-0.473, p =0.020). Yet there was no such correlation in the control group. After calibration, no significant correlation was found between the clinical symptoms and the concentrations of the metabolites. The concentration of glutamate in the vemtromedial prefrontal cortex of patients with schizophrenia was abnormal, whereas the concentration of GABA in the anterior cingulate cortex decreased, supporting the hypothesis of abnormal glutamate -GABA in the brains of those individuals with schizophrenia. In patients with schizophrenia, the GABA in the anterior cingulate cortex had an accelerated decline with age. The clinical symptoms may be correlated to the metabolite concentration of the anterior cingulate cortex.

Brain distribution and molecular cloning of the bovine GABA rho1 receptor.

PubMed

Rosas-Arellano, Abraham; Ochoa-de la Paz, Lenin David; Miledi, Ricardo; Martínez-Torres, Ataúlfo

2007-03-01

GABA(C) receptors were originally found in the mammalian retina and recent evidence shows that they are also expressed in several areas of the brain, including caudate nucleus, brain stem, pons and corpus callosum. In this study, plasma membranes from the caudate nucleus were microinjected into X. laevis oocytes. This led the oocyte plasma membrane to incorporate functional bicuculline-resistant, Cl(-) conducting bovine GABA receptors, similar to those of the retina. Immunolocalization of the GABA rho1 subunit revealed its expression in bovine neurons in the head of the caudate as well as in the olive, cuneiform and reticular nuclei of the brain stem. The same antibodies failed to show expression in the callosum and pons, where the GABA rho1 mRNA was previously detected. The cloned GABA rho1 sequence predicts a protein with 473 amino acids and 74-93% similarity to other GABA rho1 subunits. Oocytes injected with the cDNA express a non-desensitizing, homomeric receptor with a GABA EC(50)=6.0 microM and a Hill coefficient of 1.8. The results confirm the presence of GABA(C) receptor mRNAs in several areas of the mammalian brain and show that some of these areas express functional GABA rho1 receptors that have the classic GABA(C) receptor characteristics.

Cell and receptor type-specific alterations in markers of GABA neurotransmission in the prefrontal cortex of subjects with schizophrenia.

PubMed

Lewis, David A; Hashimoto, Takanori; Morris, Harvey M

2008-10-01

Impairments in cognitive control, such as those involved in working memory, are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC) in individuals with schizophrenia. This dysfunction appears to result, at least in part, from abnormalities in GABA-mediated neurotransmission. In this paper, we review recent findings indicating that the altered DLPFC circuitry in subjects with schizophrenia reflects changes in the expression of genes that encode selective presynaptic and postsynaptic components of GABA neurotransmission. Specifically, using a combination of methods, we found that subjects with schizophrenia exhibited expression deficits in GABA-related transcripts encoding presynaptic regulators of GABA neurotransmission, neuropeptide markers of specific subpopulations of GABA neurons, and certain subunits of the GABA(A) receptor. In particular, alterations in the expression of the neuropeptide somatostatin suggested that GABA neurotransmission is impaired in the Martinotti subset of GABA neurons that target the dendrites of pyramidal cells. In contrast, none of the GABA-related transcripts assessed to date were altered in the DLPFC of monkeys chronically exposed to antipsychotic medications, suggesting that the effects observed in the human studies reflect the disease process and not its treatment. In concert with previous findings, these data suggest that working memory dysfunction in schizophrenia may be attributable to altered GABA neurotransmission in specific DLPFC microcircuits.

The GABA(A) receptor RDL acts in peptidergic PDF neurons to promote sleep in Drosophila.

PubMed

Chung, Brian Y; Kilman, Valerie L; Keath, J Russel; Pitman, Jena L; Allada, Ravi

2009-03-10

Sleep is regulated by a circadian clock that times sleep and wake to specific times of day and a homeostat that drives sleep as a function of prior wakefulness. To analyze the role of the circadian clock, we have used the fruit fly Drosophila. Flies display the core behavioral features of sleep, including relative immobility, elevated arousal thresholds, and homeostatic regulation. We assessed sleep-wake modulation by a core set of circadian pacemaker neurons that express the neuropeptide PDF. We find that disruption of PDF function increases sleep during the late night in light:dark and the first subjective day of constant darkness. Flies deploy genetic and neurotransmitter pathways to regulate sleep that are similar to those of their mammalian counterparts, including GABA. We find that RNA interference-mediated knockdown of the GABA(A) receptor gene, Resistant to dieldrin (Rdl), in PDF neurons reduces sleep, consistent with a role for GABA in inhibiting PDF neuron function. Patch-clamp electrophysiology reveals GABA-activated picrotoxin-sensitive chloride currents on PDF+ neurons. In addition, RDL is detectable most strongly on the large subset of PDF+ pacemaker neurons. These results suggest that GABAergic inhibition of arousal-promoting PDF neurons is an important mode of sleep-wake regulation in vivo.

Gaba mediated long-term depression (LTD) in the rat medial vestibular nuclei.

PubMed

Grassi, S; Della Torre, G; Zampolini, M; Pettorossi, V E

1995-01-01

As previously demonstrated, high frequency stimulation (HFS) of the primary vestibular afferents always induces a clear, long lasting depression of the polysynaptic (N2) component of the field potentials recorded in the dorsal portion of the medial vestibular nuclei (MVN). The induction of the HFS effect was mediated by the activation of glutamate NMDA receptors, since it was blocked by AP5. The mechanisms at the basis of such a depression were studied. Our results demonstrate that Gaba, acting on both GabaA and GabaB receptors, is involved in mediating this phenomenon. In fact, HFS applied during Bicuculline and Saclofen perfusion, was no longer able to induce an N2 depression, but provoked a slight potentiation. However, the N2 depression clearly emerged after drug wash-out. Furthermore, Bicuculline and Saclofen fully abolished the N2 depression and highlighted the potentiation, when administered after HFS. The possibility that the N2 depression is the result of a homosynaptic LTD can be excluded on the basis of our results. On the contrary, our findings suggest that the depression is due to an enhancement of the Gaba inhibitory effect due to an HFS dependent increase in gabaergic interneuron activity, which resets vestibular neuron excitability at a lower level.

S-nitrosylation of GAD65 is implicated in decreased GAD activity and oxygen-induced seizures.

PubMed

Gasier, Heath G; Demchenko, Ivan T; Tatro, Lynn G; Piantadosi, Claude A

2017-07-13

Breathing oxygen at partial pressures ≥2.5 atmospheres absolute, which can occur in diving and hyperbaric oxygen (HBO 2 ) therapy, can rapidly become toxic to the central nervous system (CNS). This neurotoxicity culminates in generalized EEG epileptiform discharges, tonic-clonic convulsions and ultimately death. Increased production of neuronal nitric oxide (NO) has been implicated in eliciting hyperoxic seizures by altering the equilibrium between glutamatergic and GABAergic synaptic transmission. Inhibition of glutamic acid decarboxylase (GAD) activity in HBO 2 promotes this imbalance; however, the mechanisms by which this occurs is unknown. Therefore, we conducted a series of experiments using mice, a species that is highly susceptible to CNS oxygen toxicity, to explore the possibility that NO modulates GABA metabolism. Mice were exposed to 100% oxygen at 4 ATA for various durations, and brain GAD and GABA transaminase (GABA-T) activity, as well as S-nitrosylation of GAD65 and GAD67 were determined. HBO 2 inhibited GAD activity by 50% and this was negatively correlated with S-nitrosylation of GAD65, whereas GABA-T activity and S-nitrosylation of GAD67 were unaltered. These results suggest a new mechanism by which NO alters GABA metabolism, leading to neuroexcitation and seizures in HBO 2 . Published by Elsevier B.V.

Synergistic GABA-Enhancing Therapy against Seizures in a Mouse Model of Dravet Syndrome

PubMed Central

Oakley, John C.; Cho, Alvin R.; Cheah, Christine S.; Scheuer, Todd

2013-01-01

Seizures remain uncontrolled in 30% of patients with epilepsy, even with concurrent use of multiple drugs, and uncontrolled seizures result in increased morbidity and mortality. An extreme example is Dravet syndrome (DS), an infantile-onset severe epilepsy caused by heterozygous loss of function mutations in SCN1A, the gene encoding the brain type-I voltage-gated sodium channel NaV1.1. Studies in Scn1a heterozygous knockout mice demonstrate reduced excitability of GABAergic interneurons, suggesting that enhancement of GABA signaling may improve seizure control and comorbidities. We studied the efficacy of two GABA-enhancing drugs, clonazepam and tiagabine, alone and in combination, against thermally evoked myoclonic and generalized tonic-clonic seizures. Clonazepam, a positive allosteric modulator of GABA-A receptors, protected against myoclonic and generalized tonic-clonic seizures. Tiagabine, a presynaptic GABA reuptake inhibitor, was protective against generalized tonic-clonic seizures but only minimally protective against myoclonic seizures and enhanced myoclonic seizure susceptibility at high doses. Combined therapy with clonazepam and tiagabine was synergistic against generalized tonic-clonic seizures but was additive against myoclonic seizures. Toxicity determined by rotorod testing was additive for combination therapy. The synergistic actions of clonazepam and tiagabine gave enhanced seizure protection and reduced toxicity, suggesting that combination therapy may be well tolerated and effective for seizures in DS. PMID:23424217

Disruption of pknG enhances production of gamma-aminobutyric acid by Corynebacterium glutamicum expressing glutamate decarboxylase.

PubMed

Okai, Naoko; Takahashi, Chihiro; Hatada, Kazuki; Ogino, Chiaki; Kondo, Akihiko

2014-01-01

Gamma-aminobutyric acid (GABA), a building block of the biodegradable plastic polyamide 4, is synthesized from glucose by Corynebacterium glutamicum that expresses Escherichia coli glutamate decarboxylase (GAD) B encoded by gadB. This strain was engineered to produce GABA more efficiently from biomass-derived sugars. To enhance GABA production further by increasing the intracellular concentration of its precursor glutamate, we focused on engineering pknG (encoding serine/threonine protein kinase G), which controls the activity of 2-oxoglutarate dehydrogenase (Odh) in the tricarboxylic acid cycle branch point leading to glutamate synthesis. We succeeded in expressing GadB in a C. glutamicum strain harboring a deletion of pknG. C. glutamicum strains GAD and GAD ∆pknG were cultured in GP2 medium containing 100 g L(-1) glucose and 0.1 mM pyridoxal 5'-phosphate. Strain GAD∆pknG produced 31.1 ± 0.41 g L(-1) (0.259 g L(-1) h(-1)) of GABA in 120 hours, representing a 2.29-fold higher level compared with GAD. The production yield of GABA from glucose by GAD∆pknG reached 0.893 mol mol(-1).

Recruitment of GABA(A) receptors and fearfulness in chicks: modulation by systemic insulin and/or epinephrine.

PubMed

Cid, Mariana Paula; Toledo, Carolina Maribel; Salvatierra, Nancy Alicia

2013-02-01

One-day-old chicks were individually assessed on their latency to peck pebbles, and categorized as low latency (LL) or high latency (HL) according to fear. Interactions between acute stress and systemic insulin and epinephrine on GABA(A) receptor density in the forebrain were studied. At 10 days of life, LL and HL chicks were intraperitoneally injected with insulin, epinephrine or saline, and immediately after stressed by partial water immersion for 15 min and killed by decapitation. Forebrains were dissected and the GABA(A) receptor density was measured ex vivo by the (3)[H]-flunitrazepam binding assay in synaptosomes. In non-stressed chicks, insulin (non-hypoglycemic dose) at 2.50 IU/kg of body weight incremented the Bmax by 40.53% in the HL chicks compared to saline group whereas no significant differences were observed between individuals in the LL subpopulation. Additionally, insulin increased the Bmax (23.48%) in the HL group with respect to the LL ones, indicating that the insulin responses were different according to the anxiety of each category. Epinephrine administration (0.25 and 0.50mg/kg) incremented the Bmax in non-stressed chicks, in the LL group by about 37% and 33%, respectively, compared to ones injected with saline. In the stressed chicks, 0.25mg/kg bw epinephrine increased the Bmax significantly in the HL group by about 24% compared to saline, suggesting that the effect of epinephrine was only observed in the HL group under acute stress conditions. Similarly, the same epinephrine doses co-administered with insulin increased the receptor density in both subpopulations and also showed that the highest dose of epinephrine did not further increase the maximum density of GABA(A)R in HL chicks. These results suggest that systemic epinephrine, perhaps by evoking central norepinephrine release, modulated the increase in the forebrain GABA(A) receptor recruitment induced by both insulin and stress in different ways depending on the subpopulation fearfulness. Copyright © 2013 Elsevier Inc. All rights reserved.

Dietary GABA and food selection by rats.

PubMed

Tews, J K; Repa, J J; Harper, A E

1986-01-01

To obtain further information pertaining to amino acid-induced alterations in feeding behavior, studies were performed to examine the food choices made by rats fed low protein diets made more or less aversive by the addition of various amino acids. When rats were allowed to choose between two diets, they preferred a low protein control, threonine-imbalanced or nonprotein diet to one containing 2.5% gamma-aminobutyric acid (GABA). Acceptance increased when GABA content was lowered to 1.5%; rats preferred this diet when the alternative diet was made sufficiently aversive. There were large individual differences among rats selecting from pairs of unacceptable diets. Avoidance of, or preference for, a given diet is clearly affected by the relative aversive qualities of the offered pair of diets.

Induced resistance in tomato fruit by γ-aminobutyric acid for the control of alternaria rot caused by Alternaria alternata.

PubMed

Yang, Jiali; Sun, Cui; Zhang, Yangyang; Fu, Da; Zheng, Xiaodong; Yu, Ting

2017-04-15

The study investigated the effect of γ-aminobutyric acid (GABA) on the control of alternaria rot in tomato fruit and the possible mechanism involved. Our results showed exogenous GABA could stimulate remarkable resistance to the alternaria rot, while it had no direct antifungal activity against Alternaria alternata. Moreover, the activities of antioxidant enzymes, including peroxidase, superoxide dismutase and catalase, along with the expression of these corresponding genes, were significantly induced in the GABA treatment. The obtained data suggested GABA induced resistance against the necrotrophic pathogen A. alternata, at least in part by activating antioxidant enzymes, restricting the levels of cell death caused by reactive oxygen species. Meanwhile, the key enzyme genes of GABA shunt, GABA transaminase and succinic-semialdehyde dehydrogenase, were found up-regulated in the GABA treatment. The activation of the GABA shunt might play a vital role in the resistance mechanism underpinning GABA-induced plant immunity. Copyright © 2016 Elsevier Ltd. All rights reserved.

GABA and homovanillic acid in the plasma of Schizophrenic and bipolar I patients.

PubMed

Arrúe, Aurora; Dávila, Ricardo; Zumárraga, Mercedes; Basterreche, Nieves; González-Torres, Miguel A; Goienetxea, Biotza; Zamalloa, Maria I; Anguiano, Juan B; Guimón, José

2010-02-01

We have determined the plasma (p) concentration of gamma-aminobutyric acid (GABA) and the dopamine metabolite homovanillic acid (HVA), and the pHVA/pGABA ratio in schizophrenic and bipolar patients. The research was undertaken in a geographic area with an ethnically homogeneous population. The HVA plasma concentrations were significantly elevated in the schizophrenic patients compared to the bipolar patients. The levels of pGABA was significantly lower in the two groups of patients compared to the control group, while the pHVA/pGABA ratio was significantly greater in the both groups of patients compared to the controls. As the levels of pHVA and pGABA are partially under genetic control it is better to compare their concentrations within an homogeneous population. The values of the ratio pHVA/pGABA are compatible with the idea of an abnormal dopamine-GABA interaction in schizophrenic and bipolar patients. The pHVA/pGABA ratio may be a good peripheral marker in psychiatric research.

γ-Aminobutyric acid addition alleviates ammonium toxicity by limiting ammonium accumulation in rice (Oryza sativa) seedlings.

PubMed

Ma, Xiaoling; Zhu, Changhua; Yang, Na; Gan, Lijun; Xia, Kai

2016-12-01

Excessive use of nitrogen (N) fertilizer has increased ammonium (NH 4 + ) accumulation in many paddy soils to levels that reduce rice vegetative biomass and yield. Based on studies of NH 4 + toxicity in rice (Oryza sativa, Nanjing 44) seedlings cultured in agar medium, we found that NH 4 + concentrations above 0.75 mM inhibited the growth of rice and caused NH 4 + accumulation in both shoots and roots. Use of excessive NH 4 + also induced rhizosphere acidification and inhibited the absorption of K, Ca, Mg, Fe and Zn in rice seedlings. Under excessive NH 4 + conditions, exogenous γ-aminobutyric acid (GABA) treatment limited NH 4 + accumulation in rice seedlings, reduced NH 4 + toxicity symptoms and promoted plant growth. GABA addition also reduced rhizosphere acidification and alleviated the inhibition of Ca, Mg, Fe and Zn absorption caused by excessive NH 4 + . Furthermore, we found that the activity of glutamine synthetase/NADH-glutamate synthase (GS; EC 6.3.1.2/NADH-GOGAT; EC1.4.1.14) in root increased gradually as the NH 4 + concentration increased. However, when the concentration of NH 4 + is more than 3 mM, GABA treatment inhibited NH 4 + -induced increases in GS/NADH-GOGAT activity. The inhibition of ammonium assimilation may restore the elongation of seminal rice roots repressed by high NH 4 + . These results suggest that mitigation of ammonium accumulation and assimilation is essential for GABA-dependent alleviation of ammonium toxicity in rice seedlings. © 2016 Scandinavian Plant Physiology Society.

Three-Step Test System for the Identification of Novel GABAA Receptor Modulating Food Plants.

PubMed

Sahin, Sümeyye; Eulenburg, Volker; Kreis, Wolfgang; Villmann, Carmen; Pischetsrieder, Monika

2016-12-01

Potentiation of γ-amino butyric acid (GABA)-induced GABA A receptor (GABA A R) activation is a common pathway to achieve sedative, sleep-enhancing, anxiolytic, and antidepressant effects. Presently, a three-component test system was established for the identification of novel GABA A R modulating food plants. In the first step, potentiation of GABA-induced response of the GABA A R was analysed by two-electrode voltage clamp (TEVC) for activity on human α1β2-GABA A R expressed in Xenopus laevis oocytes. Positively tested food plants were then subjected to quantification of GABA content by high-performance liquid chromatography with fluorescence detection (HPLC-FLD) to exclude test foods, which evoke a TEVC-response by endogenous GABA. In the third step, specificity of GABA A -modulating activity was assessed by TEVC analysis of Xenopus laevis oocytes expressing the homologous glycine receptor (GlyR). The three-component test was then applied to screen 10 aqueous extracts of food plants for their GABA A R activity. Thus, hop cones (Humulus lupulus) and Sideritis sipylea were identified as the most potent specific GABA A R modulators eliciting significant potentiation of the current by 182 ± 27 and 172 ± 19 %, respectively, at the lowest concentration of 0.5 μg/mL. The extracts can now be further evaluated by in vivo studies and by structural evaluation of the active components.

Reconstruction of a metabolic regulatory network in Escherichia coli for purposeful switching from cell growth mode to production mode in direct GABA fermentation from glucose.

PubMed

Soma, Yuki; Fujiwara, Yuri; Nakagawa, Takuya; Tsuruno, Keigo; Hanai, Taizo

2017-09-01

γ-aminobutyric acid (GABA) is a drug and functional food additive and is used as a monomer for producing the biodegradable plastic, polyamide 4. Recently, direct GABA fermentation from glucose has been developed as an alternative to glutamate-based whole cell bioconversion. Although total productivity in fermentation is determined by the specific productivity and cell amount responsible for GABA production, the optimal metabolic state for GABA production conflicts with that for bacterial cell growth. Herein, we demonstrated metabolic state switching from the cell growth mode based on the metabolic pathways of the wild type strain to a GABA production mode based on a synthetic metabolic pathway in Escherichia coli through rewriting of the metabolic regulatory network and pathway engineering. The GABA production mode was achieved by multiple strategies such as conditional interruption of the TCA and glyoxylate cycles, engineering of GABA production pathway including a bypass for precursor metabolite supply, and upregulation of GABA transporter. As a result, we achieved 3-fold improvement in total GABA production titer and yield (4.8g/L, 49.2% (mol/mol glucose)) in batch fermentation compared to the case without metabolic state switching (1.6g/L, 16.4% (mol/mol glucose)). This study reports the highest GABA production performance among previous reports on GABA fermentation from glucose using engineered E. coli. Copyright © 2017 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

γ-Aminobutyric acid (GABA) signalling in plants.

PubMed

Ramesh, Sunita A; Tyerman, Stephen D; Gilliham, Matthew; Xu, Bo

2017-05-01

The role of γ-aminobutyric acid (GABA) as a signal in animals has been documented for over 60 years. In contrast, evidence that GABA is a signal in plants has only emerged in the last 15 years, and it was not until last year that a mechanism by which this could occur was identified-a plant 'GABA receptor' that inhibits anion passage through the aluminium-activated malate transporter family of proteins (ALMTs). ALMTs are multigenic, expressed in different organs and present on different membranes. We propose GABA regulation of ALMT activity could function as a signal that modulates plant growth, development, and stress response. In this review, we compare and contrast the plant 'GABA receptor' with mammalian GABA A receptors in terms of their molecular identity, predicted topology, mode of action, and signalling roles. We also explore the implications of the discovery that GABA modulates anion flux in plants, its role in signal transduction for the regulation of plant physiology, and predict the possibility that there are other GABA interaction sites in the N termini of ALMT proteins through in silico evolutionary coupling analysis; we also explore the potential interactions between GABA and other signalling molecules.

Design and Mechanism of Tetrahydrothiophene-Based γ-Aminobutyric Acid Aminotransferase Inactivators

DOE Office of Scientific and Technical Information (OSTI.GOV)

Le, Hoang V.; Hawker, Dustin D.; Wu, Rui

Low levels of gamma-aminobutyric acid (GABA), one of two major neurotransmitters that regulate brain neuronal activity, are associated with many neurological disorders, such as epilepsy, Parkinsons disease, Alzheimers disease, Huntingtons disease, and cocaine addiction. One of the main methods to raise the GABA level in human brain is to use small molecules that cross the bloodbrain barrier and inhibit the activity of gamma-aminobutyric acid aminotransferase (GABA-AT), the enzyme that degrades GABA. We have designed a series of conformationally restricted tetrahydrothiophene-based GABA analogues with a properly positioned leaving group that could facilitate a ring-opening mechanism, leading to inactivation of GABA-AT. Onemore » compound in the series is 8 times more efficient an inactivator of GABA-AT than vigabatrin, the only FDA-approved inactivator of GABA-AT. Our mechanistic studies show that the compound inactivates GABA-AT by a new mechanism. The metabolite resulting from inactivation does not covalently bind to amino acid residues of GABA-AT but stays in the active site via H-bonding interactions with Arg-192, a pi-pi interaction with Phe-189, and a weak nonbonded (SO)-O-...=C interaction with Glu-270, thereby inactivating the enzyme.« less

Design and mechanism of tetrahydrothiophene-based γ-aminobutyric acid aminotransferase inactivators.

PubMed

Le, Hoang V; Hawker, Dustin D; Wu, Rui; Doud, Emma; Widom, Julia; Sanishvili, Ruslan; Liu, Dali; Kelleher, Neil L; Silverman, Richard B

2015-04-08

Low levels of γ-aminobutyric acid (GABA), one of two major neurotransmitters that regulate brain neuronal activity, are associated with many neurological disorders, such as epilepsy, Parkinson's disease, Alzheimer's disease, Huntington's disease, and cocaine addiction. One of the main methods to raise the GABA level in human brain is to use small molecules that cross the blood-brain barrier and inhibit the activity of γ-aminobutyric acid aminotransferase (GABA-AT), the enzyme that degrades GABA. We have designed a series of conformationally restricted tetrahydrothiophene-based GABA analogues with a properly positioned leaving group that could facilitate a ring-opening mechanism, leading to inactivation of GABA-AT. One compound in the series is 8 times more efficient an inactivator of GABA-AT than vigabatrin, the only FDA-approved inactivator of GABA-AT. Our mechanistic studies show that the compound inactivates GABA-AT by a new mechanism. The metabolite resulting from inactivation does not covalently bind to amino acid residues of GABA-AT but stays in the active site via H-bonding interactions with Arg-192, a π-π interaction with Phe-189, and a weak nonbonded S···O═C interaction with Glu-270, thereby inactivating the enzyme.

Enhancement of gama-aminobutyric acid (GABA) and other health-related metabolites in germinated red rice (Oryza sativa L.) by ultrasonication.

PubMed

Ding, Junzhou; Ulanov, Alexander V; Dong, Mengyi; Yang, Tewu; Nemzer, Boris V; Xiong, Shanbai; Zhao, Siming; Feng, Hao

2018-01-01

Red rice (Oryza sativa L.) that has a red (reddish brown) bran layer in de-hulled rice is known to contain rich biofunctional components. Germination is an effective technique to improve the nutritional quality, digestibility, and flavor of de-hulled rice. Ultrasonication, a form of physical stimulation, has been documented as a novel approach to improve the nutritional quality of plant-based food. This study was undertaken to test the use of ultrasound to enhance the nutritional value of red rice. Ultrasonication (5min, 16W/L) was applied to rice during soaking or after 66h germination. Changes of metabolites (amino acids, sugars, and organic acids) in red rice treated by ultrasonication were determined using a GC/MS plant primary metabolomics analysis platform. Differential expressed metabolites were identified through multivariate statistical analysis. Results showed that γ-aminobutyric acid (GABA) and riboflavin (vitamin B 2 ) in red rice significantly increased after germination for 72h, and then experienced a further increase after treatment by ultrasound at different stages during germination. The metabolomics analysis showed that some plant metabolites, i.e. GABA, O-phosphoethanolamine, and glucose-6-phosphate were significantly increased after the ultrasonic treatment (VIP>1.5) in comparison with the untreated germinated rice. The findings of this study showed that controlled germination with ultrasonic stress is an effective method to enhance GABA and other health-promoted components in de-hulled rice. Copyright © 2017 Elsevier B.V. All rights reserved.

GABAA receptor: a unique modulator of excitability, Ca2+ signaling, and catecholamine release of rat chromaffin cells.

PubMed

Alejandre-García, Tzitzitlini; Peña-Del Castillo, Johanna G; Hernández-Cruz, Arturo

2018-01-01

The role of gamma-aminobutyric acid (GABA) in adrenal medulla chromaffin cell (CC) function is just beginning to unfold. GABA is stored in catecholamine (CA)-containing dense core granules and is presumably released together with CA, ATP, and opioids in response to physiological stimuli, playing an autocrine-paracrine role on CCs. The reported paradoxical "dual action" of GABA A -R activation (enhancement of CA secretion and inhibition of synaptically evoked CA release) is only one aspect of GABA's multifaceted actions. In this review, we discuss recent physiological experiments on rat CCs in situ which suggest that GABA regulation of CC function may depend on the physiological context: During non-stressful conditions, GABA A -R activation by endogenous GABA tonically inhibits acetylcholine release from splanchnic nerve terminals and decreases spontaneous Ca 2+ fluctuations in CCs, preventing unwanted CA secretion. During intense stress, splanchnic nerve terminals release acetylcholine, which depolarizes CCs and allows the Ca 2+ influx that triggers the release of CA and GABA. With time, CA secretion declines, due to voltage-independent inhibition of Ca 2+ channels and desensitization of cholinergic nicotinic receptors. Nonetheless, acute activation of GABA A -R is depolarizing in about 50% of CCs, and thus GABA, acting as an autocrine/paracrine mediator, could help to maintain CA exocytosis under stress. GABA A -R activation is not excitatory in about half of CCs' population because it hyperpolarizes them or elicits no response. This percentage possibly varies, depending on functional demands, since GABA A -R-mediated actions are determined by the intracellular chloride concentration ([Cl - ] i ) and therefore on the activity of cation-chloride co transporters, which is functionally regulated. These findings underscore a potential importance of a novel and complex GABA-mediated regulation of CC function and of CA secretion.

GABA production and structure of gadB/gadC genes in Lactobacillus and Bifidobacterium strains from human microbiota.

PubMed

Yunes, R A; Poluektova, E U; Dyachkova, M S; Klimina, K M; Kovtun, A S; Averina, O V; Orlova, V S; Danilenko, V N

2016-12-01

Gamma-amino butyric acid (GABA) is an active biogenic substance synthesized in plants, fungi, vertebrate animals and bacteria. Lactic acid bacteria are considered the main producers of GABA among bacteria. GABA-producing lactobacilli are isolated from food products such as cheese, yogurt, sourdough, etc. and are the source of bioactive properties assigned to those foods. The ability of human-derived lactobacilli and bifidobacteria to synthesize GABA remains poorly characterized. In this paper, we screened our collection of 135 human-derived Lactobacillus and Bifidobacterium strains for their ability to produce GABA from its precursor monosodium glutamate. Fifty eight strains were able to produce GABA. The most efficient GABA-producers were Bifidobacterium strains (up to 6 g/L). Time profiles of cell growth and GABA production as well as the influence of pyridoxal phosphate on GABA production were studied for L. plantarum 90sk, L. brevis 15f, B. adolescentis 150 and B. angulatum GT102. DNA of these strains was sequenced; the gadB and gadC genes were identified. The presence of these genes was analyzed in 14 metagenomes of healthy individuals. The genes were found in the following genera of bacteria: Bacteroidetes (Bacteroides, Parabacteroides, Alistipes, Odoribacter, Prevotella), Proteobacterium (Esherichia), Firmicutes (Enterococcus), Actinobacteria (Bifidobacterium). These data indicate that gad genes as well as the ability to produce GABA are widely distributed among lactobacilli and bifidobacteria (mainly in L. plantarum, L. brevis, B. adolescentis, B. angulatum, B. dentium) and other gut-derived bacterial species. Perhaps, GABA is involved in the interaction of gut microbiota with the macroorganism and the ability to synthesize GABA may be an important feature in the selection of bacterial strains - psychobiotics. Copyright © 2016 Elsevier Ltd. All rights reserved.

Determination and comparison of γ-aminobutyric acid (GABA) content in pu-erh and other types of Chinese tea.

PubMed

Zhao, Ming; Ma, Yan; Wei, Zhen-zhen; Yuan, Wen-xia; Li, Ya-li; Zhang, Chun-hua; Xue, Xiao-ting; Zhou, Hong-jie

2011-04-27

Two previous studies have reported that pu-erh tea contains a high level of γ-aminobutyric acid (GABA), which is the major inhibitory neurotransmitter in the central nervous system and has several physiological functions. However, two other researchers have demonstrated that the GABA content of several pu-erh teas was low. Due to the high value and health benefits of GABA, analysis of mass-produced pu-erh tea is necessary to determine whether it is actually enriched with GABA. A high-performance liquid chromatography (HPLC) method was developed for the determination of GABA in tea, the results of which were verified by amino acid analysis using an Amino Acid Analyzer (AAA). A total of 114 samples of various types of Chinese tea, including 62 pu-erh teas, 13 green teas, 8 oolong teas, 8 black teas, 3 white teas, 4 GABA teas, and 16 process samples from two industrial fermentations of pu-erh tea (including the raw material and the first to seventh turnings), were analyzed using HPLC. Statistical analysis demonstrated that the GABA content in pu-erh tea was significantly lower than that in other types of tea (p < 0.05) and that the GABA content decreased during industrial fermentation of pu-erh tea (p < 0.05). This mass analysis and comparison suggested GABA was not a major bioactive constituent and resolved the disagreement GABA content in pu-erh tea. In addition, the GABA content in white tea was found to be significantly higher than that in the other types of tea (p < 0.05), leading to the possibility of producing GABA-enriched white tea.

GABAergic inhibition shapes frequency tuning and modifies response properties in the superior olivary nucleus of the leopard frog.

PubMed

Zheng, W; Hall, J C

2000-01-01

The role of gamma-aminobutyric acid (GABA)ergic inhibition in shaping the excitatory frequency tuning of 74 neurons in the superior olivary nucleus of the leopard frog, Rana pipiens, was studied using iontophoretic application of the GABA(A) receptor antagonist, bicuculline methiodide. For 37 neurons, bicuculline application broadened and/or changed the configuration of the excitatory frequency-tuning curve. Results indicate that GABA-mediated inhibition not only sharpens the tuning curves of neurons but also plays a critical role in creating new frequency tuning properties in the superior olivary nucleus. Bicuculline application affected other neuronal response properties as well. Spontaneous firing rate increased 11-338% for 18 of 59 neurons. For 32 of 58 neurons there was an increase in stimulus-evoked discharge rate and a change in rate-level function. There was no qualitative effect on the discharge pattern of 60 neurons, though 2 tonically responding neurons did show an increase (> 30%) in response duration. Additional roles for GABAergic inhibition in monaural signal analysis are discussed.

Cortical GABA markers identify a molecular subtype of psychotic and bipolar disorders.

PubMed

Volk, D W; Sampson, A R; Zhang, Y; Edelson, J R; Lewis, D A

2016-09-01

Deficits in gamma aminobutyric acid (GABA) neuron-related markers, including the GABA-synthesizing enzyme GAD67, the calcium-binding protein parvalbumin, the neuropeptide somatostatin, and the transcription factor Lhx6, are most pronounced in a subset of schizophrenia subjects identified as having a 'low GABA marker' (LGM) molecular phenotype. Furthermore, schizophrenia shares degrees of genetic liability, clinical features and cortical circuitry abnormalities with schizoaffective disorder and bipolar disorder. Therefore, we determined the extent to which a similar LGM molecular phenotype may also exist in subjects with these disorders. Transcript levels for GAD67, parvalbumin, somatostatin, and Lhx6 were quantified using quantitative PCR in prefrontal cortex area 9 of 184 subjects with a diagnosis of schizophrenia (n = 39), schizoaffective disorder (n = 23) or bipolar disorder (n = 35), or with a confirmed absence of any psychiatric diagnoses (n = 87). A blinded clustering approach was employed to determine the presence of a LGM molecular phenotype across all subjects. Approximately 49% of the subjects with schizophrenia, 48% of the subjects with schizoaffective disorder, and 29% of the subjects with bipolar disorder, but only 5% of unaffected subjects, clustered in the cortical LGM molecular phenotype. These findings support the characterization of psychotic and bipolar disorders by cortical molecular phenotype which may help elucidate more pathophysiologically informed and personalized medications.

Parvalbumin and GAD65 Interneuron Inhibition in the Ventral Hippocampus Induces Distinct Behavioral Deficits Relevant to Schizophrenia

PubMed Central

Nguyen, Robin; Morrissey, Mark D.; Mahadevan, Vivek; Cajanding, Janine D.; Woodin, Melanie A.; Yeomans, John S.; Takehara-Nishiuchi, Kaori

2014-01-01

Hyperactivity within the ventral hippocampus (vHPC) has been linked to both psychosis in humans and behavioral deficits in animal models of schizophrenia. A local decrease in GABA-mediated inhibition, particularly involving parvalbumin (PV)-expressing GABA neurons, has been proposed as a key mechanism underlying this hyperactive state. However, direct evidence is lacking for a causal role of vHPC GABA neurons in behaviors associated with schizophrenia. Here, we probed the behavioral function of two different but overlapping populations of vHPC GABA neurons that express either PV or GAD65 by selectively inhibiting these neurons with the pharmacogenetic neuromodulator hM4D. We show that acute inhibition of vHPC GABA neurons in adult mice results in behavioral changes relevant to schizophrenia. Inhibiting either PV or GAD65 neurons produced distinct behavioral deficits. Inhibition of PV neurons, affecting ∼80% of the PV neuron population, robustly impaired prepulse inhibition of the acoustic startle reflex (PPI), startle reactivity, and spontaneous alternation, but did not affect locomotor activity. In contrast, inhibiting a heterogeneous population of GAD65 neurons, affecting ∼40% of PV neurons and 65% of cholecystokinin neurons, increased spontaneous and amphetamine-induced locomotor activity and reduced spontaneous alternation, but did not alter PPI. Inhibition of PV or GAD65 neurons also produced distinct changes in network oscillatory activity in the vHPC in vivo. Together, these findings establish a causal role for vHPC GABA neurons in controlling behaviors relevant to schizophrenia and suggest a functional dissociation between the GABAergic mechanisms involved in hippocampal modulation of sensorimotor processes. PMID:25378161

Effects of chronic ethanol consumption on rat GABA(A) and strychnine-sensitive glycine receptors expressed by lateral/basolateral amygdala neurons.

PubMed

McCool, Brian A; Frye, Gerald D; Pulido, Marisa D; Botting, Shaleen K

2003-02-14

It is well known that the anxiolytic potential of ethanol is maintained during chronic exposure. We have confirmed this using a light-dark box paradigm following chronic ethanol ingestion via a liquid diet. However, cessation from chronic ethanol exposure is known to cause severe withdrawal anxiety. These opposing effects on anxiety likely result from neuro-adaptations of neurotransmitter systems within the brain regions regulating anxiety. Recent work highlights the importance of amygdala ligand-gated chloride channels in the expression of anxiety. We have therefore examined the effects of chronic ethanol exposure on GABA(A) and strychnine-sensitive glycine receptors expressed by acutely isolated adult rat lateral/basolateral amygdala neurons. Chronic ethanol exposure increased the functional expression of GABA(A) receptors in acutely isolated basolateral amygdala neurons without altering strychnine-sensitive glycine receptors. Neither the acute ethanol nor benzodiazepine sensitivity of either receptor system was affected. We explored the likelihood that subunit composition might influence each receptor's response to chronic ethanol. Importantly, when expressed in a mammalian heterologous system, GABA(A) receptors composed of unique alpha subunits were differentially sensitive to acute ethanol. Likewise, the presence of the beta subunit appeared to influence the acute ethanol sensitivity of glycine receptors containing the alpha(2) subunit. Our results suggest that the facilitation of GABA(A) receptors during chronic ethanol exposure may help explain the maintenance of ethanol's anti-anxiety effects during chronic ethanol exposure. Furthermore, the subunit composition of GABA(A) and strychnine-sensitive glycine receptors may ultimately influence the response of each system to chronic ethanol exposure.

Decreased occipital cortical glutamate levels in response to successful cognitive-behavioral therapy and pharmacotherapy for major depressive disorder.

PubMed

Abdallah, Chadi G; Niciu, Mark J; Fenton, Lisa R; Fasula, Madonna K; Jiang, Lihong; Black, Anne; Rothman, Douglas L; Mason, Graeme F; Sanacora, Gerard

2014-01-01

Previous studies have demonstrated that antidepressant medication and electroconvulsive therapy increase occipital cortical γ-aminobutyric acid (GABA) in major depressive disorder (MDD), but a small pilot study failed to show a similar effect of cognitive-behavioral therapy (CBT) on occipital GABA. In light of these findings we sought to determine if baseline GABA levels predict treatment response and to broaden the analysis to other metabolites and neurotransmitters in this larger study. A total of 40 MDD outpatients received baseline proton magnetic resonance spectroscopy (1H-MRS), and 30 subjects completed both pre- and post-CBT 1H-MRS; 9 CBT nonresponders completed an open-label medication phase followed by an additional/3rd 1H-MRS. The magnitude of treatment response was correlated with occipital amino acid neurotransmitter levels. Baseline GABA did not predict treatment outcome. Furthermore, there was no significant effect of CBT on GABA levels. However, we found a significant group × time interaction (F1, 28 = 6.30, p = 0.02), demonstrating reduced glutamate in CBT responders, with no significant glutamate change in CBT nonresponders. These findings corroborate the lack of effect of successful CBT on occipital cortical GABA levels in a larger sample. A reduction in glutamate levels following treatment, on the other hand, correlated with successful CBT and antidepressant medication response. Based on this finding and other reports, decreased occipital glutamate may be an antidepressant response biomarker. Healthy control comparator and nonintervention groups may shed light on the sensitivity and specificity of these results.

Glutamic acid decarboxylase 65: a link between GABAergic synaptic plasticity in the lateral amygdala and conditioned fear generalization.

PubMed

Lange, Maren D; Jüngling, Kay; Paulukat, Linda; Vieler, Marc; Gaburro, Stefano; Sosulina, Ludmila; Blaesse, Peter; Sreepathi, Hari K; Ferraguti, Francesco; Pape, Hans-Christian

2014-08-01

An imbalance of the gamma-aminobutyric acid (GABA) system is considered a major neurobiological pathomechanism of anxiety, and the amygdala is a key brain region involved. Reduced GABA levels have been found in anxiety patients, and genetic variations of glutamic acid decarboxylase (GAD), the rate-limiting enzyme of GABA synthesis, have been associated with anxiety phenotypes in both humans and mice. These findings prompted us to hypothesize that a deficiency of GAD65, the GAD isoform controlling the availability of GABA as a transmitter, affects synaptic transmission and plasticity in the lateral amygdala (LA), and thereby interferes with fear responsiveness. Results indicate that genetically determined GAD65 deficiency in mice is associated with (1) increased synaptic length and release at GABAergic connections, (2) impaired efficacy of GABAergic synaptic transmission and plasticity, and (3) reduced spillover of GABA to presynaptic GABAB receptors, resulting in a loss of the associative nature of long-term synaptic plasticity at cortical inputs to LA principal neurons. (4) In addition, training with high shock intensities in wild-type mice mimicked the phenotype of GAD65 deficiency at both the behavioral and synaptic level, indicated by generalization of conditioned fear and a loss of the associative nature of synaptic plasticity in the LA. In conclusion, GAD65 is required for efficient GABAergic synaptic transmission and plasticity, and for maintaining extracellular GABA at a level needed for associative plasticity at cortical inputs in the LA, which, if disturbed, results in an impairment of the cue specificity of conditioned fear responses typifying anxiety disorders.

Glutamic Acid Decarboxylase 65: A Link Between GABAergic Synaptic Plasticity in the Lateral Amygdala and Conditioned Fear Generalization

PubMed Central

Lange, Maren D; Jüngling, Kay; Paulukat, Linda; Vieler, Marc; Gaburro, Stefano; Sosulina, Ludmila; Blaesse, Peter; Sreepathi, Hari K; Ferraguti, Francesco; Pape, Hans-Christian

2014-01-01

An imbalance of the gamma-aminobutyric acid (GABA) system is considered a major neurobiological pathomechanism of anxiety, and the amygdala is a key brain region involved. Reduced GABA levels have been found in anxiety patients, and genetic variations of glutamic acid decarboxylase (GAD), the rate-limiting enzyme of GABA synthesis, have been associated with anxiety phenotypes in both humans and mice. These findings prompted us to hypothesize that a deficiency of GAD65, the GAD isoform controlling the availability of GABA as a transmitter, affects synaptic transmission and plasticity in the lateral amygdala (LA), and thereby interferes with fear responsiveness. Results indicate that genetically determined GAD65 deficiency in mice is associated with (1) increased synaptic length and release at GABAergic connections, (2) impaired efficacy of GABAergic synaptic transmission and plasticity, and (3) reduced spillover of GABA to presynaptic GABAB receptors, resulting in a loss of the associative nature of long-term synaptic plasticity at cortical inputs to LA principal neurons. (4) In addition, training with high shock intensities in wild-type mice mimicked the phenotype of GAD65 deficiency at both the behavioral and synaptic level, indicated by generalization of conditioned fear and a loss of the associative nature of synaptic plasticity in the LA. In conclusion, GAD65 is required for efficient GABAergic synaptic transmission and plasticity, and for maintaining extracellular GABA at a level needed for associative plasticity at cortical inputs in the LA, which, if disturbed, results in an impairment of the cue specificity of conditioned fear responses typifying anxiety disorders. PMID:24663011

Neuron-specific feeding RNAi in C. elegans and its use in a screen for essential genes required for GABA neuron function.

PubMed

Firnhaber, Christopher; Hammarlund, Marc

2013-11-01

Forward genetic screens are important tools for exploring the genetic requirements for neuronal function. However, conventional forward screens often have difficulty identifying genes whose relevant functions are masked by pleiotropy. In particular, if loss of gene function results in sterility, lethality, or other severe pleiotropy, neuronal-specific functions cannot be readily analyzed. Here we describe a method in C. elegans for generating cell-specific knockdown in neurons using feeding RNAi and its application in a screen for the role of essential genes in GABAergic neurons. We combine manipulations that increase the sensitivity of select neurons to RNAi with manipulations that block RNAi in other cells. We produce animal strains in which feeding RNAi results in restricted gene knockdown in either GABA-, acetylcholine-, dopamine-, or glutamate-releasing neurons. In these strains, we observe neuron cell-type specific behavioral changes when we knock down genes required for these neurons to function, including genes encoding the basal neurotransmission machinery. These reagents enable high-throughput, cell-specific knockdown in the nervous system, facilitating rapid dissection of the site of gene action and screening for neuronal functions of essential genes. Using the GABA-specific RNAi strain, we screened 1,320 RNAi clones targeting essential genes on chromosomes I, II, and III for their effect on GABA neuron function. We identified 48 genes whose GABA cell-specific knockdown resulted in reduced GABA motor output. This screen extends our understanding of the genetic requirements for continued neuronal function in a mature organism.

GABAergic drug use and global, cognitive, and motor functional outcomes after stroke.

PubMed

Schwitzguébel, A J-P; Benaïm, C; Carda, S; Torea Filgueira, A M; Frischknecht, R; Rapin, P-A

2016-12-01

In animal models and healthy volunteers, the use of GABA A receptor agonists (GABA-AGs) seem deleterious for functional recovery. The agents are widely used for subacute stroke, but their effect on functional recovery remains unclear. We aimed to evaluate the association between GABA-AG use and functional recovery after stroke. We retrospectively recruited 434 survivors of subacute stroke admitted for inpatient rehabilitation between 2000 and 2013 in our institution (107 with and 327 without GABA-AG use). We used multivariate regression to assess the association of GABA-AG use and successful functional recovery, defined as reaching, between admission and discharge, the minimal clinically important difference (MCID) of 22 points on the global Functional Independence Measure (FIM). Secondary analyses were the associations of GABA-AG with cognitive and motor FIM MCID and constant GABA-AG exposure (24h/24 GABA-AG) with global, cognitive and motor FIM MCID. A new estimation of the MCID was performed with the standard error of measurement. Reaching the global FIM MCID was associated with GABA-AG use (adjusted odds ratio [aOR] 0.54 [95% CI 0.31-0.91], P=0.02) as well as 24h/24 GABA-AG use (aOR 0.25 [0.08-0.83]; P=0.02). Furthermore, GABA-AG and 24h/24 GABA-AG use was inversely but not always significantly associated with reaching the cognitive FIM MCID (aOR 0.56, P=0.07; aOR 0.26, P=0.06, respectively) and motor FIM MCID (aOR 0.51, P=0.07; aOR 0.13, P=0.01, respectively). The estimated MCID was 19 for global FIM, 4 for cognitive FIM, and 16 for motor FIM. GABA-AG use is associated with not reaching successful functional recovery during stroke rehabilitation. Randomised trials are needed to formally establish the potential deleterious effect of GABA-AG use on functional recovery. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Delta Subunit-Containing Gamma-Aminobutyric Acid A Receptor Disinhibits Lateral Amygdala and Facilitates Fear Expression in Mice.

PubMed

Liu, Zhi-Peng; He, Qing-Hai; Pan, Han-Qing; Xu, Xiao-Bin; Chen, Wen-Bing; He, Ye; Zhou, Jin; Zhang, Wen-Hua; Zhang, Jun-Yu; Ying, Xiao-Ping; Han, Ren-Wen; Li, Bao-Ming; Gao, Tian-Ming; Pan, Bing-Xing

2017-06-15

Maintaining gamma-aminobutyric acidergic (GABAergic) inhibition in the amygdala within a physiological range is critical for the appropriate expression of emotions such as fear and anxiety. The synaptic GABA type A receptor (GABA A R) is generally known to mediate the primary component of amygdala inhibition and prevent inappropriate expression of fear. However, little is known about the contribution of the extrasynaptic GABA A R to amygdala inhibition and fear. By using mice expressing green fluorescent protein in interneurons (INs) and lacking the δ subunit-containing GABA A R (GABA A (δ)R), which is exclusively situated in the extrasynaptic membrane, we systematically investigated the role of GABA A (δ)R in regulating inhibition in the lateral amygdala (LA) and fear learning using the combined approaches of immunohistochemistry, electrophysiology, and behavior. In sharp contrast to the established role of synaptic GABA A R in mediating LA inhibition, we found that either pharmacological or physiological recruitment of GABA A (δ)R resulted in the weakening of GABAergic transmission onto projection neurons in LA while leaving the glutamatergic transmission unaltered, suggesting disinhibition by GABA A (δ)R. The disinhibition arose from IN-specific expression of GABA A (δ)R with its activation decreasing the input resistance of local INs and suppressing their activation. Genetic deletion of GABA A (δ)R attenuated its role in suppressing LA INs and disinhibiting LA. Importantly, the GABA A (δ)R facilitated long-term potentiation in sensory afferents to LA and permitted the expression of learned fear. Our findings suggest that GABA A (δ)R serves as a brake rather than a mediator of GABAergic inhibition in LA. The disinhibition by GABA A (δ)R may help to prevent excessive suppression of amygdala activity and thus ensure the expression of emotion. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Multiple functions of GABA A and GABA B receptors during pattern processing in the zebrafish olfactory bulb.

PubMed

Tabor, Rico; Yaksi, Emre; Friedrich, Rainer W

2008-07-01

gamma-Aminobutyric acid (GABA)ergic synapses are thought to play pivotal roles in the processing of activity patterns in the olfactory bulb (OB), but their functions have been difficult to study during odor responses in the intact system. We pharmacologically manipulated GABA(A) and GABA(B) receptors in the OB of zebrafish and analysed the effects on odor responses of the output neurons, the mitral cells (MCs), by electrophysiological recordings and temporally deconvolved two-photon Ca2+ imaging. The blockade of GABA(B) receptors enhanced presynaptic Ca2+ influx into afferent axon terminals, and changed the amplitude and time course of a subset of MC responses, indicating that GABA(B) receptors have a modulatory influence on OB output activity. The blockade of GABA(A) receptors induced epileptiform firing, enhanced excitatory responses and abolished fast oscillations in the local field potential. Moreover, the topological reorganization and decorrelation of MC activity patterns during the initial phase of the response was perturbed. These results indicate that GABA(A) receptor-containing circuits participate in the balance of excitation and inhibition, the regulation of total OB output activity, the synchronization of odor-dependent neuronal ensembles, and the reorganization of odor-encoding activity patterns. GABA(A) and GABA(B) receptors are therefore differentially involved in multiple functions of neuronal circuits in the OB.