Sample records for amino-butyric acid gaba

  1. EFFECT OF LEAD ON GAMMA AMINO BUTYRIC ACID SYNTHESIS

    EPA Science Inventory

    The project studies the inhibitory effect of lead on the enzymatic activity of brain glutamic amino acid decarboxylase (GADC). The enzyme is responsible for the catalytic formation of gamma amino butyric acid (GABA) inhibitory neurons which is believed to be involved with the tra...

  2. The effect of intraruminal infusions of amines and gamma amino butyric acid on rumen fermentation parameters and food intake of steers offered grass silage

    Microsoft Academic Search

    L. E. R. Dawson; C. S. Mayne

    1996-01-01

    An experiment was carried out to assess the role of amines and gamma amino butyric acid (GABA) in food intake control with steers offered grass silage based diets. The effect of the amines, putrescine (P) and tyramine (T), and GABA (G) on voluntary food intake were investigated at three levels of addition: 2 g kg?1 DM (1); 4 g kg?1

  3. A Role of  Amino Butyric Acid (GABA) and Glutamate in Control of Puberty in Female Rhesus Monkeys: Effect of an Antisense Oligodeoxynucleotide for GAD67 Messenger Ribonucleic Acid and MK801 on Luteinizing Hormone-Releasing Hormone Release

    Microsoft Academic Search

    ETSUKO KASUYA; CHRISTOPHER L. NYBERG; KAZUTAKA MOGI; EI TERASAWA

    1999-01-01

    Previously we have shown that g-aminobutyric acid (GABA) is an inhibitory neurotransmitter restricting the pubertal increase in LHRH release in juvenile monkeys, and that interfering with GABA synthesis with an antisense oligodeoxynucleotide (AS) for glutamic acid decarboxylase (GAD67) mRNA results in an increase in LHRH release in prepubertal monkeys. GAD67 is a catalytic enzyme that synthesizes GABA from glutamate. To

  4. Induction of oxidants in tomato leaves treated with DL -?-Amino butyric acid (BABA) and infected with Clavibacter michiganensis ssp. michiganensis

    Microsoft Academic Search

    Ömür Baysal; Y. Ziya Gürsoy; Hakan Örnek; Ahmet Duru

    2005-01-01

    Bacterial canker is an economically important disease of tomato. Resistance induced by DL-?-Amino butyric acid against bacterial canker caused by Clavibacter michiganensis ssp. michiganensis in tomato plants was investigated. Different doses of DL-?-Amino butyric acid (250–1000 ?g ml?1 doses) were tested on 3-week old plants inoculated with a 108 CFU  ml?1 bacterial suspension, and disease development was evaluated after inoculation and treatment. Although

  5. LeProT1, a transporter for proline, glycine betaine, and gamma-amino butyric acid in tomato pollen.

    PubMed Central

    Schwacke, R; Grallath, S; Breitkreuz, K E; Stransky, E; Stransky, H; Frommer, W B; Rentsch, D

    1999-01-01

    During maturation, pollen undergoes a period of dehydration accompanied by the accumulation of compatible solutes. Solute import across the pollen plasma membrane, which occurs via proteinaceous transporters, is required to support pollen development and also for subsequent germination and pollen tube growth. Analysis of the free amino acid composition of various tissues in tomato revealed that the proline content in flowers was 60 times higher than in any other organ analyzed. Within the floral organs, proline was confined predominantly to pollen, where it represented >70% of total free amino acids. Uptake experiments demonstrated that mature as well as germinated pollen rapidly take up proline. To identify proline transporters in tomato pollen, we isolated genes homologous to Arabidopsis proline transporters. LeProT1 was specifically expressed both in mature and germinating pollen, as demonstrated by RNA in situ hybridization. Expression in a yeast mutant demonstrated that LeProT1 transports proline and gamma-amino butyric acid with low affinity and glycine betaine with high affinity. Direct uptake and competition studies demonstrate that LeProT1 constitutes a general transporter for compatible solutes. PMID:10072398

  6. Valproic Acid Alters GnRH-GABA Interactions in Cycling Female Rats

    Microsoft Academic Search

    Dinesh Lakhanpal; Gurcharan Kaur

    2007-01-01

    Summary of the aims Women with epilepsy using antiepileptic drug valproic acid (VPA) often suffer from reproductive endocrine disorders, menstrual\\u000a disorders and polycystic ovaries. Valproic acid exerts anticonvulsive effects via gamma amino butyric acid (GABA) neurotransmitter\\u000a system, which also acts as a neurochemical regulator of gonadotropin-releasing hormone (GnRH) neurons and suggests possibility\\u000a of valproic acid mediated interruption in gonadotropin releasing

  7. Upregulation of genes related to bone formation by ?-amino butyric acid and ?-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

  8. Biodistribution and Dosimetry of Carbon11- Methoxyprogabidic Acid, a Possible Ligand for GABA-Receptors in the Brain

    Microsoft Academic Search

    Patrick Santens; Filip De Vos; Hubert Thierens; Danny Decoo; Guido Siegers; Rudi A. Dierckx; Jacques De Reuck

    1998-01-01

    Carbon-11 -methoxyprogabidic acid (11C-MPGA)was recently syn- thetized as a possible ligand for PET studies of gamma-amino- butyric acid (GABA) receptors in the brain. The data for human absorbed dose estimates are calculated based on the biodistribu- tion of 11C-MPGA in mice and humans. Methods: Eighteen mice were killed at preset time intervals after an intravenous bolus injection of 3.7 MBq

  9. Crayfish sensory terminals and motor neurones exhibit two distinct types of GABA receptors

    Microsoft Academic Search

    E. Pearstein; D. Cattaert; F. Clarac

    1996-01-01

    Motor neurones of the crayfish walking system display inhibitory responses evoked either by ?-amino butyric acid (GABA) or\\u000a glutamate, possibly involving the same receptor (Pearlstein et al. 1994). In order to test if this sensibility to both GABA\\u000a and glutamate was a specific property of crayfish GABA receptors, pharmacological characteristics of GABA-evoked responses\\u000a in both sensory terminals from CB chordotonal

  10. Distribution of GABA-like immunoreactive neurons in the slug Limax maximus

    Microsoft Academic Search

    Ian R. C. Cooke; Alan Gelperin

    1988-01-01

    Immunohistochemical techniques were used to study the distribution of gamma-amino butyric acid (GABA)-like immunoreactive neurons in the nervous system of the slug Limax maximus. Approximately 170 GABA-like immunoreactive cell bodies were found in the central nervous system. These were located in the cerebral, buccal and pedal ganglia. Most GABA-like immunoreactive neurons had small cell bodies, which were aggregated into discrete

  11. Increases in GABA concentrations during cerebral ischaemia: a microdialysis study of extracellular amino acids

    PubMed Central

    Hutchinson, P; O'Connell, M; Al-Rawi, P; Kett-White, C; Gupta, A; Maskell, L; Pickard, J; Kirkpatrick, P

    2002-01-01

    Objectives: Increases in the extracellular concentration of the excitatory amino acids glutamate and aspartate during cerebral ischaemia in patients are well recognised. Less emphasis has been placed on the concentrations of the inhibitory amino acid neurotransmitters, notably ?-amino-butyric acid (GABA), despite evidence from animal studies that GABA may act as a neuroprotectant in models of ischaemia. The objective of this study was to investigate the concentrations of various excitatory, inhibitory and non-transmitter amino acids under basal conditions and during periods of cerebral ischaemia in patients with head injury or a subarachnoid haemorrhage. Methods: Cerebral microdialysis was established in 12 patients with head injury (n=7) or subarachnoid haemorrhage (n=5). Analysis was performed using high performance liquid chromatography for a total of 19 (excitatory, inhibitory and non-transmitter) amino acids. Patients were monitored in neurointensive care or during aneurysm clipping. Results: During stable periods of monitoring the concentrations of amino acids were relatively constant enabling basal values to be established. In six patients, cerebral ischaemia was associated with increases (up to 1350 fold) in the concentration of GABA, in addition to the glutamate and aspartate. Parallel increases in the concentration of glutamate and GABA were found (r=0.71, p<0.005). Conclusions: The results suggest that, in the human brain, acute cerebral ischaemia is not accompanied by an imbalance between excitatory and inhibitory amino acids, but by an increase in all neurotransmitter amino acids. These findings concur with the animal models of ischaemia and raise the possibility of an endogenous GABA mediated neuroprotective mechanism in humans. PMID:11784833

  12. Distribution of GABA-like immunoreactive neurons in the slug Limax maximus.

    PubMed

    Cooke, I R; Gelperin, A

    1988-07-01

    Immunohistochemical techniques were used to study the distribution of gamma-amino butyric acid (GABA)-like immunoreactive neurons in the nervous system of the slug Limax maximus. Approximately 170 GABA-like immunoreactive cell bodies were found in the central nervous system. These were located in the cerebral, buccal and pedal ganglia. Most GABA-like immunoreactive neurons had small cell bodies, which were aggregated into discrete clusters within the cerebral and pedal ganglia. Three pairs of longer, uniquely identifiable, GABA-like immunoreactive cells were found in the cerebral ganglion. GABA-like immunoreactive nerve fibres were also found in all of the central ganglia but were absent from peripheral nerves. These results suggest that GABA acts as a central neurotransmitter in the slug. The possible roles of GABA-ergic neurotransmission in the slug are discussed. PMID:2458189

  13. The role of GABA in the regulation of GnRH neurons

    PubMed Central

    Watanabe, Miho; Fukuda, Atsuo; Nabekura, Junichi

    2014-01-01

    Gonadotropin-releasing hormone (GnRH) neurons form the final common pathway for the central regulation of reproduction. Gamma-amino butyric acid (GABA) has long been implicated as one of the major players in the regulation of GnRH neurons. Although GABA is typically an inhibitory neurotransmitter in the mature adult central nervous system, most mature GnRH neurons show the unusual characteristic of being excited by GABA. While many reports have provided much insight into the contribution of GABA to the activity of GnRH neurons, the precise physiological role of the excitatory action of GABA on GnRH neurons remains elusive. This brief review presents the current knowledge of the role of GABA signaling in GnRH neuronal activity. We also discuss the modulation of GABA signaling by neurotransmitters and neuromodulators and the functional consequence of GABAergic inputs to GnRH neurons in both the physiology and pathology of reproduction. PMID:25506316

  14. Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments

    Microsoft Academic Search

    J H Krystal; G Sanacora; H Blumberg; A Anand; D S Charney; G Marek; C N Epperson; A Goddard; G F Mason

    2002-01-01

    Glutamate and ?-amino butyric acid (GABA) systems are emerging as targets for development of medications for mood disorders. There is increasing preclinical and clinical evidence that antidepressant drugs directly or indirectly reduce N-methyl-D-aspartate glutamate receptor function. Drugs that reduce glutamatergic activity or glutamate receptor-related signal transduction may also have antimanic effects. Recent studies employing magnetic resonance spectroscopy also suggest that

  15. Production of gaba (? – Aminobutyric acid) by microorganisms: a review

    PubMed Central

    Dhakal, Radhika; Bajpai, Vivek K.; Baek, Kwang-Hyun

    2012-01-01

    GABA (?-aminobutyric acid) is a four carbon non-protein amino acid that is widely distributed in plants, animals and microorganisms. As a metabolic product of plants and microorganisms produced by the decarboxylation of glutamic acid, GABA functions as an inhibitory neurotransmitter in the brain that directly affects the personality and the stress management. A wide range of traditional foods produced by microbial fermentation contain GABA, in which GABA is safe and eco-friendly, and also has the possibility of providing new health-benefited products enriched with GABA. Synthesis of GABA is catalyzed by glutamate decarboxylase, therefore, the optimal fermentation condition is mainly based on the biochemical properties of the enzyme. Major GABA producing microorganisms are lactic acid bacteria (LAB), which make food spoilage pathogens unable to grow and act as probiotics in the gastrointestinal tract. The major factors affecting the production of GABA by microbial fermentation are temperature, pH, fermentation time and different media additives, therefore, these factors are summarized to provide the most up-dated information for effective GABA synthesis. There has been a huge accumulation of knowledge on GABA application for human health accompanying with a demand on natural GABA supply. Only the GABA production by microorganisms can fulfill the demand with GABA-enriched health beneficial foods. PMID:24031948

  16. Suppression of ?-aminobutyric acid (GABA) transaminases induces prominent GABA accumulation, dwarfism and infertility in the tomato (Solanum lycopersicum L.).

    PubMed

    Koike, Satoshi; Matsukura, Chiaki; Takayama, Mariko; Asamizu, Erika; Ezura, Hiroshi

    2013-05-01

    Tomatoes accumulate ?-aminobutyric acid (GABA) at high levels in the immature fruits. GABA is rapidly converted to succinate during fruit ripening through the activities of GABA transaminase (GABA-T) and succinate semialdehyde dehydrogenase (SSADH). Although three genes encoding GABA-T and both pyruvate- and ?-ketoglutarate-dependent GABA-T activities have been detected in tomato fruits, the mechanism underlying the GABA-T-mediated conversion of GABA has not been fully understood. In this work, we conducted loss-of-function analyses utilizing RNA interference (RNAi) transgenic plants with suppressed pyruvate- and glyoxylate-dependent GABA-T gene expression to clarify which GABA-T isoforms are essential for its function. The RNAi plants with suppressed SlGABA-T gene expression, particularly SlGABA-T1, showed severe dwarfism and infertility. SlGABA-T1 expression was inversely associated with GABA levels in the fruit at the red ripe stage. The GABA contents in 35S::SlGABA-T1(RNAi) lines were 1.3-2.0 times and 6.8-9.2 times higher in mature green and red ripe fruits, respectively, than the contents in wild-type fruits. In addition, SlGABA-T1 expression was strongly suppressed in the GABA-accumulating lines. These results indicate that pyruvate- and glyoxylate-dependent GABA-T is the essential isoform for GABA metabolism in tomato plants and that GABA-T1 primarily contributes to GABA reduction in the ripening fruits. PMID:23435575

  17. Comparing the inferior colliculus of young and old gerbils (Meriones unguiculatus) with an emphasis on GABA.

    PubMed

    Gleich, Otto; Netz, Judith; Strutz, Jürgen

    2014-09-01

    Indicators of an age-dependent down-regulation of GABA (gamma amino butyric acid) have been well-documented in the inferior colliculus (IC) of several rat strains. In the present study, we performed a quantitative light microscopic analysis of GABA-immunostained IC sections to characterize the effect of age on the cross-sectional area of the IC, the number and density of GABAergic cells and the expression of GABA in gerbils. Compared to young gerbils, a significant shrinkage of the IC but no loss of GABAergic cells was found resulting in an increased density of GABAergic cells in old gerbils. The expression of GABA in neurons and the neuropil of the IC did not differ between young and old gerbils. The results in the gerbil differ considerably from age-dependent changes described for the rat IC, showing clear species-specific differences. PMID:24879972

  18. Mutation of the Drosophila vesicular GABA transporter disrupts visual figure detection

    PubMed Central

    Fei, Hao; Chow, Dawnis M.; Chen, Audrey; Romero-Calderón, Rafael; Ong, Wei S.; Ackerson, Larry C.; Maidment, Nigel T.; Simpson, Julie H.; Frye, Mark A.; Krantz, David E.

    2010-01-01

    The role of gamma amino butyric acid (GABA) release and inhibitory neurotransmission in regulating most behaviors remains unclear. The vesicular GABA transporter (VGAT) is required for the storage of GABA in synaptic vesicles and provides a potentially useful probe for inhibitory circuits. However, specific pharmacologic agents for VGAT are not available, and VGAT knockout mice are embryonically lethal, thus precluding behavioral studies. We have identified the Drosophila ortholog of the vesicular GABA transporter gene (which we refer to as dVGAT), immunocytologically mapped dVGAT protein expression in the larva and adult and characterized a dVGATminos mutant allele. dVGAT is embryonically lethal and we do not detect residual dVGAT expression, suggesting that it is either a strong hypomorph or a null. To investigate the function of VGAT and GABA signaling in adult visual flight behavior, we have selectively rescued the dVGAT mutant during development. We show that reduced GABA release does not compromise the active optomotor control of wide-field pattern motion. Conversely, reduced dVGAT expression disrupts normal object tracking and figure–ground discrimination. These results demonstrate that visual behaviors are segregated by the level of GABA signaling in flies, and more generally establish dVGAT as a model to study the contribution of GABA release to other complex behaviors. PMID:20435823

  19. -Aminobutyric Acid (GABA) and Pentobarbital Induce Different Conformational Rearrangements in the GABAA

    E-print Network

    Kemnitz, Joseph

    . For 1K221C 2 receptors, pentobarbital decreased the rate of cysteine modification whereas GABA had no effect. For 1 2K215C receptors, pentobarbital had no effect whereas GABA increased the modification rate-Aminobutyric Acid (GABA) and Pentobarbital Induce Different Conformational Rearrangements

  20. Interactions of ? -aminobutyric acid (GABA), pentobarbital, and homopantothenic acid (HOPA) on internally perfused frog sensory neurons

    Microsoft Academic Search

    Norio Akaike; Yutaka Oomura

    1985-01-01

    Summary 1.Augmentatory actions among Cl? currents (ICl) induced by?-aminobutyric acid (GABA), pentobarbital (PB), and homopantothenic acid (HOPA) were investigated in isolated frog sensory neurons after suppression of Na+, K+, and Ca2+ currents using a suction pipette technique which combines internal perfusion with voltage clamp.2.GABA-sensitive neurons responded to both PB and HOPA, and the responses behaved as a simple Cl? electrode

  1. GABA and Homovanillic Acid in the Plasma of Schizophrenic and Bipolar I Patients

    Microsoft Academic Search

    Aurora Arrúe; Ricardo Dávila; Mercedes Zumárraga; Nieves Basterreche; Miguel A. González-Torres; Biotza Goienetxea; Maria I. Zamalloa; Juan B. Anguiano; José Guimón

    2010-01-01

    We have determined the plasma (p) concentration of gamma-aminobutyric acid (GABA) and the dopamine metabolite homovanillic\\u000a acid (HVA), and the pHVA\\/pGABA ratio in schizophrenic and bipolar patients. The research was undertaken in a geographic area\\u000a with an ethnically homogeneous population. The HVA plasma concentrations were significantly elevated in the schizophrenic\\u000a patients compared to the bipolar patients. The levels of pGABA

  2. 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

  3. Regulation of cell surface GABA(B) receptors: contribution to synaptic plasticity in neurological diseases.

    PubMed

    Benke, Dietmar; Balakrishnan, Karthik; Zemoura, Khaled

    2015-01-01

    ?-Amino butyric acid (GABA(B)) receptors are heterodimeric G protein-coupled receptors expressed throughout the central nervous system in virtually all neurons. They control the excitability of neurons via activation of different downstream effector systems in pre- and postsynaptic neurons and as such regulate all major brain functions including synaptic plasticity, neuronal network activity, and neuronal development. Accordingly, GABA(B) receptors have been implicated in a variety of neurological disorders and thus are regarded as promising drug targets. A key factor determining the extent of GABA(B) receptor-mediated inhibition is the level of receptors at the cell surface available for signaling. There is increasing evidence that cell surface expression of functional GABA(B) receptors is affected in neurological diseases. This diminishes inhibitory control of neuronal excitation and may contribute to the disease state. Here, we discuss recent findings on mechanisms involved in regulating cell surface expression of GABA(B) receptors in addiction, neuropathic pain, and brain ischemia. PMID:25637437

  4. Decreased GABA receptor in the cerebral cortex of epileptic rats: effect of Bacopa monnieri and Bacoside-A

    PubMed Central

    2012-01-01

    Abstact Background Gamma amino butyric acid (GABA), the principal inhibitory neurotransmitter in the cerebral cortex, maintains the inhibitory tones that counter balances neuronal excitation. When this balance is perturbed, seizures may ensue. Methods In the present study, alterations of the general GABA, GABAA and GABAB receptors in the cerebral cortex of the epileptic rat and the therapeutic application of Bacopa monnieri were investigated. Results Scatchard analysis of [3H]GABA, [3H]bicuculline and [3H]baclofen in the cerebral cortex of the epileptic rat showed significant decrease in Bmax (P < 0.001) compared to control. Real Time PCR amplification of GABA receptor subunits such as GABAA?1, GABAA?, GABAA?, GABAB and GAD where down regulated (P < 0.001) in epileptic rats. GABAA?5 subunit and Cyclic AMP responsible element binding protein were up regulated. Confocal imaging study confirmed the decreased GABA receptors in epileptic rats. Epileptic rats have deficit in radial arm and Y maze performance. Conclusions Bacopa monnieri and Bacoside-A treatment reverses epilepsy associated changes to near control suggesting that decreased GABA receptors in the cerebral cortex have an important role in epileptic occurrence; Bacopa monnieri and Bacoside-A have therapeutic application in epilepsy management. PMID:22364254

  5. Involvement of GABA A and GABA B receptors in the mediation of discriminative stimulus effects of ?-hydroxybutyric acid

    Microsoft Academic Search

    Giancarlo Colombo; Roberta Agabio; Carla Lobina; Roberta Reali; Gian Luigi Gessa

    1998-01-01

    COLOMBO, G., R. AGABIO, C. LOBINA, R. REALI AND G.L. GESSA. Involvement of GABAA and GABAB receptors in the mediation of discriminative stimulus effects of ?-hydroxybutyric acid. PHYSIOL BEHAV 64(3) 293–302, 1998.—The present study was designed to further investigate the pharmacological profile of the discriminative stimulus effects of ?-hydroxybutyric acid (GHB). Drugs acting at the ?-aminobutyric acid (GABA)B receptor (baclofen

  6. Friedreich ataxia: failure of GABA-ergic and glycinergic synaptic transmission in the dentate nucleus.

    PubMed

    Koeppen, Arnulf H; Ramirez, R Liane; Becker, Alyssa B; Feustel, Paul J; Mazurkiewicz, Joseph E

    2015-02-01

    Atrophy of large neurons in the dentate nucleus (DN) is an important pathologic correlate of neurologic disability in patients with Friedreich ataxia (FA). Thinning of the DN was quantified in 29 autopsy cases of FA and 2 carriers by measuring the thickness of the gray matter ribbon on stains with anti-glutamic acid decarboxylase, the rate-limiting enzyme in the biosynthesis of ?-amino-butyric acid (GABA). The DN was thinner than normal in all cases of FA, and atrophy correlated inversely with disease duration but not with age at onset or length of the homozygous guanine-adenine-adenine trinucleotide expansions. In 13 of the FA cases, frozen DN tissue was available for assay of frataxin. Dentate nucleus atrophy was more severe when frataxin was very low. Immunohistochemical staining for glutamic acid decarboxylase revealed grumose reaction and preservation of small GABA-ergic neurons in the DN of FA patients. Residual small DN neurons and varicose axons also contained the glycine transporter 2, identifying them as glycinergic. Immunohistochemistry also confirmed severe loss of GABA-A and glycine receptors in the DN with comparable depletion of the receptor-anchoring protein gephyrin. Thus, loss of gephyrin and failure to position GABA-A and glycine receptors correctly may reduce trophic support of large DN neurons and contribute to their atrophy. By contrast, Purkinje cells may escape retrograde atrophy in FA by issuing new axonal sprouts to small surviving DN neurons where they form reparative grumose clusters. PMID:25575136

  7. Effects of Chlorotrifluoroethylene Oligomer Fatty Acids on Recombinant GABA Receptors Expressed in Xenopus Oocytes

    Microsoft Academic Search

    N. J. DelRaso; Y. Huang; L. Lu

    1996-01-01

    .   GABA-activated Cl? current was expressed in Xenopus oocytes after injecting cRNA that had been transcribed in vitro from complementary DNA (cDNA) coding for a single GABA ?i-subunit cloned from human retina. The expressed current was insensitive to 100 ?m bicuculline, but was activated by the GABA analogue trans-4-aminocrontonic acid (TACA). Anion-selective permeability of the\\u000a expressed ?1-subunit was determined by

  8. Synthesis and pharmacological evaluation of 6-aminonicotinic acid analogues as novel GABA(A) receptor agonists.

    PubMed

    Petersen, Jette G; Sørensen, Troels; Damgaard, Maria; Nielsen, Birgitte; Jensen, Anders A; Balle, Thomas; Bergmann, Rikke; Frølund, Bente

    2014-09-12

    A series of 6-aminonicotinic acid analogues have been synthesized and pharmacologically characterized at native and selected recombinant GABA(A) receptors. 6-Aminonicotinic acid (3) as well as 2- and 4-alkylated analogues (9-11, 14-16) display low to mid-micromolar GABA(A)R binding affinities to native GABA(A) receptors (K(i) 1.1-24 ?M). The tetrahydropyridine analogue of 3 (22) shows low-nanomolar affinity (K(i) 0.044 ?M) and equipotency as an agonist to GABA itself as well as the standard GABA(A) agonist isoguvacine. Cavities surrounding the core of the GABA binding pocket were predicted by molecular interaction field calculations and docking studies in a ?1?2?2 GABA(A) receptor homology model, and were confirmed by affinities of substituted analogues of 3. The tight steric requirements observed for the remarkably few GABA(A)R agonists reported to date is challenged by our findings. New openings for agonist design are proposed which potentially could facilitate the exploration of different pharmacological profiles within the GABA(A)R area. PMID:25038482

  9. Modulation of ?-aminobutyric acid (GABA) receptors and the feeding response by neurosteroids in Hydra vulgaris

    Microsoft Academic Search

    A Concas; P Pierobon; M. C Mostallino; G Marino; R Minei; G Biggio

    1998-01-01

    ?-aminobutyric acid (GABA) receptors are present in membrane preparations from Hydra vulgaris, one of the most primitive organisms with a nervous system. These receptors are sensitive to muscimol and benzodiazepines and appear to be important in the regulation of the feeding response. The effects of neurosteroids, general anaesthetics, and GABA antagonists on GABAA receptors in membranes prepared from hydra and

  10. GABA(B) receptor-mediated activation of astrocytes by gamma-hydroxybutyric acid.

    PubMed

    Gould, Timothy; Chen, Lixin; Emri, Zsuzsa; Pirttimaki, Tiina; Errington, Adam C; Crunelli, Vincenzo; Parri, H Rheinallt

    2014-10-19

    The gamma-aminobutyric acid (GABA) metabolite gamma-hydroxybutyric acid (GHB) shows a variety of behavioural effects when administered to animals and humans, including reward/addiction properties and absence seizures. At the cellular level, these actions of GHB are mediated by activation of neuronal GABA(B) receptors (GABA(B)Rs) where it acts as a weak agonist. Because astrocytes respond to endogenous and exogenously applied GABA by activation of both GABA(A) and GABA(B)Rs, here we investigated the action of GHB on astrocytes on the ventral tegmental area (VTA) and the ventrobasal (VB) thalamic nucleus, two brain areas involved in the reward and proepileptic action of GHB, respectively, and compared it with that of the potent GABA(B)R agonist baclofen. We found that GHB and baclofen elicited dose-dependent (ED50: 1.6 mM and 1.3 µM, respectively) transient increases in intracellular Ca(2+) in VTA and VB astrocytes of young mice and rats, which were accounted for by activation of their GABA(B)Rs and mediated by Ca(2+) release from intracellular store release. In contrast, prolonged GHB and baclofen exposure caused a reduction in spontaneous astrocyte activity and glutamate release from VTA astrocytes. These findings have key (patho)physiological implications for our understanding of the addictive and proepileptic actions of GHB. PMID:25225100

  11. Pu-Erh tea and GABA attenuates oxidative stress in kainic acid-induced status epilepticus

    PubMed Central

    2011-01-01

    Background Pu-Erh tea is one of the most-consumed beverages due to its taste and the anti-anxiety-producing effect of the gamma-aminobutyric acid (GABA) if contains. However the protective effects of Pu-Erh tea and its constituent, GABA to kainic acid (KA)-induced seizure have not been fully investigated. Methods We analyzed the effect of Pu-Erh tea leaf (PETL) and GABA on KA-induced neuronal injury in vivo and in vitro. Results PETL and GABA reduced the maximal seizure classes, predominant behavioral seizure patterns, and lipid peroxidation in male FVB mice with status epilepticus. PETL extracts and GABA were effective in protecting KA-treated PC12 cells in a dose-dependent manner and they decreased Ca2+ release, ROS production and lipid peroxidation from KA-stressed PC12 cells. Western blot results revealed that mitogen-activated protein kinases (MAPKs), RhoA and cyclo-oxygenase-2 (COX-2) expression were increased in PC12 cells under KA stress, and PETL and GABA significantly reduced COX-2 and p38 MAPK expression, but not that of RhoA. Furthermore, PETL and GABA reduced PGE2 production from KA-induced PC12 cells. Conclusions Taken together, PETL and GABA have neuroprotective effects against excitotoxins that may have clinical applications in epilepsy. PMID:22014163

  12. Differential effects of GABA in modulating nociceptive vs. non-nociceptive synapses.

    PubMed

    Wang, Y; Summers, T; Peterson, W; Miiller, E; Burrell, B D

    2015-07-01

    GABA (?-amino-butyric acid) -mediated signaling is normally associated with synaptic inhibition due to ionotropic GABA receptors that gate an inward Cl(-) current, hyperpolarizing the membrane potential. However, there are also situations where ionotropic GABA receptors trigger a Cl(-) efflux that results in depolarization. The well-characterized central nervous system of the medicinal leech was used to study the functional significance of opposing effects of GABA at the synaptic circuit level. Specifically, we focused on synapses made by the nociceptive N cell and the non-nociceptive P (pressure) cell that converge onto a common postsynaptic target. It is already known that GABA hyperpolarizes the P cell, but depolarizes the N cell and that inhibition of ionotropic GABA receptors by bicuculline (BIC) has opposing effects on the synapses made by these two inputs; enhancing P cell synaptic transmission, but depressing N cell synapses. The goal of the present study was to determine whether the opposing effects of GABA were due to differences in Cl(-) homeostasis between the two presynaptic neurons. VU 0240551 (VU), an inhibitor of the Cl(-) exporter K-Cl co-transporter isoform 2 (KCC2), attenuated GABA-mediated hyperpolarization of the non-nociceptive afferent while bumetanide (BUM), an inhibitor of the Cl(-) importer Na-K-Cl co-transporter isoform 1 (NKCC1), reduced GABA-mediated depolarization of the nociceptive neuron. VU treatment also enhanced P cell synaptic signaling, similar to the previously observed effects of BIC and consistent with the idea that GABA inhibits synaptic signaling at the presynaptic level. BUM treatment depressed N cell synapses, again similar to what is observed following BIC treatment and suggests that GABA has an excitatory effect on these synapses. The opposing effects of GABA could also be observed at the behavioral level with BIC and VU increasing responsiveness to non-nociceptive stimulation while BIC and BUM decreased responsiveness to nociceptive stimulation. These findings demonstrate that distinct synaptic inputs within a shared neural circuit can be differentially modulated by GABA in a functionally relevant manner. PMID:25931332

  13. Induction of the GABA cell phenotype: an in vitro model for studying neurodevelopmental disorders.

    PubMed

    Subburaju, Sivan; Benes, Francine M

    2012-01-01

    Recent studies of the hippocampus have suggested that a network of genes is associated with the regulation of the GAD?? (GAD1) expression and may play a role in ?-amino butyric acid (GABA) dysfunction in schizophrenia (SZ) and bipolar disorder (BD). To obtain a more detailed understanding of how GAD?? regulation may result in GABAergic dysfunction, we have developed an in vitro model in which GABA cells are differentiated from the hippocampal precursor cell line, HiB5. Growth factors, such as PDGF, and BDNF, regulate the GABA phenotype by inducing the expression of GAD?? and stimulating the growth of cellular processes, many with growth cones that form appositions with the cell bodies and processes of other GAD??-positive cells. These changes are associated with increased expression of acetylated tubulin, microtubule-associated protein 2 (MAP2) and the post-synaptic density protein 95 (PSD95). The addition of BDNF, together with PDGF, increases the levels of mRNA and protein for GAD??, as well as the high affinity GABA uptake protein, GAT1. These changes are associated with increased concentrations of GABA in the cytoplasm of "differentiated" HiB5 neurons. In the presence of Ca²? and K?, newly synthesized GABA is released extracellularly. When the HiB5 cells appear to be fully differentiated, they also express GAD??, parvalbumin and calbindin, and GluR subtypes as well as HDAC1, DAXX, PAX5, Runx2, associated with GAD?? regulation. Overall, these results suggest that the HiB5 cells can differentiate into functionally mature GABA neurons in the presence of gene products that are associated with GAD?? regulation in the adult hippocampus. PMID:22457755

  14. Effects of chlorotrifluoroethylene oligomer fatty acids on recombinant GABA receptors expressed in Xenopus oocytes.

    PubMed

    DelRaso, N J; Huang, Y; Lu, L

    1996-01-01

    GABA-activated Cl- current was expressed in Xenopus oocytes after injecting cRNA that had been transcribed in vitro from complementary DNA (cDNA) coding for a single GABA rho i-subunit cloned from human retina. The expressed current was insensitive to 100 microM bicuculline, but was activated by the GABA analogue trans-4-aminocrontonic acid (TACA). Anion-selective permeability of the expressed rho 1-subunit was determined by isotonically replacing the extracellular Cl- with different anions. The anion permeability was very similar to the native GABAA receptor/channel following a sequence of SCN- > I- > NO3- > Br- > or = Cl-. Halogenated fatty acids, such as chlorotrifluoroethylene (CTFE) and perfluorinated oligomer acids inhibited the GABA-induced current in oocytes expressing the human retinal GABA rho 1-subunit or rat brain GABAA receptor alpha 1,beta 2,gamma 2 subunits. The inhibitory effect of halogenated fatty acids demonstrated a carbon chain length-dependent manner of: C10 > C8 > C6 > C4. Perfluorinated C8-oligomer acid (PFOA) was less effective at blocking this channel than the C8-CTFE oligomer acid. Radiolabeled GABA binding assay indicated that CTFE oligomer acids do not interfere at the GABA binding site of the receptor. Furthermore, the C8-CTFE oligomer fatty acid did not compete with picrotoxin for binding sites within the pore of the channel. These studies demonstrated that the heterologous expression system is useful for studying the molecular interaction between potential neurotoxic agents and neuroreceptors. Our results provide detailed information that should contribute to our understanding of the structure and function of retinal GABA receptors. PMID:8825526

  15. [GABA-ergic mechanism of cerebrovascular and antiischemic effects of docosahexaenoic acid].

    PubMed

    Mirzoian, R S; Gan'shina, T S; Gnezdilova, A V; Kovalev, G I; Firstova, Iu Iu; Bezuglov, V V; Gretskaia, N M

    2015-01-01

    In experiments on rats, measurements of the local blood flow in the cortex of cerebrum with the aid of a laser Doppler flow meter showed that docosahexaenoic acid (DHA) enhanced the local cerebral circulation in animals with global transient cerebral ischemia, while not influencing that in intact animals. This vasodilatory effect of DHA in ischemized rats is blocked by bicuculline (specific GABA(A) receptor blocker), which is indicative of a GABA-ergic mechanisms of the vascular tone regulation. The results of radioligand binding assay in vitro showed the possibility of direct DHA interaction with cerebrovascular GABA(A) receptors. PMID:25826869

  16. Connections between EM2-containing terminals and GABA/?-opioid receptor co-expressing neurons in the rat spinal trigeminal caudal nucleus

    PubMed Central

    Li, Meng-Ying; Wu, Zhen-Yu; Lu, Ya-Cheng; Yin, Jun-Bin; Wang, Jian; Zhang, Ting; Dong, Yu-Lin; Wang, Feng

    2014-01-01

    Endomorphin-2 (EM2) demonstrates a potent antinociceptive effect via the ?-opioid receptor (MOR). To provide morphological evidence for the pain control effect of EM2, the synaptic connections between EM2-immunoreactive (IR) axonal terminals and ?-amino butyric acid (GABA)/MOR co-expressing neurons in lamina II of the spinal trigeminal caudal nucleus (Vc) were investigated in the rat. Dense EM2-, MOR- and GABA-IR fibers and terminals were mainly observed in lamina II of the Vc. Within lamina II, GABA- and MOR-neuronal cell bodies were also encountered. The results of immunofluorescent histochemical triple-staining showed that approximately 14.2 or 18.9% of GABA-IR or MOR-IR neurons also showed MOR- or GABA-immunopositive staining in lamina II; approximately 45.2 and 36.1% of the GABA-IR and MOR-IR neurons, respectively, expressed FOS protein in their nuclei induced by injecting formalin into the left lower lip of the mouth. Most of the GABA/MOR, GABA/FOS, and MOR/FOS double-labeled neurons made close contacts with EM2-IR fibers and terminals. Immuno-electron microscopy confirmed that the EM2-IR terminals formed synapses with GABA-IR or MOR-IR dendritic processes and neuronal cell bodies in lamina II of the Vc. These results suggest that EM2 might participate in pain transmission and modulation by binding to MOR-IR and GABAergic inhibitory interneuron in lamina II of the Vc to exert inhibitory effect on the excitatory interneuron in lamina II and projection neurons in laminae I and III. PMID:25386121

  17. Contents of Neo-flavored Tea (GABA Kintaro) Containing ?-Aminobutyric Acid

    NASA Astrophysics Data System (ADS)

    Shiraki, Yoshiya

    The contents of ?-aminobutyric acid (GABA), catechins, theaflavins, caffeine and pheophorbide-a in neo-flavored tea (GABA Kintaro tea) were analyzed. 1)The amounts of GABA were increased over 1.5mg/g by means of infrared ray irradiation with agitation treatment. 2)There was a tendency for the amount of catechins to be decreased by this treatment, whereas the amount of theaflavins tended to increase with the same treatment. The composition of these contents in this GABA Kintaro tea was almost the same as that of black tea. 3)There was a tendency for the amount of caffeine to be decreased by this treatment. 4)There was a tendency for the amount of pheophorbide-a to be increased by this treatment. 5)The result of this study showed that the amounts of GABA and theaflavins in this GABA Kintaro tea were higher than ordinary green tea but contained few catechins.It became clear that the amount of pheophorbide-a in this GABA Kintaro tea was less than the standard value established in processed chlorella.

  18. ?-Aminobutyric acid (GABA) homeostasis regulates pollen germination and polarized growth in Picea wilsonii.

    PubMed

    Ling, Yu; Chen, Tong; Jing, Yanping; Fan, Lusheng; Wan, Yinglang; Lin, Jinxing

    2013-11-01

    ?-Aminobutyric acid (GABA) is a four-carbon non-protein amino acid found in a wide range of organisms. Recently, GABA accumulation has been shown to play a role in the stress response and cell growth in angiosperms. However, the effect of GABA deficiency on pollen tube development remains unclear. Here, we demonstrated that specific concentrations of exogenous GABA stimulated pollen tube growth in Picea wilsonii, while an overdose suppressed pollen tube elongation. The germination percentage of pollen grains and morphological variations in pollen tubes responded in a dose-dependent manner to treatment with 3-mercaptopropionic acid (3-MP), a glutamate decarboxylase inhibitor, while the inhibitory effects could be recovered in calcium-containing medium supplemented with GABA. Using immunofluorescence labeling, we found that the actin cables were disorganized in 3-MP treated cells, followed by the transition of endo/exocytosis activating sites from the apex to the whole tube shank. In addition, variations in the deposition of cell wall components were detected upon labeling with JIM5, JIM7, and aniline blue. Our results demonstrated that calcium-dependent GABA signaling regulates pollen germination and polarized tube growth in P. wilsonii by affecting actin filament patterns, vesicle trafficking, and the configuration and distribution of cell wall components. PMID:23900837

  19. Cloning of the. gamma. -aminobutyric acid (GABA). rho. sub 1 cDNA: A GABA receptor subunit highly expressed in the retina

    SciTech Connect

    Cutting, G.R.; Lu, Luo; Kasch, L.M.; Montrose-Rafizadeh, C.; Antonarakis, S.E.; Guggino, W.B.; Kazazian, H.H. Jr. (Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States)); O'Hara, B.F.; Donovan, D.M.; Shimada, Shoichi (National Inst. on Drug Abuse, Baltimore, MD (United States)); Uhl, G.R. (National Inst. on Drug Abuse, Baltimore, MD (United States) Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States))

    1991-04-01

    Type A {gamma}-aminobutyric acid (GABA{sub A}) receptors are a family of ligand-gated chloride channels that are the major inhibitory neurotransmitter receptors in the nervous system. Molecular cloning has revealed diversity in the subunits that compose this heterooligomeric receptor, but each previously elucidated subunit displays amino acid similarity in conserved structural elements. The authors have used these highly conserved regions to identify additional members of this family by using the polymerase chain reaction (PCR). One PCR product was used to isolate a full-length cDNA from a human retina cDNA library. The mature protein predicted from this cDNA sequence is 458 amino acids long and displays between 30 and 38% amino acid similarity to the previously identified GABA{sub A} subunits. This gene is expressed primarily in the retina but transcripts are also detected in the brain, lung, and thymus. Injection of Xenopus oocytes with RNA transcribed in vitro produces a GABA-responsive chloride conductance and expression of the cDNA in COS cells yields GABA-displaceable muscimol binding. These features are consistent with our identification of a GABA subunit, GABA {rho}{sub 1}, with prominent retinal expression that increases the diversity and tissue specificity of this ligand-gated ion-channel receptor family.

  20. Gabapentin increases aminooxyacetic acid-induced GABA accumulation in several regions of rat brain.

    PubMed

    Löscher, W; Hönack, D; Taylor, C P

    1991-07-22

    Gabapentin exerts anticonvulsant effects in different animal models of seizure states and in epileptic patients with different seizure types, but the mechanism of action of these effects is unknown. In the present study, the gamma-aminobutyric acid (GABA) accumulation induced by aminooxyacetic acid (AOAA) was used as a method to study the effects of gabapentin on regional turnover of GABA in the rat brain. Gabapentin was administered at a dose of 23 mg/kg i.p. (the ED95 against tonic electroconvulsions in rats) 1, 2 and 8 h prior to injection of AOAA, 100 mg/kg, i.p. Gabapentin significantly increased the AOAA-induced GABA accumulation in most of the 12 brain regions examined, but the time course of the increases in GABA accumulation differed from region to region. Regions in which the time course of the increase in GABA accumulation was similar to the anticonvulsant time course of gabapentin included substantia nigra, amygdala and thalamus. The data suggest that an effect of gabapentin on GABA synthesis might be involved in its mechanism of anticonvulsant action. PMID:1945036

  1. Neuronal gamma-aminobutyric acid (GABA) type A receptors undergo cognate ligand chaperoning in the endoplasmic reticulum by endogenous GABA

    PubMed Central

    Wang, Ping; Eshaq, Randa S.; Meshul, Charles K.; Moore, Cynthia; Hood, Rebecca L.; Leidenheimer, Nancy J.

    2015-01-01

    GABAA receptors mediate fast inhibitory neurotransmission in the brain. Dysfunction of these receptors is associated with various psychiatric/neurological disorders and drugs targeting this receptor are widely used therapeutic agents. Both the efficacy and plasticity of GABAA receptor-mediated neurotransmission depends on the number of surface GABAA receptors. An understudied aspect of receptor cell surface expression is the post-translational regulation of receptor biogenesis within the endoplasmic reticulum (ER). We have previously shown that exogenous GABA can act as a ligand chaperone of recombinant GABAA receptors in the early secretory pathway leading us to now investigate whether endogenous GABA facilitates the biogenesis of GABAA receptors in primary cerebral cortical cultures. In immunofluorescence labeling experiments, we have determined that neurons expressing surface GABAA receptors contain both GABA and its degradative enzyme GABA transaminase (GABA-T). Treatment of neurons with GABA-T inhibitors, a treatment known to increase intracellular GABA levels, decreases the interaction of the receptor with the ER quality control protein calnexin, concomittantly increasing receptor forward-trafficking and plasma membrane insertion. The effect of GABA-T inhibition on the receptor/calnexin interaction is not due to the activation of surface GABAA or GABAB receptors. Consistent with our hypothesis that GABA acts as a cognate ligand chaperone in the ER, immunogold-labeling of rodent brain slices reveals the presence of GABA within the rough ER. The density of this labeling is similar to that present in mitochondria, the organelle in which GABA is degraded. Lastly, the effect of GABA-T inhibition on the receptor/calnexin interaction was prevented by pretreatment with a GABA transporter inhibitor. Together, these data indicate that endogenous GABA acts in the rough ER as a cognate ligand chaperone to facilitate the biogenesis of neuronal GABAA receptors. PMID:26041994

  2. ?-Aminobutyric acid (GABA) concentration inversely correlates with basal perfusion in human occipital lobe

    PubMed Central

    Donahue, Manus J; Rane, Swati; Hussey, Erin; Mason, Emily; Pradhan, Subechhya; Waddell, Kevin W; Ally, Brandon A

    2014-01-01

    Commonly used neuroimaging approaches in humans exploit hemodynamic or metabolic indicators of brain function. However, fundamental gaps remain in our ability to relate such hemo-metabolic reactivity to neurotransmission, with recent reports providing paradoxical information regarding the relationship among basal perfusion, functional imaging contrast, and neurotransmission in awake humans. Here, sequential magnetic resonance spectroscopy (MRS) measurements of the primary inhibitory neurotransmitter, ?-aminobutyric acid (GABA+macromolecules normalized by the complex N-acetyl aspartate-N-acetyl aspartyl glutamic acid: [GABA+]/[NAA–NAAG]), and magnetic resonance imaging (MRI) measurements of perfusion, fractional gray-matter volume, and arterial arrival time (AAT) are recorded in human visual cortex from a controlled cohort of young adult male volunteers with neurocognitive battery-confirmed comparable cognitive capacity (3?T; n=16; age=23±3 years). Regression analyses reveal an inverse correlation between [GABA+]/[NAA–NAAG] and perfusion (R=?0.46; P=0.037), yet no relationship between AAT and [GABA+]/[NAA–NAAG] (R=?0.12; P=0.33). Perfusion measurements that do not control for AAT variations reveal reduced correlations between [GABA+]/[NAA–NAAG] and perfusion (R=?0.13; P=0.32). These findings largely reconcile contradictory reports between perfusion and inhibitory tone, and underscore the physiologic origins of the growing literature relating functional imaging signals, hemodynamics, and neurotransmission. PMID:24398941

  3. Determination and comparison of ?-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 ?-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. PMID:21395338

  4. Cloning of the gamma-Aminobutyric Acid (GABA) rho_1 cDNA: A GABA Receptor Subunit Highly Expressed in the Retina

    Microsoft Academic Search

    Garry R. Cutting; Luo Lu; Bruce F. O'Hara; Laura M. Kasch; Chahrzad Montrose-Rafizadeh; David M. Donovan; Shoichi Shimada; Stylianos E. Antonarakis; William B. Guggino; George R. Uhl; Haig H. Kazazian Jr.

    1991-01-01

    Type A gamma-aminobutyric acid (GABA_A) receptors are a family of ligand-gated chloride channels that are the major inhibitory neurotransmitter receptors in the nervous system. Molecular cloning has revealed diversity in the subunits that compose this heterooligomeric receptor, but each previously elucidated subunit displays amino acid similarity in conserved structural elements. We have used these highly conserved regions to identify additional

  5. Calpain Cleavage of Brain Glutamic Acid Decarboxylase 65 Is Pathological and Impairs GABA Neurotransmission

    PubMed Central

    Buddhala, Chandana; Suarez, Marjorie; Modi, Jigar; Prentice, Howard; Ma, Zhiyuan; Tao, Rui; Wu, Jang Yen

    2012-01-01

    Previously, we have shown that the GABA synthesizing enzyme, L-glutamic acid decarboxylase 65 (GAD65) is cleaved to form its truncated form (tGAD65) which is 2–3 times more active than the full length form (fGAD65). The enzyme responsible for cleavage was later identified as calpain. Calpain is known to cleave its substrates either under a transient physiological stimulus or upon a sustained pathological insult. However, the precise role of calpain cleavage of fGAD65 is poorly understood. In this communication, we examined the cleavage of fGAD65 under diverse pathological conditions including rats under ischemia/reperfusion insult as well as rat brain synaptosomes and primary neuronal cultures subjected to excessive stimulation with high concentration of KCl. We have shown that the formation of tGAD65 progressively increases with increasing stimulus concentration both in rat brain synaptosomes and primary rat embryo cultures. More importantly, direct cleavage of synaptic vesicle - associated fGAD65 by calpain was demonstrated and the resulting tGAD65 bearing the active site of the enzyme was detached from the synaptic vesicles. Vesicular GABA transport of the newly synthesized GABA was found to be reduced in calpain treated SVs. Furthermore, we also observed that the levels of tGAD65 in the focal cerebral ischemic rat brain tissue increased corresponding to the elevation of local glutamate as indicated by microdialysis. Moreover, the levels of tGAD65 was also proportional to the degree of cell death when the primary neuronal cultures were exposed to high KCl. Based on these observations, we conclude that calpain-mediated cleavage of fGAD65 is pathological, presumably due to decrease in the activity of synaptic vesicle - associated fGAD65 resulting in a decrease in the GABA synthesis - packaging coupling process leading to reduced GABA neurotransmission. PMID:22427928

  6. Synthesis of ?-aminobutyric acid (GABA) by Lactobacillus plantarum DSM19463: functional grape must beverage and dermatological applications

    Microsoft Academic Search

    Raffaella Di Cagno; Francesco Mazzacane; Carlo Giuseppe Rizzello; Maria De Angelis; Giammaria Giuliani; Marisa Meloni; Barbara De Servi; Marco Gobbetti

    2010-01-01

    Agriculture surplus were used as substrates to synthesize ?-aminobutyric acid (GABA) by Lactobacillus plantarum DSM19463 for the manufacture of a functional beverage or as a novel application for dermatological purposes. Dilution of\\u000a the grape must to 1 or 4% (w\\/v) of total carbohydrates favored higher cell yield and synthesis of GABA with respect to whey milk. Optimal conditions for\\u000a synthesizing

  7. Stimulation of GABA-Induced Ca2+ Influx Enhances Maturation of Human Induced Pluripotent Stem Cell-Derived Neurons

    PubMed Central

    Rushton, David J.; Mattis, Virginia B.; Svendsen, Clive N.; Allen, Nicholas D.; Kemp, Paul J.

    2013-01-01

    Optimal use of patient-derived, induced pluripotent stem cells for modeling neuronal diseases is crucially dependent upon the proper physiological maturation of derived neurons. As a strategy to develop defined differentiation protocols that optimize electrophysiological function, we investigated the role of Ca2+ channel regulation by astrocyte conditioned medium in neuronal maturation, using whole-cell patch clamp and Ca2+ imaging. Standard control medium supported basic differentiation of induced pluripotent stem cell-derived neurons, as assayed by the ability to fire simple, single, induced action potentials. In contrast, treatment with astrocyte conditioned medium elicited complex and spontaneous neuronal activity, often with rhythmic and biphasic characteristics. Such augmented spontaneous activity correlated with astrocyte conditioned medium-evoked hyperpolarization and was dependent upon regulated function of L-, N- and R-type Ca2+ channels. The requirement for astrocyte conditioned medium could be substituted by simply supplementing control differentiation medium with high Ca2+ or ?-amino butyric acid (GABA). Importantly, even in the absence of GABA signalling, opening Ca2+ channels directly using Bay K8644 was able to hyperpolarise neurons and enhance excitability, producing fully functional neurons. These data provide mechanistic insight into how secreted astrocyte factors control differentiation and, importantly, suggest that pharmacological modulation of Ca2+ channel function leads to the development of a defined protocol for improved maturation of induced pluripotent stem cell-derived neurons. PMID:24278369

  8. Regulation of ?-aminobutyric acid (GABA) release in cerebral cortex in the ?-hydroxybutyric acid (GHB) model of absence seizures in rat

    Microsoft Academic Search

    R. Q Hu; P. K Banerjee; O. C Snead III

    2000-01-01

    ?-Hydroxybutyric acid (GHB) has the ability to induce absence seizures. The precise way in which GHB causes seizures remains unclear, but GABAB- and\\/or GHB-mediated presynaptic mechanisms within thalamocortical circuitry may play a role. In the present study, we determined the basal and K+-evoked release of GABA and glutamate in the superficial laminae of frontal cortex during GHB-induced absence seizures. Our

  9. Molecular and Therapeutic Potential and Toxicity of Valproic Acid

    PubMed Central

    Chateauvieux, Sébastien; Morceau, Franck; Dicato, Mario; Diederich, Marc

    2010-01-01

    Valproic acid (VPA), a branched short-chain fatty acid, is widely used as an antiepileptic drug and a mood stabilizer. Antiepileptic properties have been attributed to inhibition of Gamma Amino Butyrate (GABA) transaminobutyrate and of ion channels. VPA was recently classified among the Histone Deacetylase Inhibitors, acting directly at the level of gene transcription by inhibiting histone deacetylation and making transcription sites more accessible. VPA is a widely used drug, particularly for children suffering from epilepsy. Due to the increasing number of clinical trials involving VPA, and interesting results obtained, this molecule will be implicated in an increasing number of therapies. However side effects of VPA are substantially described in the literature whereas they are poorly discussed in articles focusing on its therapeutic use. This paper aims to give an overview of the different clinical-trials involving VPA and its side effects encountered during treatment as well as its molecular properties. PMID:20798865

  10. Dopaminergic and GABA-ergic markers of impulsivity in rats: evidence for anatomical localisation in ventral striatum and prefrontal cortex.

    PubMed

    Jupp, Bianca; Caprioli, Daniele; Saigal, Niel; Reverte, Ingrid; Shrestha, Saurav; Cumming, Paul; Everitt, Barry J; Robbins, Trevor W; Dalley, Jeffrey W

    2013-05-01

    Accumulating evidence indicates that impulsivity, in its multiple forms, involves cortical and subcortical mechanisms and abnormal dopamine (DA) transmission. Although decreased DA D2/D3 receptor availability in the nucleus accumbens (NAcb) predicts trait-like impulsivity in rats it is unclear whether this neurochemical marker extends to both the NAcb core (NAcbC) and shell (NAcbS) and whether markers for other neurotransmitter systems implicated in impulsivity such as serotonin (5-HT), endogenous opioids and ?-amino-butyric acid (GABA) are likewise altered in impulsive rats. We therefore used autoradiography to investigate DA transporter (DAT), 5-HT transporter (5-HTT) and D1, D2/D3, ?-opioid and GABA(A) receptor binding in selected regions of the prefrontal cortex and striatum in rats expressing low and high impulsive behaviour on the five-choice serial reaction-time task. High-impulsive (HI) rats exhibited significantly lower binding for DAT and D2/D3 receptors in the NAcbS and for D1 receptors in the NAcbC compared with low-impulsive (LI) rats. HI rats also showed significantly lower GABA(A) receptor binding in the anterior cingulate cortex. For all regions where receptor binding was altered in HI rats, binding was inversely correlated with impulsive responding on task. There were no significant differences in binding for 5-HTT or ?-opioid receptors in any of the regions investigated. These results indicate that altered D2/D3 receptor binding is localised to the NAcbS of trait-like impulsive rats and is accompanied by reduced binding for DAT. Alterations in binding for D1 receptors in the NAcbC and GABA(A) receptors in the anterior cingulate cortex demonstrate additional markers and putative mechanisms underlying the expression of behavioural impulsivity. PMID:23368520

  11. Presence of Gamma-Aminobutyric Acid (Gaba) in the Pedal Mucus of the Critically Endangered Species Patella ferruginea.

    PubMed

    Rivera-Ingraham, G A; Espinosa, F; Krock, B

    2015-05-01

    Patella ferruginea is a giant patellid limpet endemic to the Mediterranean Sea. It presently is in danger of extinction, and many have called for developing conservation measures including the mass production of spats for re-introduction projects. However, so far all attempts have been relatively unsuccessful. Previous work analyzing the effects of gamma-aminobutyric acid (GABA) on the recruitment of patellid limpets has shown that larvae respond to the presence of this signaling molecule. This response could explain the gregarious distribution typical of this species. In the present study, we demonstrated that GABA is naturally secreted by P. ferruginea in the pedal mucus. GABA is preferentially secreted during the summer, coinciding with the reproductive resting period of the species. Further research should aim to analyze the effects of GABA on larval development and metamorphosis in order to assess its potential use to improve conservation efforts. PMID:25902959

  12. Isolation, characterization, and utilization of ?-aminobutyric acid (GABA)-producing lactic acid bacteria from Myanmar fishery products fermented with boiled rice

    Microsoft Academic Search

    Su Myo Thwe; Takeshi Kobayashi; Tianyao Luan; Takaaki Shirai; Munenaka Onodera; Naoko Hamada-Sato; Chiaki Imada

    2011-01-01

    ?-Aminobutyric acid (GABA)-producing lactic acid bacteria (LAB) were isolated from four types of Myanmar traditional fermented\\u000a fishery products with boiled rice. All of them belonged to the genus Lactobacillus, and comparison of the effects of these representatives on GABA accumulation in fermented fishery products with boiled rice\\u000a revealed that Lactobacillus farciminis D323 is the most effective strain as a starter

  13. Exogenous ?-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

    ?-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

  14. 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...

  15. Synthesis and Characterization of N,N-Dichlorinated Amino Acids: Taurine, Homotaurine, GABA and L-Leucine

    Microsoft Academic Search

    N. M. van Gelder; R. J. Bowers

    2001-01-01

    Epilepsy, trauma and other circumstances leading to hyperexcitable conditions in the CNS tend neurochemically to be associated with excessive stimulated release of glutamic acid and\\/or a failure of GABA modulated inhibition. Somewhat to a lesser extent, taurine and its homologue homotaurine, have also been shown to antagonize the excitatory actions of glutamic acid. Here we report the successful synthesis and

  16. Modulation of the ?-aminobutyric acid (GABA) system by Passiflora incarnata L.

    PubMed

    Appel, Kurt; Rose, Thorsten; Fiebich, Bernd; Kammler, Thomas; Hoffmann, Christine; Weiss, Gabriele

    2011-06-01

    Passiflora incarnata L. (Passifloraceae) is important in herbal medicine for treating anxiety or nervousness, Generalized Anxiety Disorder (GAD), symptoms of opiate withdrawal, insomnia, neuralgia, convulsion, spasmodic asthma, ADHD, palpitations, cardiac rhythm abnormalities, hypertension, sexual dysfunction and menopause. However, the mechanism of action is still under discussion. Despite gaps in our understanding of neurophysiological processes, it is increasingly being recognized that dysfunction of the GABA system is implicated in many neuropsychiatric conditions, including anxiety and depressive disorders. Therefore, the in vitro effects of a dry extract of Passiflora incarnata (sole active ingredient in Pascoflair® 425 mg) on the GABA system were investigated. The extract inhibited [(3) H]-GABA uptake into rat cortical synaptosomes but had no effect on GABA release and GABA transaminase activity. Passiflora incarnata inhibited concentration dependently the binding of [(3) H]- SR95531 to GABA(A) -receptors and of [(3) H]-CGP 54626 to GABA(B) -receptors. Using the [(35) S]-GTP?S binding assay Passiflora could be classified as an antagonist of the GABA(B) receptor. In contrast, the ethanol- and the benzodiazepine-site of the GABA(A) -receptor were not affected by this extract. In conclusion, the first evidence was shown that numerous pharmacological effects of Passiflora incarnata are mediated via modulation of the GABA system including affinity to GABA(A) and GABA(B) receptors, and effects on GABA uptake. PMID:21089181

  17. Endogenous kynurenic acid regulates extracellular GABA levels in the rat prefrontal cortex.

    PubMed

    Beggiato, Sarah; Tanganelli, Sergio; Fuxe, Kjell; Antonelli, Tiziana; Schwarcz, Robert; Ferraro, Luca

    2014-07-01

    The tryptophan metabolite kynurenic acid (KYNA) is an endogenous antagonist of the ?7 nicotinic acetylcholine receptor (?7nAChR) and, at higher concentrations, inhibits ionotropic glutamate receptors. Increases in KYNA levels are seen in brain and cerebrospinal fluid in individuals with schizophrenia (SZ) and may be causally related to cognitive deficits in SZ and other psychiatric diseases. As dysfunction of circuits involving GABAergic neurons in the prefrontal cortex (PFC) likely plays a role in the cognitive impairments seen in these disorders, we examined the effects of KYNA on extracellular GABA in this brain area. Applied to awake rats for 2 h by reverse dialysis, KYNA concentration-dependently and reversibly reduced extracellular GABA levels, with 300 nM KYNA causing a nadir of ?45% of baseline concentrations. This effect was not duplicated by reverse dialysis of the selective glycineB receptor antagonist 7-Cl-KYNA (100 nM) or the AMPA/kainate receptor antagonist CNQX (100 ?M), and was prevented by co-application of galantamine (5 ?M), a positive allosteric modulator of the ?7nAChR. Conversely, inhibition of endogenous KYNA formation by reverse dialysis of (S)-4-(ethylsulfonyl)benzoylalanine (ESBA; 5 mM) reversibly increased GABA levels in the PFC, reaching a peak of ?160% of baseline concentrations. Co-infusion of 30 nM KYNA neutralized this effect. Taken together, these results demonstrate a role for endogenous KYNA in the bi-directional control of GABAergic neurotransmission in the PFC. Pharmacological manipulation of KYNA may therefore be useful in the treatment of GABAergic impairments in SZ and other brain disorders involving the PFC. PMID:24607890

  18. Modulatory role of gamma-aminobutyric acid (GABA) in the regulation of gonadotropin secretion in patients with chronic renal failure.

    PubMed

    Elias, A N; Pahl, M; Stone, S; Vaziri, N D; Valenta, L J

    1982-01-01

    The role of gamma-aminobutyric acid (GABA) in the regulation of gonadotropin secretion in renal failure, was studied in 5 patients with chronic renal failure who were on maintenance dialysis. Di-n-propylacetic acid (valproic acid-VA), a GABA-transaminase inhibitor which has been shown to increase brain GABA levels, was used in the study. VA produced no significant change in the basal serum LH and FSH concentrations, or in E2 or T concentrations in the renal failure patients, or the E2 and P concentrations in normal controls, but augmented the delta LH (maximum increment above baseline) and delta FSH response to LH-RH. delta LH rose from 30.4 +/- 12.7 mIU/ml (mean +/- SD) to 41.1 +/- 16.8 mIU/ml (p less than 0.01) after VA, while delta FSH rose from 2.8 +/- 1.8 mIU/ml to 3.8 +/- 1.6 mIU/ml (p less than 0.05). The findings support a modulatory role for GABA in gonadotropin secretion in chronic renal failure. PMID:6802771

  19. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase

    Microsoft Academic Search

    Steinunn Baekkeskov; Henk-Jan Aanstoot; Stephan Christgai; Annette Reetz; Michele Solimena; Marilia Cascalho; Franco Folli; Hanne Richter-Olesen; Pietro-De Camilli

    1990-01-01

    The pancreatic islet beta-cell autoantigen of relative molecular mass 64,000 (64K), which is a major target of autoantibodies associated with the development of insulin-dependent diabetes mel-litus (IDDM) has been identified as glutamic acid decarboxylase, the biosynthesizing enzyme of the inhibitory neurotransmitter GABA (gamma-aminobutyric acid). Pancreatic beta cells and a subpopulation of central nervous system neurons express high levels of this

  20. Synthesis and characterization of N,N-dichlorinated amino acids: taurine, homotaurine, GABA and L-leucine.

    PubMed

    van Gelder, N M; Bowers, R J

    2001-06-01

    Epilepsy, trauma and other circumstances leading to hyperexcitable conditions in the CNS tend neurochemically to be associated with excessive stimulated release of glutamic acid and/or a failure of GABA modulated inhibition. Somewhat to a lesser extent, taurine and its homologue homotaurine, have also been shown to antagonize the excitatory actions of glutamic acid. Here we report the successful synthesis and isolation in pure form of N,N-dichlorinated GABA, taurine, homotaurine and leucine. These compounds are much more lipophilic than their parent compounds and may therefore more readily penetrate the blood-brain barrier systems into the neural tissue, where they can be easily dechlorinated. Very preliminary biological testing shows that this may indeed occur. The synthesis and purification methodology will likely also be applicable to a number of other amino acids as well as certain peptides or selected proteins. PMID:11519717

  1. The GABA Receptors

    Microsoft Academic Search

    S. J. Enna

    ?-Aminobutyric acid (GABA), an amino acid neurotransmitter, is widely distributed throughout the neuraxis. Two pharmacologically\\u000a and molecularly distinct GABA receptors have been identified, GABAA and GABAB. GABAA receptors are pentameric ligand-gated chloride-ion channels, whereas GABAB receptors are heterodimeric G protein-coupled sites. Although GABAA receptor subtypes can display pharmacological differences, the two molecularly distinct GABAB receptors have similar substrate specificities, limiting

  2. Lysophosphatidic Acid Stimulates Neurotransmitter-Like Conductance Changes that Precede GABA and L-Glutamate in Early, Presumptive Cortical Neuroblasts

    Microsoft Academic Search

    Adrienne E. Dubin; Tristram Bahnson; Joshua A. Weiner; Nobuyuki Fukushima; Jerold Chun

    1999-01-01

    During neurogenesis in the embryonic cerebral cortex, the clas- sical neurotransmitters GABA and L-glutamate stimulate ionic conductance changes in ventricular zone (VZ) neuroblasts. Ly- sophosphatidic acid (LPA) is a bioactive phospholipid produc- ing myriad effects on cells including alterations in membrane conductances (for review, see Moolenaar et al., 1995). Devel- opmental expression patterns of its first cloned receptor gene, lpA1

  3. Detection of amino acid neurotransmitters by surface enhanced Raman scattering and hollow core photonic crystal fiber

    NASA Astrophysics Data System (ADS)

    Tiwari, Vidhu S.; Khetani, Altaf; Monfared, Ali Momenpour T.; Smith, Brett; Anis, Hanan; Trudeau, Vance L.

    2012-03-01

    The present work explores the feasibility of using surface enhanced Raman scattering (SERS) for detecting the neurotransmitters such as glutamate (GLU) and gamma-amino butyric acid (GABA). These amino acid neurotransmitters that respectively mediate fast excitatory and inhibitory neurotransmission in the brain, are important for neuroendocrine control, and upsets in their synthesis are also linked to epilepsy. Our SERS-based detection scheme enabled the detection of low amounts of GLU (10-7 M) and GABA (10-4 M). It may complement existing techniques for characterizing such kinds of neurotransmitters that include high-performance liquid chromatography (HPLC) or mass spectrography (MS). This is mainly because SERS has other advantages such as ease of sample preparation, molecular specificity and sensitivity, thus making it potentially applicable to characterization of experimental brain extracts or clinical diagnostic samples of cerebrospinal fluid and saliva. Using hollow core photonic crystal fiber (HC-PCF) further enhanced the Raman signal relative to that in a standard cuvette providing sensitive detection of GLU and GABA in micro-litre volume of aqueous solutions.

  4. Contribution of GABA A and GABA B Receptors to the Discriminative Stimulus Produced by Gamma-Hydroxybutyric Acid

    Microsoft Academic Search

    Carla Lobina; Roberta Agabio; Roberta Reali; Gian Luigi Gessa; Giancarlo Colombo

    1999-01-01

    The present study examined the involvement of GABAA and GABAB receptors in the discriminative stimulus effects of gamma-hydroxybutyric acid (GHB). Rats were trained to discriminate either 300 or 700 mg\\/kg GHB IG from water using a T-maze, food-reinforced drug-discrimination procedure. The direct GABAB agonist, baclofen, substituted completely for both training doses of GHB; its potency to substitute for GHB increased

  5. Allosteric ligands and their binding sites define ?-aminobutyric acid (GABA) type A receptor subtypes.

    PubMed

    Olsen, Richard W

    2015-01-01

    GABAA receptors (GABA(A)Rs) mediate rapid inhibitory transmission in the brain. GABA(A)Rs are ligand-gated chloride ion channel proteins and exist in about a dozen or more heteropentameric subtypes exhibiting variable age and brain regional localization and thus participation in differing brain functions and diseases. GABA(A)Rs are also subject to modulation by several chemotypes of allosteric ligands that help define structure and function, including subtype definition. The channel blocker picrotoxin identified a noncompetitive channel blocker site in GABA(A)Rs. This ligand site is located in the transmembrane channel pore, whereas the GABA agonist site is in the extracellular domain at subunit interfaces, a site useful for low energy coupled conformational changes of the functional channel domain. Two classes of pharmacologically important allosteric modulatory ligand binding sites reside in the extracellular domain at modified agonist sites at other subunit interfaces: the benzodiazepine site and the high-affinity, relevant to intoxication, ethanol site. The benzodiazepine site is specific for certain GABA(A)R subtypes, mainly synaptic, while the ethanol site is found at a modified benzodiazepine site on different, extrasynaptic, subtypes. In the transmembrane domain are allosteric modulatory ligand sites for diverse chemotypes of general anesthetics: the volatile and intravenous agents, barbiturates, etomidate, propofol, long-chain alcohols, and neurosteroids. The last are endogenous positive allosteric modulators. X-ray crystal structures of prokaryotic and invertebrate pentameric ligand-gated ion channels, and the mammalian GABA(A)R protein, allow homology modeling of GABA(A)R subtypes with the various ligand sites located to suggest the structure and function of these proteins and their pharmacological modulation. PMID:25637441

  6. Probing Structural Features and Binding Mode of 3-Arylpyrimidin-2,4-diones within Housefly ?-Aminobutyric Acid (GABA) Receptor

    PubMed Central

    Li, Qinfan; Zhang, Lihui; Ma, Zhi; Kong, Xiangya; Wang, Fangfang; Zhang, Hong; Wang, Yonghua

    2011-01-01

    In order to obtain structural features of 3-arylpyrimidin-2,4-diones emerged as promising inhibitors of insect ?-aminobutyric acid (GABA) receptor, a set of ligand-/receptor-based 3D-QSAR models for 60 derivatives are generated using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA). The statistically optimal CoMSIA model is produced with highest q2 of 0.62, r2ncv of 0.97, and r2pred of 0.95. A minor/bulky electronegative hydrophilic polar substituent at the 1-/6-postion of the uracil ring, and bulky substituents at the 3?-, 4?- and 5?-positions of the benzene ring are beneficial for the enhanced potency of the inhibitors as revealed by the obtained 3D-contour maps. Furthermore, homology modeling, molecular dynamics (MD) simulation and molecular docking are also carried out to gain a better understanding of the probable binding modes of these inhibitors, and the results show that residues Ala-183(C), Thr-187(B), Thr-187(D) and Thr-187(E) in the second transmembrane domains of GABA receptor are responsible for the H-bonding interactions with the inhibitor. The good correlation between docking observations and 3D-QSAR analyses further proves the model reasonability in probing the structural features and the binding mode of 3-arylpyrimidin-2,4-dione derivatives within the housefly GABA receptor. PMID:22016659

  7. Determination of theanine, GABA, and other amino acids in green, oolong, black, and Pu-erh teas with dabsylation and high-performance liquid chromatography.

    PubMed

    Syu, Kai-Yang; Lin, Chih-Li; Huang, Hsiu-Chen; Lin, Jen-Kun

    2008-09-10

    Dabsyl chloride (dimethylaminoazobenzene sulfonyl chloride), a useful chromophoric labeling reagent for amino acids and amines, was developed in this laboratory in 1975. Although several methods have been developed to determine various types of amino acids, a quick and easy method of determining theanine, GABA, and other amino acids has not been developed in one HPLC system. In this paper are analyzed the free amino acid contents of theanine and GABA in different teas (green tea, black tea, oolong tea, Pu-erh tea, and GABA tea) with a dabsylation and reverse phase high-performance liquid chromatography (HPLC) system coupled with a detector at 425 nm absorbance. Two reverse phase columns, Hypersil GOLD and Zorbax ODS, were used and gave different resolutions of dabsyl amino acids in the gradient elution program. The data suggest that the tea source or the steps of tea-making may contribute to the theanine contents variations. High theanine contents of high-mountain tea were observed in both green tea and oolong tea. Furthermore, the raw (natural fermented) Pu-erh tea contained more theanine than ripe (wet fermented) Pu-erh tea, and the GABA contents in normal teas were generally lower than that in GABA tea. PMID:18652476

  8. Effects of intrahypothalamic injections of GABA, muscimol, pentobarbital, and L-glutamic acid on feed intake of satiated sheep.

    PubMed

    Wandji, S A; Seoane, J R; Roberge, A G; Bédard, L; Thibault, L

    1989-01-01

    Five wethers were surgically prepared with cranial implants to study the role of gabaminergic neural pathways on the hypothalamic control of feeding behaviour in ruminants. In the first experiment, the animals were injected (1 microL) with a physiological Tyrode (0.95%) solution, muscimol (0.5 and 1.0 nmol), GABA (0.5 and 1.0 nmol), and L-glutamic acid (0.5 and 1.0 nmol). Feed intake following injections of muscimol (1.0 nmol) and L-glutamic acid (0.5 and 1.0 nmol) was twice as large as that following the Tyrode solution, at 60-min postinjections. These results, however, were not statistically significant (p = 0.12-0.15). In the second experiment, the animals were injected (1 microL) with saline, muscimol (0.8 nmol), L-glutamic acid (0.8 nmol), and pentobarbital (0.26 mumol). Fifteen minutes after the injections, pentobarbital had induced a significant feeding response when compared with control values (p less than 0.01), whereas the effect of L-glutamic acid was not significant. However, 30 min after the injections, feed intake of sheep having received L-glutamic acid was higher than that obtained with the control injections (p less than 0.01). The response to pentobarbital was stronger than that to either muscimol or L-glutamic acid. Histological analyses of brain tissue indicated that injections were performed in the ventromedial hypothalamus of four sheep and in the dorsomedial hypothalamus of the other. The data indicate that L-glutamic acid stimulates feed intake by acting either as a precursor of GABA or by a direct stimulation of glutaminergic neural pathways involved in the control of feed intake. PMID:2565753

  9. Gamma aminobutyric acid B and 5-hydroxy tryptamine 2A receptors functional regulation during enhanced liver cell proliferation by GABA and 5-HT chitosan nanoparticles treatment.

    PubMed

    Shilpa, Joy; Pretty, Mary Abraham; Anitha, Malat; Paulose, Cheramadathikudyil Skaria

    2013-09-01

    Liver is one of the major organs in vertebrates and hepatocytes are damaged by many factors. The liver cell maintenance and multiplication after injury and treatment gained immense interest. The present study investigated the role of Gamma aminobutyric acid (GABA) and serotonin or 5-hydroxytryptamine (5-HT) coupled with chitosan nanoparticles in the functional regulation of Gamma aminobutyric acid B and 5-hydroxy tryptamine 2A receptors mediated cell signaling mechanisms, extend of DNA methylation and superoxide dismutase activity during enhanced liver cell proliferation. Liver injury was achieved by partial hepatectomy of male Wistar rats and the GABA and 5-HT chitosan nanoparticles treatments were given intraperitoneally. The experimental groups were sham operated control (C), partially hepatectomised rats with no treatment (PHNT), partially hepatectomised rats with GABA chitosan nanoparticle (GCNP), 5-HT chitosan nanoparticle (SCNP) and a combination of GABA and 5-HT chitosan nanoparticle (GSCNP) treatments. In GABA and 5-HT chitosan nanoparticle treated group there was a significant decrease (P<0.001) in the receptor expression of Gamma aminobutyric acid B and a significant increase (P<0.001) in the receptor expression of 5-hydroxy tryptamine 2A when compared to PHNT. The cyclic adenosine monophosphate content and its regulatory protein, presence of methylated DNA and superoxide dismutase activity were decreased in GCNP, SCNP and GSCNP when compared to PHNT. The Gamma aminobutyric acid B and 5-hydroxy tryptamine 2A receptors coupled signaling elements played an important role in GABA and 5-HT chitosan nanoparticles induced liver cell proliferation which has therapeutic significance in liver disease management. PMID:23748019

  10. The channel-lining 6? amino acid in the second membrane-spanning region of ionotropic GABA receptors has more profound effects on 4?-ethynyl-4- n -propylbicycloorthobenzoate binding than the 2? amino acid

    Microsoft Academic Search

    Kazutoshi Hisano; Fumiyo Ozoe; Jia Huang; Xiangyu Kong; Yoshihisa Ozoe

    2007-01-01

    The noncompetitive antagonist of ionotropic ?-aminobutyric acid (GABA) receptors 4?-ethynyl-4-n-propylbicycloorthobenzoate (EBOB) is a useful tool to probe the antagonist-binding site. In the present study, four mutants\\u000a of the human GABAA receptor ?3 subunit were stably expressed in S2 cells and examined for their abilities to bind [3H]EBOB to identify the binding site of EBOB. The homo-oligomeric ?3 GABA receptor was

  11. A GABA(B) mystery: the search for pharmacologically distinct GABA(B) receptors.

    PubMed

    Enna, S J

    2001-10-01

    The classification of neurotransmitter receptors into distinct pharmacological subtypes is of major importance in drug discovery. This quest is particularly important for neurotransmitter systems that are widely distributed. Because gamma-aminobutyric acid (GABA) receptors, both GABA(A) and GABA(B), are found throughout the neuroaxis, they are likely involved in all central nervous system functions. Accordingly, the therapeutic promise of GABA(B) receptor manipulation depends upon the identification of subtypes than can be specifically targeted. PMID:14993343

  12. Systematic study of association of four GABAergic genes: glutamic acid decarboxylase 1 gene, glutamic acid decarboxylase 2 gene, GABA(B) receptor 1 gene and GABA(A) receptor subunit beta2 gene, with schizophrenia using a universal DNA microarray.

    PubMed

    Zhao, Xu; Qin, Shengying; Shi, Yongyong; Zhang, Aiping; Zhang, Jing; Bian, Li; Wan, Chunling; Feng, Guoyin; Gu, Niufan; Zhang, Guangqi; He, Guang; He, Lin

    2007-07-01

    Several studies have suggested the dysfunction of the GABAergic system as a risk factor in the pathogenesis of schizophrenia. In the present study, case-control association analysis was conducted in four GABAergic genes: two glutamic acid decarboxylase genes (GAD1 and GAD2), a GABA(A) receptor subunit beta2 gene (GABRB2) and a GABA(B) receptor 1 gene (GABBR1). Using a universal DNA microarray procedure we genotyped a total of 20 SNPs on the above four genes in a study involving 292 patients and 286 controls of Chinese descent. Statistically significant differences were observed in the allelic frequencies of the rs187269C/T polymorphism in the GABRB2 gene (P=0.0450, chi(2)=12.40, OR=1.65) and the -292A/C polymorphism in the GAD1 gene (P=0.0450, chi(2)=14.64 OR=1.77). In addition, using an electrophoretic mobility shift assay (EMSA), we discovered differences in the U251 nuclear protein binding to oligonucleotides representing the -292 SNP on the GAD1 gene, which suggests that the -292C allele has reduced transcription factor binding efficiency compared with the 292A allele. Using the multifactor-dimensionality reduction method (MDR), we found that the interactions among the rs187269C/T polymorphism in the GABRB2 gene, the -243A/G polymorphism in the GAD2 gene and the 27379C/T and 661C/T polymorphisms in the GAD1 gene revealed a significant association with schizophrenia (P<0.001). These findings suggest that the GABRB2 and GAD1 genes alone and the combined effects of the polymorphisms in the four GABAergic system genes may confer susceptibility to the development of schizophrenia in the Chinese population. PMID:17412563

  13. Analysis of ?-aminobutyric acid (GABA) type A receptor subtypes using isosteric and allosteric ligands.

    PubMed

    Olsen, Richard W

    2014-10-01

    The GABAA receptors (GABAARs) play an important role in inhibitory transmission in the brain. The GABAARs could be identified using a medicinal chemistry approach to characterize with a series of chemical structural analogues, some identified in nature, some synthesized, to control the structural conformational rigidity/flexibility so as to define the 'receptor-specific' GABA agonist ligand structure. In addition to the isosteric site ligands, these ligand-gated chloride ion channel proteins exhibited modulation by several chemotypes of allosteric ligands, that help define structure and function. The channel blocker picrotoxin identified a noncompetitive channel blocker site in GABAARs. This ligand site is located in the transmembrane channel pore, whereas the GABA agonist site is in the extracellular domain at subunit interfaces, a site useful for low energy coupled conformational changes of the functional channel domain. Also in the trans-membrane domain are allosteric modulatory ligand sites, mostly positive, for diverse chemotypes with general anesthetic efficacy, namely, the volatile and intravenous agents: barbiturates, etomidate, propofol, long-chain alcohols, and neurosteroids. The last are apparent endogenous positive allosteric modulators of GABAARs. These binding sites depend on the GABAAR heteropentameric subunit composition, i.e., subtypes. Two classes of pharmacologically very important allosteric modulatory ligand binding site reside in the extracellular domain at modified agonist sites at other subunit interfaces: the benzodiazepine site, and the low-dose ethanol site. The benzodiazepine site is specific for certain subunit combination subtypes, mainly synaptically localized. In contrast, the low-dose (high affinity) ethanol site(s) is found at a modified benzodiazepine site on different, extrasynaptic, subtypes. PMID:25015397

  14. Closing the loop on the GABA shunt in plants: are GABA metabolism and signaling entwined?

    PubMed Central

    Michaeli, Simon; Fromm, Hillel

    2015-01-01

    ?-Aminobutyric acid (GABA) is a non-proteinogenic amino acid that is found in uni- and multi-cellular organisms and is involved in many aspects of plant life cycle. GABA metabolism occurs by the action of evolutionary conserved enzymes that constitute the GABA shunt, bypassing two steps of the TCA cycle. The central position of GABA in the interface between plant carbon and nitrogen metabolism is well established. In parallel, there is evidence to support a role for GABA as a signaling molecule in plants. Here we cover some of the recent findings on GABA metabolism and signaling in plants and further suggest that the metabolic and signaling aspects of GABA may actually be inseparable.

  15. Molecular Human Reproduction vol.3 no.8 pp. 677683, 1997 -Aminobutyric acid (GABA) induces the acrosome reaction in

    E-print Network

    Museo Nacional de Ciencias Naturales

    ­Whitten­Whittingham medium with 0.35% bovine serum albumin underwent acrosome reactions in response to GABA, with maximal of enzymes necessary for penetration of the egg vestments, and allows the spermatozoon to fuse

  16. Presynaptic GABA Band ?-hydroxybutyric acid-mediated mechanisms in generalized absence seizures

    Microsoft Academic Search

    O. C. Snead

    1996-01-01

    ?-Hydroxybutyric acid (GHB) is a naturally occurring compound which has the ability to induce generalized absence seizures when given to animals. This effect of GHB may be blocked by either GHB or GABAB receptor antagonists. We sought to test the hypothesis that pre-synaptic GHB- and GABAB-mediated mechanisms in thalamus and cortex are operative in the GHB model of generalized absence

  17. Synthesis and resolution of ?-(aminomethyl)-4-chlorobenzeneethanesulfinic acid a potent gaba B receptor ligand

    Microsoft Academic Search

    Nicholas I. Carruthers; James M. Spitler; Shing-Chun Wong; David J. Blythin; Xiao Chen; Ho-Jane Shue; Stanley Mittelman

    1995-01-01

    The synthesis and resolution of ?-(Aminomethyl)-4-chlorobenzeneethanesulfinic acid together with the GABAB receptor affinity for the racemate and enantiomers is described. In addition the synthesis and GABAB receptor affinity of the enantiomers of the known GABAB antagonist (Saclofen) is reported for the first time

  18. Variations nycthmrales de l'incorporation de l'acide ?-aminobutyrique (GABA) et

    E-print Network

    Paris-Sud XI, Université de

    injected and their concentration both in pineal gland and cerebellum were measured at several times along in the uptake of two neurotransmitters, y-aminobutyric acid (GABAJ and taurine in CD mice. Pineal uptake of two uptake was high during the night, when the gland was active and low during the day. It corresponded

  19. Endogenous GABA Receptor Ligands in Hypophysial Portal Blood

    Microsoft Academic Search

    Rory Mitchell; Grant Grieve; Ron Dow; George Fink

    1983-01-01

    The concentrations of endogenous ?-aminobutyric acid (GABA) receptor ligands were measured in hypophysial portal plasma by a sensitive and specific radioreceptor assay. Portal plasma contained higher concentrations of GABA receptor ligands than peripheral controls, although this increase was not due to authentic GABA but an unknown low-affinity ligand. Evidence is presented to support the hypothesis that the dipeptide homocarnosine may

  20. Structure-activity relationships in a new series of insecticidally active dioxatricycloalkenes derived by structural comparison of the GABA (. gamma. -aminobutyric acid) antagonists bicycloorthocarboxylates and endosulfan

    SciTech Connect

    Ozoe, Yoshihisa; Sawada, Yoshihiro; Mochida, Kazuo; Nakamura, Toshiie (Shimane Univ. (Japan)); Matsumura, Fumio (Univ. of California, Davis (USA))

    1990-05-01

    To study structural requirements for picrotoxinin-type GABA ({gamma}-aminobutyric acid) antagonists to interact with the receptor site, 5-substituted 4,6-dioxatricyclo(7.2.1.0{sup 2,8})dodec-10-enes and related compounds were prepared and examined for their insecticidal activity and potency in displacing ({sup 35}S)tert-butylbicyclophosphorothionate (TBPS) binding. Compounds with high insecticidal activity possessed a phenyl group with an electron-withdrawing para substituent, a cycloalkyl group, or a C{sub 3}-C{sub 5} straight-chain alkyl group at the 5-position. The effect of the 5-substituents on insecticidal activity was very similar to that of the 1-substituents of the bicyloorthocarboxylate GABA antagonists. Representative dioxatricycloalkenes displaced the binding of the GABA antagonist ({sup 35}S)TBPS to housefly head membranes by 29-53% at 10 {mu}M. X-ray crystal structure analysis demonstrated that this class of compounds had structures superimposable on those of 4-tert-butylbicycloorthocarboxylates. These findings indicate that the dioxatricycloalkenes and some other analogues occupy the picrotoxinin binding site in such a way that the fourth interacting subsite of the receptor site accommodates the 5-substituent.

  1. GABA B receptor-mediated increase of neurosteroids by ?-hydroxybutyric acid

    Microsoft Academic Search

    M. L. Barbaccia; G. Colombo; D. Affricano; M. A. M. Carai; G. Vacca; S. Melis; R. H. Purdy; G. L. Gessa

    2002-01-01

    Among the pharmacological actions of ?-hydroxybutyric acid (GHB), some may involve GABAA receptor-mediated mechanisms. GHB, however, fails to directly interact with sites for agonists and modulators on the GABAA receptor complex. We hypothesized that, in vivo, GHB may interfere with GABAA receptor function by altering the brain concentrations of the neurosteroids 3?-hydroxy-5?-pregnan-20-one (allopregnanolone, AP) and 3?,21-dihydroxy-5?-pregnan-20-one (allotetrahydrodeoxycorticosterone, THDOC), positive allosteric

  2. Central effects of 1,4-butanediol are mediated by GABA(B) receptors via its conversion into gamma-hydroxybutyric acid.

    PubMed

    Carai, Mauro A M; Colombo, Giancarlo; Reali, Roberta; Serra, Salvatore; Mocci, Ignazia; Castelli, M Paola; Cignarella, Giorgio; Gessa, Gian Luigi

    2002-04-26

    The aliphatic alcohol 1,4-butanediol in converted into gamma-hydroxybutyric acid (GHB) via two enzymatic steps: first, it is oxidised by alcohol dehydrogenase in gamma-hydroxybutyraldehyde; second, the latter is transformed, likely by aldehyde dehydrogenase, into GHB. Initially, the present study compared the sedative/hypnotic effect of GHB and 1,4-butanediol, measured as loss of righting reflex. 1,4-Butanediol was more potent than GHB, presumably because of a more rapid penetration of the blood brain barrier. Further alcohol dehydrogenase inhibitors, 4-methylpyrazole and ethanol, totally prevented the sedative/hypnotic effect of 1,4-butanediol; the aldehyde dehydrogenase inhibitor disulfiram partially blocked the sedative/hypnotic effect of 1,4-butanediol. Finally, the sedative/hypnotic effect of 1,4-butanediol was antagonised by the GABA(B) receptor antagonists, SCH 50911 [(2S)(+)-5,5-dimethyl-2-morpholineacetic acid] and CGP 46381 [(3-aminopropyl)(cyclohexylmethyl)phosphinic acid], but not by the putative GHB receptor antagonist NCS-382 (6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid), indicating that it is mediated by GABA(B) but not GHB receptors. Taken together, these results suggest that the sedative/hypnotic effect of 1,4-butanediol is mediated by its conversion in vivo into GHB which, in turn, binds to GABA(B) receptors. Accordingly 1,4-butanediol, unlike GHB, failed to displace [(3)H]GHB and [(3)H]baclofen in brain membranes. PMID:12063087

  3. Gamma-aminobutyric acid (GABA) and neuropeptides in neural areas mediating motion-induced emesis

    NASA Technical Reports Server (NTRS)

    Damelio, F.; Daunton, Nancy G.; Fox, Robert A.

    1991-01-01

    Immunocytochemical methods were employed to localize the neurotransmitter amino acid gamma-aminobutyric acid and the neuropeptides substance P and Met-enkephalin in the area postrema (AP), area subpostrema (ASP), nucleus of the tractus solitarius (NTS), dorsal motor nucleus of the vagus nerve (DMNV), and lateral vestibular nucleus (LVN). Glutamic acid decarboxylase immunoreactive (GAD-IR) terminals and fibers were observed in the AP and particularly in the ASP. A gradual decrease in the density of terminals was seen towards the solitary complex. The DMNV revealed irregularly scattered GAD-IR terminals within the neuropil or closely surrounding neuronal cell bodies. The LVN, particularly the dorsal division, showed numerous axon terminals which were mostly localize around large neurons and their proximal dendrites. Substance P immunoreactive (SP-IR) terminals and fibers showed high density in the solitary complex, in particular within the lateral division. The ASP showed medium to low density of SP-IR fibers and terminals. The AP exhibited a small number of fibers and terminals irregularly distributed. The DMNV revealed a high density of SP-IR terminals and fibers that were mainly concentrated in the periphery. Very few terminals were detected in the LVN. Met-enkephalin immunoreactive (Met-Enk-IR) fibers and terminals showed high density and uniform distribution in the DMNV. Scattered terminals and fibers were observed in the AP, ASP, and NTS (particularly the lateral division). The very few fibers were observed in the LVN surrounded the neuronal cell bodies. The present report is part of a study designed to investigate the interaction between neuropeptides and conventional neurotransmitters under conditions producing motion sickness and in the process of sensory-motor adaptation.

  4. Alteration of brain levels of neurotransmitters and amino acids in male F344 rats induced by three-week repeated inhalation exposure to 1-bromopropane.

    PubMed

    Suda, Megumi; Honma, Takeshi; Miyagawa, Muneyuki; Wang, Rui-Sheng

    2008-08-01

    The present study investigated the effects of 1-bromopropane (1BP) on brain neuroactive substances of rats to determine the extent of its toxicity to the central nervous system (CNS). We measured the changes in neurotransmitters (acetylcholine, catecholamine, serotonin and amino acids) and their metabolites or precursors in eight brain regions after inhalation exposure to 1BP at 50 to 1,000 ppm for 8 h per day for 7 d per week for 3 wk. Rats were sacrificed at 2 h (Case 1), or at 19 h (Case 2) after the end of exposure. In Case 1, the level of 5-hydroxyindoleacetic acid (5HIAA) was lowered in some brain regions by 1BP exposure. The decrease of 5HIAA in the frontal cortex was statistically significant at 50 ppm 1BP exposure. In Case 2, gamma-amino butyric acid (GABA) and taurine were decreased in many brain regions of exposed rats, and a significant decrease of taurine in the midbrain occurred at 50 ppm 1BP exposure. In both cases of 2-h and 19-h intervals from the end of exposure to sacrifice, aspartate and glutamine levels were elevated in many brain regions, but the acetylcholine level did not change in any brain region. Three-week repeated exposure to 1BP produced significantly changes in amino acid contents of rat brains, particularly at 1,000 ppm. PMID:18716383

  5. 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…

  6. GABA AND RESPONSES TO GABA IN THE STOMATOGASTRIC GANGLION OF THE CRAB CANCER BOREALIS

    Microsoft Academic Search

    ANDREW M. SWENSEN; JORGE GOLOWASCH; ANDREW E. CHRISTIE; MELISSA J. COLEMAN; MICHAEL P. NUSBAUM; EVE MARDER

    The multifunctional neural circuits in the crustacean stomatogastric ganglion (STG) are influenced by many small-molecule transmitters and neuropeptides that are co- localized in identified projection neurons to the STG. We describe the pattern of ?-aminobutyric acid (GABA) immunoreactivity in the stomatogastric nervous system of the crab Cancer borealis and demonstrate biochemically the presence of authentic GABA in C. borealis. No

  7. Possible ameliorative effects of antioxidants on propionic acid / clindamycin - induced neurotoxicity in Syrian hamsters

    PubMed Central

    2013-01-01

    Background Propionic acid (PA) found in some foods and formed as a metabolic product of gut bacteria has been reported to mimic/mediate the effects of autism. The present study was undertaken to compare the effect of orally administered PA with that of clindamycin-induced PA-microbial producers in inducing persistent biochemical autistic features in hamsters. The neuroprotective potency of carnosine and carnitine supplements against PA toxicity was also investigated. Methods The following groups were studied. 1. Control group, which received phosphate buffered saline orally, 2. Propionic acid treated group which were given PA at a dose of 250 mg/kg body weight/day for 3 days orally, 3. Clindamycin treated group which received a single dose of the antibiotic orogastrically at a dose of 30 mg/kg on the day of the experiment, 4. Carnosine-treated group which were given carnosine at a dose of 10 mg/kg body weight/day orally for one week, 5. Carnitine treated group given 50 mg/kg body weight/day carnitine orally daily for one week. Group 6. Carnosine followed by PA, Group 7. Carnitine followed by PA. Dopamine, adrenaline and noradrenaline, serotonin and Gamma amino-butyric acid (GABA) were measured in the cortex and medulla of the nine studied groups. Results PA administration caused significant decrease in the neurotransmitters in the brains of treated hamsters while clindamycin caused a significant decrease only in dopamine in hamster brains (cortex and medulla) and GABA in the cerebral cortex of the treated hamsters. Administration of carnosine and carnitine which are known antioxidants caused no significant changes in the levels of neurotransmitters when administered alone to hamsters. However when administered with PA both carnosine and carnitine restored the altered neurotransmitters to near normal levels. Conclusion Carnosine and carnitine may be used as supplements to protect against PA neurotoxicity. PMID:24188374

  8. Functional milk beverage fortified with phenolic compounds extracted from olive vegetation water, and fermented with functional lactic acid bacteria.

    PubMed

    Servili, M; Rizzello, C G; Taticchi, A; Esposto, S; Urbani, S; Mazzacane, F; Di Maio, I; Selvaggini, R; Gobbetti, M; Di Cagno, R

    2011-05-14

    Functional milk beverages (FMB100 and FMB200) fortified with phenolic compounds (100 and 200mg/l) extracted from olive vegetable water, and fermented with ?-amino butyric acid (GABA)-producing (Lactobacillus plantarum C48) and autochthonous human gastro-intestinal (Lactobacillus paracasei 15N) lactic acid bacteria were manufactured. A milk beverage (MB), without addition of phenolic compounds, was used as the control. Except for a longer latency phase of FMB200, the three beverages showed an almost similar kinetic of acidification, consumption of lactose and synthesis of lactic acid. Apart from the beverage, Lb. plantarum C48 showed a decrease of ca. Log 2.52-2.24 cfu/ml during storage. The cell density of functional Lb. paracasei 15N remained always above the value of Log 8.0 cfu/ml. During fermentation, the total concentration of free amino acids markedly increased without significant (P > 0.05) differences between beverages. The concentration of GABA increased during fermentation and further storage (63.0 ± 0.6-67.0 ± 2.1mg/l) without significant (P > 0.05) differences between beverages. After fermentation, FMB100 and FMB200 showed the same phenolic composition of the phenol extract from olive vegetable water but a different ratio between 3,4-DHPEA and 3,4-DHPEA-EDA. During storage, the concentrations of 3,4-DHPEA-EDA, p-HPEA and verbascoside of both FMB100 and FMB200 decreased. Only the concentration of 3,4-DHPEA increased. As shown by SPME-GC-MS analysis, diactetyl, acetoin and, especially, acetaldehyde were the main volatile compounds found. The concentration of phenolic compounds does not interfere with the volatile composition. Sensory analyses based on triangle and paired comparison tests showed that phenolic compounds at the concentrations of 100 or 200mg/l were suitable for addition to functional milk beverages. PMID:21458095

  9. Mutations in Plastidial 5-Aminolevulinic Acid Biosynthesis Genes Suppress a Pleiotropic Defect in Shoot Development of a Mitochondrial GABA Shunt Mutant in Arabidopsis.

    PubMed

    Toyokura, Koichi; Yamaguchi, Katsushi; Shigenobu, Shuji; Fukaki, Hidehiro; Tatematsu, Kiyoshi; Okada, Kiyotaka

    2015-06-01

    Plant developmental processes are co-ordinated with the status of cell metabolism, not only in mitochondria but also in plastids. In Arabidopsis thaliana, succinic semialdehyde (SSA), a GABA shunt metabolite, links the specific mitochondrial metabolic pathway to shoot development. To understand the mechanism of SSA-mediated development, we isolated a succinic semialdehyde dehydrogenase (ssadh) suppressor mutant, affected in its ability to catalyze SSA to succinic acid. We found that pleiotropic developmental phenotypes of ssadh are suppressed by a mutation in GLUTAMATE-1-SEMIALDEHYDE 2, 1-AMINOMUTASE 2 (GSA2), which encodes a plastidial enzyme converting glutatamate-1-semialdehyde to 5-aminolevulinic acid (5-ALA). In addition, a mutation in either HEMA1 or GSA1, two other enzymes for 5-ALA synthesis, also suppressed ssadh fully and partially, respectively. Furthermore, exogenous application of 5-ALA and SSA disturbed leaf development. These results suggest that metabolism in both mitochondria and plastids affect shoot development. PMID:25840087

  10. Magnetic resonance spectroscopy studies of GABA in neuropsychiatric disorders.

    PubMed

    Chang, Linda; Cloak, Christine C; Ernst, Thomas

    2003-01-01

    Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system and is integral to managing brain excitability. GABA concentrations vary according to age, gender, and brain region. Magnetic resonance spectroscopy (MRS), with editing or with localized 2-dimensional chemical shift methods, can measure GABA levels in vivo, ex vivo, or in vitro, particularly at ultra-high magnetic field strengths. Proton ((1)H) MRS studies have found reduced or abnormal GABA concentrations in several neuropsychiatric disorders, including epilepsy, anxiety disorders, major depression, and drug addiction. Disorders with low GABA levels may be treated by augmentation of GABAergic function, such as by medications that block the degradation or reuptake of GABA. Examples of such a rational therapeutic approach include anticonvulsants that elevate brain GABA levels and are effective for the treatment of epilepsy and anxiety disorder. PMID:12662128

  11. GABA (?-aminobutyric acid), a non-protein amino acid counters the ?-adrenergic cascade-activated oncogenic signaling in pancreatic cancer: a review of experimental evidence.

    PubMed

    Al-Wadei, Hussein A N; Ullah, Mohammad F; Al-Wadei, Mohammed

    2011-12-01

    GABA is a bioactive constituent of fruits, vegetables, cereals and is believed to play a role in defense against stress in plants. In animals, it acts as an inhibitory neurotransmitter in brain while also expressed in non-neuronal cells. Studies have implicated the regulator of fight or flight stress responses, ?-AR signaling cascade, as mediators of cancer growth and progression in in vitro and in vivo models of pancreatic malignancies. Pancreatic cancer is the fourth leading cause of cancer mortality in western countries. This malignancy is generally unresponsive to conventional radio- and chemotherapy, resulting in mortality rate near 100% within 6 months of diagnosis. We review a series of experiments from our laboratory and those of others examining the contribution of this signaling network to pancreatic and other human malignancies. Stimulation of the ?-adrenergic receptor by lifestyle and environmental factors, as well as a pre-existing risk of neoplasm, activates downstream effector molecules that lead to pro-oncogenic signaling and thereby aid cancer growth. GABAergic signaling mediated by the serpentine receptor GABA(B) acts as an antagonist to ?-adrenergic cascade by intercepting adenylyl cyclase. These evidences enhance the pharmacological value of human diets rich in GABA for use as an adjuvant to standard therapies. PMID:21805621

  12. Development and Validation of a HPTLC Method for Simultaneous Estimation of L-Glutamic Acid and ?-Aminobutyric Acid in Mice Brain.

    PubMed

    Sancheti, J S; Shaikh, M F; Khatwani, P F; Kulkarni, Savita R; Sathaye, Sadhana

    2013-11-01

    A new robust, simple and economic high performance thin layer chromatographic method was developed for simultaneous estimation of L-glutamic acid and ?-amino butyric acid in brain homogenate. The high performance thin layer chromatographic separation of these amino acid was achieved using n-butanol:glacial acetic acid:water (22:3:5 v/v/v) as mobile phase and ninhydrin as a derivatising agent. Quantitation of the method was achieved by densitometric method at 550 nm over the concentration range of 10-100 ng/spot. This method showed good separation of amino acids in the brain homogenate with Rf value of L-glutamic acid and ?-amino butyric acid as 21.67±0.58 and 33.67±0.58, respectively. The limit of detection and limit of quantification for L-glutamic acid was found to be 10 and 20 ng and for ?-amino butyric acid it was 4 and 10 ng, respectively. The method was also validated in terms of accuracy, precision and repeatability. The developed method was found to be precise and accurate with good reproducibility and shows promising applicability for studying pathological status of disease and therapeutic significance of drug treatment. PMID:24591747

  13. Characteristic Expressions of GABA Receptors and GABA Producing/Transporting Molecules in Rat Kidney

    PubMed Central

    Takano, Kozue; Yatabe, Midori Sasaki; Abe, Asami; Suzuki, Yu; Sanada, Hironobu; Watanabe, Tsuyoshi; Kimura, Junko; Yatabe, Junichi

    2014-01-01

    Gamma-aminobutyric acid (GABA) is an important neurotransmitter, but recent reports have revealed the expression of GABAergic components in peripheral, non-neural tissues. GABA administration induces natriuresis and lowers blood pressure, suggesting renal GABA targets. However, systematic evaluation of renal GABAergic components has not been reported. In this study, kidney cortices of Wistar-Kyoto rats (WKY) were used to assay for messenger RNAs of GABA-related molecules using RT-PCR. In WKY kidney cortex, GABAA receptor subunits, ?1, ?3, ?, ? and ?, in addition to both types of GABAB receptors, R1 and R2, and GABAC receptor ?1 and ?2 subunit mRNAs were detected. Kidney cortex also expressed mRNAs of glutamate decarboxylase (GAD) 65, GAD67, 4-aminobutyrate aminotransferase and GABA transporter, GAT2. Western blot and/or immunohistochemistry were performed for those molecules detected by RT-PCR. By immunofluorescent observation, co-staining of ?1, ?3, and ? subunits was observed mainly on the apical side of cortical tubules, and immunoblot of kidney protein precipitated with ? subunit antibody revealed ?1 and ?3 subunit co-assembly. This is the first report of GABAA receptor ? subunit in the kidney. In summary, unique set of GABA receptor subunits and subtypes were found in rat kidney cortex. As GABA producing enzymes, transporters and degrading enzyme were also detected, a possible existence of local renal GABAergic system with an autocrine/paracrine mechanism is suggested. PMID:25188493

  14. The effect of GABA receptor ligands in experimental spina bifida occulta

    Microsoft Academic Search

    Wayne Briner

    2001-01-01

    BACKGROUND: The pathophysiology behind spina bifida and other neural tube defects (NTDs) is unclear. Folic acid is one variable, but other factors remain. Studies suggest that substances active at the GABA receptor may produce NTDs. To test this hypothesis pregnant rats were exposed to either the GABA a agonist muscimol (1, 2 or 4 mg\\/kg), the GABA a antagonist bicuculline

  15. Lens GABA receptors are a target of GABA-related agonists that mitigate experimental myopia.

    PubMed

    Frederikse, Peter H; Kasinathan, Chinnaswamy

    2015-06-01

    Coordinated growth of eye tissues is required to achieve visual acuity. However, visual experience also guides this process. Experimental myopia can be produced by altering light entering the eye, but also by changing light/dark regimens. Drug discovery studies demonstrated that ?-aminobutyric acid (GABA)-related agonists (e.g., baclofen) will mitigate experimental myopia, and are also drugs studied for their capacity to affect neurodevelopmental disorders that include Fragile X Syndrome and related autism spectrum disorders. GABA receptors thought to mediate these responses in the eye have been studied in the neural retina as well as the cornea and sclera which are both innervated tissues. In addition to neurons, lenses express GAD25/65/67 GABA metabolic enzymes and at least 13 GABA receptor subunits with developmental expression profiles that match neural development. Evidence that lens GABA receptors are expressed in a cell environment comparable to neurons is seen in the lens expression of AMPA and NMDA glutamate receptors together with an unexpectedly comprehensive array of associated signaling proteins that include post-synaptic-density 95 (PSD95), calcium calmodulin kinase II? (CaMKII?), Fragile X Syndrome mental retardation protein (FMRP), ephrin receptors, Ca(V)1.2, 1.3 channels, cyclin-dependent kinase 5 (Cdk5), and neuronal C-src among others. Moreover, lens cells share fundamental molecular regulatory mechanisms that integrate the regulation and function of these genes at the DNA, RNA, and protein levels in neurons. GABA has trophic, growth promoting effects early in neuron development and later assumes its classic inhibitory role in the adult neural system. We hypothesize that the extensive parallels between GABA and glutamate receptor biology in lens and brain identifies the lens as a site of GABA agonist drug action affecting experimental myopia, acting through lens GABA receptors to similarly affect growth in both elongated cell types. PMID:25841296

  16. UNIVERSITE PARIS-SUD 11 UFR SCIENTIFIQUE D'ORSAY

    E-print Network

    Paris-Sud XI, Université de

    Carrier Protein ADN Acide Désoxyribonucléique ADN-T ADN-Transfert ARN Acide Ribonucléique At Agrobacterium tumefaciens DNA Deoxyribonucleic Acid GABA Gamma-Amino Butyric Acid GBL Gamma-Butyro Lactone GHB Gamma-Hydroxy Butyrate Kd Constante de dissociation (dissociation constant) Mb Megabase OC6HSL 3-oxo

  17. A practical guide to robust detection of GABA in human brain by J-difference spectroscopy at 3 T using a standard volume coil

    Microsoft Academic Search

    Kevin W. Waddell; Malcolm J. Avison; James M. Joers; John C. Gore

    2007-01-01

    ?-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in human brain and has been implicated in several neuropsychiatric disorders. In vivo human brain GABA concentrations are near the detection limit for magnetic resonance spectroscopy (?1 mM), and because of overlap with more abundant compounds, spectral editing is generally necessary to detect GABA. In previous reports, GABA spectra edited by J-difference

  18. Neurochemical correlates of. gamma. -aminobutyrate (GABA) inhibition in cat visual cortex

    SciTech Connect

    Balcar, V.J.; Dreher, B. (Univ. of Sydney (Australia))

    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 and 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.

  19. Cloning and expression of the UGA4 gene coding for the inducible GABA-specific transport protein of Saccharomyces cerevisiae

    Microsoft Academic Search

    Bruno André; Claudine Hein; Marcelle Grenson; Jean-Claude Jauniaux

    1993-01-01

    Transport of 4-aminobutyric acid (GABA) in Saccharomyces cerevisiae is mediated by three transport systems: the general amino acid permease (GAP1 gene), the proline permease (PUT4 gene), and a specific GABA permease (UGA4 gene) which is induced in the presence of GABA. The UGA4 gene encoding the inducible GABA-specific transporter was cloned and sequenced and its expression analyzed. The predicted amino

  20. Therapeutic potential of GABA(B) receptor ligands in drug addiction, anxiety, depression and other CNS disorders.

    PubMed

    Kumar, Kushal; Sharma, Sorabh; Kumar, Puneet; Deshmukh, Rahul

    2013-09-01

    Glutamate and ?-aminobutyric acid (GABA) are the major excitatory and inhibitory neurotransmitter systems, respectively in the central nervous system (CNS). Dysregulation, in any of these or both, has been implicated in various CNS disorders. GABA acts via ionotropic (GABA(A) and GABA(C) receptor) and metabotropic (GABA(B)) receptor. Dysregulation of GABAergic signaling and alteration in GABA(B) receptor expression has been implicated in various CNS disorders. Clinically, baclofen-a GABA(B) receptor agonist is available for the treatment of spasticity, dystonia etc., associated with various neurological disorders. Moreover, GABAB receptor ligands has also been suggested to be beneficial in various neuropsychiatric and neurodegenerative disorders. The present review is aimed to discuss the role of GABA(B) receptors and the possible outcomes of GABA(B) receptor modulation in CNS disorders. PMID:23872369

  1. Glutamate Uptake Triggers Transporter-Mediated GABA Release from Astrocytes

    PubMed Central

    Héja, László; Barabás, Péter; Nyitrai, Gabriella; Kékesi, Katalin A.; Lasztóczi, Bálint; T?ke, Orsolya; Tárkányi, Gábor; Madsen, Karsten; Schousboe, Arne; Dobolyi, Árpád; Palkovits, Miklós; Kardos, Julianna

    2009-01-01

    Background Glutamate (Glu) and ?-aminobutyric acid (GABA) transporters play important roles in regulating neuronal activity. Glu is removed from the extracellular space dominantly by glial transporters. In contrast, GABA is mainly taken up by neurons. However, the glial GABA transporter subtypes share their localization with the Glu transporters and their expression is confined to the same subpopulation of astrocytes, raising the possibility of cooperation between Glu and GABA transport processes. Methodology/Principal Findings Here we used diverse biological models both in vitro and in vivo to explore the interplay between these processes. We found that removal of Glu by astrocytic transporters triggers an elevation in the extracellular level of GABA. This coupling between excitatory and inhibitory signaling was found to be independent of Glu receptor-mediated depolarization, external presence of Ca2+ and glutamate decarboxylase activity. It was abolished in the presence of non-transportable blockers of glial Glu or GABA transporters, suggesting that the concerted action of these transporters underlies the process. Conclusions/Significance Our results suggest that activation of Glu transporters results in GABA release through reversal of glial GABA transporters. This transporter-mediated interplay represents a direct link between inhibitory and excitatory neurotransmission and may function as a negative feedback combating intense excitation in pathological conditions such as epilepsy or ischemia. PMID:19777062

  2. GABA Predicts Time Perception

    PubMed Central

    Russo, Sonia; Near, Jamie; Stagg, Charlotte J.; Cohen Kadosh, Roi

    2014-01-01

    Our perception of time constrains our experience of the world and exerts a pivotal influence over a myriad array of cognitive and motor functions. There is emerging evidence that the perceived duration of subsecond intervals is driven by sensory-specific neural activity in human and nonhuman animals, but the mechanisms underlying individual differences in time perception remain elusive. We tested the hypothesis that elevated visual cortex GABA impairs the coding of particular visual stimuli, resulting in a dampening of visual processing and concomitant positive time-order error (relative underestimation) in the perceived duration of subsecond visual intervals. Participants completed psychophysical tasks measuring visual interval discrimination and temporal reproduction and we measured in vivo resting state GABA in visual cortex using magnetic resonance spectroscopy. Time-order error selectively correlated with GABA concentrations in visual cortex, with elevated GABA associated with a rightward horizontal shift in psychometric functions, reflecting a positive time-order error (relative underestimation). These results demonstrate anatomical, neurochemical, and task specificity and suggest that visual cortex GABA contributes to individual differences in time perception. PMID:24647956

  3. Edited Magnetic Resonance Spectroscopy Detects an Age-related Decline in Brain GABA Levels

    PubMed Central

    Gao, Fei; Edden, Richard A.E.; Li, Muwei; Puts, Nicolaas A.J.; Wang, Guangbin; Liu, Cheng; Zhao, Bin; Wang, Huiquan; Bai, Xue; Zhao, Chen; Wang, Xin; Barker, Peter B.

    2013-01-01

    Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain. Although measurements of GABA levels in vivo in the human brain using edited proton magnetic resonance spectroscopy (1H-MRS) have been established for some time, it is has not been established how regional GABA levels vary with age in the normal human brain. In this study, 49 healthy men and 51 healthy women aged between 20 and 76 years were recruited and J-difference edited spectra were recorded at 3 Tesla to determine the effect of age on GABA levels, and to investigate whether there are regional and gender differences in GABA in mesial frontal and parietal regions. Because the signal detected at 3.02 ppm using these experimental parameters is also expected to contain contributions from both macromolecules (MM) and homocarnosine, in this study the signal is labeled GABA+ rather than GABA. Significant negative correlations were observed between age and GABA+ in both regions studied (GABA+/Cr: frontal region, r = -0.68, p< 0.001, parietal region, r = -0.54, p< 0.001; GABA+/NAA: frontal region, r = -0.58, p< 0.001, parietal region, r = -0.49, p< 0.001). The decrease in GABA+ with age in the frontal region was more rapid in women than men. Evidence of a measureable decline in GABA is important in considering the neurochemical basis of the cognitive decline that is associated with normal aging. PMID:23587685

  4. GABA Acts as a Ligand Chaperone in the Early Secretory Pathway to Promote Cell Surface Expression of GABAA Receptors

    PubMed Central

    Eshaq, Randa S.; Stahl, Letha D.; Stone, Randolph; Smith, Sheryl S.; Robinson, Lucy C.; Leidenheimer, Nancy J.

    2010-01-01

    GABA (?-aminobutyric acid) is the primary inhibitory neurotransmitter in brain. The fast inhibitory effect of GABA is mediated through the GABAA receptor, a postsynaptic ligand-gated chloride channel. We propose that GABA can act as a ligand chaperone in the early secretory pathway to facilitate GABAA receptor cell surface expression. Forty-two hrs of GABA treatment increased the surface expression of recombinant receptors expressed in HEK 293 cells, an effect accompanied by an increase in GABA-gated chloride currents. In time-course experiments, a 1 hr GABA exposure, followed by a 5 hr incubation in GABA-free medium, was sufficient to increase receptor surface expression. A shorter GABA exposure could be used in HEK 293 cells stably transfected with the GABA transporter GAT-1. In rGAT-1HEK 293 cells, the GABA effect was blocked by the GAT-1 inhibitor NO-711, indicating that GABA was acting intracellularly. The effect of GABA was prevented by brefeldin A (BFA), an inhibitor of early secretory pathway trafficking. Coexpression of GABAA receptors with the GABA synthetic enzyme glutamic acid decarboxylase 67 (GAD67) also resulted in an increase in receptor surface levels. GABA treatment failed to promote the surface expression of GABA binding site mutant receptors, which themselves were poorly expressed at the surface. Consistent with an intracellular action of GABA, we show that GABA does not act by stabilizing surface receptors. Furthermore, GABA treatment rescued the surface expression of a receptor construct that was retained within the secretory pathway. Lastly, the lipophilic competitive antagonist (+)bicuculline promoted receptor surface expression, including the rescue of an secretory pathway-retained receptor. Our results indicate that a neurotransmitter can act as a ligand chaperone in the early secretory pathway to regulate the surface expression of its receptor. This effect appears to rely on binding site occupancy, rather than agonist-induced structural changes, since chaperoning is observed with both an agonist and a competitive antagonist. PMID:20580636

  5. Effect of experimental diabetes on GABA-mediated inhibition of neurally induced contractions in rat isolated trachea.

    PubMed

    Ozdem, S S; Sadan, G; Usta, C; Ta?atargil, A

    2000-04-01

    1. In the present study, we investigated the effect of GABA and selective GABA agonists and antagonists on neurally induced tracheal contractions in streptozotocin (STZ) diabetic rats. 2. Contractile responses to electrical field stimulation (EFS) in rat tracheal rings were completely abolished by atropine and tetrodotoxin, but were unaffected by the ganglion blocker hexamethonium, indicating that they were mediated via neuronal release of acetylcholine (ACh). 3. Contractions induced by EFS, but not by exogenous ACh, were inhibited by GABA and the selective GABA(B) receptor agonist baclofen, but not by the selective GABA(A) receptor agonist 3-aminopropane sulphonic acid. The inhibitory effects of GABA or baclofen were not affected by the GABA(A) antagonist bicuculline, but were significantly reversed by the GABA(B) antagonist phaclofen. 4. The inhibitory effects of both GABA and baclofen were found to be significantly greater in trachea from control rats compared with tissues from diabetic rats. 5. Non-adrenergic, non-cholinergic relaxation responses elicited by EFS in precontracted tracheal rings from diabetic and control rats were similar in magnitude and were unaffected by GABA or GABA analogues. 6. These results suggest that GABA decreases the response to EFS by directly inhibiting the evoked release of ACh through GABA(B) receptors in rat trachea and that STZ-induced diabetes causes an impairment in the inhibitory effect of GABA on neurally induced contractions in this tissue. PMID:10779129

  6. Light and electron microscopic immunohistochemical demonstration of GABA-immunoreactive astrocytes in the brain stem of the rat

    Microsoft Academic Search

    Anders Blomqvist; Jonas Broman

    1988-01-01

    Summary An antiserum against ?-aminobutyric acid (GABA) was used in an immunohistochemical investigation of the nature of GABA-immunoreactive profiles in various regions of the brain stem of the rat. In accordance with findings in previous biochemical studies, but at discrepancy with recent immunohistochemical results, GABA-like immunoreactivity was demonstrated not only in neurons but also in glial cells. Electron microscopy revealed

  7. Mapping convulsants' binding to the GABA-A receptor chloride ionophore: A proposed model for channel binding sites

    E-print Network

    Kalueff, Allan V.

    Mapping convulsants' binding to the GABA-A receptor chloride ionophore: A proposed model Abstract Gamma-aminobutyric acid (GABA) type A receptors play a key role in brain inhibitory (5-HT3) and N-acetylcholine receptors by GABA-A channel blockers, and examine the applicability

  8. 3H-GABA uptake selectively labels identifiable neurons in the leech central nervous system

    SciTech Connect

    Cline, H.T.

    1983-04-10

    Segmental ganglia of the leech ventral nerve cord synthesize the neurotransmitter gamma-aminobutyric acid (GABA) when incubated in the presence of the precursor glutamate, suggesting that there may be GABA-ergic neurons in the leech nerve cord. GABA-accumulating neurons of the two taxonomically distant leech species, Haementeria ghilianii and Hirudo medicinalis, have been labeled by taking advantage of their high-affinity uptake system for the neurotransmitter. Autoradiography of sectioned segmental ganglia previously exposed to 3H-GABA reveals a reproducible pattern of about thirty 3H-GABA-labeled neuronal cell bodies per ganglion. The majority of 3H-GABA-labeled neuronal cell bodies are bilaterally paired, although some apparently unpaired cell bodies also accumulate label. Neuronal processes were reproducibly labeled by GABA uptake and could be traced in the neuropil through commissures and fiber tracts into the segmental nerve roots and interganglionic connectives, respectively.

  9. A Gut Feeling about GABA: Focus on GABAB Receptors

    PubMed Central

    Hyland, Niall P.; Cryan, John F.

    2010-01-01

    ?-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the body and hence GABA-mediated neurotransmission regulates many physiological functions, including those in the gastrointestinal (GI) tract. GABA is located throughout the GI tract and is found in enteric nerves as well as in endocrine-like cells, implicating GABA as both a neurotransmitter and an endocrine mediator influencing GI function. GABA mediates its effects via GABA receptors which are either ionotropic GABAA or metabotropic GABAB. The latter which respond to the agonist baclofen have been least characterized, however accumulating data suggest that they play a key role in GI function in health and disease. Like GABA, GABAB receptors have been detected throughout the gut of several species in the enteric nervous system, muscle, epithelial layers as well as on endocrine-like cells. Such widespread distribution of this metabotropic GABA receptor is consistent with its significant modulatory role over intestinal motility, gastric emptying, gastric acid secretion, transient lower esophageal sphincter relaxation and visceral sensation of painful colonic stimuli. More intriguing findings, the mechanisms underlying which have yet to be determined, suggest GABAB receptors inhibit GI carcinogenesis and tumor growth. Therefore, the diversity of GI functions regulated by GABAB receptors makes it a potentially useful target in the treatment of several GI disorders. In light of the development of novel compounds such as peripherally acting GABAB receptor agonists, positive allosteric modulators of the GABAB receptor and GABA producing enteric bacteria, we review and summarize current knowledge on the function of GABAB receptors within the GI tract. PMID:21833169

  10. GABA heteroreceptors modulate noradrenaline release in human dental pulp.

    PubMed

    Parker, D A S; Marino, V

    2013-11-01

    ?-aminobutyric-acid-containing neurons and GABA(B) receptors have been identified in human dental pulp; however, their significance in pulpal physiology is unclear. The purpose of this study was to determine whether pre-synaptic GABAergic heteroreceptors influence the release of noradrenaline (NA). Segments of vital pulp were incubated in [(3)H]NA (0.6 ?M) and superfused with Krebs solution. GABA, a GABA(B) receptor agonist (baclofen), GABA(A and B) receptor antagonists [bicuculline and (+)-(S)-5, 5-dimethylmorpholinyl-2-acetic acid (Sch 50911), respectively], and a GABA(A) receptor-mediated Cl(-) channel inhibitor (picrotoxin) were added to the superfusion medium at least 10 min prior to the second period of stimulation (S2). Sympathetic nerves were stimulated electrically after 70 (S1) and 115 (S2) min. We determined the effects of agonists/antagonists by comparing the overflow of [(3)H]NA at S2 with that at S1 in the presence and absence of the compound. Baclofen (3 µM) inhibited the release of [(3)H]NA (IC50 = 2 µM), an action reversed by Sch 50911 (10 µM). GABA (100 µM) inhibited the release of [(3)H]NA (IC50 = 75 µM), an effect reversed by Sch 50911 (10 µM) but not by bicuculline (10 µM). However, picrotoxin (100 µM) prevented the inhibitory action of GABA. GABA(B) and GABA(A) heteroceptors mediate the release of NA from sympathetic nerves in human dental pulp in vitro. PMID:24056226

  11. Anxiolytic activity of a brain delivery system for GABA

    Microsoft Academic Search

    W. R. Anderson; J. W. Simpkins; P. A. Woodard; D. Winwood; W. C. Stern; N. Bodor

    1987-01-01

    We evaluated the anxiolytic property of a brain-specific gamma-aminobutyric acid delivery system (GABA-CDS) in male rats by means of a drink-foot shock conflict procedure. Brain-specific delivery of the active compound was achieved by combination of GABA benzyl ester with an interconvertible dihydropyridine?pyridinium salt carrier, which is “locked in” to the brain upon its oxidation. Pharmacokinetic studies revealed that the hydrophilic

  12. Taurine and GABA release from mouse cerebral cortex slices: Effects of structural analogues and drugs

    Microsoft Academic Search

    Pirjo Kontro; Simo S. Oja

    1987-01-01

    The effects of structural analogues, excitatory amino acids and certain drugs on spontaneous and potassium-stimulated exogenous taurine and GABA release were investigated in mouse cerebral cortex slices using a superfusion system. Spontaneous efflux of both amino acids was rather slow but could be enhanced by their uptake inhibitors. Taurine efflux was facilitated by exogenous taurine, hypotaurine, ß-alanine and GABA, whereas

  13. Insights into GABA receptor signalling in TM3 Leydig cells.

    PubMed

    Doepner, Richard F G; Geigerseder, Christof; Frungieri, Monica B; Gonzalez-Calvar, Silvia I; Calandra, Ricardo S; Raemsch, Romi; Fohr, Karl; Kunz, Lars; Mayerhofer, Artur

    2005-01-01

    Gamma-aminobutyric acid (GABA) is an emerging signalling molecule in endocrine organs, since it is produced by endocrine cells and acts via GABA(A) receptors in a paracrine/autocrine fashion. Testicular Leydig cells are producers and targets for GABA. These cells express GABA(A) receptor subunits and in the murine Leydig cell line TM3 pharmacological activation leads to increased proliferation. The signalling pathway of GABA in these cells is not known in this study. We therefore attempted to elucidate details of GABA(A) signalling in TM3 and adult mouse Leydig cells using several experimental approaches. TM3 cells not only express GABA(A )receptor subunits, but also bind the GABA agonist [(3)H]muscimol with a binding affinity in the range reported for other endocrine cells (K(d) = 2.740 +/- 0.721 nM). However, they exhibit a low B(max) value of 28.08 fmol/mg protein. Typical GABA(A) receptor-associated events, including Cl(-) currents, changes in resting membrane potential, intracellular Ca(2+) or cAMP, were not measurable with the methods employed in TM3 cells, or, as studied in part, in primary mouse Leydig cells. GABA or GABA(A) agonist isoguvacine treatment resulted in increased or decreased levels of several mRNAs, including transcription factors (c-fos, hsf-1, egr-1) and cell cycle-associated genes (Cdk2, cyclin D1). In an attempt to verify the cDNA array results and because egr-1 was recently implied in Leydig cell development, we further studied this factor. RT-PCR and Western blotting confirmed a time-dependent regulation of egr-1 in TM3. In the postnatal testis egr-1 was seen in cytoplasmic and nuclear locations of developing Leydig cells, which bear GABA(A) receptors and correspond well to TM3 cells. Thus, GABA acts via an atypical novel signalling pathway in TM3 cells. Further details of this pathway remain to be elucidated. PMID:16276116

  14. P2 receptor web: Complexity and fine-tuning Cinzia Volont a,, Susanna Amadio a

    E-print Network

    Burnstock, Geoffrey

    here that while decoding the inputs of various related extracellular ligands, P2 receptors are a clear2Y receptors; they have very heterogeneous ligands and binding characteristics, molecular properties-coupled receptors; GABA, - amino butyric acid; 5-HT, 5-hydroxytryptamine; IP3, inositol triphosphate; ,-me

  15. Relation of the [ 3H]?-hydroxybutyric acid (ghb) binding site to the ?-aminobutyric acid b (gaba b) receptor in rat brain

    Microsoft Academic Search

    O. Carter Snead

    1996-01-01

    Hydroxybutyric acid (GHB) is a naturally occurring compound that has the ability to induce generalized absence seizures when given to animals. GHB has been hypothesized to induce this effect via the postsynaptic ?-aminobutyric acidB (GABAB) receptor. We sought to test this hypothesis by examining the affinity of GABAB agonists and antagonists for the [3H]GHB binding site, the affinity of GHB

  16. Expression and Functional Characterization of GABA Transporters in Crayfish Neurosecretory Cells

    Microsoft Academic Search

    Julieta Garduno; Sergio Elenes; Jorge Cebada; Elizabeth Becerra; Ubaldo Garcia

    2002-01-01

    The effect of GABA on membrane potential and ionic cur- rents of X-organ neurons isolated from the crayfish eyestalk was investigated. Under voltage-clamp conditions, GABA elicited an inward Na current followed by a sustained out- ward chloride current. Sodium current was partially blocked in a dose-dependent manner by antagonists of GABA plasma membrane transporters such as -alanine, nipecotic acid, 1-(2(((diphenylmethylene)imino)oxy)ethyl)-1,2,5,6-tetrahydro-3-

  17. GABA A receptors in the thalamus: ? 4 subunit expression and alcohol sensitivity

    Microsoft Academic Search

    Fan Jia; Leonardo Pignataro; Neil L. Harrison

    2007-01-01

    The inhibitory neurotransmitter ?-aminobutyric acid (GABA) has long been implicated in the anxiolytic, amnesic, and sedative behavioral effects of alcohol. A large number of studies have investigated the interactions of alcohol with GABA receptors. Many investigators have reported effects of “high concentrations” (50–100mM) of alcohol on GABA-mediated synaptic inhibition, but effects of the “low concentrations” (1–30mM) of alcohol normally associated with

  18. (-)Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor

    Microsoft Academic Search

    N. G. Bowery; D. R. Hill; A. L. Hudson

    1980-01-01

    The existence of a receptor for gamma-aminobutyric acid (GABA) on neurones of the mammalian central nervous system (CNS) is now firmly established1-3. It is generally accepted that bicuculline (and its methohalide salts) is an antagonist of the actions of GABA4,5, although resistance to bicuculline has been described6,7. The view that bicuculline prevents GABA from interacting with a membrane recognition site

  19. Pharmacology of GABA receptor CI channels in rat retinal bipolar cells

    Microsoft Academic Search

    Andreas Feigenspan; Heinz Wässle; Joachim Bormann

    1993-01-01

    gamma-AMlNOBUTYRlC acid (GABA), a major inhibitory neurotransmitter in the mammalian nervous system, is known to operate bicuculline-sensitive CI- channels through GABAA receptors and bicuculline-insensitive cation channels through GABAB receptors1,2. Recent observations indicate that the retina may contain GABA receptors with unusual pharmacological properties3-5. Here we report that GABA gates bicuculline-insensitive CI- channels in rod bipolar cells of the rat retina,

  20. GABA and GABA receptors in the gastrointestinal tract: from motility to inflammation.

    PubMed

    Auteri, Michelangelo; Zizzo, Maria Grazia; Serio, Rosa

    2015-03-01

    Although an extensive body of literature confirmed ?-aminobutyric acid (GABA) as mediator within the enteric nervous system (ENS) controlling gastrointestinal (GI) function, the true significance of GABAergic signalling in the gut is still a matter of debate. GABAergic cells in the bowel include neuronal and endocrine-like cells, suggesting GABA as modulator of both motor and secretory GI activity. GABA effects in the GI tract depend on the activation of ionotropic GABAA and GABAC receptors and metabotropic GABAB receptors, resulting in a potential noteworthy regulation of both the excitatory and inhibitory signalling in the ENS. However, the preservation of GABAergic signalling in the gut could not be limited to the maintenance of physiologic intestinal activity. Indeed, a series of interesting studies have suggested a potential key role of GABA in the promising field of neuroimmune interaction, being involved in the modulation of immune cell activity associated with different systemic and enteric inflammatory conditions. Given the urgency of novel therapeutic strategies against chronic immunity-related pathologies, i.e. multiple sclerosis and Inflammatory Bowel Disease, an in-depth comprehension of the enteric GABAergic system in health and disease could provide the basis for new clinical application of nerve-driven immunity. Hence, in the attempt to drive novel researches addressing both the physiological and pathological importance of the GABAergic signalling in the gut, we summarized current evidence on GABA and GABA receptor function in the different parts of the GI tract, with particular focus on the potential involvement in the modulation of GI motility and inflammation. PMID:25526825

  1. 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 ?m) and SKF89976-A (100 ?m), but was unaffected by 100 ?m picrotoxin. Prior application of 100 ?m 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

  2. In vivo measurements of glutamate, GABA, and NAAG in schizophrenia.

    PubMed

    Rowland, Laura M; Kontson, Kimberly; West, Jeffrey; Edden, Richard A; Zhu, He; Wijtenburg, S Andrea; Holcomb, Henry H; Barker, Peter B

    2013-09-01

    The major excitatory and inhibitory neurotransmitters, glutamate (Glu) and gamma-aminobutyric acid (GABA), respectively, are implicated in the pathophysiology of schizophrenia. N-acetyl-aspartyl-glutamate (NAAG), a neuropeptide that modulates the Glu system, may also be altered in schizophrenia. This study investigated GABA, Glu + glutamine (Glx), and NAAG levels in younger and older subjects with schizophrenia. Forty-one subjects, 21 with chronic schizophrenia and 20 healthy controls, participated in this study. Proton magnetic resonance spectroscopy ((1)H-MRS) was used to measure GABA, Glx, and NAAG levels in the anterior cingulate (AC) and centrum semiovale (CSO) regions. NAAG in the CSO was higher in younger schizophrenia subjects compared with younger control subjects. The opposite pattern was observed in the older groups. Glx was reduced in the schizophrenia group irrespective of age group and brain region. There was a trend for reduced AC GABA in older schizophrenia subjects compared with older control subjects. Poor attention performance was correlated to lower AC GABA levels in both groups. Higher levels of CSO NAAG were associated with greater negative symptom severity in schizophrenia. These results provide support for altered glutamatergic and GABAergic function associated with illness course and cognitive and negative symptoms in schizophrenia. The study also highlights the importance of studies that combine MRS measurements of NAAG, GABA, and Glu for a more comprehensive neurochemical characterization of schizophrenia. PMID:23081992

  3. A deficit of functional GABA A receptors in neurons of ? 3 subunit knockout mice

    Microsoft Academic Search

    Matthew D Krasowski; Caroline E Rick; Neil L Harrison; Leonard L Firestone; Gregg E Homanics

    1998-01-01

    Mice whose ?-aminobutyric acid type A (GABAA) ?3 subunit gene is inactivated (`?3 knockout mice') have been previously shown to have epilepsy, hypersensitive behavior, cleft palate, and a high incidence of neonatal mortality. In this study, we analyze whole-cell responses to GABA in neurons from ?3+\\/+, ?3+\\/? and ?3?\\/? mice. We demonstrate markedly decreased responses to GABA in both hippocampal

  4. GABA receptors and benzodiazepine binding sites modulate hippocampal acetylcholine release in vivo

    Microsoft Academic Search

    Eytan Moor; Peter DeBoer; Ben H. C Westerink

    1998-01-01

    In the present study, the regulation of acetylcholine release from the ventral hippocampus by ?-aminobutyric acid (GABA) was investigated in vivo. GABA receptor agonists and antagonists were administered locally in the medial septum and the adjacent vertical limb of the diagonal band of Broca, or in the hippocampus by retrograde dialysis. Acetylcholine release was measured in the ventral hippocampus. In

  5. The GABAA Receptor 1 Subunit Pro174 Segment Is Involved in GABA

    E-print Network

    Kemnitz, Joseph

    The GABAA Receptor 1 Subunit Pro174 -Asp191 Segment Is Involved in GABA Binding and Channel Gating: GABA (-aminobutyric acid); GABAAR (GABAA receptor); (SCAM (substituted-cysteine accessibility method. Characterization of receptor-ligand interactions using site-directed mutagenesis and photo-labeling studies

  6. GABA Accumulation Causes Cell Elongation Defects and a Decrease in Expression of Genes Encoding Secreted and Cell Wall-Related Proteins in Arabidopsis thaliana

    PubMed Central

    Renault, Hugues; El Amrani, Abdelhak; Palanivelu, Ravishankar; Updegraff, Emily P.; Yu, Agnès; Renou, Jean-Pierre; Preuss, Daphne; Bouchereau, Alain; Deleu, Carole

    2011-01-01

    GABA (?-aminobutyric acid), a non-protein amino acid, is a signaling factor in many organisms. In plants, GABA is known to accumulate under a variety of stresses. However, the consequence of GABA accumulation, especially in vegetative tissues, remains poorly understood. Moreover, gene expression changes as a consequence of GABA accumulation in plants are largely unknown. The pop2 mutant, which is defective in GABA catabolism and accumulates GABA, is a good model to examine the effects of GABA accumulation on plant development. Here, we show that the pop2 mutants have pollen tube elongation defects in the transmitting tract of pistils. Additionally, we observed growth inhibition of primary root and dark-grown hypocotyl, at least in part due to cell elongation defects, upon exposure to exogenous GABA. Microarray analysis of pop2-1 seedlings grown in GABA-supplemented medium revealed that 60% of genes whose expression decreased encode secreted proteins. Besides, functional classification of genes with decreased expression in the pop2-1 mutant showed that cell wall-related genes were significantly enriched in the microarray data set, consistent with the cell elongation defects observed in pop2 mutants. Our study identifies cell elongation defects caused by GABA accumulation in both reproductive and vegetative tissues. Additionally, our results show that genes that encode secreted and cell wall-related proteins may mediate some of the effects of GABA accumulation. The potential function of GABA as a growth control factor under stressful conditions is discussed. PMID:21471118

  7. GABA as an Inhibitory Neurotransmitter in Human Cerebral Cortex

    Microsoft Academic Search

    DAVID A. MCCORMICK

    1989-01-01

    1. The possible role of y-aminobutyric acid (GABA) as an in- hibitory neurotransmitter in the human cerebral cortex was in- vestigated with the use of intracellular recordings from neocorti- cal slices maintained in vitro. 2. Electrical stimulation of afferents to presumed pyramidal cells resulted in an initial excitatory postsynaptic potential (EPSP) followed by fast and slow inhibitory postsynaptic potentials (IPSPs).

  8. Dark-rearing-induced reduction of GABA and GAD and prevention of the effect by BDNF in the mouse retina

    Microsoft Academic Search

    Eun-Jin Lee; Tricia L. Gibo; Norberto M. Grzywacz

    2006-01-01

    Gamma-aminobutyric acid (GABA) is an important retinal neurotransmitter. We studied the expression of GABA, glutamate decarboxylase 65 (GAD65) and GAD67 by immunocytochemistry and Western blot, in the retinas of control and dark-reared C57BL ? 6J black mice. This study asked three questions. First, is visual input necessary for the normal expression of GABA, GAD65 and GAD67? Second, can the retina

  9. GABA modulation of SVZ-derived progenitor ventral cell migration.

    PubMed

    Hsieh, Yi-Chun; Puche, Adam C

    2015-08-01

    The subventricular zone (SVZ) is a proliferative region that provides neurons to olfactory bulb throughout life. The new neurons undergo cell migration from SVZ and travel until they reach their final destination. We previously showed in the early postnatal mouse a ventral migratory subpopulation from SVZ targets the Islands of Calleja (ICC) in the basal forebrain. However, unlike the well-characterized rostral migratory stream, little is known about the guidance mechanisms operating in the ventrally directed migratory pathway. In this study, we examined the role of neurotransmitter ?-aminobutyric acid (GABA) in SVZ-derived progenitor ventral migration and the involvement of this neurotransmitter in the cytoarchitectual organization of dispersed cells into the tight clusters of the ICC. Our results show that the ventral SVZ cell migration rate was enhanced by GABA acting through a GABAA receptor and that GABA acts as a directional guidance cue for ventral migrating cells. Furthermore, disruption of GABA signaling inhibited the formation of Island clusters in vitro. Taken together, these data suggest that GABA is an important guidance and organizational cue for the Island of Calleja. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 75: 791-804, 2015. PMID:25421254

  10. The effects of stiripentol on GABA(A) receptors.

    PubMed

    Fisher, Janet L

    2011-04-01

    The anticonvulsant stiripentol (Diacomittm) has been shown to have a positive impact on control of seizures for many patients with Dravet syndrome. As with most antiepileptic drugs, stiripentol has multiple mechanisms of action. Its direct anticonvulsant activity is likely due to enhancement of inhibitory, ?-aminobutyric acid (GABA)ergic neurotransmission. Stiripentol was shown to increase the activity of both neuronal and recombinant GABA(A) receptors at clinically relevant concentrations. At recombinant receptors, stiripentol was found to act through a unique site in a subunit-dependent manner. Positive modulation by stiripentol was most effective at GABA(A) receptors containing an ?3 subunit. The expression of the ?3 subunit is developmentally regulated, with highest levels in the immature brain. This subunit selectivity may explain the greater clinical efficacy of stiripentol in childhood-onset epilepsies, including Dravet syndrome. PMID:21463286

  11. Ontogenesis and properties of the convulsant recognition site(s) of the gamma-aminobutyric acid (GABA) receptor complex in chicken embryo.

    PubMed

    Seifert, J

    1988-07-14

    Ontogenesis of the convulsant (picrotoxinin or t-butylbicyclophosphorothionate (TBPS] site(s) was defined in chicken embryonic brain with the radioligands [35S]TBPS and [3H]t-butylbicycloorthobenzoate [( 3H]TBOB). Binding of the radioligands is detectable from day 6 of incubation. The increase in binding after day 14 of incubation is due to an increase in the number of binding sites. The pharmacological properties of the embryonic recognition site(s) do not undergo significant changes during hatching based on the affinity of embryonic and chick brain membranes for [3H]TBOB; the rate of association and dissociation for TBOB; non-competitive inhibition of [3H]TBOB binding and modulation of 1R, alpha S-cis-cypermethrin interaction with the recognition site(s) by GABA; and inhibition of radioligand binding by endrin, picrotoxinin and TBPS. Early development and in vitro susceptibility of the recognition site to convulsive toxicants makes the embryo a possible target for a variety of drugs and environmental toxicants acting at this site. PMID:2850922

  12. Competitive antagonism of insect GABA receptors by 4-substituted 5-(4-piperidyl)-3-isothiazolols.

    PubMed

    Liu, Genyan; Furuta, Kenjiro; Nakajima, Hiromitsu; Ozoe, Fumiyo; Ozoe, Yoshihisa

    2014-09-01

    ?-Aminobutyric acid (GABA) receptors are important targets of parasiticides/insecticides. Several 4-substituted analogs of the partial GABAA receptor agonist 5-(4-piperidyl)-3-isothiazolol (Thio-4-PIOL) were synthesized and examined for their antagonism of insect GABA receptors expressed in Drosophila S2 cells or Xenopus oocytes. Thio-4-PIOL showed weak antagonism of three insect GABA receptors. The antagonistic activity of Thio-4-PIOL was enhanced by introducing bicyclic aromatic substituents into the 4-position of the isothiazole ring. The 2-naphthyl and the 3-biphenylyl analogs displayed antagonist potencies with half maximal inhibitory concentrations in the low micromolar range. The 2-naphthyl analog induced a parallel rightward shift of the GABA concentration-response curve, suggesting competitive antagonism by these analogs. Both compounds exhibited weak insecticidal activities against houseflies. Thus, the orthosteric site of insect GABA receptors might be a potential target site of insecticides. PMID:25112550

  13. GABA-shunt enzymes activity in GH3 cells with reduced level of PMCA2 or PMCA3 isoform

    SciTech Connect

    Kowalski, Antoni, E-mail: antoni.kowalski@umed.lodz.pl [Department of Molecular Neurochemistry, Medical University of Lodz, 6/8 Mazowiecka Str., 92-215 Lodz (Poland)] [Department of Molecular Neurochemistry, Medical University of Lodz, 6/8 Mazowiecka Str., 92-215 Lodz (Poland); Zylinska, Ludmila, E-mail: ludmila.zylinska@umed.lodz.pl [Department of Molecular Neurochemistry, Medical University of Lodz, 6/8 Mazowiecka Str., 92-215 Lodz (Poland)] [Department of Molecular Neurochemistry, Medical University of Lodz, 6/8 Mazowiecka Str., 92-215 Lodz (Poland); Boczek, Tomasz, E-mail: tomasz.boczek@umed.lodz.pl [Department of Molecular Neurochemistry, Medical University of Lodz, 6/8 Mazowiecka Str., 92-215 Lodz (Poland)] [Department of Molecular Neurochemistry, Medical University of Lodz, 6/8 Mazowiecka Str., 92-215 Lodz (Poland); Rebas, Elzbieta, E-mail: elzbieta.rebas@umed.lodz.pl [Department of Molecular Neurochemistry, Medical University of Lodz, 6/8 Mazowiecka Str., 92-215 Lodz (Poland)] [Department of Molecular Neurochemistry, Medical University of Lodz, 6/8 Mazowiecka Str., 92-215 Lodz (Poland)

    2011-08-12

    Highlights: {yields} Suppression of PMCA2 or PMCA3 slows down proliferation of GH3 cells. {yields} PMCA2 suppression lowers the activity of GABA-shunt enzymes. {yields} PMCA3 suppression increases the expression of glutamate decarboxylase 65. {yields} PMCA2 and PMCA3 function appears to be linked to regulation of GABA metabolism. -- Abstract: GABA ({gamma}-aminobutyric acid) is important neurotransmitter and regulator of endocrine functions. Its metabolism involves three enzymes: glutamate decarboxylase (GAD65 and GAD67), GABA aminotransferase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH). As many cellular processes GABA turnover can depend on calcium homeostasis, which is maintained by plasma membrane calcium ATPases (PMCAs). In excitable cells PMCA2 and PMCA3 isoforms are particularly important. In this study we focused on GABA-metabolizing enzymes expression and activity in rat anterior pituitary GH3 cells with suppressed expression of PMCA2 or PMCA3. We observed that PMCA3-reduced cells have increased GAD65 expression. Suppression of PMCA2 caused a decrease in total GAD and GABA-T activity. These results indicate that PMCA2 and PMCA3 presence may be an important regulatory factor in GABA metabolism. Results suggest that PMCA2 and PMCA3 function is rather related to regulation of GABA synthesis and degradation than supplying cells with metabolites, which can be potentially energetic source.

  14. GABA Concentration in Posterior Cingulate Cortex Predicts Putamen Response during Resting State fMRI

    PubMed Central

    Arrubla, Jorge; Tse, Desmond H. Y.; Amkreutz, Christin; Neuner, Irene; Shah, N. Jon

    2014-01-01

    The role of neurotransmitters in the activity of resting state networks has been gaining attention and has become a field of research with magnetic resonance spectroscopy (MRS) being one of the key techniques. MRS permits the measurement of ?-aminobutyric acid (GABA) and glutamate levels, the central biochemical constituents of the excitation-inhibition balance in vivo. The inhibitory effects of GABA in the brain have been largely investigated in relation to the activity of resting state networks in functional magnetic resonance imaging (fMRI). In this study GABA concentration in the posterior cingulate cortex (PCC) was measured using single voxel spectra acquired with standard point resolved spectroscopy (PRESS) from 20 healthy male volunteers at 3 T. Resting state fMRI was consecutively measured and the values of GABA/Creatine+Phosphocreatine ratio (GABA ratio) were included in a general linear model matrix as a step of dual regression analysis in order to identify voxels whose neuroimaging metrics during rest were related to individual levels of the GABA ratio. Our data show that the connection strength of putamen to the default-mode network during resting state has a negative linear relationship with the GABA ratio measured in the PCC. These findings highlight the role of PCC and GABA in segregation of the motor input, which is an inherent condition that characterises resting state. PMID:25184505

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

    SciTech Connect

    Earle, M.E.; Concas, A.; Wamsley, J.K.; Yamamura, H.I.

    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 at 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.

  16. Pharmacological characteristics of two different types of inhibitory GABA receptors on Achatina fulica neurones.

    PubMed

    Kim, K H; Takeuchi, H

    1990-06-21

    GABA (gamma-aminobutyric acid) receptors of Achatina fulica neurones have been classified into two types associated with neuronal inhibition and one type with excitation. The pharmacological features of muscimol I and baclofen types associated with inhibition were investigated in this study. Activation of muscimol I type receptors on TAN (tonically autoactive neurone) by GABA, muscimol and trans-4-aminocrotonic acid (TACA) produced a transient outward current (Iout) with an increase in membrane conductance (g). Their relative potencies at GABA ED50 (approximately 10(-4) M) were: GABA: muscimol: TACA = 1:0.6:0.3. The relation between Iout and g increase (delta g) induced by various concentrations of these compounds was linear. The Hill coefficients for GABA were close to 1.0. The GABA effects were potentiated by pentobarbitone, antagonized competitively by pitrazepin and non-competitively by picrotoxin and diazepam, and unaffected by bicuculline. The reversal potentials of the effects of GABA, muscimol and TACA on TAN changed under various [Cl-]0 according to the Nernst equation for Ec1, but not under various [K+]0 and [Na+]0. Activation of baclofen type GABA receptors on RPeNLN (right pedal nerve large neurone) by GABA and (+/-)-baclofen produced a slow Iout with an increase in g. The two compounds were almost equipotent (ED50: approximately 3 x 10(-4) M). The relation between Iout and delta g produced by various concentrations was linear. The Hill coefficients for GABA were also close to 1.0. The reversal potentials of GABA and (+/-)-baclofen on RPeNLN changed under various [K+]0 according to the Nernst equation for EK, but not under various [Cl-]0 and [Na+]0. The two compounds hardly affected the voltage-gated and slowly inactivating calcium current. The Iout produced by GABA and (+/-)-baclofen was reduced by tetraethylammonium chloride, but was unaffected by 4-aminopyridine, bicuculline, pitrazepin and picrotoxin. In conclusion, the pharmacological features of muscimol I type GABA receptors are partly comparable to those of mammalian GABAA receptors, except for the influences of bicuculline and diazepam: the features of the baclofen type GABA receptor, which did not occur with muscimol I type receptors in the same neurone, were similar to those of GABAB. PMID:2169426

  17. Cerebral GABA-ergic and glutamatergic function in hepatic encephalopathy

    Microsoft Academic Search

    Roger F. Butterworth; Joël Lavoie; Jean-François Giguère; Gilles Pomier Layrargues; Marcelle Bergeron

    1987-01-01

    Measurement of amino acids in brain tissue obtained at autopsy from cirrhotic patients dying in hepatic coma revealed a threefold\\u000a increase in glutamine and a concomitant decrease in brain glutamate. The GABA levels were found to be unaltered. Studies using\\u000a an animal model of portal-systemic encephalopathy gave similar results. Glutamic acid decarboxylase (GAD) activities were\\u000a within normal limits, both in

  18. Gamma-hydroxybutyrate reduces GABA(A)-mediated inhibitory postsynaptic potentials in the CA1 region of hippocampus.

    PubMed

    Cammalleri, Maurizio; Brancucci, Alfredo; Berton, Fulvia; Loche, Antonella; Gessa, Gian Luigi; Francesconi, Walter

    2002-12-01

    Gamma-hydroxybutyric acid (GHB) is a psychoactive drug and a putative neurotransmitter, derived from gamma-aminobutyric acid (GABA). At micromolar concentrations GHB binds to specific high and low affinity binding sites present in discrete areas of the brain, while at millimolar concentrations GHB also binds to GABA(B) receptors. Previous studies indicated that GHB inhibits both NMDA and AMPA receptor mediated excitatory postsynaptic potentials in hippocampal CA1 pyramidal neurons. This action of GHB occurs in the presence of GABA(B) blockade and is antagonized by NCS-382, a specific GHB receptor antagonist, suggesting that it is mediated by GHB receptors. In the present study, we have investigated the effect of GHB on GABA(A) mediated inhibitory postsynaptic potentials (GABA(A)-IPSP) elicited in CA1 hippocampal pyramidal neurons by stimulation of Schaffer collateral-commissural fibers. We observed that GHB inhibited GABA(A)-IPSPs by about 40% at concentrations of 300-600 microM. GHB inhibition was blocked by NCS-382 (500 microM), which per se failed to modify GABA(A)-IPSPs. Moreover, GHB failed to modify cell membrane depolarization induced by the brief pressure application of GABA in the presence of tetrodotoxin (TTX), indicating that GHB does not inhibit postsynaptic GABA responses. However, GHB reduced the amplitude of GABA(A)-IPSPs elicited in pyramidal neurons by paired pulse stimulation and enhanced paired pulse facilitation with respect to control condition, suggesting that GHB reduces GABA release from nerve terminals. Finally, GHB failed to reduce the amplitude of GABA(A)-IPSPs in the presence of BaCl(2), suggesting that the effect of GHB is due to GHB receptor-mediated presynaptic inhibition of Ca(2)+ influx. PMID:12464453

  19. Differences in cardiovascular responses to peripherally administered GABA as influenced by basal conditions and type of anaesthesia.

    PubMed Central

    Giuliani, S.; Maggi, C. A.; Meli, A.

    1986-01-01

    The cardiovascular (blood pressure, heart rate, cardiac contractility) effects of i.v. gamma-aminobutyric acid (GABA) were investigated in guinea-pigs anaesthetized with barbitone or urethane. GABA (0.1-10 mg kg-1) produced a transient 'depressive' effect on cardiovascular parameters which in barbitone-anaesthetized animals was followed by a transient 'excitatory' effect. Resting cardiovascular parameters were higher in urethane-as compared to barbitone-anaesthetized animals. Picrotoxin pretreatment (2 mg kg-1, i.v.) barely affected the cardiovascular changes produced by GABA in barbitone-anaesthetized animals. In picrotoxin pretreated animals anaesthetized with urethane, GABA produced an initial depression of cardiovascular parameters followed by an excitatory phase. Hexamethonium (20 mg kg-1, i.v.) suppressed or reduced markedly the GABA-induced cardiovascular changes both in barbitone- or urethane- anaesthetized animals. Reserpine pretreatment lowered resting cardiovascular parameters. In these animals, regardless of type of anaesthesia, the effects of i.v. GABA were of the 'excitatory' type only. Reserpine pretreated animals anaesthetized with barbitone were selected for further experiments. Various GABAA receptor agonists (homotaurine, muscimol, THIP, 5-aminovaleric acid) mimicked the 'excitatory' effect of GABA in reserpine pretreated animals anesthetized with barbitone and prevented the effects of subsequent GABA administration. On the other hand (+/-)-baclofen, a selective GABAB receptor agonist, had a slight depressant effect and did not prevent the 'excitatory' cardiovascular effects of GABA. Neither bicuculline nor picrotoxin pretreatment prevented the 'excitatory' cardiovascular effect of i.v. GABA in reserpine pretreated, guinea-pigs anaesthetized with barbitone. In adrenalectomized guinea-pigs or in preparations receiving i.v. phentolamine plus propranolol, GABA produced only a small 'depressant' effect on cardiovascular parameters. These findings demonstrate that GABA exerts a neuromodulatory effect on cardiovascular function via peripheral actions which is influenced by: type of anaesthesia resting values of cardiovascular parameters degree of activity of the sympathetic nervous system and catecholamine release from the adrenal medulla. PMID:3742154

  20. Early Evolution of Ionotropic GABA Receptors and Selective Regimes Acting on the Mammalian-Specific Theta and Epsilon Subunits

    Microsoft Academic Search

    Christopher J. Martyniuk; Stéphane Aris-Brosou; Guy Drouin; Joel Cahn; Vance L. Trudeau

    2007-01-01

    Background. The amino acid neurotransmitter GABA is abundant in the central nervous system (CNS) of both invertebrates and vertebrates. Receptors of this neurotransmitter play a key role in important processes such as learning and memory. Yet, little is known about the mode and tempo of evolution of the receptors of this neurotransmitter. Here, we investigate the phylogenetic relationships of GABA

  1. Different Residues in the GABAA Receptor 1T60-1K70 Region Mediate GABA and SR-95531 Actions*

    E-print Network

    Kemnitz, Joseph

    Different Residues in the GABAA Receptor 1T60- 1K70 Region Mediate GABA and SR-95531 Actions A (GABAA), receptor and explored the conformational changes that occur within the GABA-binding site during, Wisconsin 53706 Although -aminobutyric acid type A receptor ago- nists and antagonists bind to a common site

  2. Early Evolution of Ionotropic GABA Receptors and Selective Regimes Acting on the Mammalian-Specific Theta and Epsilon Subunits

    Microsoft Academic Search

    Christopher J. Martyniuk; Stéphane Aris-Brosou; Guy Drouin; Joel Cahn; Vance L. Trudeau; Jason Stajich

    2007-01-01

    BackgroundThe amino acid neurotransmitter GABA is abundant in the central nervous system (CNS) of both invertebrates and vertebrates. Receptors of this neurotransmitter play a key role in important processes such as learning and memory. Yet, little is known about the mode and tempo of evolution of the receptors of this neurotransmitter. Here, we investigate the phylogenetic relationships of GABA receptor

  3. The Memory-Impairing Effects of Septal GABA Receptor Activation Involve GABAergic Septo-Hippocampal Projection Neurons

    ERIC Educational Resources Information Center

    Krebs-Kraft, Desiree L.; Wheeler, Marina G.; Parent, Marise B.

    2007-01-01

    Septal infusions of the [gamma]-aminobutyric acid (GABA)[subscript A] agonist muscimol impair memory, and the effect likely involves the hippocampus. GABA[subscript A] receptors are present on the perikarya of cholinergic and GABAergic septo-hippocampal (SH) projections. The current experiments determined whether GABAergic SH projections are…

  4. Focal Uncaging of GABA Reveals a Temporally Defined Role for GABAergic Inhibition during Appetitive Associative Olfactory Conditioning in Honeybees

    ERIC Educational Resources Information Center

    Raccuglia, Davide; Mueller, Uli

    2013-01-01

    Throughout the animal kingdom, the inhibitory neurotransmitter ?-aminobutyric acid (GABA) is a key modulator of physiological processes including learning. With respect to associative learning, the exact time in which GABA interferes with the molecular events of learning has not yet been clearly defined. To address this issue, we used two…

  5. Tiagabine antinociception in rodents depends on GABA B receptor activation: parallel antinociception testing and medial thalamus GABA microdialysis

    Microsoft Academic Search

    Alessandra Ipponi; Claudia Lamberti; Antonio Medica; Alessandro Bartolini; Petra Malmberg-Aiello

    1999-01-01

    The effects of a new antiepileptic drug, tiagabine, (R)-N-[4,4-di-(3-methylthien-2-yl)but-3-enyl] nipecotic acid hydrochloride, were studied in mice and rats in antinociceptive tests, using three kinds of noxious stimuli: mechanical (paw pressure), chemical (abdominal constriction) and thermal (hot plate). In vivo microdialysis was performed in parallel in awake, freely moving rats in order to evaluate possible alterations in extracellular ?-aminobutyric acid (GABA)

  6. Elevated levels of GABA+ in migraine detected using (1) H-MRS.

    PubMed

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

    2015-07-01

    ?-Aminobutyric acid (GABA) has been implicated in several pain conditions, yet no study has systematically evaluated GABA levels in migraine using (1) H-MRS. The accurate detection, separation and quantification of GABA in individuals with migraine could elucidate the role of this neurotransmitter in migraine pathophysiology. Such information may eventually be useful in the diagnosis and development of more effective treatments for migraine. The aims of this study were therefore to compare the concentration of GABA+ in individuals with migraine with that in asymptomatic individuals, and to determine the diagnostic potential of GABA+ in the classification of those with or without migraine. In this case-control study, GABA+ levels in the brain were determined in 19 participants with migraine and 19 matched controls by (1) H-MRS using Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence. The diagnostic accuracy of GABA+ for the detection of migraine and the optimal cut-off value were determined by receiver operating characteristic analysis. GABA+ levels were significantly higher (p = 0.002) in those with migraine [median, 1.41 institutional units (IU); interquartile range, 1.31-1.50 IU] than in controls (median, 1.18 IU; interquartile range, 1.12-1.35 IU). The GABA+ concentration appears to have good accuracy for the classification of individuals with or without migraine [area under the curve (95% confidence interval), 0.837 (0.71-0.96); p < 0.001]. The optimal GABA+ cut-off value for migraine was 1.30 IU, with a sensitivity of 84.2%, specificity of 68.4% and positive likelihood ratio of +2.67. The outcomes of this study suggest altered GABA metabolism in migraine. These results add to the scarce evidence on the putative role of GABA in migraine and provide a basis to further explore the causal relationship between GABA+ and the pathophysiology of migraine. This study also demonstrates that GABA+ concentration has good diagnostic accuracy for migraine. These findings offer new research and practice directions for migraine diagnosis. Copyright © 2015 John Wiley & Sons, Ltd. PMID:25997981

  7. Gat1 (Gaba:Na+:Cl?) Cotransport Function

    PubMed Central

    Lu, Chin-Chih; Hilgemann, Donald W.

    1999-01-01

    Neurotransmitter transporters are reported to mediate transmembrane ion movements that are poorly coupled to neurotransmitter transport and to exhibit complex “channel-like” behaviors that challenge the classical “alternating access” transport model. To test alternative models, and to develop an improved model for the Na+- and Cl?-dependent ?-aminobutyric acid (GABA) transporter, GAT1, we expressed GAT1 in Xenopus oocytes and analyzed its function in detail in giant membrane patches. We detected no Na+- or Cl?- dependent currents in the absence of GABA, nor did we detect activating effects of substrates added to the trans side. Outward GAT1 current (“reverse” transport mode) requires the presence of all three substrates on the cytoplasmic side. Inward GAT1 current (“forward” transport mode) can be partially activated by GABA and Na+ on the extracellular (pipette) side in the nominal absence of Cl?. With all three substrates on both membrane sides, reversal potentials defined with specific GAT1 inhibitors are consistent with the proposed stoichiometry of 1GABA:2Na+:1Cl?. As predicted for the “alternating access” model, addition of a substrate to the trans side (120 mM extracellular Na+) decreases the half-maximal concentration for activation of current by a substrate on the cis side (cytoplasmic GABA). In the presence of extracellular Na+, the half-maximal cytoplasmic GABA concentration is increased by decreasing cytoplasmic Cl?. In the absence of extracellular Na+, half-maximal cytoplasmic substrate concentrations (8 mM Cl?, 2 mM GABA, 60 mM Na+) do not change when cosubstrate concentrations are reduced, with the exception that reducing cytoplasmic Cl? increases the half-maximal cytoplasmic Na+ concentration. The forward GAT1 current (i.e., inward current with all extracellular substrates present) is inhibited monotonically by cytoplasmic Cl? (Ki, 8 mM); cytoplasmic Na+ and cytoplasmic GABA are without effect in the absence of cytoplasmic Cl?. In the absence of extracellular Na+, current–voltage relations for reverse transport current (i.e., outward current with all cytoplasmic substrates present) can be approximated by shallow exponential functions whose slopes are consistent with rate-limiting steps moving 0.15–0.3 equivalent charges. The slopes of current–voltage relations change only little when current is reduced four- to eightfold by lowering each cosubstrate concentration; they increase twofold upon addition of 100 mM Na+ to the extracellular (pipette) side. PMID:10469733

  8. Effects of prenatal exposure to 2,4-D\\/2,4,5-T mixture on postnatal changes in rat brain glutamate, GABA, protein, and nucleic acid levels

    Microsoft Academic Search

    F. K. Mohammad; V. E. V. St. Omer

    1988-01-01

    The opportunity of maternal exposure to various chemicals in the work place and the general environments have increased, and the fetus and neonate may be at greater risk than the adult. However, the embryotoxic and teratogenic effects of the chlorinated phenoxy herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), the main chemicals in Agent Orange, are well documented only in

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

    SciTech Connect

    Kamei, Yuka; Tamura, Takayuki [Department of Bioscience, Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura, Nagahama, Shiga 526-0829 (Japan)] [Department of Bioscience, Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura, Nagahama, Shiga 526-0829 (Japan); Yoshida, Ryo [Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871 (Japan)] [Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871 (Japan); Ohta, Shinji [Department of Bioscience, Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura, Nagahama, Shiga 526-0829 (Japan)] [Department of Bioscience, Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura, Nagahama, Shiga 526-0829 (Japan); Fukusaki, Eiichiro [Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871 (Japan)] [Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871 (Japan); Mukai, Yukio, E-mail: y_mukai@nagahama-i-bio.ac.jp [Department of Bioscience, Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura, Nagahama, Shiga 526-0829 (Japan)] [Department of Bioscience, Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura, Nagahama, Shiga 526-0829 (Japan)

    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)-dependent 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.

  10. Cellular and molecular action of the putative GABA-mimetic, gabapentin

    Microsoft Academic Search

    Y. P. Maneuf; M. I. Gonzalez; K. S. Sutton; F.-Z. Chung; R. D. Pinnock; K. Lee

    2003-01-01

    Gabapentin was originally designed as an anticonvulsant %-aminobutyric acid (GABA) mimetic capable of crossing the blood-brain barrier. In the present review we show that although gabapentin is not a GABA mimetic, it has great utility as an add-on therapy for epilepsy and as a first-line treatment for neuropathic pain. We summarise the studies that have been performed which demonstrate that

  11. Site-specific fluorescence reveals distinct structural changes with GABA receptor activation and antagonism

    Microsoft Academic Search

    Yongchang Chang; David S. Weiss

    2002-01-01

    Neurotransmitter-operated ion channels, such as the GABA (?-aminobutyric acid) receptor, are important in fast synaptic transmission between neurons. Using site-specific fluorescent labeling and simultaneous electrophysiological analysis in Xenopus laevis oocytes expressing recombinant ?1 GABA receptors, we identified agonist-mediated molecular rearrangements at three positions within and near the agonist-binding pocket that were highly correlated with receptor activation. We also show that

  12. Steroid Hormone Metabolites are Barbiturate-Like Modulators of the GABA Receptor

    Microsoft Academic Search

    Maria Dorota Majewska; Neil L. Harrison; Rochelle D. Schwartz; Jeffery L. Barker; Steven M. Paul

    1986-01-01

    Two metabolites of the steroid hormones progesterone and deoxycorticosterone, 3alpha -hydroxy-5alpha -dihydroprogesterone and 3alpha ,5alpha -tetrahydrodeoxycorticosterone, are potent barbiturate-like ligands of the gamma -aminobutyric acid (GABA) receptor--chloride ion channel complex. At concentrations between 10-7 and 10-5 M both steroids inhibited binding of the convulsant t-butylbicyclophosphorothionate to the GABA-receptor complex and increased the binding of the benzodiazepine flunitrazepam; they also stimulated

  13. GABA May Act as a Self-Limiting Trophic Factor at Developing Synapses

    NSDL National Science Digital Library

    Arnold R. Kriegstein (Columbia College of Physicians and Surgeons; Department of Neurology and Department of Pathology and at the Center for Neurobiology and Behavior REV)

    2001-08-14

    Early in development, synapses with glycine or ?-aminobutyric acid (GABA)-gated chloride channels exhibit the ability to depolarize postsynaptic cells. As the synapses mature and the gradient of chloride ions across the cell membrane is altered, these neurotransmitters signal an inhibitory response, hyperpolarizing the membrane and decreasing neuronal excitability. Kriegstein and Owens discuss how GABA-stimulated up-regulation of the expression of the potassium chloride cotransporter KCC2 may be the mechanism underlying this synaptic switch.

  14. Ionotropic GABA Receptors and Distal Retinal ON and OFF Responses

    PubMed Central

    Popova, E.

    2014-01-01

    In the vertebrate retina, visual signals are segregated into parallel ON and OFF pathways, which provide information for light increments and decrements. The segregation is first evident at the level of the ON and OFF bipolar cells in distal retina. The activity of large populations of ON and OFF bipolar cells is reflected in the b- and d-waves of the diffuse electroretinogram (ERG). The role of gamma-aminobutyric acid (GABA), acting through ionotropic GABA receptors in shaping the ON and OFF responses in distal retina, is a matter of debate. This review summarized current knowledge about the types of the GABAergic neurons and ionotropic GABA receptors in the retina as well as the effects of GABA and specific GABAA and GABAC receptor antagonists on the activity of the ON and OFF bipolar cells in both nonmammalian and mammalian retina. Special emphasis is put on the effects on b- and d-waves of the ERG as a useful tool for assessment of the overall function of distal retinal ON and OFF channels. The role of GABAergic system in establishing the ON-OFF asymmetry concerning the time course and absolute and relative sensitivity of the ERG responses under different conditions of light adaptation in amphibian retina is also discussed. PMID:25143858

  15. Action of tremorgenic mycotoxins on GABA/sub A/ receptor

    SciTech Connect

    Gant, D.B.; Cole, R.J.; Valdes, J.J.; Eldefrawi, M.E.; Eldefrawi, A.T.

    1987-11-09

    The effects of four tremorgenic and one nontremorgenic mycotoxins were studied on ..gamma..-aminobutyric acid (GABA/sub A/) receptor binding and function in rat brain and on binding of a voltage-operated Cl/sup -/ channel in Torpedo electric organ. None of the mycotoxins had significant effect on (/sup 3/H)muscimol or (/sup 3/H)flunitrazepam binding to the GAMA/sup A/ receptor. However, only the four tremorgenic mycotoxins inhibited GABA-induced /sup 36/Cl/sup -/ influx and (/sup 35/S)t-butylbicyclophosphorothionate ((/sup 35/S)TBPS) binding in rate brain membranes, while the nontremorgenic verruculotoxin had no effect. Inhibition of (/sup 35/S)TBPS binding by paspalinine was non-competitive. This suggests that tremorgenic mycotoxins inhibit GABA/sub A/ receptor function by binding close to the receptor's Cl/sup -/ channel. On the voltage-operated Cl/sup -/ channel, only high concentrations of verruculogen and verruculotoxin caused significant inhibition of the channel's binding of (/sup 35/S)TBPS. The data suggest that the tremorgenic action of these mycotoxins may be due in part to their inhibition of GABA/sub A/ receptor function. 21 references, 4 figures, 2 tables.

  16. Stimulation of GABA release by scorpion venom in an isolated synapse in the crayfish (Astacus leptodactylus).

    PubMed

    Purali, Nuhan

    2003-03-01

    Effects of various types of scorpion venom on gamma-aminobutyric acid (GABA) release were studied in an isolated synapse in the crayfish. Post-synaptic GABA-induced currents were recorded to monitor the GABA release from the pre-synaptic site. In 20mM tetraethylammonium (TEA) chloride solution the GABA-induced currents increased 71%. Exposing the preparations to Leiurus quinquestriatus hebraeus, Leiurus quinquestriatus quinquestriatus or Tityus serrulatus venom (0.1mg/ml) increased GABA-induced currents 4-5 fold. The effect was present in the presence of tetrodotoxin (TTX) but diminished significantly when verapamil was applied. Exposing the preparations Androctonus australis or Buthus tamulus venom did not affect the GABA-induced currents. The results indicate that stimulation of the GABA release by some of the scorpion venoms may partly be due to a possible block of pre-synaptic potassium channels, but not due to an abnormal increase in sodium channel activation. PMID:12565762

  17. 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, ?-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. PMID:26052150

  18. Effects of tiagabine and vigabatrin on GABA uptake into primary cultures of rat cortical astrocytes.

    PubMed

    Leach, J P; Sills, G J; Majid, A; Butler, E; Carswell, A; Thompson, G G; Brodie, M J

    1996-09-01

    Tiagabine (TGB) and vigabatrin (VGB) are two novel anticonvulsant compounds reported to exert their pharmacological effects via an action on the gamma-aminobutyric acid (GABA) system. We have investigated the effects of acute exposure of these drugs on the uptake of GABA into rat cortical astrocytes in primary culture. Astrocytes were prepared from the cerebral cortices of one day-old rat pups by a mechanical dissociation technique and were assayed for GABA uptake activity after 21 days in culture. Tiagabine (100-300 nM) and VGB (100 microM) reduced GABA uptake when compared to control at four hours post-exposure. GABA uptake was also reduced following eight and 24 hour exposures to 200 nM TGB. A combination of TGB (200 nM) and VGB (100 microM) treatments reduced GABA uptake when compared to both control and VGB treated cultures. These results support the efficacy of TGB as a GABA uptake inhibitor and suggest that VGB may also exert an effect by this mechanism. PMID:8902926

  19. 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.

  20. GABAergic Deafferentation Hypothesis of Brain Aging and Alzheimer’s Disease Revisited

    Microsoft Academic Search

    Thaddeus J. Marczynski

    1998-01-01

    Considering the mechanisms responsible for age- and Alzheimer’s disease (AD)-related neuronal degeneration, little attention was paid to the opposing relationships between the energy-rich phosphates, mainly the availability of the adenosine triphosphate (ATP), and the activity of the glutamic acid decarboxylase (GAD), the rate-limiting enzyme synthesizing the ?-amino butyric acid (GABA). Here, it is postulated that in all neuronal phenotypes the

  1. Developmental Kinetics of GAD Family mRNAs Parallel Neurogenesis in the Rat Spinal Cord

    Microsoft Academic Search

    Roland Somogyi; Xiling Wen; Wu Ma; Jeffery L. Barker

    1995-01-01

    GABA (y-amino butyric acid), a fast-acting synaptic trans- mitter in the mature CNS, is synthesized from glutamate by GAD (glutamic acid decarboxylase). We have developed an ultrasensitive PCR technique to quantify the expression of GAD-related mRNAs during the development of the rat cer- vical spinal cord and have localized them using in situ hy- bridization. GAD65, GAD67, and an alternatively

  2. 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. ?-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. PMID:25542346

  3. ? Subunit isoform influences GABA A receptor modulation by propofol

    Microsoft Academic Search

    M. D. Krasowski; S. M. O'Shea; C. E. M. Rick; P. J. Whiting; K. L. Hadingham; C. Czajkowski; N. L. Harrison

    1997-01-01

    We have investigated the role of the ? subunit in the modulation of ?-aminobutyric acid type A (GABAA) receptors by the general anesthetic propofol, using whole-cell patch clamp recordings made from distinct stable fibroblast cell lines which expressed only ?1?3?2 or ?6?3?2 GABAA receptors. At clinically relevant anesthetic concentrations, propofol potentiated submaximal GABA currents in ?1?3?2 receptors to a far

  4. Induction of CYP1A1 by GABA Receptor Ligands

    Microsoft Academic Search

    Marianne D. Sadar; Anna Westlind; Fredrik Blomstrand; Tommy B. Andersson

    1996-01-01

    The induction of CYP1A1 is mediated via the aromatic hydrocarbon (Ah) receptor. Studies from our laboratory show CYP1A1 induction by picrotoxin and phenobarbital which prompted us to examine if other ligands of the ?-aminobutyric acid (GABA) receptor could also induce CYP1A1. Here we report the nuclear translocation of the Ah receptor and its DNA binding activity to radiolabeled double-stranded synthetic

  5. Ultrastructure and immunocytochemical distribution of GABA in layer III of the rat medial entorhinal cortex following aminooxyacetic acid-induced seizures

    Microsoft Academic Search

    Tore Eid; Robert Schwarcz; Ole Petter Ottersen

    1999-01-01

    Layer III of the entorhinal cortex (EC) is lesioned in patients with temporal lobe epilepsy (TLE). A similar neuropathology\\u000a is also present in different animal models of TLE. For example, injection of the ”indirect” excitotoxin aminooxyacetic acid\\u000a (AOAA) into the EC of rats causes behavioral seizures and preferential loss of neurons in layer III of the medial EC. The\\u000a animals

  6. Lack of coupling between GABA release and GABA synthesis in the rat brain via GABA B autoreceptors

    Microsoft Academic Search

    A. Aguilar-García; B. González-Frankenberger; T. Ramón-Frías; B. J. Méndez-Franco; M. Pérez de la Mora

    2000-01-01

    Summary.   GABA is synthesized within GABA terminals through a highly compartmentalized process in which glial-derived glutamine is\\u000a a major precursor and its release is modulated by GABAB autoreceptors. The aim of this work was to ascertain whether or not GABA synthesis and release are coupled in the rat brain\\u000a through a GABAB autoreceptor-mediated modulation. It was found that (?)baclofen (30

  7. Excitatory actions of GABA in developing chick vestibular afferents: effects on resting electrical activity.

    PubMed

    Cortes, Celso; Galindo, Fabian; Galicia, Salvador; Cebada, Jorge; Flores, Amira

    2013-07-01

    The aim of this study was to characterize the effect of ?-aminobutyric acid (GABA) in the resting multiunit activity of the vestibular afferents during development using the isolated inner ear of embryonic and postnatal chickens (E15-E21 and P5). GABA (10(-3) to 10(-5) M; n?=?133) and muscimol (10(-3) M) elicited an increase in the frequency of the basal discharge of the vestibular afferents. We found that GABA action was dose-dependent and inversely related to animal age. Thus, the largest effect was observed in embryonic ages such as E15 and E17 and decreases in E21 and P5. The GABAA receptor antagonists, bicuculline (10(-5) M; n?=?10) and picrotoxin (10(-4) M; n?=?10), significantly decreased the excitatory action of GABA and muscimol (10(-3) M). Additionally, CNQX 10(-6) M, MCPG 10(-5) M and 7ClKyn 10(-5) M (n?=?5) were co-applied by bath substitution (n?=?5). Both the basal discharge and the GABA action significantly decreased in these experimental conditions. The chloride channel blocker 9-AC 0.5 mM produced an important reduction in the effect of GABA 10(-3) (n?=?5) and 10(-4) M (n?=?5). Thus, our results suggest an excitatory role of GABA in the resting activity of the vestibular afferents that can be explained by changes in the gradient of concentration of Cl(-) during development. We show for the first time that the magnitude of this GABA effect decreases at later stages of embryonic and early postnatal development. Taking into account the results with glutamatergic antagonists, we conclude that GABA has a presynaptic action but is not the neurotransmitter in the vestibular afferent synapses, although it could act as a facilitator of the spontaneous activity and may regulate glutamate release. PMID:23401185

  8. Microtransplantation of cellular membranes from squid stellate ganglion reveals ionotropic GABA receptors.

    PubMed

    Conti, Luca; Limon, Agenor; Palma, Eleonora; Miledi, Ricardo

    2013-02-01

    The squid has been the most studied cephalopod, and it has served as a very useful model for investigating the events associated with nerve impulse generation and synaptic transmission. While the physiology of squid giant axons has been extensively studied, very little is known about the distribution and function of the neurotransmitters and receptors that mediate inhibitory transmission at the synapses. In this study we investigated whether ?-aminobutyric acid (GABA) activates neurotransmitter receptors in stellate ganglia membranes. To overcome the low abundance of GABA-like mRNAs in invertebrates and the low expression of GABA in cephalopods, we used a two-electrode voltage clamp technique to determine if Xenopus laevis oocytes injected with cell membranes from squid stellate ganglia responded to GABA. Using this method, membrane patches containing proteins and ion channels from the squid's stellate ganglion were incorporated into the surface of oocytes. We demonstrated that GABA activates membrane receptors in cellular membranes isolated from squid stellate ganglia. Using the same approach, we were able to record native glutamate-evoked currents. The squid's GABA receptors showed an EC(50) of 98 ?mol l(-1) to GABA and were inhibited by zinc (IC(50) = 356 ?mol l(-1)). Interestingly, GABA receptors from the squid were only partially blocked by bicuculline. These results indicate that the microtransplantation of native cell membranes is useful to identify and characterize scarce membrane proteins. Moreover, our data also support the role of GABA as an ionotropic neurotransmitter in cephalopods, acting through chloride-permeable membrane receptors. PMID:23493508

  9. The role of nucleus accumbens shell GABA receptors on ventral tegmental area intracranial self-stimulation and a potential role for the 5HT2C receptor

    Microsoft Academic Search

    Dave J Hayes; John Hoang; Andrew J Greenshaw

    2011-01-01

    Brain ?-aminobutyric acid (GABA) and 5-hydroxytryptamine (5-HT)2C receptors are implicated in the neuronal regulation of reward- and aversion-related behaviour. Within the mesocorticolimbic pathways of the brain, relationships between GABA containing neurons and 5-HT2C receptor activity may be important in this context. The primary aim of this study was to investigate the role of NAc shell GABA receptors on ventral tegmental

  10. “Brain MR spectroscopy in autism spectrum disorder—the GABA excitatory/inhibitory imbalance theory revisited”

    PubMed Central

    Brix, Maiken K.; Ersland, Lars; Hugdahl, Kenneth; Grüner, Renate; Posserud, Maj-Britt; Hammar, Åsa; Craven, Alexander R.; Noeske, Ralph; Evans, C. John; Walker, Hanne B.; Midtvedt, Tore; Beyer, Mona K.

    2015-01-01

    Magnetic resonance spectroscopy (MRS) from voxels placed in the left anterior cingulate cortex (ACC) was measured from 14 boys with Autism Spectrum Disorder (ASD) and 24 gender and age-matched typically developing (TD) control group. Our main aims were to compare the concentration of ?-aminobutyric acid (GABA) between the two groups, and to investigate the relationship between brain metabolites and autism symptom severity in the ASD group. We did find a significant negative correlation in the ASD group between Autism Spectrum Screening Questionnaire (ASSQ) and GABA+/Cr, which may imply that severity of symptoms in ASD is associated with differences in the level of GABA in the brain, supporting the excitatory/inhibitory (E/I) imbalance theory. However we did not find a significant difference between the two groups in GABA levels. PMID:26157380

  11. GABA and GABA receptors in the central nervous system and other organs

    Microsoft Academic Search

    Masahito Watanabe; Kentaro Maemura; Kiyoto Kanbara; Takumi Tamayama; Hana Hayasaki

    2002-01-01

    ?-Aminobutyrate (GABA) is a major inhibitory neurotransmitter in the adult mammalian brain. GABA is also considered to be a multifunctional molecule that has different situational functions in the central nervous system, the peripheral nervous system, and in some nonneuronal tissues. GABA is synthesized primarily from glutamate by glutamate decarboxylase (GAD), but alternative pathways may be important under certain situations. Two

  12. Mood regulation. GABA/glutamate co-release controls habenula output and is modified by antidepressant treatment.

    PubMed

    Shabel, Steven J; Proulx, Christophe D; Piriz, Joaquin; Malinow, Roberto

    2014-09-19

    The lateral habenula (LHb), a key regulator of monoaminergic brain regions, is activated by negatively valenced events. Its hyperactivity is associated with depression. Although enhanced excitatory input to the LHb has been linked to depression, little is known about inhibitory transmission. We discovered that ?-aminobutyric acid (GABA) is co-released with its functional opponent, glutamate, from long-range basal ganglia inputs (which signal negative events) to limit LHb activity in rodents. At this synapse, the balance of GABA/glutamate signaling is shifted toward reduced GABA in a model of depression and increased GABA by antidepressant treatment. GABA and glutamate co-release therefore controls LHb activity, and regulation of this form of transmission may be important for determining the effect of negative life events on mood and behavior. PMID:25237099

  13. Substantia Nigra: Site of Anticonvulsant Activity Mediated by gamma -aminobutyric Acid

    Microsoft Academic Search

    Michael J. Iadarola; Karen Gale

    1982-01-01

    Localization of the anatomic substrate for anticonvulsant activity mediated by gamma -aminobutyric acid (GABA) was examined using intracerebral injections of GABA agonists. Blockade of tonic hindlimb extension in the maximal electroshock test and blockade of tonic and clonic seizures produced by pentylenetetrazole and bicuculline were obtained by elevating GABA in the ventral midbrain tegmentum. Elevation of GABA in forebrain and

  14. Synthesis of novel cognition enhancers with pyrazolo[5,1-c][1,2,4]benzotriazine core acting at ?-aminobutyric acid type A (GABA(A)) receptor.

    PubMed

    Guerrini, Gabriella; Ciciani, Giovanna; Costanzo, Annarella; Daniele, Simona; Martini, Claudia; Ghelardini, Carla; Di Cesare Mannelli, Lorenzo; Ciattini, Samuele

    2013-04-15

    Memory dysfunction associated with aging, neurodegenerative and psychiatric disorders represents an increasing medical need. Advances in research exploring the biological mechanisms underlying learning and memory have opened new potential approaches for development of memory-enhancing therapies addressed to selective neuronal targets. In this work, we synthesized some derivatives with a pyrazolo[5,1-c][1,2,4]benzotriazine core to identify ligands on GABAA receptors subtype (benzodiazepine site on GABAA-receptor) endowed with the potential of enhancing cognition activity without the side effects usually associated with non-selective GABAA modulators. In fact, there is much evidence that GABAA-R (?-aminobutyric acid, type A receptor) subtype ligands have relevance in learning and memory. In vitro and in vivo tests have been performed. Pharmacological data indicate that compounds 7, 13, 14 and 22 act as dual functional modulators of GABAA-Rs (promnemonic and anxiolytic agents) while only compounds 3 and 10 stand out as selectively displaying good antiamnesic and procognitive activity (1 and 3 mg/kg, respectively). PMID:23490154

  15. Binding of antibodies in sera from Type 1 (insulin-dependent) diabetic patients to glutamate decarboxylase from rat tissues. Evidence for antigenic and non-antigenic forms of the enzyme

    Microsoft Academic Search

    M. R. Christie; T. J. Brown; D. Cassidy

    1992-01-01

    Summary  An islet protein of Mr 64000, identified as the -amino butyric acid (GABA)-synthesizing enzyme, glutamate decarboxylase, is a major target for antibodies in Type 1 (insulin-dependent) diabetes mellitus. This enzyme is also expressed in brain and in some other tissues and may exist in multiple forms. The aim of this study was to determine the ability of antibodies from diabetic

  16. Different effects of GABAergic receptors located in the ventral tegmental area on the expression of morphine-induced conditioned place preference in rat

    Microsoft Academic Search

    Hedayat Sahraei; Yar-Ali Amiri; Ali Haeri-Rohani; Houri Sepehri; Seyed Hossein Salimi; Ali Pourmotabbed; Hassan Ghoshooni; Ali Zahirodin; Homeira Zardooz

    2005-01-01

    In the present study, an unbiased conditioned place preference paradigm was used to study the effects of intra-ventral tegmental area injections of Gama-amino-butyric acid (GABA)-A and B (GABAA and GABAB) receptor agonists and antagonists on the expression of morphine-induced conditioned place preference (CPP) in rats. Subcutaneous (s.c.) injections of morphine sulfate (5 mg\\/kg) induced CPP. Intra-ventral tegmental area administration of

  17. Hearing Loss Prevents the Maturation of GABAergic Transmission in the Auditory Cortex

    Microsoft Academic Search

    Vibhakar C. Kotak; Anne E. Takesian; Dan H. Sanes

    2008-01-01

    Inhibitory neurotransmission is a critical determinant of neuronal networkgainanddynamicrange,suggestingthatnetworkproperties are shaped by activity during development. A previous study demonstrated that sensorineural hearing loss (SNHL) in gerbils leads to smaller inhibitory potentials in L2\\/3 pyramidal neurons in the thalamorecipient auditory cortex, ACx. Here, we explored the mechanisms that account for proper maturation of g-amino butyric acid (GABA)ergic transmission. SNHL was induced

  18. Duplication of the Rdl GABA receptor subunit gene in an insecticide-resistant aphid, Myzus persicae

    Microsoft Academic Search

    N. Anthony; T. Unruh; D. Ganser; R. ffrench-Constant

    1998-01-01

    Resistance to cyclodiene insecticides is associated with replacements of a single amino acid (alanine 302) in a ?-aminobutyric acid (GABA) receptor subunit encoded by the single-copy gene Resistance to dieldrin (Rdl). Alanine 302 is predicted to reside within the second membrane-spanning region of the Rdl receptor, a region that is thought to line the integral chloride ion channel pore. In

  19. Genome Sequence of Lactococcus lactis subsp. lactis NCDO 2118, a GABA-Producing Strain

    PubMed Central

    Oliveira, Letícia C.; Saraiva, Tessália D. L.; Soares, Siomar C.; Ramos, Rommel T. J.; Sá, Pablo H. C. G.; Carneiro, Adriana R.; Miranda, Fábio; Freire, Matheus; Renan, Wendel; Júnior, Alberto F. O.; Santos, Anderson R.; Pinto, Anne C.; Souza, Bianca M.; Castro, Camila P.; Diniz, Carlos A. A.; Rocha, Clarissa S.; Mariano, Diego C. B.; de Aguiar, Edgar L.; Folador, Edson L.; Barbosa, Eudes G. V.; Aburjaile, Flavia F.; Gonçalves, Lucas A.; Guimarães, Luís C.; Azevedo, Marcela; Agresti, Pamela C. M.; Silva, Renata F.; Tiwari, Sandeep; Almeida, Sintia S.; Hassan, Syed S.; Pereira, Vanessa B.; Abreu, Vinicius A. C.; Pereira, Ulisses P.; Dorella, Fernanda A.; Carvalho, Alex F.; Pereira, Felipe L.; Leal, Carlos A. G.; Figueiredo, Henrique C. P.; Silva, Artur; Miyoshi, Anderson

    2014-01-01

    Lactococcus lactis subsp. lactis NCDO 2118 is a nondairy lactic acid bacterium, a xylose fermenter, and a gamma-aminobutyric acid (GABA) producer isolated from frozen peas. Here, we report the complete genome sequence of L. lactis NCDO 2118, a strain with probiotic potential activity. PMID:25278529

  20. Structure, function, and plasticity of GABA transporters

    PubMed Central

    Scimemi, Annalisa

    2014-01-01

    GABA transporters belong to a large family of neurotransmitter:sodium symporters. They are widely expressed throughout the brain, with different levels of expression in different brain regions. GABA transporters are present in neurons and in astrocytes and their activity is crucial to regulate the extracellular concentration of GABA under basal conditions and during ongoing synaptic events. Numerous efforts have been devoted to determine the structural and functional properties of GABA transporters. There is also evidence that the expression of GABA transporters on the cell membrane and their lateral mobility can be modulated by different intracellular signaling cascades. The strength of individual synaptic contacts and the activity of entire neuronal networks may be finely tuned by altering the density, distribution and diffusion rate of GABA transporters within the cell membrane. These findings are intriguing because they suggest the existence of complex regulatory systems that control the plasticity of GABAergic transmission in the brain. Here we review the current knowledge on the structural and functional properties of GABA transporters and highlight the molecular mechanisms that alter the expression and mobility of GABA transporters at central synapses. PMID:24987330

  1. 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

    ?-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

  2. Early development of GABA-like immunoreactive cells in the retina of turtle embryos.

    PubMed

    Versaux-Botteri, C; Hergueta, S; Pieau, C; Wasowicz, M; Dalil-Thiney, N; Nguyen-Legros, J

    1994-11-18

    Gamma aminobutyric acid (GABA) is one of the earliest neuroactive substances appearing in the developing central nervous system. The distribution and the time course of the appearance of GABA-like immunoreactivity in the retina of the turtle Emys orbicularis were investigated from embryonic stage 13 to hatching. The first GABA-like immunoreactive cells were observed at stage 14. These cells were located in both the scleral third of the neuroblastic layer and the inner layers of the retina. They were identified as presumptive immature horizontal cells and amacrine cells, respectively. The observation of numerous labelled fibers in the nerve fiber layer suggests that some of the GABA-like immunoreactive cells in the layers were ganglion cells. The development of GABA-like immunoreactive cells followed a gradient of maturation from central to peripheral retina. At hatching, the central retina appeared nearly morphologically mature. In conclusion, GABA is present before the morphofunctional maturation of the retina and this precocious existence supports the idea of its involvement in a neurotrophic role preceding the establishment of synaptic connections and neurotransmitter function. PMID:7697864

  3. Prefrontal cortical GABA transmission modulates discrimination and latent inhibition of conditioned fear: relevance for schizophrenia.

    PubMed

    Piantadosi, Patrick T; Floresco, Stan B

    2014-09-01

    Inhibitory gamma-aminobutyric acid (GABA) transmission within the prefrontal cortex (PFC) regulates numerous functions, and perturbations in GABAergic transmission within this region have been proposed to contribute to some of the cognitive and behavioral abnormalities associated with disorders such as schizophrenia. These abnormalities include deficits in emotional regulation and aberrant attributions of affective salience. Yet, how PFC GABA regulates these types of emotional processes are unclear. To address this issue, we investigated the contribution of PFC GABA transmission to different aspects of Pavlovian emotional learning in rats using translational discriminative fear conditioning and latent inhibition (LI) assays. Reducing prelimbic PFC GABAA transmission via infusions of the antagonist bicuculline before the acquisition or expression of fear conditioning eliminated the ability to discriminate between an aversive conditioned stimulus (CS+) paired with footshock vs a neutral CS-, resembling similar deficits observed in schizophrenic patients. In a separate experiment, blockade of PFC GABAA receptors before CS preexposure (PE) and conditioning did not affect subsequent expression of LI, but did enhance fear in rats that were not preexposed to the CS. In contrast, PFC GABA-blockade before a fear expression test disrupted the recall of learned irrelevance and abolished LI. These data suggest that normal PFC GABA transmission is critical for regulating and mitigating multiple aspects of aversive learning, including discrimination between fear vs safety signals and recall of information about the irrelevance of stimuli. Furthermore, they suggest that similar deficits in emotional regulation observed in schizophrenia may be driven in part by deficient PFC GABA activity. PMID:24784549

  4. Effects of intraventricular taurine, homotaurine and GABA on serum prolactin and thyrotropin levels in female and in male rats.

    PubMed

    Mäkinen, M; Ahtee, L; Rosenqvist, K; Tuominen, R K; Männistö, P

    1993-01-01

    Serum prolactin and thyrotropin levels of conscious, unrestrained male and female rats were compared after intracerebroventricular (i.c.v.) administration of taurine, gamma-aminobutyric acid (GABA) and homotaurine. The amino acids studied had no clear effect on serum basal thyrotropin levels in male or female rats. All amino acids elevated serum prolactin levels in female rats at the dose of 5 mumol/rat; homotaurine by about 18-fold, taurine and GABA by 3-fold. Only homotaurine elevated serum prolactin of male rats at this dose, but its effect was less pronounced (p < 0.01) in male than in female rats. Although homotaurine was clearly more potent than the two other amino acids, at the dose of 10 mumol/rat taurine and GABA also elevated serum prolactin in male rats. These findings show that there are gender-related differences in the responses of serum prolactin levels to homotaurine, taurine and GABA in rats. The tuberoinfundibular dopaminergic pathway, which exerts tonic inhibitory influence on prolactin secretion, is sexually differentiated. Hence the gender-related differences in the effects of the amino acids on prolactin secretion suggest that they might inhibit dopamine release from the median eminence. In case of homotaurine, the gender effect was most pronounced. The less clear dependence of GABA's effect on the gender is in accordance with the suggestions that GABA influences the secretion of serum prolactin by more than one mechanism. PMID:8123228

  5. Thalamic GABA Predicts Fine Motor Performance in Manganese-Exposed Smelter Workers

    PubMed Central

    Long, Zaiyang; Li, Xiang-Rong; Xu, Jun; Edden, Richard A. E.; Qin, Wei-Ping; Long, Li-Ling; Murdoch, James B.; Zheng, Wei; Jiang, Yue-Ming; Dydak, Ulrike

    2014-01-01

    Overexposure to manganese (Mn) may lead to parkinsonian symptoms including motor deficits. The main inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is known to play a pivotal role in the regulation and performance of movement. Therefore this study was aimed at testing the hypothesis that an alteration of GABA following Mn exposure may be associated with fine motor performance in occupationally exposed workers and may underlie the mechanism of Mn-induced motor deficits. A cohort of nine Mn-exposed male smelter workers from an Mn-iron alloy factory and 23 gender- and age-matched controls were recruited and underwent neurological exams, magnetic resonance spectroscopy (MRS) measurements, and Purdue pegboard motor testing. Short-echo-time MRS was used to measure N-Acetyl-aspartate (NAA) and myo-inositol (mI). GABA was detected with a MEGA-PRESS J-editing MRS sequence. The mean thalamic GABA level was significantly increased in smelter workers compared to controls (p?=?0.009). Multiple linear regression analysis reveals (1) a significant association between the increase in GABA level and the duration of exposure (R2?=?0.660, p?=?0.039), and (2) significant inverse associations between GABA levels and all Purdue pegboard test scores (for summation of all scores R2?=?0.902, p?=?0.001) in the smelter workers. In addition, levels of mI were reduced significantly in the thalamus and PCC of smelter workers compared to controls (p?=?0.030 and p?=?0.009, respectively). In conclusion, our results show clear associations between thalamic GABA levels and fine motor performance. Thus in Mn-exposed subjects, increased thalamic GABA levels may serve as a biomarker for subtle deficits in motor control and may become valuable for early diagnosis of Mn poisoning. PMID:24505436

  6. 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 ?-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

  7. Cortical GABA Levels in Primary Insomnia

    PubMed Central

    Morgan, Peter T.; Pace-Schott, Edward F.; Mason, Graeme F.; Forselius, Erica; Fasula, Madonna; Valentine, Gerald W.; Sanacora, Gerard

    2012-01-01

    Study Objectives: GABA is increasingly recognized as an important neurotransmitter for the initiation and maintenance of sleep. We sought to measure cortical GABA content through proton magnetic resonance spectroscopy (MRS) in persons with and without primary insomnia, and relate brain GABA levels to polysomnographic sleep measures. Design: Two-group comparison study. Setting: Outpatient study at a university research clinic. Participants: Non-medicated persons with primary insomnia (N = 16) and no sleep complaints (N = 17). Interventions: Participants kept sleep diaries and a regular time-in-bed schedule for 9 days, culminating in 2 consecutive nights of ambulatory polysomnography and a single proton MRS session. The main outcome measure was occipital GABA/creatine ratios; secondary measures included sleep measurements and relationship between polysomnographically measured time awake after sleep onset and occipital GABA content. Measurements and Results: The primary insomnia group was distinguished from persons with no sleep complaints on self-reported and polysomnographically measured sleep. The two groups did not differ in age, sex, body mass index, habitual bed- and wake-times, napping, use of caffeine, or use of cigarettes. Mean occipital GABA level was 12% higher in persons with insomnia than in persons without sleep complaints (P < 0.05). In both groups, GABA levels correlated negatively with polysomnographically measured time awake after sleep onset (P < 0.05). Conclusions: Increased GABA levels in persons with insomnia may reflect an allostatic response to chronic hyperarousal. The preserved, negative relationship between GABA and time awake after sleep onset supports this notion, indicating that the possible allostatic response is adaptive. Citation: Morgan PT; Pace-Schott EF; Mason GF; Forselius E; Fasula M; Valentine GW; Sanacora G. Cortical GABA levels in primary insomnia. SLEEP 2012;35(6):807-814. PMID:22654200

  8. Comparison of cellular and medium insulin and GABA content as markers for living beta-cells.

    PubMed

    Wang, Chen; Ling, Zhidong; Pipeleers, Daniel

    2005-02-01

    Experimental and therapeutic use of islet cell preparations could benefit from assays that measure variations in the mass of living beta-cells. Because processes of cell death can be followed by depletion and/or discharge of cell-specific substances, we examined whether in vitro conditions of beta-cell death resulted in changes in tissue and medium content of insulin and of gamma-aminobutyric acid (GABA), two beta-cell-specific compounds with different cellular localization and turnover. Exposure of rat purified beta-cells to streptozotocin (5 mM, 120 min) or to the nitric oxide donor GEA-3162 (GEA; 50 microM, 120 min) caused 80% necrosis within 24 h; at the end of this period, cellular insulin content was not significantly decreased, but cellular GABA content was reduced by 70%; when cultured at basal glucose (6 mM), the toxin-exposed cells did not discharge less insulin but released 80% less GABA in the period 8-24 h. As in rat beta-cell purification, GABA comigrated with insulin during human islet cell isolation. Twenty-four hours after GEA (500 microM, 120 min), human islet cell preparations exhibited 90% dead cells and a 45 and 90% reduction, respectively, in tissue insulin and GABA content; in the period 9-24 h, insulin discharge in the medium was not reduced, but GABA release was decreased by 90%. When rat beta-cells were cultured for 24 h with nontoxic interleukin (IL)-1beta concentrations that suppressed glucose-induced insulin release, cellular GABA content was not decreased and GABA release increased by 90% in the period 8-24 h. These data indicate that a reduction in cellular and medium GABA levels is more sensitive than insulin as a marker for the presence of dead beta-cells in isolated preparations. Pancreatic GABA content also rapidly decreased after streptozotocin injection and remained unaffected by 12 h of hyperglycemia. At further variance with insulin, GABA release from living beta-cells depends little on its cellular content but increases with IL-1beta-induced alterations in beta-cell phenotype. PMID:15454397

  9. Novel Properties of a Mouse c-Aminobutyric Acid Transporter (GAT4) M.H. Karakossian1

    E-print Network

    Eskandari, Sepehr

    is followed by rapid GABA-induced translo- cation of the ligands across the plasma membrane. Thus, Na+ binding resting level of GABA in the brain extracellular fluid and, hence, prevent GABA receptor desensitization-aminobutyric acid (GABA) transporter GAT4 (homologous to rat/ human GAT-3) in Xenopus laevis oocytes and examined

  10. ORIGINAL ARTICLE -Aminolevulinic acid and its methyl ester induce

    E-print Network

    Lübbert, Hermann

    -dependent with considerably different kinetics for both compounds. While partial inhibition occurred using L-arginine, Pp root ganglion F12 Nutrient mixture F12 GABA -Aminobutyric acid GAT GABA transporter L-Arg L-Arginine

  11. Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases.

    PubMed

    Yuan, Hongjie; Low, Chian-Ming; Moody, Olivia A; Jenkins, Andrew; Traynelis, Stephen F

    2015-07-01

    The advent of whole exome/genome sequencing and the technology-driven reduction in the cost of next-generation sequencing as well as the introduction of diagnostic-targeted sequencing chips have resulted in an unprecedented volume of data directly linking patient genomic variability to disorders of the brain. This information has the potential to transform our understanding of neurologic disorders by improving diagnoses, illuminating the molecular heterogeneity underlying diseases, and identifying new targets for therapeutic treatment. There is a strong history of mutations in GABA receptor genes being involved in neurologic diseases, particularly the epilepsies. In addition, a substantial number of variants and mutations have been found in GABA receptor genes in patients with autism, schizophrenia, and addiction, suggesting potential links between the GABA receptors and these conditions. A new and unexpected outcome from sequencing efforts has been the surprising number of mutations found in glutamate receptor subunits, with the GRIN2A gene encoding the GluN2A N-methyl-d-aspartate receptor subunit being most often affected. These mutations are associated with multiple neurologic conditions, for which seizure disorders comprise the largest group. The GluN2A subunit appears to be a locus for epilepsy, which holds important therapeutic implications. Virtually all ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor mutations, most of which occur within GRIA3, are from patients with intellectual disabilities, suggesting a link to this condition. Similarly, the most common phenotype for kainate receptor variants is intellectual disability. Herein, we summarize the current understanding of disease-associated mutations in ionotropic GABA and glutamate receptor families, and discuss implications regarding the identification of human mutations and treatment of neurologic diseases. PMID:25904555

  12. GABA tea prevents cardiac fibrosis by attenuating TNF-alpha and Fas/FasL-mediated apoptosis in streptozotocin-induced diabetic rats.

    PubMed

    Cherng, Shur-Hueih; Huang, Chih-Yang; Kuo, Wei-Wen; Lai, Shue-Er; Tseng, Chien-Yu; Lin, Yueh-Min; Tsai, Fuu-Jen; Wang, Hsueh-Fang

    2014-03-01

    GABA tea is a tea product that contains a high level of gamma-aminobutyric acid (GABA). This study investigated the effects of GABA tea on the heart in a diabetic rat model. Male Wistar rats were injected with 55mg/kg streptozotocin (STZ) to induce diabetes for 2weeks and then orally given dosages of 4.55 and 45.5mg/kg/day GABA tea extract for 6weeks. The results revealed that fasting blood glucose levels returned to normal levels in GABA tea-treated diabetic rats, but not in the untreated diabetic rats. Additionally, GABA tea effectively inhibited cardiac fibrosis induced by STZ. Further experiments showed that the STZ-induced protein levels of tumor necrosis factor-alpha (TNF-alpha), Fas, activated caspase-8 and caspase-3 were significantly inhibited by the GABA tea treatment. Therefore, our data suggest that the inhibiting effect of GABA tea on STZ-induced cardiac fibrosis in diabetic rats may be mediated by reducing blood glucose and further attenuating TNF-alpha expression and/or Fas/Fas ligand (FasL)-mediated apoptosis. These findings will provide implications for the potential anti-diabetic properties of GABA tea. PMID:24374093

  13. The glutamine-glutamate/GABA cycle: function, regional differences in glutamate and GABA production and effects of interference with GABA metabolism.

    PubMed

    Walls, Anne B; Waagepetersen, Helle S; Bak, Lasse K; Schousboe, Arne; Sonnewald, Ursula

    2015-02-01

    The operation of a glutamine-glutamate/GABA cycle in the brain consisting of the transfer of glutamine from astrocytes to neurons and neurotransmitter glutamate or GABA from neurons to astrocytes is a well-known concept. In neurons, glutamine is not only used for energy production and protein synthesis, as in other cells, but is also an essential precursor for biosynthesis of amino acid neurotransmitters. An excellent tool for the study of glutamine transfer from astrocytes to neurons is [(14)C]acetate or [(13)C]acetate and the glial specific enzyme inhibitors, i.e. the glutamine synthetase inhibitor methionine sulfoximine and the tricarboxylic acid cycle (aconitase) inhibitors fluoro-acetate and -citrate. Acetate is metabolized exclusively by glial cells, and [(13)C]acetate is thus capable when used in combination with magnetic resonance spectroscopy or mass spectrometry, to provide information about glutamine transfer. The present review will give information about glutamine trafficking and the tools used to map it as exemplified by discussions of published work employing brain cell cultures as well as intact animals. It will be documented that considerably more glutamine is transferred from astrocytes to glutamatergic than to GABAergic neurons. However, glutamine does have an important role in GABAergic neurons despite their capability of re-utilizing their neurotransmitter by re-uptake. PMID:25380696

  14. Effects of taurine, homotaurine and GABA on hypothalamic and striatal dopamine metabolism

    Microsoft Academic Search

    Elina Panula-Lehto; Minna Mäkinen; Liisa Ahtee

    1992-01-01

    To elucidate the effects of taurine on hypothalamic and striatal dopaminergic neurotransmission we compared its effects to those of ?-aminobutyric acid (GABA) and homotaurine (a GABAA-receptor agonist) on hypothalamic and striatal concentrations of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and, in the case of striatum, 3-methoxytyramine (3-MT) in rats. In addition, hypothalamic and striatal 5-hydroxytryptamine

  15. 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, ?-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 ?5, ?2, ?3, and ? 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

  16. Effects of Yoga Versus Walking on Mood, Anxiety, and Brain GABA Levels: A Randomized Controlled MRS Study

    PubMed Central

    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

    2010-01-01

    Abstract Objectives Yoga and exercise have beneficial effects on mood and anxiety. ?-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. Methods 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. Results 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. Conclusions 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. PMID:20722471

  17. An Arginine Involved in GABA Binding and Unbinding But Not Gating of the GABAA Receptor

    Microsoft Academic Search

    David A. Wagner; Cynthia Czajkowski; Mathew V. Jones

    2004-01-01

    GABAA receptor function can be conceptually divided into interactions between ligand and receptor (binding) and the opening and closing of the ligand-bound channel (gating). The relationship between binding, gating, and receptor structure remains unclear. Studies of mutations have identified many amino acid residues that contribute to the GABAbinding site. Most of these studies assayed changes in GABA dose-response curves, which

  18. Quantitative Autoradiography Reveals Selective Changes in Cerebellar GABA Receptors of the Rat Mutant Dystonic

    Microsoft Academic Search

    Mitchell Beales; Joan F. Lorden; Elizabeth Walz; Gary A. Oltmansl

    1990-01-01

    In the rat mutant dystonic (df), glutamic acid decarboxylase (GAD) activity in the deep cerebellar nuclei (DCN) is elevated compared to normal littermates. The distribution of this in- crease within the DCN, and the effect upon GABA receptor density, was assessed in 25d-old animals. GAD activity was increased 45, 41, and 74% in the medial, interpositus, and lateral divisions of

  19. Anticonvulsant and antiepileptogenic effects of GABA A receptor ligands in pentylenetetrazole-kindled mice

    Microsoft Academic Search

    Suzanne L Hansen; Bonnie B Sperling; Connie Sánchez

    2004-01-01

    Although animal models based on pentylenetetrazole (PTZ) are widely used, the mechanism by which PTZ elicits its action is not very well understood. At the molecular level, a generally accepted mechanism of PTZ is noncompetitive antagonism of the ?-aminobutyric acid (GABA)A receptor complex. By a systematic pharmacological investigation of various GABAA receptor ligands, our aim was to gain a better

  20. Proton inhibition of GABA-activated current in rat primary sensory neurons

    Microsoft Academic Search

    J. Zhai; Robert W. Peoples; Chaoying Li

    1998-01-01

    The modulation of the Cl– current activated by ?-aminobutyric acid (GABA) by changes in extracellular pH in freshly isolated rat dorsal root ganglia\\u000a (DRG) neurons was studied using the whole-cell patch-clamp technique. In the pH range of 5.0–9.0, increased extracellular\\u000a pH enhanced, and decreased extracellular pH suppressed, current activated by 10 ?M GABA in a reversible and concentration-dependent\\u000a manner with an

  1. SDF and GABA interact to regulate axophilic migration of GnRH neurons

    PubMed Central

    Casoni, Filippo; Ian Hutchins, B.; Donohue, Duncan; Fornaro, Michele; Condie, Brian G.; Wray, Susan

    2012-01-01

    Summary Stromal derived growth factor (SDF-1) and gamma-aminobutyric acid (GABA) are two extracellular cues that regulate the rate of neuronal migration during development and may act synergistically. The molecular mechanisms of this interaction are still unclear. Gonadotropin releasing hormone-1 (GnRH) neurons are essential for vertebrate reproduction. During development, these neurons emerge from the nasal placode and migrate through the cribriform plate into the brain. Both SDF-1 and GABA have been shown to regulate the rate of GnRH neuronal migration by accelerating and slowing migration, respectively. As such, this system was used to explore the mechanism by which these molecules act to produce coordinated cell movement during development. In the present study, GABA and SDF-1 are shown to exert opposite effects on the speed of cell movement by activating depolarizing or hyperpolarizing signaling pathways, GABA via changes in chloride and SDF-1 via changes in potassium. GABA and SDF-1 were also found to act synergistically to promote linear rather than random movement. The simultaneous activation of these signaling pathways, therefore, results in tight control of cellular speed and improved directionality along the migratory pathway of GnRH neurons. PMID:22976302

  2. GABA-like immunoreactivity in nonspiking interneurons of the locust metathoracic ganglion.

    PubMed

    Wildman, M; Ott, S R; Burrows, M

    2002-12-01

    Nonspiking interneurons are important components of the premotor circuitry in the thoracic ganglia of insects. Their action on postsynaptic neurons appears to be predominantly inhibitory, but it is not known which transmitter(s) they use. Here, we demonstrate that many but not all nonspiking local interneurons in the locust metathoracic ganglion are immunopositive for GABA (gamma-aminobutyric acid). Interneurons were impaled with intracellular microelectrodes and were shown physiologically to be nonspiking. They were further characterized by defining their effects on known leg motor neurons when their membrane potential was manipulated by current injection. Lucifer Yellow was then injected into these interneurons to reveal their cell bodies and the morphology of their branches. Some could be recognised as individuals by comparison with previous detailed descriptions. Ganglia were then processed for GABA immunohistochemistry. Fifteen of the 17 nonspiking interneurons studied were immunopositive for GABA, but two were not. The results suggest that the majority of these interneurons might exert their well-characterized effects on other neurons through the release of GABA but that some appear to use a transmitter other than GABA. These nonspiking interneurons are therefore not an homogeneous population with regard to their putative transmitter. PMID:12409491

  3. Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke.

    PubMed

    Clarkson, Andrew N; Huang, Ben S; Macisaac, Sarah E; Mody, Istvan; Carmichael, S Thomas

    2010-11-11

    Stroke is a leading cause of disability, but no pharmacological therapy is currently available for promoting recovery. The brain region adjacent to stroke damage-the peri-infarct zone-is critical for rehabilitation, as it shows heightened neuroplasticity, allowing sensorimotor functions to re-map from damaged areas. Thus, understanding the neuronal properties constraining this plasticity is important for the development of new treatments. Here we show that after a stroke in mice, tonic neuronal inhibition is increased in the peri-infarct zone. This increased tonic inhibition is mediated by extrasynaptic GABA(A) receptors and is caused by an impairment in GABA (?-aminobutyric acid) transporter (GAT-3/GAT-4) function. To counteract the heightened inhibition, we administered in vivo a benzodiazepine inverse agonist specific for ?5-subunit-containing extrasynaptic GABA(A) receptors at a delay after stroke. This treatment produced an early and sustained recovery of motor function. Genetically lowering the number of ?5- or ?-subunit-containing GABA(A) receptors responsible for tonic inhibition also proved beneficial for recovery after stroke, consistent with the therapeutic potential of diminishing extrasynaptic GABA(A) receptor function. Together, our results identify new pharmacological targets and provide the rationale for a novel strategy to promote recovery after stroke and possibly other brain injuries. PMID:21048709

  4. The role of the GABA system in amphetamine-type stimulant use disorders.

    PubMed

    Jiao, Dongliang; Liu, Yao; Li, Xiaohong; Liu, Jinggen; Zhao, Min

    2015-01-01

    Abuse of amphetamine-type stimulants (ATS) has become a global public health problem. ATS causes severe neurotoxicity, which could lead to addiction and could induce psychotic disorders or cognitive dysfunctions. However, until now, there has been a lack of effective medicines for treating ATS-related problems. Findings from recent studies indicate that in addition to the traditional dopamine-ergic system, the GABA (gamma-aminobutyric acid)-ergic system plays an important role in ATS abuse. However, the exact mechanisms of the GABA-ergic system in amphetamine-type stimulant use disorders are not fully understood. This review discusses the role of the GABA-ergic system in ATS use disorders, including ATS induced psychotic disorders and cognitive dysfunctions. We conclude that the GABA-ergic system are importantly involved in the development of ATS use disorders through multiple pathways, and that therapies or medicines that target specific members of the GABA-ergic system may be novel effective interventions for the treatment of ATS use disorders. PMID:25999814

  5. The “Stop” and “Go” of Nicotine Dependence: Role of GABA and Glutamate

    PubMed Central

    D’Souza, Manoranjan S.; Markou, Athina

    2013-01-01

    Nicotine plays an important role in the initiation and maintenance of tobacco smoking. Importantly, chronic nicotine exposure alters the function of brain reward systems, resulting in the development of a nicotine-dependent state. This nicotine-dependent state is associated with aversive affective and somatic signs upon abstinence from smoking, often leading to relapse in abstinent smokers. This article reviews the role of the major excitatory and inhibitory neurotransmitters glutamate and ?-aminobutyric acid (GABA), respectively, in both the reinforcing effects of nicotine and development of nicotine dependence. Evidence suggests that blockade of glutamatergic neurotransmission attenuates both nicotine intake and nicotine seeking. In contrast, both nicotine intake and nicotine seeking are attenuated when GABA neurotransmission is facilitated. In conclusion, medications that either attenuate/negatively modulate glutamatergic neurotransmission or facilitate/positively modulate GABA neurotransmission may be useful for promoting smoking cessation in humans. PMID:23732855

  6. Repeated phencyclidine administration alters glutamate release and decreases GABA markers in the prefrontal cortex of rats

    PubMed Central

    Amitai, Nurith; Kuczenski, Ronald; Behrens, M. Margarita; Markou, Athina

    2011-01-01

    Repeated phencyclidine (PCP) administration induces cognitive disruptions resembling those seen in schizophrenia. Alterations in glutamate transmission and ?-aminobutyric acid (GABA) function in the prefrontal cortex (PFC) have been implicated in these PCP-induced deficits, as well as in cognitive symptoms of schizophrenia. PCP-induced cognitive deficits are reversed by chronic treatment with the atypical antipsychotic clozapine in rats. We investigated the effects of a single injection vs. repeated administration of PCP on glutamate levels in the PFC using in vivo microdialysis. Furthermore, we examined how these PCP regimens affect GABA neuronal markers in the PFC. Finally, we investigated the effects of clozapine on disruptions in glutamate levels and GABA neuronal markers induced by repeated PCP administration. Acute PCP administration (2 mg/kg) increased extracellular PFC glutamate; this increase appeared blunted, but was not eliminated, after repeated PCP pretreatment. PCP administration also strongly decreased levels of parvalbumin and glutamic acid decarboxylase-67 (two markers of GABA function) in the PFC, an effect that was maintained after a 10 day drug-free washout period and unaltered by the resumption of repeated PCP injections. All of the observed PCP effects were attenuated by chronic treatment with clozapine, an atypical antipsychotic that has partial effectiveness on cognitive impairment in schizophrenia. These findings suggest that abnormal cortical glutamate transmission, possibly driven by pathological changes in GABA function in parvalbumin-positive fast-spiking interneurons, may underlie some of the cognitive deficits in schizophrenia. A better understanding of glutamate and GABA dysregulation in schizophrenia may uncover new treatment targets for schizophrenia-related cognitive dysfunction. PMID:21238466

  7. Effects of benzodiazepines and non-benzodiazepine compounds on the GABA-induced response in frog isolated sensory neurones.

    PubMed

    Yakushiji, T; Fukuda, T; Oyama, Y; Akaike, N

    1989-11-01

    1. The effects of benzodiazepines and non-benzodiazepine compounds on the gamma-aminobutyric acid (GABA)-induced chloride current (ICl) were studied in frog isolated sensory neurones by use of a concentration-jump (termed 'concentration-clamp') technique, under single-electrode voltage-clamp conditions. The drugs used were classified into four categories as follows: full benzodiazepine receptor agonists (diazepam, clonazepam, nitrazepam, midazolam, clotiazepam and etizolam), partial agonists (CL 218,872, Ro 16-6028, Ro 17-1812 and Ro 23-0364), inverse agonists (Ro 15-3505, FG 7142 and beta-CCE) and a benzodiazepine receptor antagonist, Ro 15-1788 (flumazenil). 2. All full agonists at concentrations of 3 x 10(-6) M or less increased dose-dependently the peak amplitude of ICl elicited by 3 x 10(-6) M GABA to twice to three times larger than the control. However, no further augmentation of the GABA response was observed at concentrations of 1 x 10(-5) M or higher. Partial agonists also showed a dose-dependent augmentation of the GABA response at concentrations ranging from 3 x 10(-8) M to 3 x 10(-5) M, but their efficacies of augmentation of the GABA response were only about half or less of those of full agonists. Of the inverse agonists, beta-CCE had a unique dose-dependent effect on the GABA response. Beta-CCE reduced dose-dependently the GABA response at concentrations of less than 3 x 10(-6) M, but augmented it at concentrations of 3 x 10(-5) M and 6 x 10(-5) M. The inverse agonists reduced dose-dependently the GABA response. The benzodiazepine antagonist, flumazenil, slightly augmented the GABA response at concentrations between 3 x 10 7M and 3 x 10 5 M. 3. These results show clear differences in the effects on the GABA response between these four categories of compounds known to affect the benzodiazepine recognition site of the GABA/ benzodiazepine receptor-chloride channel complex. Our experimental system of frog isolated sensory neurones and a 'concentration-clamp' technique appears to be useful for evaluating efficacy of compounds on responses mediated by the GABA/benzodiazepine receptor-chloride channel complex. PMID:2574062

  8. GABAÂ?s Control of Stem and Cancer Cell Proliferation in Adult Neural and Peripheral Niches

    NSDL National Science Digital Library

    Stephanie Z. Young (Yale University Neurosurgery)

    2009-06-01

    Aside from traditional neurotransmission and regulation of secretion, {gamma}-amino butyric acid (GABA) through GABAA receptors negatively regulates proliferation of pluripotent and neural stem cells in embryonic and adult tissue. There has also been evidence that GABAergic signaling and its control over proliferation is not only limited to the nervous system, but is widespread through peripheral organs containing adult stem cells. GABA has emerged as a tumor signaling molecule in the periphery that controls the proliferation of tumor cells and perhaps tumor stem cells. Here, we will discuss GABAÂ?s presence as a near-universal signal that may be altered in tumor cells resulting in modified mitotic activity.

  9. Effects of taurine, homotaurine and GABA on hypothalamic and striatal dopamine metabolism.

    PubMed

    Panula-Lehto, E; Mäkinen, M; Ahtee, L

    1992-07-01

    To elucidate the effects of taurine on hypothalamic and striatal dopaminergic neurotransmission we compared its effects to those of gamma-aminobutyric acid (GABA) and homotaurine (a GABAA-receptor agonist) on hypothalamic and striatal concentrations of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and, in the case of striatum, 3-methoxytyramine (3-MT) in rats. In addition, hypothalamic and striatal 5-hydroxytryptamine (5-HT) und 5-hydroxyindoleacetic acid, hypothalamic noradrenaline (NA) and 3-methoxy-4-hydroxyphenylglycol sulfate, and pituitary DA concentrations were also measured. The amino acids were injected into the lateral brain ventricles of conscious male rats in doses of 10 and 36 mumol/rat, and rat were sacrificed 15 and 60 min later, respectively. Homotaurine (by 11%) but not the other two amino acids elevated striatal DA, whereas hypothalamic DA was increased by both taurine (36%) and homotaurine (31%). All three amino acids at 36 mumol elevated striatal DOPAC, homotaurine (51%) more than taurine (31%) or GABA (30%), and hypothalamic DOPAC, both taurine (102%) and homotaurine (82%) clearly more than GABA (34%). Neither striatal nor hypothalamic HVA was altered by any of the amino acids. At 10 mumol the amino acids decreased striatal 3-MT by about 40%. At 36 mumol taurine and homotaurine reduced 3-MT by about 70%, whereas increasing the dose of GABA did not further reduce 3-MT. Both taurine and homotaurine at 36 mumol decreased hypothalamic NA content. Neither hypothalamic nor striatal 5-HT metabolism was altered. In the neurointermediate lobe of the pituitary gland taurine at 10 mumol but not at 36 mumol slightly (20%) increased DA.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1407006

  10. The benzodiazepine site of the GABA A receptor: an old target with new potential?

    Microsoft Academic Search

    Alan N Bateson

    2004-01-01

    The gamma-aminobutyric acid-A (GABAA) receptors is the target for the most widely prescribed sleep medicines. It is a ligand-gated ion channel, activated by the amino acid neurotransmitter GABA, which normally results in hyperpolarization of neurons leading to reduced action potential firing, and thereby a reduction in neuronal activity. It has a rich pharmacology with a number of separate modulator binding

  11. GABA-ergic neurons in the leach central nervous system

    SciTech Connect

    Cline, H.T.

    1985-01-01

    GABA is a candidate for an inhibitory neurotransmitter in the leech central nervous system because of the well-documented inhibitory action of GABA in other invertebrates. To demonstrate that GABA meets the criteria used to identify a substance as a neurotransmitter, the author examined GABA metabolism and synaptic interactions of inhibitory motor neurons in two leech species, Hirudo medicinalis and Haementeria ghilianii. Segmental ganglia of the leech ventral nerve cord and identified inhibitors have the capacity to synthesize GABA when incubated in the presence of the precursor glutamate. Application of GABA to cell bodies of excitatory motor neurons or muscle fibers innervated by the inhibitors hyperpolarizes the membrane potential of the target cell and activates a chloride ion conductance channel, similar to the inhibitory membrane response following intracellular stimulation of the inhibitor. Bicuculline methiodide (5 x 10/sup -5/M), GABA receptor antagonist, blocks reversibly the response to applied GABA and the inhibitory synaptic inputs onto the postsynaptic neurons or muscle fibers without interfering with their excitatory inputs. Furthermore, the inhibitors are included among approximately 25 neurons per segmental ganglion that take up GABA by a high affinity uptake system, as revealed by /sup 3/H-GABA-autoradiography. The development of the capacities to synthesize and to take up GABA were examined in leech embryos. The embryos are able to synthesize GABA at early stages of the development of the nervous system, before any neurons have extended neutrites.

  12. Locally infused taurine, GABA and homotaurine alter differently the striatal extracellular concentrations of dopamine and its metabolites in rats.

    PubMed

    Ruotsalainen, M; Majasaari, M; Salimäki, J; Ahtee, L

    1998-01-01

    We studied in vivo the effects of locally infused taurine (50, 150, and 450 mM) on the striatal dopamine and its metabolites in comparison with those of GABA and homotaurine, a GABAA receptor agonist, in freely moving rats. The extracellular dopamine concentration was elevated maximally 2.5-, 2- and 4-fold by taurine, GABA and homotaurine, respectively. At 150 mM concentration, at which the maximum effects occurred, homotaurine increased the extracellular dopamine more than taurine or GABA. When taurine and GABA were infused simultaneously with tetrodotoxin the output of dopamine did not differ from that in the presence of tetrodotoxin alone. In comparison, tetrodotoxin did not inhibit the increase in extracellular dopamine caused by homotaurine. Furthermore, omission of calcium from the perfusion fluid inhibited the increase of extracellular dopamine caused by GABA. However, it did not block the increase of dopamine caused by taurine or homotaurine. The present study suggests that the effects of intrastriatal taurine, GABA and homotaurine on the striatal extracellular dopamine differ. Thus, these amino acids seem to affect the striatal dopaminergic neurons via more than one mechanism. PMID:9871492

  13. Effects of benzodiazepines and non-benzodiazepine compounds on the GABA-induced response in frog isolated sensory neurones.

    PubMed Central

    Yakushiji, T.; Fukuda, T.; Oyama, Y.; Akaike, N.

    1989-01-01

    1. The effects of benzodiazepines and non-benzodiazepine compounds on the gamma-aminobutyric acid (GABA)-induced chloride current (ICl) were studied in frog isolated sensory neurones by use of a concentration-jump (termed 'concentration-clamp') technique, under single-electrode voltage-clamp conditions. The drugs used were classified into four categories as follows: full benzodiazepine receptor agonists (diazepam, clonazepam, nitrazepam, midazolam, clotiazepam and etizolam), partial agonists (CL 218,872, Ro 16-6028, Ro 17-1812 and Ro 23-0364), inverse agonists (Ro 15-3505, FG 7142 and beta-CCE) and a benzodiazepine receptor antagonist, Ro 15-1788 (flumazenil). 2. All full agonists at concentrations of 3 x 10(-6) M or less increased dose-dependently the peak amplitude of ICl elicited by 3 x 10(-6) M GABA to twice to three times larger than the control. However, no further augmentation of the GABA response was observed at concentrations of 1 x 10(-5) M or higher. Partial agonists also showed a dose-dependent augmentation of the GABA response at concentrations ranging from 3 x 10(-8) M to 3 x 10(-5) M, but their efficacies of augmentation of the GABA response were only about half or less of those of full agonists. Of the inverse agonists, beta-CCE had a unique dose-dependent effect on the GABA response. Beta-CCE reduced dose-dependently the GABA response at concentrations of less than 3 x 10(-6) M, but augmented it at concentrations of 3 x 10(-5) M and 6 x 10(-5) M. The inverse agonists reduced dose-dependently the GABA response.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2574062

  14. Age-related Hearing Loss: GABA, Nicotinic Acetylcholine and NMDA Receptor Expression Changes in Spiral Ganglion Neurons of the Mouse

    PubMed Central

    Tang, Xiaolan; Zhu, Xiaoxia; Ding, Bo; Walton, Joseph P.; Frisina, Robert D.; Su, Jiping

    2014-01-01

    Age-related hearing loss – presbycusis – is the number one communication disorder and most prevalent neurodegenerative condition of our aged population. Although speech understanding in background noise is quite difficult for those with presbycusis, there are currently no biomedical treatments to prevent, delay or reverse this condition. A better understanding of the cochlear mechanisms underlying presbycusis will help lead to future treatments. Objectives of the present study were to investigate gamma-amino butyric acid A (GABAA) receptor subunit ?1, nicotinic acetylcholine (nACh) receptor subunit ?2, and N-methyl-D-aspartate (NMDA) receptor subunit NR1 mRNA and protein expression changes in spiral ganglion neurons of the CBA/CaJ mouse cochlea, that occur in age-related hearing loss, utilizing quantitative immunohistochemistry and semi-quantitative RT-PCR techniques. We found that auditory brainstem response (ABR) thresholds shifted over 40 dB from 3–48 kHz in old mice compared to young adults. DPOAE thresholds also shifted over 40 dB from 6–49 kHz in old mice, and their amplitudes were significantly decreased or absent in the same frequency range. Spiral ganglion neuron (SGN) density decreased with age in basal, middle and apical turns, and SGN density of the basal turn declined the most. A positive correlation was observed between SGN density and ABR wave 1 amplitude. mRNA and protein expression of GABAAR ?1 and AChR ?2 decreased with age in SGNs in the old mouse cochlea. mRNA and protein expression of NMDAR NR1 increased with age in SGNs of the old mice. These findings demonstrate that there are functionally-relevant age-related changes of GABAAR, nAChR, NMDAR expression in CBA mouse SGNs reflecting their degeneration, which may be related to functional changes in cochlear synaptic transmission with age, suggesting biological mechanisms for peripheral age-related hearing loss. PMID:24316061

  15. Valerian Inhibits Rat Hepatocarcinogenesis by Activating GABA(A) Receptor-Mediated Signaling

    PubMed Central

    Kakehashi, Anna; Kato, Ayumi; Ishii, Naomi; Wei, Min; Morimura, Keiichirou; Fukushima, Shoji; Wanibuchi, Hideki

    2014-01-01

    Valerian is widely used as a traditional medicine to improve the quality of sleep due to interaction of several active components with the ?-aminobutyric acid (GABA) A receptor (GABA(A)R) system. Recently, activation of GABA signaling in stem cells has been reported to suppress cell cycle progression in vivo. Furthermore, possible inhibitory effects of GABA(A)R agonists on hepatocarcinogenesis have been reported. The present study was performed to investigate modulating effects of Valerian on hepatocarcinogenesis using a medium-term rat liver bioassay. Male F344 rats were treated with one of the most powerful Valerian species (Valeriana sitchensis) at doses of 0, 50, 500 and 5000 ppm in their drinking water after initiation of hepatocarcinogenesis with diethylnitrosamine (DEN). Formation of glutathione S-transferase placental form positive (GST-P+) foci was significantly inhibited by Valerian at all applied doses compared with DEN initiation control rats. Generation of 8-hydroxy-2?-deoxyguanosine in the rat liver was significantly suppressed by all doses of Valerian, likely due to suppression of Nrf2, CYP7A1 and induction of catalase expression. Cell proliferation was significantly inhibited, while apoptosis was induced in areas of GST-P+ foci of Valerian groups associated with suppression of c-myc, Mafb, cyclin D1 and induction of p21Waf1/Cip1, p53 and Bax mRNA expression. Interestingly, expression of the GABA(A)R alpha 1 subunit was observed in GST-P+ foci of DEN control rats, with significant elevation associated with Valerian treatment. These results indicate that Valerian exhibits inhibitory effects on rat hepatocarcinogenesis by inhibiting oxidative DNA damage, suppressing cell proliferation and inducing apoptosis in GST-P+ foci by activating GABA(A)R-mediated signaling. PMID:25419570

  16. Effects of Valeriana Officinalis Extracts on [ 3 H]Flunitrazepam Binding, Synaptosomal [ 3 H]GABA Uptake, and Hippocampal [ 3 H]GABA Release

    Microsoft Academic Search

    José G. Ortiz; Jennifer Nieves-Natal; Pedro Chavez

    1999-01-01

    Extracts of Valeriana officinalis have been used in folkloric medicine for its sedative, hypnotic, tranquilizer and anticonvulsant effects, and may interact with ?-aminobutyric acid (GABA) and\\/or benzodiazepine sites. At low concentrations, valerian extracts enhance [3H]flunitrazepam binding (EC50 4.13 × 10-10 mg\\/ml). However, this increased [3H]flunitrazepam binding is replaced by an inhibition at higher concentrations (IC50 of 4.82 × 10-1 mg\\/ml).

  17. Free radical modification of high-affinity GABA transport in the central nervous system

    SciTech Connect

    Debler, E.A.

    1985-01-01

    Presynaptic nerve terminals of DNS neurons can be characterized as dynamic self-contained subunits of the overall neuron. These neuron subunits together with the adjacent post-synaptic terminals constitute the functional unit of neurotransmission. One major function of the presynaptic nerve terminal in neurotransmission is its role in the release and subsequent reuptake of neurotransmitters. Neurochemical and morphological analysis of this high-affinity uptake process, for the amino acid neurotransmitter gamma-aminobutyric acid (GABA), revealed that free radical modification (lipid peroxidation) of presynaptic nerve terminal membrane structures resulted in a decrease in high-affinity (/sup 14/C)GABA uptake. Depolarized nerve terminals exposed to horseradish peroxidase (HRP)-generated superoxide radicals (.O/sub 2//sup -/) exhibited an alteration of synaptic vesicle membrane structure and a reduction of high-affinity (/sup 14/C)GABA uptake. In the kinetic analysis of high affinity (/sup 14/C)GABA uptake, hypoxanthine/xanthine oxidase (HPX/XOD)-treated synaptosomes exhibited a significant reduction in V/sub max/ but no significant alteration of K/sub m/. This HPX/XOD treatment also resulted in significant structural alterations of both the synaptic vesicle membrane and the synaptosomal plasma membrane. Structural and functional correlates appear to exist between synaptic vesicle and plasma membrane systems and high-affinity (/sup 14/C)GABA uptake. Together, the selectivity of the .O/sub 2//sup -/ toxicity and that of the high-K/sup +//Na/sup +/-free effect support the idea of two separate and different amino acid uptake systems in CNS tissue.

  18. Double isotopic method using dansyl chloride for the determination of GABA in rat C6 astrocytoma cell cultures

    SciTech Connect

    Kohl, R.L.; Quay, W.B.; Perez-Polo, J.R.

    1986-01-01

    Methods are described for the quantitative measurement of GABA in culture. The method can be adapted to any amino acid or dansyl-chloride-reactive species. The sensitivity and selectivity of the procedure result from the double isotopic design in which (/sup 14/C)-labeled internal standard was added to the samples before reaction with (3M)-labeled dansyl chloride. Values obtained by ion-exchange amino acid analysis of cultures agree closely with the values obtained by the double isotopic method. This method is sensitive enough to measure GABA intracellularly and the condition medium.

  19. Activation of presynaptic GABA(B(1a,2)) receptors inhibits synaptic transmission at mammalian inhibitory cholinergic olivocochlear-hair cell synapses.

    PubMed

    Wedemeyer, Carolina; Zorrilla de San Martín, Javier; Ballestero, Jimena; Gómez-Casati, María Eugenia; Torbidoni, Ana Vanesa; Fuchs, Paul A; Bettler, Bernhard; Elgoyhen, Ana Belén; Katz, Eleonora

    2013-09-25

    The synapse between olivocochlear (OC) neurons and cochlear mechanosensory hair cells is cholinergic, fast, and inhibitory. The inhibitory sign of this cholinergic synapse is accounted for by the activation of Ca(2+)-permeable postsynaptic ?9?10 nicotinic receptors coupled to the opening of hyperpolarizing Ca(2+)-activated small-conductance type 2 (SK2)K(+) channels. Acetylcholine (ACh) release at this synapse is supported by both P/Q- and N-type voltage-gated calcium channels (VGCCs). Although the OC synapse is cholinergic, an abundant OC GABA innervation is present along the mammalian cochlea. The role of this neurotransmitter at the OC efferent innervation, however, is for the most part unknown. We show that GABA fails to evoke fast postsynaptic inhibitory currents in apical developing inner and outer hair cells. However, electrical stimulation of OC efferent fibers activates presynaptic GABA(B(1a,2)) receptors [GABA(B(1a,2))Rs] that downregulate the amount of ACh released at the OC-hair cell synapse, by inhibiting P/Q-type VGCCs. We confirmed the expression of GABA(B)Rs at OC terminals contacting the hair cells by coimmunostaining for GFP and synaptophysin in transgenic mice expressing GABA(B1)-GFP fusion proteins. Moreover, coimmunostaining with antibodies against the GABA synthetic enzyme glutamic acid decarboxylase and synaptophysin support the idea that GABA is directly synthesized at OC terminals contacting the hair cells during development. Thus, we demonstrate for the first time a physiological role for GABA in cochlear synaptic function. In addition, our data suggest that the GABA(B1a) isoform selectively inhibits release at efferent cholinergic synapses. PMID:24068816

  20. GABA receptor binding with 3H (+) bicuculline-methiodide in rat CNS

    Microsoft Academic Search

    H. Möhler; T. Okada

    1977-01-01

    NEUROTRANSMITTER receptors might be identified biochemically in binding studies with synaptic membrane preparations using labelled receptor agonists or antagonists as ligands1. In attempts to identify the GABA receptor 3H-GABA has been used as ligand. 3H-GABA, however, also binds to glial and neuronal GABA uptake sites and to enzymes metabolising GABA. Thus, Na+-dependent 3H-GABA-binding2,3, in contrast to Na+-independent 3H-GABA-binding is possibly

  1. GnRH neuron firing and response to GABA in vitro depend on acute brain slice thickness and orientation.

    PubMed

    Constantin, Stephanie; Piet, Richard; Iremonger, Karl; Hwa Yeo, Shel; Clarkson, Jenny; Porteous, Robert; Herbison, Allan E

    2012-08-01

    The GnRH neurons exhibit long dendrites and project to the median eminence. The aim of the present study was to generate an acute brain slice preparation that enabled recordings to be undertaken from GnRH neurons maintaining the full extent of their dendrites or axons. A thick, horizontal brain slice was developed, in which it was possible to record from the horizontally oriented GnRH neurons located in the anterior hypothalamic area (AHA). In vivo studies showed that the majority of AHA GnRH neurons projected outside the blood-brain barrier and expressed c-Fos at the time of the GnRH surge. On-cell recordings compared AHA GnRH neurons in the horizontal slice (AHAh) with AHA and preoptic area (POA) GnRH neurons in coronal slices [POA coronal (POAc) and AHA coronal (AHAc), respectively]. AHAh GnRH neurons exhibited tighter burst firing compared with other slice orientations. Although ?-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) excited GnRH neurons in all preparations, ?-aminobutyric acid (GABA) was excitatory in AHAc and POAc but inhibitory in AHAh slices. GABA(A) receptor postsynaptic currents were the same in AHAh and AHAc slices. Intriguingly, direct activation of GABA(A) or GABA(B) receptors respectively stimulated and inhibited GnRH neurons regardless of slice orientation. Subsequent experiments indicated that net GABA effects were determined by differences in the ratio of GABA(A) and GABA(B) receptor-mediated effects in "long" and "short" dendrites of GnRH neurons in the different slice orientations. These studies document a new brain slice preparation for recording from GnRH neurons with their extensive dendrites/axons and highlight the importance of GnRH neuron orientation relative to the angle of brain slicing in studying these neurons in vitro. PMID:22719049

  2. GABA-agonists induce the formation of low-affinity GABA-receptors on cultured cerebellar granule cells via preexisting high affinity GABA receptors

    Microsoft Academic Search

    Bo Belhage; Eddi Meier; Arne Schousboe

    1986-01-01

    The kinetics of specific GABA-binding to membranes isolated from cerebellar granule cells, cultured for 12 days from dissociated cerebella of 7-day-old rats was studied using [3H]GABA as the ligand. The granule cells were cultured in the presence of the specific GABA receptor agonist 4, 5, 6, 7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 150 µM) or THIP plus the antagonist bicuculline methobromide (150 µM of

  3. Prebiotic syntheses of vitamin coenzymes: II. Pantoic acid, pantothenic acid, and the composition of coenzyme A

    NASA Technical Reports Server (NTRS)

    Miller, S. L.; Schlesinger, G.

    1993-01-01

    Pantoic acid can by synthesized in good prebiotic yield from isobutyraldehyde or alpha-ketoisovaleric acid + H2CO + HCN. Isobutyraldehyde is the Strecker precursor to valine and alpha-ketoisovaleric acid is the valine transamination product. Mg2+ and Ca2+ as well as several transition metals are catalysts for the alpha-ketoisovaleric acid reaction. Pantothenic acid is produced from pantoyl lactone (easily formed from pantoic acid) and the relatively high concentrations of beta-alanine that would be formed on drying prebiotic amino acid mixtures. There is no selectivity for this reaction over glycine, alanine, or gamma-amino butyric acid. The components of coenzyme A are discussed in terms of ease of prebiotic formation and stability and are shown to be plausible choices, but many other compounds are possible. The gamma-OH of pantoic acid needs to be capped to prevent decomposition of pantothenic acid. These results suggest that coenzyme A function was important in the earliest metabolic pathways and that the coenzyme A precursor contained most of the components of the present coenzyme.

  4. Regulation of GABA and Glutamate Release from Proopiomelanocortin Neuron Terminals in Intact Hypothalamic Networks

    PubMed Central

    Dicken, Matthew S.; Tooker, Ryan E.; Hentges, Shane T.

    2012-01-01

    Hypothalamic proopiomelanocortin (POMC) neurons and their peptide products mediate important aspects of energy balance, analgesia, and reward. In addition to peptide products, there is evidence that POMC neurons can also express the amino acid transmitters GABA and glutamate, suggesting these neurons may acutely inhibit or activate downstream neurons. However, the release of amino acid transmitters from POMC neurons has not been thoroughly investigated in an intact system. In the present study, the light-activated cation channel channelrhodopsin-2 (ChR2) was used to selectively evoke transmitter release from POMC neurons. Whole-cell electrophysiologic recordings were made in brain slices taken from POMC-Cre transgenic mice that had been injected with a viral vector containing a floxed ChR2 sequence. Brief pulses of blue light depolarized POMC-ChR2 neurons and induced the release of GABA and glutamate onto unidentified neurons within the arcuate nucleus, as well as onto other POMC neurons. To determine if the release of GABA and glutamate from POMC terminals can be readily modulated, opioid and GABAB receptor agonists were applied. Agonists for mu and kappa, but not delta, opioid receptors inhibited transmitter release from POMC neurons, as did the GABAB receptor agonist baclofen. This regulation indicates that opioids and GABA released from POMC neurons may act at presynaptic receptors on POMC terminals in an autoregulatory manner to limit continued transmission. The results show that in addition to the relatively slow and long-lasting actions of peptides, POMC neurons can rapidly affect the activity of downstream neurons via GABA and glutamate release. PMID:22442070

  5. Presynaptic Na+-dependent transport and exocytose of GABA and glutamate in brain in hypergravity.

    NASA Astrophysics Data System (ADS)

    Borisova, T.; Pozdnyakova, N.; Krisanova, N.; Himmelreich, N.

    ?-Aminobutyric acid (GABA) and L-glutamate are the most widespread neurotransmitter amino acids in the mammalian central nervous system. GABA is now widely recognized as the major inhibitory neurotransmitter. L-glutamate mediates the most of excitatory synaptic neurotransmission in the brain. They involved in the main aspects of normal brain function. The nerve terminals (synaptosomes) offer several advantages as a model system for the study of general mechanisms of neurosecretion. Our data allowed to conclude that exposure of animals to hypergravity (centrifugation of rats at 10G for 1 hour) had a profound effect on synaptic processes in brain. Comparative analysis of uptake and release of GABA and glutamate have demonstrated that hypergravity loading evokes oppositely directed alterations in inhibitory and excitatory signal transmission. We studied the maximal velocities of [^3H]GABA reuptake and revealed more than twofold enhancement of GABA transporter activity (Vmax rises from 1.4 |pm 0.3 nmol/min/mg of protein in the control group to 3.3 ± 0.59 nmol/min/mg of protein for animals exposed to hypergravity (P ? 0.05)). Recently we have also demonstrated the significant lowering of glutamate transporter activity (Vmax of glutamate reuptake decreased from 12.5 ± 3.2 nmol/min/mg of protein in the control group to 5.6 ± 0.9 nmol/min/mg of protein in the group of animals, exposed to the hypergravity stress (P ? 0.05)). Significant changes occurred in release of neurotransmitters induced by stimulating exocytosis with the agents, which depolarized nerve terminal plasma membrane. Depolarization-evoked Ca2+-stimulated release was more abundant for GABA (7.2 ± 0.54% and 11,74 ±1,2 % of total accumulated label for control and hypergravity, respectively (P?0.05)) and was essentially less for glutamate (14.4 ± 0.7% and 6.2 ± 1.9%) after exposure of animals to centrifuge induced artificial gravity. Changes observed in depolarization-evoked exocytotic release seem to be in a concert with alterations of plasma membrane transporters activity studied. Perhaps, lowering of glutamate transporter activity and increase of the velocity of GABA uptake correlated with diminution and augmentation of exocytotic release of these neurotransmitters, respectively. It is possible to suggest that observed changes in the activity of the processes responsible for the uptake and release of excitatory and inhibitory neurotransmitters are likely to be physiologically important and reflect making protective mechanisms more active for neutralization of harm influence of hypergravity stress.

  6. Altered glutamate/GABA equilibrium in aged mice cortex influences cortical plasticity.

    PubMed

    Liguz-Lecznar, Monika; Lehner, Malgorzata; Kaliszewska, Aleksandra; Zakrzewska, Renata; Sobolewska, Alicja; Kossut, Malgorzata

    2015-05-01

    Age-related molecular changes in the synapse can cause plasticity decline. We found an impairment of experience-dependent cortical plasticity is induced by short lasting sensory conditioning in aged mice. However, extending the training procedure from 3 to 7 days triggered plasticity in the aged cortex of the same range as in young mice. Additionally, GABAergic markers (GABA, GAD67, VGAT) in young and aged groups that showed the plastic changes were upregulated. This effect was absent in the aged group with impaired plasticity, while the expression of Vglut1 increased in all trained groups. This may reflect the inefficiency of inhibitory mechanisms in the aging brain used to control increased excitation after training and to shape proper signal to noise ratio, which is essential for appropriate stimuli processing. HPLC analysis showed that the glutamate/GABA ratio was significantly reduced in aged animals due to a significant decrease in glutamate level. We also observed a decreased expression of several presynaptic markers involved in excitatory (vesicular glutamate transporter-vglut2) and inhibitory (glutamic acid decarboxylase-GAD67, vesicular GABA transporter VGAT) transmission in the aged barrel cortex. These changes may weaken the plasticity potential of neurons and impede the experience-dependent reorganization of cortical connections. We suggest that the imbalance toward inhibition resulting from a decrease of glutamate content in the aging cerebral cortex, together with GABAergic system ineffectiveness in upregulating GABA level after sensory training, contributes to the impairment of learning-dependent cortical plasticity. PMID:24659256

  7. Structural determinants of activity at the GABAB receptor. A comparison of phosphoethanolamine and related GABA analogs.

    PubMed

    Klunk, W E; McClure, R J; Xu, C J; Pettegrew, J W

    1995-09-01

    Phosphoethanolamine is a phosphomonoester that is reduced in Alzheimer disease brain. Despite its close structural similarity to GABA and the GABAB partial agonist 3-aminopropylphosphonic acid, phosphoethanolamine binds very poorly to GABAB receptors (IC50 = 7.5 +/- 0.8 mM). In this study, we examined whether the marked decrease in binding affinity associated with the presence of an ester oxygen in place of the alpha-CH2 group of GABAergic compounds also occurred in sulfonates and used high resolution solution NMR and molecular mechanics calculations to determine the structural basis of this decrease in activity. The sulfonate analog of GABA, 3-amino-propylsulfonic acid, became > 2500-fold less potent when the alpha-CH2 was replaced by an ester oxygen. Structural studies showed that the active alpha-CH2 compounds (GABA, 3-aminopropylphosphonic acid, and 3-aminopropylsulfonic acid) prefer a fully extended conformation. The inactive compounds, phosphoethanolamine and ethanolamine-O-sulfate, exist in a gauche conformation around the C beta-C gamma bond. This study, which suggests conformational differences, may explain how PE can be so efficiently excluded from GABAB receptors, despite being present in millimolar concentrations in brain. Exclusion of phosphoethanolamine from GABAB receptors may be an important physiologic control mechanism in the regulation of inhibitory neurotransmission. PMID:8588821

  8. THE PHARMACOLOGY OF ?-AMINOBUTYRIC ACID AND ACETYLCHOLINE RECEPTORS AT THE ECHINODERM NEUROMUSCULAR JUNCTION

    Microsoft Academic Search

    C. LEAH DEVLIN

    This review describes the various subtypes of ?- aminobutyric acid (GABA) receptors found at the echinoderm neuromuscular junction (NMJ), based on pharmacological and physiological studies. The review focuses mainly on holothurian GABA receptors at the NMJ located between the radial nerve and longitudinal muscle of the body wall (LMBW) and compares them to GABA receptors described at other echinoderm NMJs.

  9. The regulation of alpha-MSH release by GABA is mediated by a chloride-dependent [Ca2+]c increase in frog melanotrope cells.

    PubMed

    Desrues, Laurence; Castel, Hélène; Malagon, Maria M; Vaudry, Hubert; Tonon, Marie-Christine

    2005-10-01

    In frog melanotrope cells, gamma-aminobutyric acid (GABA) induces a biphasic effect, i.e. a transient stimulation followed by a more sustained inhibition of alpha-MSH release, and both phases of the GABA effect are mediated by GABAA receptors. We have previously shown that the stimulatory phase evoked by GABAA receptor agonists can be accounted for by calcium entry. In the present study, we have investigated the involvement of the chloride flux on GABA-induced [Ca2+]c increase and alpha-MSH release. We show that GABA evokes a concentration-dependent [Ca2+]c rise through specific activation of the GABAA receptor. The GABA-induced [Ca2+]c increase results from opening of voltage-activated L- and N-type calcium channels, and sodium channels. Variations of the extracellular Cl- concentration revealed that GABA-induced [Ca2+]c rise and alpha-MSH release both depend on the Cl- flux direction and driving force. These observations suggest for the first time that GABA-gated Cl- efflux provokes an increase in [Ca2+]c increase that is responsible for hormone secretion. PMID:15990198

  10. Effects of intraventricular taurine, homotaurine and GABA on serum prolactin and thyrotropin levels in female and in male rats

    Microsoft Academic Search

    M. Miikinen; L. Ahtee; K. Rosenqvist; R. K. Tuominen; P. Miinnistii

    1993-01-01

    Summary Serum prolactin and thyrotropin levels of conscious, unrestrained male and female rats were compared after intracerebroventricular (i.c.v.) administration of taurine, ?-aminobutyric acid (GABA) and homotaurine. The amino acids studied had no clear effect on serum basal thyrotropin levels in male or female rats. All amino acids elevated serum prolactin levels in female rats at the dose of 5 µmol\\/rat;

  11. 3D GABA imaging with real-time motion correction, shim update and reacquisition of adiabatic spiral MRSI.

    PubMed

    Bogner, Wolfgang; Gagoski, Borjan; Hess, Aaron T; Bhat, Himanshu; Tisdall, M Dylan; van der Kouwe, Andre J W; Strasser, Bernhard; Marja?ska, Ma?gorzata; Trattnig, Siegfried; Grant, Ellen; Rosen, Bruce; Andronesi, Ovidiu C

    2014-12-01

    Gamma-aminobutyric acid (GABA) and glutamate (Glu) are the major neurotransmitters in the brain. They are crucial for the functioning of healthy brain and their alteration is a major mechanism in the pathophysiology of many neuro-psychiatric disorders. Magnetic resonance spectroscopy (MRS) is the only way to measure GABA and Glu non-invasively in vivo. GABA detection is particularly challenging and requires special MRS techniques. The most popular is MEscher-GArwood (MEGA) difference editing with single-voxel Point RESolved Spectroscopy (PRESS) localization. This technique has three major limitations: a) MEGA editing is a subtraction technique, hence is very sensitive to scanner instabilities and motion artifacts. b) PRESS is prone to localization errors at high fields (?3T) that compromise accurate quantification. c) Single-voxel spectroscopy can (similar to a biopsy) only probe steady GABA and Glu levels in a single location at a time. To mitigate these problems, we implemented a 3D MEGA-editing MRS imaging sequence with the following three features: a) Real-time motion correction, dynamic shim updates, and selective reacquisition to eliminate subtraction artifacts due to scanner instabilities and subject motion. b) Localization by Adiabatic SElective Refocusing (LASER) to improve the localization accuracy and signal-to-noise ratio. c) K-space encoding via a weighted stack of spirals provides 3D metabolic mapping with flexible scan times. Simulations, phantom and in vivo experiments prove that our MEGA-LASER sequence enables 3D mapping of GABA+ and Glx (Glutamate+Gluatmine), by providing 1.66 times larger signal for the 3.02ppm multiplet of GABA+ compared to MEGA-PRESS, leading to clinically feasible scan times for 3D brain imaging. Hence, our sequence allows accurate and robust 3D-mapping of brain GABA+ and Glx levels to be performed at clinical 3T MR scanners for use in neuroscience and clinical applications. PMID:25255945

  12. Does gabapentin act as an agonist at native GABA B receptors?

    Microsoft Academic Search

    Jen-Kun Cheng; Sun-Zhi Lee; Jia-Rung Yang; Chien-Hua Wang; Yan-Yu Liao; Chien-Chuan Chen; Lih-Chu Chiou

    2004-01-01

    Gabapentin, a novel anticonvulsant and analgesic, is a ?-aminobutyric acid (GABA) analogue but was shown initially to have little affinity at GABAA or GABAB receptors. It was recently reported to be a selective agonist at GABAB receptors containing GABAB1a-GABAB2 heterodimers, although several subsequent studies disproved that conclusion. In the present study, we examined whether gabapentin is an agonist at native

  13. Comment on "Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring".

    PubMed

    Bambini-Junior, Victorio; Nunes, Gustavo Della Flora; Schneider, Tomasz; Gottfried, Carmem

    2014-10-10

    Tyzio et al. (Reports, 7 February 2014, p. 675) reported that bumetanide restored the impaired oxytocin-mediated ?-aminobutyric acid (GABA) excitatory-inhibitory shift during delivery in animal models of autism, ameliorating some autistic-like characteristics in the offspring. However, standard practices in the study of these models, such as the use of sex-dimorphic or males-only analyses and implementation of tests measuring social behavior, are lacking to definitely associate their findings to autism. PMID:25301610

  14. Structural Rearrangements in Loop F of the GABA Receptor Signal Ligand Binding, Not Channel Activation

    Microsoft Academic Search

    Alpa Khatri; Anna Sedelnikova; David S. Weiss

    2009-01-01

    Structure-function studies of the Cys loop family of ionotropic neurotransmitter receptors (GABA, nACh, 5-HT3, and glycine receptors) have resulted in a six-loop (A–F) model of the agonist-binding site. Key amino acids have been identified in these loops that associate with, and stabilize, bound ligand. The next step is to identify the structural rearrangements that couple agonist binding to channel opening.

  15. Localization of messenger RNAs encoding three GABA transporters in rat brain: an in situ hybridization study

    Microsoft Academic Search

    Margaret M. Durkin; Kelli E. Smith; Laurence A. Borden; Richard L. Weinshank; Theresa A. Branchek; Eric L. Gustafson

    1995-01-01

    Localization of the messenger RNAs encoding three ?-aminobutyric acid (GABA) transporters, termed GAT-1, GAT-2, and GAT-3, has been carried out in rat brain using radiolabeled oligonucleotide probes and in situ hybridization histochemistry. Hybridization signals for GAT-1 mRNA were observed over many regions of the rat brain, including the retina, olfactory bulb, neocortex, ventral pallidum, hippocampus, and cerebellum. At the microscopic

  16. Synthesis of  -Aminobutyric Acid by Lactic Acid Bacteria Isolated from a Variety of Italian Cheeses

    Microsoft Academic Search

    S. Siragusa; M. De Angelis; R. Di Cagno; C. G. Rizzello; R. Coda; M. Gobbetti

    2007-01-01

    The concentrations of -aminobutyric acid (GABA) in 22 Italian cheese varieties that differ in several technological traits markedly varied from 0.26 to 391 mg kg1. Presumptive lactic acid bacteria were isolated from each cheese variety (total of 440 isolates) and screened for the capacity to synthesize GABA. Only 61 isolates showed this activity and were identified by partial sequencing of

  17. Fine structure of the dorsal lateral geniculate nucleus of the turtle, Emys orbicularis: a Golgi, combined HRP tracing and GABA immunocytochemical study.

    PubMed

    Kenigfest, N B; Repérant, J; Rio, J P; Belekhova, M G; tumanova, N L; Ward, R; Vesselkin, N P; Herbin, M; Chkeidze, D D; Ozirskaya, E V

    1995-06-12

    The afferent and efferent cortical projections of the dorsal lateral geniculate nucleus (GLD) of adult specimens of the turtle Emys orbicularis were investigated after intraocular or intracortical injections of horseradish peroxidase (HRP), and the distribution of gamma aminobutyric acid (GABA) immunoreactivity in the nucleus was carried out by immunocytochemical techniques, both techniques being combined with light and electron microscopy. In addition, some specimens were prepared for double-labeling of HRP and GABA immunoreactivity, and additional samples impregnated by a rapid Golgi technique. On purely morphological grounds, four types of neurons can be distinguished by light microscopy: two types of large cells in the cell plate which project to the cortex, and two types of smaller cells in the neuropil and optic tract which do not. The small cells are consistently GABA-immunoreactive, while the former are, with extremely rare exceptions, immunonegative for GABA. The supposition that the small neurons of the neuropil are interneurons is supported by electron microscopic observations; these strongly GABA-immunoreactive cells have large plicated nuclei surrounded by a thin layer of cytoplasm poorly endowed with organelles. The dendrites of these cells may contain pleomorphic synaptic vesicles (DCSVs) and appear to be presynaptic to other dendritic profiles. These DCSVs are occasionally contacted by GABA-immunoreactive axon terminals, and more frequently by retinal terminals consistently immunonegative for GABA. The latter, frequently organized in glomeruli, also make synaptic contacts with immunonegative dendrites arising from corticopetal neurons of the cell plate. Two major categories of GABA-immunoreactive axon terminals can be distinguished, and we are led to the conclusion that one of these represents an intrinsic GABAergic innervation of the GLD, while the second is tentatively interpreted as an extrinsic source of GABA to the nucleus, possibly from ventral thalamic structures. The fine structure of the dorsal lateral geniculate nucleus of Emys orbicularis thus shows many similarities with that of mammals. PMID:7560269

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

    PubMed

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

    2008-11-01

    The aim of this study was to evaluate the effects of cocaine on gamma-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 (IC(50) 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 (IC(50) 13 microm) current-evoked spikes and TTX-sensitive sodium currents in a use-dependent manner. In VTA DA neurons, cocaine reduced IPSCs (IC(50) 13 microm), 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

  19. 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 ?-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 ?m) current-evoked spikes and TTX-sensitive sodium currents in a use-dependent manner. In VTA DA neurons, cocaine reduced IPSCs (IC50 13 ?m), 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

  20. Response to Comment on "Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring".

    PubMed

    Eftekhari, Sanaz; Shahrokhi, Amene; Tsintsadze, Vera; Nardou, Romain; Brouchoud, Corinne; Conesa, Magali; Burnashev, Nail; Ferrari, Diana C; Ben-Ari, Yehezkel

    2014-10-10

    Bambini-Junior et al. questioned whether our treatment in two rodent models of autism has a long-lasting effect into adulthood. In response, we show that bumetanide treatment around delivery attenuates autistic behavioral features in adult offspring. Therefore, the polarity of ?-aminobutyric acid (GABA) actions during delivery exerts long-lasting priming actions after birth. PMID:25301611

  1. Quantitative Effects of GABA and Bicuculline Meth on Receptive Field Properties of Neurons in Real and Simulated Whisker Barrels

    Microsoft Academic Search

    HAROLD T. KYRIAZI; GEORGE E. CARVELL; JOSHUA C. BRUMBERG; DANIEL J. SIMONS

    simulated neurons, they also possess GABAB receptors, which are unaffected by BMI. 1. Carbon fiber multibarrel glass microelectrodes were used to 8. We conclude that the inhibitory receptive field properties of record extracellular single-unit activity during microiontophoretic barrel neurons can be explained by intrabarrel inhibition and that application of y-aminobutyric acid (GABA) or bicuculline methio- the expansion of receptive field

  2. Colocalization of serotonin and GABA in retinal neurons of Ichthyophis kohtaoensis (amphibia; Gymnophiona).

    PubMed

    Dünker, N

    1998-01-01

    Ichthyophis kohtaoensis, a member of the limbless Gymnophiona, has a specialized subterranean burrowing mode of life and a predominantly olfactory-guided orientation. The only visually guided behavior seems to be negative phototaxis. As these animals possess extremely small eyes (only 540 microm in diameter in adults), functional investigations of single retinal cells by electrophysiological methods have so far failed. Therefore, the content and distribution of retinal transmitters have been investigated as indications of a functioning sense organ in an animal that is supposed to be blind. Previous immunohistochemical investigation of the retinal transmitter system revealed immunoreactivity for gamma-aminobutyric acid (GABA), serotonin, dopamine and tyrosine hydroxylase, the rate-limiting enzyme in the catecholamine synthetic pathway. The present studies have been performed in order to determine a possible colocalization of serotonin and GABA in retinal neurons of the caecilian retina. Therefore retinal cryostat sections of various developmental stages have been investigated by the indirect fluorescence method. In single-label preparations, serotonin is localized to cells in the inner nuclear layer and the ganglion cell layer. GABA immunocytochemistry labels a variety of cell types in the inner nuclear layer as well as cell bodies in the ganglion cell layer. In double-label preparations, some of the serotonergic cells are found to express GABA immunoreactivity and some GABAergic neurons also label for serotonin immunocytochemistry. Thus, despite the fact that caecilians mainly rely on olfaction and are believed to have a reduced visual system, their retina exhibits a surprisingly "normal" distribution of neurotransmitters and neuromodulators, also typical of other anamniotes with a well-developed visual system, including the partial colocalization of serotonin and GABA at all developmental stages of I. kohtaoensis. These results indicate that a functional system that is under no strong selective pressure obviously has a long evolutionary persistence irrespective of its need for use. PMID:9462859

  3. Developing dual functional allosteric modulators of GABA(A) receptors.

    PubMed

    Liu, Xiaodong F; Chang, Hui-Fang; Schmiesing, Richard Jon; Wesolowski, Steven S; Knappenberger, Katharine S; Arriza, Jeffrey L; Chapdelaine, Marc J

    2010-12-01

    Positive modulators at benzodiazepine sites of ?2- and ?3-containing GABA(A) receptors are believed to be anxiolytic. Negative allosteric modulators of ?5-containing GABA(A) receptors enhance cognition. By oocyte two-electrode voltage clamp and subsequent structure-activity relationship studies, we discovered cinnoline and quinoline derivatives that were both positive modulators at ?2-/?3-containing GABA(A) receptors and negative modulators at ?5-containing GABA(A) receptors. In addition, these compounds showed no functional activity at ?1-containing GABA(A) receptors. Such dual functional modulators of GABA(A) receptors might be useful for treating comorbidity of anxiety and cognitive impairments in neurological and psychiatric illnesses. PMID:20980155

  4. Separation of gamma-aminobutyric acid from fermented broth

    Microsoft Academic Search

    Haixing Li; Ting Qiu; Yan Chen; Yusheng Cao

    Gamma-aminobutyric acid (GABA) is a non-proteinaceous amino acid that is widely distributed in nature and acts as the major\\u000a inhibitory neurotransmitter in the mammalian brain. This study aimed to find a separation method for getting high-purity GABA\\u000a from a fermented broth. Firstly, a fermented broth with a high content of GABA (reaching 997 ± 51 mM) was prepared by fermentation\\u000a with Lactobacillus brevis

  5. 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 Central

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

    2014-01-01

    Although focal cortical malformations are considered neuronal migration disorders, their formation mechanisms remain unknown. We addressed how the ?-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 Ca2+ 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 Ca2+ oscillation in KCC2-downregulated microgyrus-forming cells, as seen in migrating cells during early neocortical development. PMID:23246779

  6. Low cumulative manganese exposure affects striatal GABA but not dopamine.

    PubMed

    Gwiazda, R H; Lee, D; Sheridan, J; Smith, D R

    2002-05-01

    The introduction of the anti-knock methylcyclopentadienyl manganese (Mn) tricarbonyl (MMT) in gasoline has raised concerns about the potential for manganese neurotoxicity. Because subpopulations such as the elderly in the early stages of neurodegenerative disease may be at increased risk for manganese toxicity, a pre-Parkinsonism rat model was used to evaluate whether sub-chronic manganese exposure can aggravate the neurochemical and behavioral dysfunctions characteristic of Parkinsonism. Sub-threshold levels of dopamine depletion of 3.5, 53 and 68% were generated via intrastriatal unilateral 6-hydroxydopamine (6-OHDA) doses. A sub-chronic dosing regimen of low cumulative manganese exposure (4.8 mg Mn/kg body weight, 3 i.p. injections per week x 5 weeks) was started 4 weeks after 6-OHDA treatments. Neurochemical and neuromotor (functional observational battery (FOB)) measures were evaluated. Manganese produced significant (P < 0.05) reductions of 30-60% in motor function. This effect was exacerbated in the presence of a pre-Parkinsonism condition [Neurotox. Teratol. 22 (2000) 851]. Manganese did not affect striatal dopamine, but resulted in significant increases in striatal y-aminobutyric acid (GABA) of 16 and 22% (P < 0.01) in both striati and a borderline non-significant 4% increase in frontal cortex (P = 0.076). Manganese treatment produced increased aspartate (P < 0.01) in the manganese and 6-OHDA treated striatum. In light of previous studies predominantly showing dopamine depletion with elevated manganese exposures, the significant effects of manganese on striatal GABA but not on striatal dopamine at the low cumulative exposure administered here suggest a progression in manganese toxicity with increasing cumulative dose, whereby GABA levels are adversely affected before striatal dopamine levels. Because these neurochemical disruptions were accompanied by motor dysfunction that was exacerbated in the presence of a pre-Parkinsonism condition, an increased environmental burden of manganese may have deleterious effects on populations with sub-threshold neurodegeneration in the basal ganglia (e.g. pre-Parkinsonism). PMID:12164549

  7. Effect of green tea rich in ?-aminobutyric acid on blood pressure of Dahl salt-sensitive rats

    Microsoft Academic Search

    Yasuhiko Abe; Satoshi Umemura; Koh-ichi Sugimoto; Nobuhito Hirawa; Yoshio Kato; Nobuyuki Yokoyama; Tomoko Yokoyama; Junichi Iwai; Masao Ishii

    1995-01-01

    ?-Aminobutyric acid (GABA) is known to be involved in the regulation of blood pressure by modulating the neurotransmitter release in the central and peripheral sympathetic nervous systems. This study investigated the antihypertensive effect of green tea rich in GABA (GABA-rich tea) in young and old Dahl salt-sensitive (S) rats. GABA-rich tea was made by fermenting fresh green tea leaves under

  8. Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring.

    PubMed

    Tyzio, Roman; Nardou, Romain; Ferrari, Diana C; Tsintsadze, Timur; Shahrokhi, Amene; Eftekhari, Sanaz; Khalilov, Ilgam; Tsintsadze, Vera; Brouchoud, Corinne; Chazal, Genevieve; Lemonnier, Eric; Lozovaya, Natalia; Burnashev, Nail; Ben-Ari, Yehezkel

    2014-02-01

    We report that the oxytocin-mediated neuroprotective ?-aminobutyric acid (GABA) excitatory-inhibitory shift during delivery is abolished in the valproate and fragile X rodent models of autism. During delivery and subsequently, hippocampal neurons in these models have elevated intracellular chloride levels, increased excitatory GABA, enhanced glutamatergic activity, and elevated gamma oscillations. Maternal pretreatment with bumetanide restored in offspring control electrophysiological and behavioral phenotypes. Conversely, blocking oxytocin signaling in naïve mothers produced offspring having electrophysiological and behavioral autistic-like features. Our results suggest a chronic deficient chloride regulation in these rodent models of autism and stress the importance of oxytocin-mediated GABAergic inhibition during the delivery process. Our data validate the amelioration observed with bumetanide and oxytocin and point to common pathways in a drug-induced and a genetic rodent model of autism. PMID:24503856

  9. Assignment of the human GABA transporter gene (GABATHG) locus to chromosome 3p24-p25

    SciTech Connect

    Huang, Fang; Fei, Jian; Guo, Li-He [Shanghai Institute of Cell Biology, Shanghai (China)] [and others] [Shanghai Institute of Cell Biology, Shanghai (China); and others

    1995-09-01

    An essential regulatory process of synaptic transmission is the inactivation of released neurotransmitters by the transmitter-specific uptake mechanism, {gamma}-Aminobutyric acid (GABA) is an inhibitory transmitter in the vertebrate central nervous system; its activity is terminated by a high-affinity Na{sup +} and Cl{sup -} -dependent specific GABA transporter (GAT), which carries the neurotransmitter to the presynaptic neuron and/or glial elements surrounding the synaptic cleft. Deficiency of the transporter may cause epilepsy and some other nervous diseases. The human GAT gene (GABATHG), approximately 25 kb in length, has been cloned and sequenced by our colleagues (7). Here the results of the in situ hybridization mapping with the gene are presented. 10 refs., 1 fig.

  10. Modulation of the release of norepinephrine by gamma-aminobutyric acid and morphine in the frontal cerebral cortex of the rat

    SciTech Connect

    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{sub 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.

  11. [GABA fluophore formation due to ninhydrin reaction in the octanolic milieu. Spectrofluorometric investigation. 1. (author's transl)].

    PubMed

    Pfister, C; Wolny, H J

    1980-01-01

    As a result of the reaction of ninhydrin with gamma-aminobutyric acid and glutamic acid in the octanolic milieu, a fluorescent product, presumably a copper-II-chelat-complex, was formed. This appears analogous to the fluorescence histochemical procedure. the reaction product displays the following spectrofluorometric properties: excitation peak at lambda = 375 nm and emission plaximum at lambda = 445 nm. Spectrofluorometric estimations during performing various steps of the reaction were indicative of possibilities of the improvement of the fluorescence histochemical GABA demonstration. PMID:6776778

  12. Gamma Hydroxybutyric Acid (GHB) Intoxication

    Microsoft Academic Search

    Phillip E. Mason; William P. Kerns II

    2002-01-01

    Gamma-aminobutyric acid (GABA) was discovered as the predominant inhibitory central nervous sys- tem (CNS) neurotransmitter in 1956. This prompted a search for a GABA analog that would cross the blood-brain barrier for possible therapeutic use. During this search, gamma-hydroxybutyric acid (GHB) was found in the brain and subsequently synthesized in the laboratory in 1964. 1,2 Since its discovery, GHB has

  13. Virus-induced gene silencing reveals control of reactive oxygen species accumulation and salt tolerance in tomato by ?-aminobutyric acid metabolic pathway.

    PubMed

    Bao, Hexigeduleng; Chen, Xianyang; Lv, Sulian; Jiang, Ping; Feng, Juanjuan; Fan, Pengxiang; Nie, Lingling; Li, Yinxin

    2015-03-01

    ?-Aminobutyric acid (GABA) accumulates in many plant species in response to environmental stress. However, the physiological function of GABA or its metabolic pathway (GABA shunt) in plants remains largely unclear. Here, the genes, including glutamate decarboxylases (SlGADs), GABA?transaminases (SlGABA-Ts) and succinic semialdehyde dehydrogenase (SlSSADH), controlling three steps of the metabolic pathway of GABA, were studied through virus-induced gene silencing approach in tomato. Silencing of SlGADs (GABA biosynthetic genes) and SlGABA-Ts (GABA catabolic genes) led to increased accumulation of reactive oxygen species (ROS) as well as salt sensitivity under 200?mm NaCl treatment. Targeted quantitative analysis of metabolites revealed that GABA decreased and increased in the SlGADs- and SlGABA-Ts-silenced plants, respectively, whereas succinate (the final product of GABA metabolism) decreased in both silenced plants. Contrarily, SlSSADH-silenced plants, also defective in GABA degradation process, showed dwarf phenotype, curled leaves and enhanced accumulation of ROS in normal conditions, suggesting the involvement of a bypath for succinic semialdehyde catabolism to ?-hydroxybutyrate as reported previously in Arabidopsis, were less sensitive to salt stress. These results suggest that GABA shunt is involved in salt tolerance of tomato, probably by affecting the homeostasis of metabolites such as succinate and ?-hydroxybutyrate and subsequent ROS accumulation under salt stress. PMID:25074245

  14. Allopregnanolone prevents dieldrin-induced NMDA receptor internalization and neurotoxicity by preserving GABA(A) receptor function.

    PubMed

    Briz, Víctor; Parkash, Jyoti; Sánchez-Redondo, Sara; Prevot, Vincent; Suñol, Cristina

    2012-02-01

    Dieldrin is an endocrine disruptor that accumulates in mammalian adipose tissue and brain. It induces convulsions due to its antagonism of the ?-aminobutyric acid A receptor (GABA(A)R). We have previously reported that long-term exposure to dieldrin causes the internalization of the N-methyl-D-aspartate receptor (NMDAR) as a result of persistent GABA(A)R inhibition. Because the neurosteroids 17?-estradiol (E2) and allopregnanolone are known to modulate the function and trafficking of GABA(A)R and NMDAR, we examined the effects of E2 and allopregnanolone on dieldrin-induced GABA(A)R inhibition, NMDAR internalization, and neuronal death in cortical neurons. We found that 1 nM E2 increased the membrane expression of NR1/NR2B receptors and postsynaptic density 95 but did not induce their physical association. In contrast, 10 nM E2 had no effect on these proteins but reduced NR2A membrane expression. We also found that exposure to 60 nM dieldrin for 6 d in vitro caused the internalization of NR1 and NR2B but not NR2A. Treatment with either 1 nM E2 or 10 ?M allopregnanolone prevented the dieldrin-induced reduction in membrane levels of the NR1/NR2B receptors. Furthermore, prolonged exposure to 200 nM dieldrin down-regulated the expression of NR2A; this was inhibited only by allopregnanolone. Although both hormones restored NMDAR function, as measured by the NMDA-induced rise in intracellular calcium, allopregnanolone (but not E2) reversed the inhibition of GABA(A)R and neuronal death caused by prolonged exposure to dieldrin. Our results indicate that allopregnanolone protects cortical neurons against the neurotoxicity caused by long-term exposure to dieldrin by maintaining GABA(A)R and NMDAR functionality. PMID:22166974

  15. An evolutionarily conserved switch in response to GABA affects development and behavior of the locomotor circuit of Caenorhabditis elegans.

    PubMed

    Han, Bingjie; Bellemer, Andrew; Koelle, Michael R

    2015-04-01

    The neurotransmitter gamma-aminobutyric acid (GABA) is depolarizing in the developing vertebrate brain, but in older animals switches to hyperpolarizing and becomes the major inhibitory neurotransmitter in adults. We discovered a similar developmental switch in GABA response in Caenorhabditis elegans and have genetically analyzed its mechanism and function in a well-defined circuit. Worm GABA neurons innervate body wall muscles to control locomotion. Activation of GABAA receptors with their agonist muscimol in newly hatched first larval (L1) stage animals excites muscle contraction and thus is depolarizing. At the mid-L1 stage, as the GABAergic neurons rewire onto their mature muscle targets, muscimol shifts to relaxing muscles and thus has switched to hyperpolarizing. This muscimol response switch depends on chloride transporters in the muscles analogous to those that control GABA response in mammalian neurons: the chloride accumulator sodium-potassium-chloride-cotransporter-1 (NKCC-1) is required for the early depolarizing muscimol response, while the two chloride extruders potassium-chloride-cotransporter-2 (KCC-2) and anion-bicarbonate-transporter-1 (ABTS-1) are required for the later hyperpolarizing response. Using mutations that disrupt GABA signaling, we found that neural circuit development still proceeds to completion but with an ?6-hr delay. Using optogenetic activation of GABAergic neurons, we found that endogenous GABAA signaling in early L1 animals, although presumably depolarizing, does not cause an excitatory response. Thus a developmental depolarizing-to-hyperpolarizing shift is an ancient conserved feature of GABA signaling, but existing theories for why this shift occurs appear inadequate to explain its function upon rigorous genetic analysis of a well-defined neural circuit. PMID:25644702

  16. Noisy Galvanic Vestibular Stimulation Promotes GABA Release in the Substantia Nigra and Improves Locomotion in Hemiparkinsonian Rats

    PubMed Central

    Samoudi, Ghazaleh; Nissbrandt, Hans; Dutia, Mayank B.; Bergquist, Filip

    2012-01-01

    Background The vestibular system is connected to spinal, cerebellar and cerebral motor control structures and can be selectively activated with external electrodes. The resulting sensation of disturbed balance can be avoided by using stochastic stimulation patterns. Adding noise to the nervous system sometimes improves function. Small clinical trials suggest that stochastic vestibular stimulation (SVS) may improve symptoms in Parkinson's disease. We have investigated this claim and possible mechanisms using the 6-hydroxydopamine (6-OHDA) hemilesion model of Parkinson's disease. Methodology/Principal Findings Animals were tested in the accelerating rod test and the Montoya staircase test of skilled forelimb use. In 6-OHDA hemilesioned animals, SVS improved rod performance by 56±11 s. At group level L-DOPA treatment had no effect, but positive responders improved time on rod by 60±19 s. Skilled forelimb use was not altered by SVS. To investigate how SVS may influence basal ganglia network activity, intracerebral microdialysis was employed in four regions of interest during and after SVS. In presence of the ?-amino buturic acid (GABA) transporter inhibitor NNC 711, SVS induced an increase in GABA to 150±15% of baseline in the substantia nigra (SN) of unlesioned animals, but had no effect in the pedunculopontine nucleus (PPN), the striatum or the ventromedial thalamus (VM). Dopamine release remained stable in all areas, as did GABA and amine concentrations in the SN of unstimulated controls. Following SVS, a sustained increase in GABA concentrations was observed in the ipsilesional, but not in the contralesional SN of 6-OHDA hemilesioned rats. In contrast, L-DOPA treatment produced a similar increase of GABA in the ipsi- and contra-lesional SN. Conclusions/Significance SVS improves rod performance in a rat model of Parkinson's disease, possibly by increasing nigral GABA release in a dopamine independent way. We propose that SVS could be useful for treating symptoms of Parkinson's disease. PMID:22238601

  17. Discovery and optimization of an azetidine chemical series as a free fatty acid receptor 2 (FFA2) antagonist: from hit to clinic.

    PubMed

    Pizzonero, Mathieu; Dupont, Sonia; Babel, Marielle; Beaumont, Stéphane; Bienvenu, Natacha; Blanqué, Roland; Cherel, Laëtitia; Christophe, Thierry; Crescenzi, Benedetta; De Lemos, Elsa; Delerive, Philippe; Deprez, Pierre; De Vos, Steve; Djata, Fatoumata; Fletcher, Stephen; Kopiejewski, Sabrina; L'Ebraly, Christelle; Lefrançois, Jean-Michel; Lavazais, Stéphanie; Manioc, Murielle; Nelles, Luc; Oste, Line; Polancec, Denis; Quénéhen, Vanessa; Soulas, Florilène; Triballeau, Nicolas; van der Aar, Ellen M; Vandeghinste, Nick; Wakselman, Emanuelle; Brys, Reginald; Saniere, Laurent

    2014-12-11

    FFA2, also called GPR43, is a G-protein coupled receptor for short chain fatty acids which is involved in the mediation of inflammatory responses. A class of azetidines was developed as potent FFA2 antagonists. Multiparametric optimization of early hits with moderate potency and suboptimal ADME properties led to the identification of several compounds with nanomolar potency on the receptor combined with excellent pharmacokinetic (PK) parameters. The most advanced compound, 4-[[(R)-1-(benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric acid 99 (GLPG0974), is able to inhibit acetate-induced neutrophil migration strongly in vitro and demonstrated ability to inhibit a neutrophil-based pharmacodynamic (PD) marker, CD11b activation-specific epitope [AE], in a human whole blood assay. All together, these data supported the progression of 99 toward next phases, becoming the first FFA2 antagonist to reach the clinic. PMID:25380412

  18. Seed-specific expression of truncated OsGAD2 produces GABA-enriched rice grains that influence a decrease in blood pressure in spontaneously hypertensive rats

    Microsoft Academic Search

    Kazuhito Akama; Junko Kanetou; Shunsuke Shimosaki; Kouhei Kawakami; Satoru Tsuchikura; Fumio Takaiwa

    2009-01-01

    Gamma-aminobutyric acid (GABA) is a four-carbon amino acid that is commonly present in living organisms and functions as a\\u000a major inhibitory neurotransmitter in mammals. It is understood to have a potentially anti-hypertensive effect in mammals.\\u000a GABA is synthesized from glutamate by glutamate decarboxylase (GAD). In plants, GAD is regulated via its calmodulin-binding\\u000a domain (CaMBD) by Ca2+\\/CaM. We have previously reported

  19. Neurosteroids and GABA-A Receptor Function

    PubMed Central

    Wang, Mingde

    2011-01-01

    Neurosteroids represent a class of endogenous steroids that are synthesized in the brain, the adrenals, and the gonads and have potent and selective effects on the GABAA-receptor. 3?-hydroxy A-ring reduced metabolites of progesterone, deoxycorticosterone, and testosterone are positive modulators of GABAA-receptor in a non-genomic manner. Allopregnanolone (3?-OH-5?-pregnan-20-one), 5?-androstane-3?, 17?-diol (Adiol), and 3?5?-tetrahydrodeoxycorticosterone (3?5?-THDOC) enhance the GABA-mediated Cl- currents acting on a site (or sites) distinct from the GABA, benzodiazepine, barbiturate, and picrotoxin binding sites. 3?5?-P and 3?5?-THDOC potentiate synaptic GABAA-receptor function and activate ?-subunit containing extrasynaptic receptors that mediate tonic currents. On the contrary, 3?-OH pregnane steroids and pregnenolone sulfate (PS) are GABAA-receptor antagonists and induce activation-dependent inhibition of the receptor. The activities of neurosteroid are dependent on brain regions and types of neurons. In addition to the slow genomic action of the parent steroids, the non-genomic, and rapid actions of neurosteroids play a significant role in the GABAA-receptor function and shift in mood and memory function. This review describes molecular mechanisms underlying neurosteroid action on the GABAA-receptor, mood changes, and cognitive functions. PMID:22654809

  20. gamma-Aminobutyric acid stimulates ethylene biosynthesis in sunflower.

    PubMed Central

    Kathiresan, A; Tung, P; Chinnappa, C C; Reid, D M

    1997-01-01

    gamma-Aminobutyric acid (GABA), a nonprotein amino acid, is often accumulated in plants following environmental stimuli that can also cause ethylene production. We have investigated the relationship between GABA and ethylene production in excised sunflower (Helianthus annuus L.) tissues. Exogenous GABA causes up to a 14-fold increase in the ethylene production rate after about 12 h. Cotyledons fed with [14C]GABA did not release substantial amounts of radioactive ethylene despite its chemical similarity to 1-aminocyclopropane-1-carboxylic acid (ACC), indicating that GABA is not likely to be an alternative precursor for ethylene. GABA causes increases in ACC synthase mRNA accumulation, ACC levels, ACC oxidase mRNA levels, and in vitro ACC oxidase activity. In the presence of aminoethoxyvinylglycine or alpha-aminoisobutyric acid, GABA did not stimulate ethylene production. We therefore conclude that GABA stimulates ethylene biosynthesis mainly by promoting ACC synthase transcript abundance. Possible roles of GABA as a signal transducer are suggested. PMID:9306696

  1. Pre and Postnatal Development of GABA Receptors in Macaca Monkey Visual Cortex

    Microsoft Academic Search

    C. Shaw; L. Cameron; D. March; M. Cynader; B. Zielinski; A. Hendrickson

    1991-01-01

    GABA is a putative inhibitory neurotransmitter in adult mam- malian visual cortex but also has been implicated as playing a crucial role in cortical information processing during de- velopment. In order to understand better the role of GABA during primate visual cortex development, we have exam- ined the time course of GABA, and GABA, receptor onto- genesis in 18 Macaca

  2. Immunocytochemical localization of amines and GABA in the optic lobe of the butterfly, Papilio xuthus.

    PubMed

    Hamanaka, Yoshitaka; Kinoshita, Michiyo; Homberg, Uwe; Arikawa, Kentaro

    2012-01-01

    Butterflies have sophisticated color vision. While the spectral organization of the compound eye has been well characterized in the Japanese yellow swallowtail butterfly, Papilio xuthus, neural mechanisms underlying its color vision are largely unexplored. Towards a better understanding of signal processing in the visual system of P. xuthus, we used immunocytochemical techniques to analyze the distribution of transmitter candidates, namely, histamine, serotonin, tyramine and ?-aminobutyric acid (GABA). Photoreceptor terminals in the lamina and medulla exhibited histamine immunoreactivity as demonstrated in other insects. The anti-histamine antiserum also labeled a few large medulla neurons. Medulla intrinsic neurons and centrifugal neurons projecting to the lamina showed serotonin immunoreactivity. Tyramine immunostaining was detected in a subset of large monopolar cells (LMCs) in the lamina, transmedullary neurons projecting to the lobula plate, and cell bodies surrounding the first optic chiasma. An anti-GABA antiserum labeled a subset of LMCs and populations of columnar and tangential neurons surrounding the medulla. Each of the four antisera also labeled a few centrifugal neurons that innervate the lobula complex from the central brain, suggesting that they have neuromodulatory roles. A distinctive feature we found in this study is the possibility that tyramine and GABA act as transmitters in LMCs of P. xuthus, which has not been reported in any other insects so far. PMID:22844431

  3. GABA and Glutamate Uptake and Metabolism in Retinal Glial (Müller) Cells

    PubMed Central

    Bringmann, Andreas; Grosche, Antje; Pannicke, Thomas; Reichenbach, Andreas

    2013-01-01

    Müller cells, the principal glial cells of the retina, support the synaptic activity by the uptake and metabolization of extracellular neurotransmitters. Müller cells express uptake and exchange systems for various neurotransmitters including glutamate and ?-aminobutyric acid (GABA). Müller cells remove the bulk of extracellular glutamate in the inner retina and contribute to the glutamate clearance around photoreceptor terminals. By the uptake of glutamate, Müller cells are involved in the shaping and termination of the synaptic activity, particularly in the inner retina. Reactive Müller cells are neuroprotective, e.g., by the clearance of excess extracellular glutamate, but may also contribute to neuronal degeneration by a malfunctioning or even reversal of glial glutamate transporters, or by a downregulation of the key enzyme, glutamine synthetase. This review summarizes the present knowledge about the role of Müller cells in the clearance and metabolization of extracellular glutamate and GABA. Some major pathways of GABA and glutamate metabolism in Müller cells are described; these pathways are involved in the glutamate-glutamine cycle of the retina, in the defense against oxidative stress via the production of glutathione, and in the production of substrates for the neuronal energy metabolism. PMID:23616782

  4. Extrasynaptic GABA(A) receptors in the brainstem and spinal cord: structure and function.

    PubMed

    Delgado-Lezama, Rodolfo; Loeza-Alcocer, Emanuel; Andrés, Carmen; Aguilar, Justo; Guertin, Pierre A; Felix, Ricardo

    2013-01-01

    ?-aminobutyric acid (GABA) plays many of its key roles in embryonic development and functioning of the central nervous system (CNS) by acting on ligand gated chloride-permeable channels known as GABAA receptors (GABAAR). Classically, GABAARmediated synaptic communication is tailored to allow rapid and precise transmission of information to synchronize the activity of large populations of cells to generate and maintain neuronal networks oscillations. An alternative type of inhibition mediated by GABAA receptors, initially described about 25 years ago, is characterized by a tonic activation of receptors that react to ambient extracellular GABA. The receptors that mediate this action are wide-spread throughout the nerve cells but are located distant from the sites of GABA release, and therefore they have been called extrasynaptic GABAA receptors. The molecular nature of the extrasynaptic GABAA receptors and the tonic inhibitory current they generate have been characterized in many brain structures, and due to its relevance in controlling neuron excitability they have become attractive pharmacological targets for a variety of neurological disorders such as schizophrenia, epilepsy and Parkinson disease. In the spinal cord, early studies have implicated these receptors in anesthesia, chronic pain, motor control, and locomotion. This review highlights past and present developments in the field of extrasynaptic GABAA receptors and emphasizes their subunit containing distribution and physiological role in the spinal cord. PMID:23360278

  5. Electrophysiological characterization of methyleugenol: a novel agonist of GABA(A) receptors.

    PubMed

    Ding, Jing; Huang, Chen; Peng, Zhong; Xie, Yuxuan; Deng, Shining; Nie, Yan-Zhen; Xu, Tian-Le; Ge, Wei-Hong; Li, Wei-Guang; Li, Fei

    2014-09-17

    Methyleugenol (ME) is a natural constituent isolated from many plant essential oils having multiple biological effects including anticonvulsant and anesthetic activities, although the underlying mechanisms remain unclear. Here, we identify ME as a novel agonist of ionotropic ?-aminobutyric acid (GABA) receptors. At lower concentrations (?30 ?M), ME significantly sensitized GABA-induced, but not glutamate- or glycine-induced, currents in cultured hippocampal neurons, indicative of a preferentially modulatory role of this compound for A type GABA receptors (GABAARs). In addition, ME at higher concentrations (?100 ?M) induced a concentration-dependent, Cl(-)-permeable current in hippocampal neurons, which was inhibited by a GABAAR channel blocker, picrotoxin, and a competitive GABAAR antagonist, bicuculline, but not a specific glycine receptor inhibitor, strychnine. Moreover, ME activated a similar current mediated by recombinant ?1-?2-?2 or ?5-?2-?2 GABAARs in human embryonic kidney (HEK) cells. Consequently, ME produced a strong inhibition of synaptically driven neuronal excitation in hippocampal neurons. Together, these results suggest that ME represents a novel agonist of GABAARs, shedding additional light on future development of new therapeutics targeting GABAARs. The present study also adds GABAAR activation to the list of molecular targets of ME that probably account for its biological activities. PMID:24980777

  6. GABA(B) receptors and opioid mechanisms involved in homotaurine-induced analgesia.

    PubMed

    Serrano, M I; Serrano, J S; Fernández, A; Asadi, I; Serrano-Martino, M C

    1998-03-01

    1. The involvement of GABA(B) receptors and opioid mechanisms in homotaurine-induced analgesia has been investigated in current models of nociception by using a GABA(B) receptor antagonist, morphine, and naloxone. CGP 35348 (50-200 mg/kg IP), a highly selective GABA(B) antagonist, was administered prior to carrying out a dose-response curve of homotaurine (22.6-445 mg/kg IP) antinociceptive effect in the abdominal constriction (mice) and tail flick (rats) tests. 2. The tail flick test was performed in animals pretreated with morphine (0.5 mg/kg SC) and naloxone (1 mg/kg), 15 min before amino acid. Animals treated with saline 10 ml/kg (mice) or 1.25 ml/kg (rats) were included as control for the vehicle used. 3. CGP 35348 antagonized the antinociceptive effect of homotaurine in both tests. The range of doses affected by the interaction depended on the test assayed, but it was coincident for the main part of the dose-response curve. 4. A subanalgesic dose of morphine potentiated the antinociceptive effect of lower doses of homotaurine in the tail flick test. Naloxone pretreatment inhibited the antinociceptive effect of homotaurine. 5. These data imply that GABA(B) receptor subpopulations and opiate mechanisms are involved in the antinociceptive effect of homotaurine. Because functional relationships have been found between GABAergic and opiate systems in analgesic effects, an interaction of the two mechanisms may be operating in the effects described for homotaurine. PMID:9510095

  7. Compartmentalization of GABA synthesis by GAD67 differs between pancreatic beta cells and neurons.

    PubMed

    Kanaani, Jamil; Cianciaruso, Chiara; Phelps, Edward A; Pasquier, Miriella; Brioudes, Estelle; Billestrup, Nils; Baekkeskov, Steinunn

    2015-01-01

    The inhibitory neurotransmitter GABA is synthesized by the enzyme glutamic acid decarboxylase (GAD) in neurons and in pancreatic ?-cells in islets of Langerhans where it functions as a paracrine and autocrine signaling molecule regulating the function of islet endocrine cells. The localization of the two non-allelic isoforms GAD65 and GAD67 to vesicular membranes is important for rapid delivery and accumulation of GABA for regulated secretion. While the membrane anchoring and trafficking of GAD65 are mediated by intrinsic hydrophobic modifications, GAD67 remains hydrophilic, and yet is targeted to vesicular membrane pathways and synaptic clusters in neurons by both a GAD65-dependent and a distinct GAD65-independent mechanism. Herein we have investigated the membrane association and targeting of GAD67 and GAD65 in monolayer cultures of primary rat, human, and mouse islets and in insulinoma cells. GAD65 is primarily detected in Golgi membranes and in peripheral vesicles distinct from insulin vesicles in ?-cells. In the absence of GAD65, GAD67 is in contrast primarily cytosolic in ?-cells; its co-expression with GAD65 is necessary for targeting to Golgi membranes and vesicular compartments. Thus, the GAD65-independent mechanism for targeting of GAD67 to synaptic vesicles in neurons is not functional in islet ?-cells. Therefore, only GAD65:GAD65 homodimers and GAD67:GAD65 heterodimers, but not the GAD67:GAD67 homodimer gain access to vesicular compartments in ?-cells to facilitate rapid accumulation of newly synthesized GABA for regulated secretion and fine tuning of GABA-signaling in islets of Langerhans. PMID:25647668

  8. Motor dysfunction in cerebellar Purkinje cell-specific vesicular GABA transporter knockout mice

    PubMed Central

    Kayakabe, Mikiko; Kakizaki, Toshikazu; Kaneko, Ryosuke; Sasaki, Atsushi; Nakazato, Yoichi; Shibasaki, Koji; Ishizaki, Yasuki; Saito, Hiromitsu; Suzuki, Noboru; Furuya, Nobuhiko; Yanagawa, Yuchio

    2014-01-01

    ?-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the adult mammalian central nervous system and plays modulatory roles in neural development. The vesicular GABA transporter (VGAT) is an essential molecule for GABAergic neurotransmission due to its role in vesicular GABA release. Cerebellar Purkinje cells (PCs) are GABAergic projection neurons that are indispensable for cerebellar function. To elucidate the significance of VGAT in cerebellar PCs, we generated and characterized PC-specific VGAT knockout (L7-VGAT) mice. VGAT mRNAs and proteins were specifically absent in the 40-week-old L7-VGAT PCs. The morphological characteristics, such as lamination and foliation of the cerebellar cortex, of the L7-VGAT mice were similar to those of the control littermate mice. Moreover, the protein expression levels and patterns of pre- (calbindin and parvalbumin) and postsynaptic (GABA-A receptor ?1 subunit and gephyrin) molecules between the L7-VGAT and control mice were similar in the deep cerebellar nuclei that receive PC projections. However, the L7-VGAT mice performed poorly in the accelerating rotarod test and displayed ataxic gait in the footprint test. The L7-VGAT mice also exhibited severer ataxia as VGAT deficits progressed. These results suggest that VGAT in cerebellar PCs is not essential for the rough maintenance of cerebellar structure, but does play an important role in motor coordination. The L7-VGAT mice are a novel model of ataxia without PC degeneration, and would also be useful for studying the role of PCs in cognition and emotion. PMID:24474904

  9. Polycomblike protein PHF1b: a transcriptional sensor for GABA receptor activity

    PubMed Central

    2013-01-01

    Background The ?-aminobutyric acid (GABA) type A receptor (GABAAR) contains the recognition sites for a variety of agents used in the treatment of brain disorders, including anxiety and epilepsy. A better understanding of how receptor expression is regulated in individual neurons may provide novel opportunities for therapeutic intervention. Towards this goal we have studied transcription of a GABAAR subunit gene (GABRB1) whose activity is autologously regulated by GABA via a 10 base pair initiator-like element (?1-INR). Methods By screening a human cDNA brain library with a yeast one-hybrid assay, the Polycomblike (PCL) gene product PHD finger protein transcript b (PHF1b) was identified as a ?1-INR associated protein. Promoter/reporter assays in primary rat cortical cells demonstrate that PHF1b is an activator at GABRB1, and chromatin immunoprecipitation assays reveal that presence of PHF1 at endogenous Gabrb1 is regulated by GABAAR activation. Results PCL is a member of the Polycomb group required for correct spatial expression of homeotic genes in Drosophila. We now show that PHF1b recognition of ?1-INR is dependent on a plant homeodomain, an adjacent helix-loop-helix, and short glycine rich motif. In neurons, it co-immunoprecipitates with SUZ12, a key component of the Polycomb Repressive Complex 2 (PRC2) that regulates a number of important cellular processes, including gene silencing via histone H3 lysine 27 trimethylation (H3K27me3). Conclusions The observation that chronic exposure to GABA reduces PHF1 binding and H3K27 monomethylation, which is associated with transcriptional activation, strongly suggests that PHF1b may be a molecular transducer of GABAAR function and thus GABA-mediated neurotransmission in the central nervous system. PMID:23879974

  10. The endogenous GABA bioactivity of camel, bovine, goat and human milks.

    PubMed

    Limon, Agenor; Gallegos-Perez, Jose-Luis; Reyes-Ruiz, Jorge M; Aljohi, Mohammad A; Alshanqeeti, Ali S; Miledi, Ricardo

    2014-02-15

    GABA orally administered has several beneficial effects on health, including the regulation of hyperglycaemic states in humans. Those effects are similar to the effects reported for camel milk (CMk); however, it is not known whether compounds with GABAergic activity are present in milk from camels or other species. We determined CMk free-GABA concentration by LS/MS and its bioactivity on human GABA receptors. We found that camel and goat milks have significantly more bioavailable GABA than cow and human milks and are able to activate GABA? receptors. The relationship between GABA and taurine concentrations suggests that whole camel milk may be more efficient to activate GABA?1 receptors than goat milk. Because GABA? receptors are normally found in enteroendocrine cells in the lumen of the digestive tract, these results suggest that GABA in camel and goat milk may participate in GABA-modulated functions of enteroendocrine cells in the GI lumen. PMID:24128504

  11. Burst firing in gonadotrophin-releasing hormone neurones does not require ionotrophic GABA or glutamate receptor activation.

    PubMed

    Lee, K; Liu, X; Herbison, A E

    2012-12-01

    Burst firing is a feature of many neuroendocrine cell types, including the hypothalamic gonadotrophin-releasing hormone (GnRH) neurones that control fertility. The role of intrinsic and extrinsic influences in generating GnRH neurone burst firing is presently unclear. In the present study, we investigated the role of fast amino acid transmission in burst firing by examining the effects of receptor antagonists on bursting displayed by green fluorescent protein GnRH neurones in sagittal brain slices prepared from adult male mice. Blockade of AMPA and NMDA glutamate receptors with a cocktail of CNQX and AP5 was found to have no effects on burst firing in GnRH neurones. The frequency of bursts, dynamics of individual bursts, or percentage of firing clustered in bursts was not altered. Similarly, GABA(A) receptor antagonists bicuculline and picrotoxin had no effects upon burst firing in GnRH neurones. To examine the importance of both glutamate and GABA ionotrophic signalling, a cocktail including picrotoxin, CNQX and AP5 was used but, again, this was found to have no effects on GnRH neurone burst firing. To further question the impact of endogenous amino acid release on burst firing, electrical activation of anteroventral periventricular nuclei GABA/glutamate inputs to GnRH neurones was undertaken and found to have no impact on burst firing. Taken together, these observations indicate that bursting in GnRH neurones is not dependent upon acute ionotrophic GABA and glutamate signalling and suggest that extrinsic inputs to GnRH neurones acting through AMPA, NMDA and GABA(A) receptors are unlikely to be required for burst initiation in these cells. PMID:22831560

  12. Nicotine self-administration differentially modulates glutamate and GABA transmission in hypothalamic paraventricular nucleus to enhance the hypothalamic-pituitary-adrenal response to stress

    PubMed Central

    Yu, Guoliang; Chen, Hao; Wu, Xingjun; Matta, Shannon G.; Sharp, Burt M.

    2010-01-01

    The Mechanisms by which chronic nicotine self-administration augments hypothalamo-pituitary-adrenal (HPA) responses to stress are only partially understood. Nicotine self-administration alters neuropeptide expression in corticotropin-releasing factor (CRF) neurons within paraventricular nucleus (PVN) and increases PVN responsiveness to norepinephrine during mild footshock stress. Glutamate and GABA also modulate CRF neurons, but their roles in enhanced HPA responsiveness to footshock during chronic self-administration are unknown. We show that nicotine self-administration augmented footshock-induced PVN glutamate release, but further decreased GABA release. In these rats, intra-PVN kynurenic acid, a glutamate receptor antagonist, blocked enhanced adrenocorticotropic hormone and corticosterone responses to footshock. In contrast, peri-PVN kynurenic acid, which decreases activity of GABA afferents to PVN, enhanced footshock-induced corticosterone secretion only in control rats self-administering saline. Additionally, in rats self-administering nicotine, footshock-induced elevation of corticosterone was significantly less than in controls after intra-PVN saclofen (GABA-B receptor antagonist). Therefore, the exaggerated reduction in GABA release by footshock during nicotine self-administration disinhibits CRF neurons. This disinhibition combined with enhanced glutamate input provides a new mechanism for HPA sensitization to stress by chronic nicotine self-administration. This mechanism, which does not preserve homeostatic plasticity, supports the concept that smoking functions as a chronic stressor that sensitizes the HPA to stress. PMID:20202080

  13. Circadian modulation of the Cl(-) equilibrium potential in the rat suprachiasmatic nuclei.

    PubMed

    Alamilla, Javier; Perez-Burgos, Azucena; Quinto, Daniel; Aguilar-Roblero, Raúl

    2014-01-01

    The suprachiasmatic nuclei (SCN) constitute a circadian clock in mammals, where ?-amino-butyric acid (GABA) neurotransmission prevails and participates in different aspects of circadian regulation. Evidence suggests that GABA has an excitatory function in the SCN in addition to its typical inhibitory role. To examine this possibility further, we determined the equilibrium potential of GABAergic postsynaptic currents (E(GABA)) at different times of the day and in different regions of the SCN, using either perforated or whole cell patch clamp. Our results indicate that during the day most neurons in the dorsal SCN have an E(GABA) close to -30 mV while in the ventral SCN they have an E(GABA) close to -60 mV; this difference reverses during the night, in the dorsal SCN neurons have an E(GABA) of -60 mV and in the ventral SCN they have an E(GABA) of -30 mV. The depolarized equilibrium potential can be attributed to the activity of the Na(+)-K(+)-2Cl(-) (NKCC) cotransporter since the equilibrium potential becomes more negative following addition of the NKCC blocker bumetanide. Our results suggest an excitatory role for GABA in the SCN and further indicate both time (day versus night) and regional (dorsal versus ventral) modulation of E(GABA) in the SCN. PMID:24949446

  14. Age-related changes in brainstem auditory neurotransmitters: measures of GABA and acetylcholine function.

    PubMed

    Raza, A; Milbrandt, J C; Arneric, S P; Caspary, D M

    1994-06-15

    This study was designed to determine if there are age-related alterations in the bio-synthetic enzyme glutamic acid decarboxylase (GAD), the degradative enzyme GABA-transaminase (GABA-T), and the uptake system for GABA in the central nucleus of the inferior colliculus (CIC), the cochlear nucleus (CN), and/or nuclei of the lateral lemniscus (NLL) of Fischer-344 rats. For purposes of comparison, the cholinergic neuronal system was studied in parallel in young adult (3-7 months), mature (15-17 months) and aged (24-26 months) rats. In young adults GAD activity was highest in the CIC (219 nmol/mg protein/h; N = 5), intermediate in NLL (82 nmol/mg protein/h), and lowest in CN (34 nmol/mg protein/h). Choline acetyltransferase (ChAT) activity was highest in NLL and CN, and approximately 35-40% lower in CIC. A more uniform pattern was observed with GABA-T activity. Reductions in GAD activity were seen in the CIC of mature (-31%) and aged (-30%) rats that were not graded with age when compared to young adult, P < 0.05 (N = 5). This effect was regionally selective, since the CN did not show any loss of GAD or ChAT activity. The neurotransmitter selectivity of this deficit in CIC is supported by the non-parallel changes in ChAT activity (-22%, aged vs. mature, P < 0.05) that occurred after the changes in GAD activity. In contrast to the loss of GABAergic biosynthetic capacity in aged CIC, high affinity uptake processes (Kd and Vmax) for 14C-GABA and 3H-D-aspartate were not significantly altered (P > 0.05). Similar to the CIC, the NLL showed remarkable age-related deficits, but these deficits were more substantial for the cholinergic system (ChAT activity: -56% aged vs. young adult, P < 0.05; GAD activity: -35% aged vs. mature). None of the areas examined showed a significant loss of GABA-T activity with aging. These data suggest: 1) Age-related loss of GABA-mediated inhibition in the CIC of Fischer-344 rats is not attributable to changes in uptake or degradation of GABA, but may be related loss of biosynthetic capacity (i.e. activity or quantity) of the GAD present; 2) processing centers of the central auditory pathway (i.e. CIC and NLL), but not necessarily primary (i.e. CN) integrative nuclei, demonstrate selective, age-related neurochemical deficits; and 3) age-related neurochemical changes in central auditory structures may contribute substantially to the abnormal perception of signals in noise and loss of speech discrimination observed in neural presbycusis. PMID:7928735

  15. GABA(A) and GABA(B) receptors have opposite effects on synaptic glutamate release on the nucleus tractus solitarii neurons.

    PubMed

    Kang, Y-H; Sun, B; Park, Y S; Park, C-S; Jin, Y-H

    2012-05-01

    Cranial visceral afferent nerve transfers information about visceral organs to nucleus tractus solitarii (NTS) by releasing the excitatory neurotransmitter glutamate. Various endogenous modulators affect autonomic reflex responses by changing glutamatergic responses in the NTS. Although the expression of GABA(A) and GABA(B) receptors in glutamatergic terminals is known, their functional contribution on glutamate release is poorly characterized. Here, we used mechanically isolated NTS neurons to examine the mechanisms by which presynaptic GABA(A) and GABA(B) receptors modulate glutamatergic excitatory postsynaptic currents (EPSCs). EPSC were isolated by clamping voltage at equilibrium potential for chloride (-49 mV) without any GABA receptors antagonists. In all neurons, GABA(A) agonist, muscimol (1 and 10 ?M), increased EPSC frequency (284.1±57% and 278.4±87% of control, respectively), but the GABA(B) agonist, baclofen (10 ?M), decreased EPSC frequency (43±8% of control). The GABA(A) antagonist, gabazine (18 ?M), decreased EPSC frequency in 50% of tested neurons, whereas GABA(B) antagonist, CGP (5 ?M), increased the EPSC frequency in 36% of tested neurons. External application of GABA (1 and 30 ?M) facilitating the EPSC frequency. The facilitation of the GABA(A) receptor-mediated release of glutamate was blocked by Na?-K?-Cl? cotransporter type 1 antagonist or Na? and Ca²? channel inhibitors indicating GABA(A) presynaptic depolarization. Thus, tonically released GABA activates GABA(A) and GABA(B) receptors to modulate the release of glutamate. These findings provide cellular mechanisms of heterosynaptic GABA-glutamate integration of peripheral visceral afferent signals in the NTS. PMID:22410341

  16. Modulation of radioligand binding to the GABA(A)-benzodiazepine receptor complex by a new component from Cyperus rotundus.

    PubMed

    Ha, Jeoung-Hee; Lee, Kwang-Youn; Choi, Hyoung-Chul; Cho, Jungsook; Kang, Byung-Soo; Lim, Jae-Chul; Lee, Dong-Ung

    2002-01-01

    Four sesquiterpenes, beta-selinene, isocurcumenol, nootkatone and aristolone and one triterpene, oleanolic acid were isolated from the ethylacetate fraction of the rhizomes of Cyperus rotundus and tested for their ability to modulate gamma-aminobutyric acid (GABA(A))-benzodiazepine receptor function by radioligand binding assays using rat cerebrocortical membranes. Among these compounds, only isocurcumenol, one of the newly identified constituents of this plant, was found to inhibit [3H]Ro15-1788 binding and enhance [3H]flunitrazepam binding in the presence of GABA. These results suggest that isocurcumenol may serve as a benzodiazepine receptor agonist and allosterically modulate GABAergic neurotransmission via enhancement of endogenous receptor ligand binding. PMID:11824542

  17. Electrophysiology of GABAergic transmission of single intergeniculate leaflet neurons in rat.

    PubMed

    Palus, Katarzyna; Chrobok, ?ukasz; Lewandowski, Marian H

    2015-01-01

    The intergeniculate leaflet (IGL) of the thalamus constitutes a small but important part of the neural network controlling circadian activity in rodents. It appears that IGL integrates photic cues from retina with non-photic information originating from different nonspecific brain systems. Subsequently, this integrated signal is passed to the master biological clock - the suprachiasmatic nuclei (SCN). The common neurotransmitter of biological clock neural structures, the gamma-amino-butyric acid (GABA) is expressed in many, if not all, IGL and SCN neurons. Whole-cell patch clamp in vitro electrophysiological experiments were performed in order to evaluate GABA's influence on single IGL neurons in rat. Most neurons were hyperpolarized by GABA application and this effect was caused by activation of GABAA as well as GABAB receptors. The presence of GABAB receptors in rat's IGL has been suggested for the first time. PMID:25856520

  18. Molecular aspects of age-related cognitive decline: the role of GABA signaling.

    PubMed

    McQuail, Joseph A; Frazier, Charles J; Bizon, Jennifer L

    2015-07-01

    Alterations in inhibitory interneurons contribute to cognitive deficits associated with several psychiatric and neurological diseases. Phasic and tonic inhibition imparted by ?-aminobutyric acid (GABA) receptors regulates neural activity and helps to establish the appropriate network dynamics in cortical circuits that support normal cognition. This review highlights basic science demonstrating that inhibitory signaling is altered in aging, and discusses the impact of age-related shifts in inhibition on different forms of memory function, including hippocampus-dependent spatial reference memory and prefrontal cortex (PFC)-dependent working memory. The clinical appropriateness and tractability of select therapeutic candidates for cognitive aging that target receptors mediating inhibition are also discussed. PMID:26070271

  19. GABA Enhances Transmission at an Excitatory Glutamatergic Synapse

    Microsoft Academic Search

    Scott Gutovitz; John T. Birmingham; Jason A. Luther; David J. Simon; Eve Marder

    2001-01-01

    GABA mediates both presynaptic and postsynaptic inhibition at many synapses. In contrast, we show that GABA enhances transmission at excitatory synapses between the lateral gastric and medial gastric motor neurons and the gastric mill 6a and 9 (gm6a, gm9) muscles and between the lateral pyloric motor neuron and pyloric 1 (p1) muscles in the stomach of the lobster Homarus americanus.

  20. Medicinal Chemistry and Molecular Pharmacology of GABA-C Receptors

    Microsoft Academic Search

    Graham A. R. Johnston

    2002-01-01

    GABAC receptors belong to the nicotinicoid superfamily of ionotropic receptors that include nicotinic acetylcholine receptors, bicuculline-sensitive GABAA receptors, strychnine-sensitive glycine receptors and 5HT3 serotonin receptors. The GABAC receptor concept arose from medicinal chemical studies of a conformationally restricted analog of GABA. Receptors matching the predicted properties of GABA C receptors were cloned from the retina. Post cloning studies revealed the

  1. Serotonin and GABA are colocalized in restricted groups of neurons in the larval sea lamprey brain: insights into the early evolution of neurotransmitter colocalization in vertebrates

    PubMed Central

    Barreiro-Iglesias, Antón; Cornide-Petronio, María Eugenia; Anadón, Ramón; Rodicio, María Celina

    2009-01-01

    Colocalization of the classic neurotransmitters serotonin (5-HT) and ?-aminobutyric acid (GABA) (or the enzyme that synthesizes the latter, glutamate decarboxylase) has been reported in a few neurons of the rat raphe magnus-obscurus nuclei. However, there are no data on the presence of neurochemically similar neurons in the brain of non-mammalian vertebrates. Lampreys are the oldest extant vertebrates and may provide important data on the phylogeny of neurochemical systems. The colocalization of 5-HT and GABA in neurons of the sea lamprey brain was studied using antibodies directed against 5-HT and GABA and confocal microscopy. Colocalization of the neurotransmitters was observed in the diencephalon and the isthmus. In the diencephalon, about 87% of the serotonergic cells of the rostral tier of the dorsal thalamus (close to the zona limitans) exhibited GABA immunoreactivity. In addition, occasional cells double-labelled for GABA and 5-HT were observed in the hypothalamic tuberal nucleus and the pretectum. Of the three serotonergic isthmic subgroups already recognized in the sea lamprey isthmus (dorsal, medial and ventral), such double-labelled cells were only observed in the ventral subgroup (about 61% of the serotonergic cells in the ventral subgroup exhibited GABA immunoreactivity). An equivalence between these lamprey isthmic cells and the serotonergic/GABAergic raphe cells of mammals is suggested. Present findings suggest that serotonergic/GABAergic neurons are more extensive in lampreys than in the rat and probably appeared before the separation of agnathans and gnathostomes. Cotransmission by release of 5-HT and GABA by the here-described lamprey brain neurons is proposed. PMID:19552725

  2. Application of bioinformatics algorithms to define the most important protein features contribute to GABA receptors diversity GABA receptors' diversity, bioinformatic applications

    Microsoft Academic Search

    Mansour Ebrahimi; Esmaeil Ebrahimie

    2010-01-01

    The importance of GABA receptors in the modulation of transmitter release and the late inhibitory postsynaptic potential and their ubiquitous distribution within the CNS promise a good deal as targets for many medical and pharmacological interventions. GABA interacts with various receptors types as A, B, C and various subtypes receptors. Various methods have been employed to distinguish between different GABA

  3. Design and mechanism of tetrahydrothiophene-based ?-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

    2015-04-01

    Low levels of ?-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 ?-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 ?-? interaction with Phe-189, and a weak nonbonded S···O?C interaction with Glu-270, thereby inactivating the enzyme. PMID:25781189

  4. Behavioral effects of 3?-androstanediol I: modulation of sexual receptivity and promotion of GABA-stimulated chloride flux

    Microsoft Academic Search

    Cheryl A. Frye; Kendall R. Van Keuren; Mary S. Erskine

    1996-01-01

    Pregnane neurosteroids may initiate sexual receptivity not only via actions at intracellular receptors, but by affecting ?-aminobutyric acid (GABA) receptor complexes (GBRs). To investigate whether GBR-mediated actions of an androgenic neurosteroid 5?-androstane-3?,17?-diol (3?-androstanediol; 3?-Diol) may influence the expression of sexual behavior, ovariectomized (ovx) rats received daily injections of 3?-Diol (0.6, 3.0, 6.0 and 7.5 mg\\/kg) or vehicle (10% (v\\/v) ethanol

  5. Correlation between GABA A receptor density and vagus nerve stimulation in individuals with drug-resistant partial epilepsy

    Microsoft Academic Search

    Francesco Marrosu; Alessandra Serra; Alberto Maleci; Monica Puligheddu; Giovanni Biggio; Mario Piga

    2003-01-01

    Vagus nerve stimulation (VNS) is an important option for the treatment of drug-resistant epilepsy. Through delivery of a battery-supplied intermittent current, VNS protects against seizure development in a manner that correlates experimentally with electrophysiological modifications. However, the mechanism by which VNS inhibits seizures in humans remains unclear. The impairment of ?-aminobutyric acid (GABA)-mediated neuronal inhibition associated with epilepsy has suggested

  6. Neurosteroids: endogenous allosteric modulators of GABA(A) receptors.

    PubMed

    Lambert, Jeremy J; Cooper, Michelle A; Simmons, Ross D J; Weir, Cameron J; Belelli, Delia

    2009-12-01

    In the mammalian central nervous system activation of the ionotropic GABA(A) receptor by the neurotransmitter GABA plays a crucial role in controlling neuronal excitability. This essential form of neuronal regulation may be subject to "fine tuning" by particular metabolites of progesterone and deoxycorticosterone, which bind directly to the GABA(A) receptor to enhance the actions of GABA. Originally such steroids were considered to act as endocrine messengers, being synthesised in peripheral glands such as the adrenals and ovaries and crossing the blood brain barrier to influence neuronal signalling. However, it is now evident that certain neurons and glia may produce such "neurosteroids" and that these locally synthesised modulators may act in a paracrine, or indeed an autocrine manner to influence neuronal activity. Neurosteroid synthesis may change dynamically in a variety of physiological situations (e.g. stress, pregnancy) and perturbations in their levels are implicated in a variety of neurological and psychiatric disorders. Here we will consider (1) evidence supporting the concept that neurosteroids act as local regulators of neuronal inhibition, (2) that extrasynaptic GABA(A) receptors appear to be a particularly important neurosteroid target and (3) recent advances in defining the neurosteroid binding site(s) on the GABA(A) receptor. PMID:19758761

  7. Uncoupling at the GABA(A) receptor with chronic ethanol in the rat medial septum/diagonal band (MS/DB)

    E-print Network

    Wallace, Kathleen Allison

    1997-01-01

    suggests that the y-aminobutyric acid typeA(GABA,) receptor is one target of ethanol where such adaptive changes by the CNS may occur. Adaptation could occur by downregulation of GABAAreceptor number or uncoupling of the GABAAreceptor sensitivity to ethanol...

  8. Immunocytochemical mapping of a C-terminus anti-peptide antibody to the GABA receptor subunit, RDL in the nervous system of Drosophila melanogaster

    Microsoft Academic Search

    J. B. Harrison; H. H. Chen; E. Sattelle; P. J. Barker; N. S. Huskisson; J. J. Rauh; D. Bai; D. B. Sattelle

    1996-01-01

    An antibody raised against a peptide based on the C-terminal derived amino acid sequence from a cloned Drosophila melanogaster (fruit fly) gene, Rdl (resistant to dieldrin), was used to investigate localization of a GABA receptor subunit in adult male D. melanogaster. Many regions in the brain and thoracic ganglia were stained with this antibody. For example, staining was detected in

  9. Use of 2-[(18)F]fluoroethylazide for the Staudinger ligation - Preparation and characterisation of GABA(A) receptor binding 4-quinolones.

    PubMed

    Gaeta, Alessandra; Woodcraft, John; Plant, Stuart; Goggi, Julian; Jones, Paul; Battle, Mark; Trigg, William; Luthra, Sajinder K; Glaser, Matthias

    2010-08-01

    The labelling reagent 2-[(18)F]fluoroethylazide was used in a traceless Staudinger ligation. This reaction was employed to obtain the GABA(A) receptor binding 6-benzyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (2-[(18)F]fluoroethyl) amide. The radiotracer was prepared with a non-decay corrected radiochemical yield of 7%, a radiochemical purity >95% and a specific radioactivity of 0.9 GBq/micromol. The compound showed low brain penetration in normal rats. A series of fluoroalkyl 4-quinolone analogues with nanomolar to sub-nanomolar affinity for the GABA(A) receptor has been prepared as well. PMID:20579877

  10. Insights into the binding of GABA to the insect RDL receptor from atomistic simulations: a comparison of models.

    PubMed

    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 ?-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-? 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-? 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. PMID:24442887

  11. Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism

    Microsoft Academic Search

    J M Hettema; S S An; M C Neale; J Bukszar; E J C G van den Oord; K S Kendler; X Chen

    2006-01-01

    Abnormalities in the gamma-aminobutyric acid (GABA) neurotransmitter system have been noted in subjects with mood and anxiety disorders. Glutamic acid decarboxylase (GAD) enzymes synthesize GABA from glutamate, and, thus, are reasonable candidate susceptibility genes for these conditions. In this study, we examined the GAD1 and GAD2 genes for their association with genetic risk across a range of internalizing disorders. We

  12. Diazepam action on ? -aminobutyric acid-activated chloride currents in internally perfused frog sensory neurons

    Microsoft Academic Search

    Kiichi Hattori; Yutaka Oomura; Norio Akaike

    1986-01-01

    Summary 1.The Cl? current (ICl) in?-aminobutyric acid (GABA)-sensitive frog sensory neuron was separated from other Na+, Ca2+, and K+ currents using a suction pipette technique which allows internal perfusion under a single-electrode voltage clamp.2.Diazepam (DZP) itself evoked no response but facilitated the dose- and time-dependently GABA-inducedICl without changing the GABA equilibrium potential (EGABA) at concentrations ranging widely, from 3 ×

  13. Studies on screening of higher ?-aminobutyric acid-producing Monascus and optimization of fermentative parameters

    Microsoft Academic Search

    Donghua JiangHao; Hao ji; Yan Ye; Jiaheng Hou

    2011-01-01

    ?-Aminobutyric acid (GABA), a hypotensive agent, can be produced by Monascus spp. Two hundred and fifteen GABA-producing Monascus strains were isolated from fermented bean curd and red-mold rice. The strain M6 with the highest production level of GABA\\u000a (3.657 g\\/L) was isolated from fermented bean curd by using PDB with 0.5% monosodium glutamate (MSG) and identified as Monascus ruber based on

  14. l-Carnitine uptake by mouse brain synaptosomal preparations: Competitive inhibition by GABA

    Microsoft Academic Search

    R. Hannuniemi; Pirjo Kontro

    1988-01-01

    The uptake ofl-carnitine was characterized in mouse brain synaptosomal preparations, with an emphasis on mutual interactions with GABA uptake systems. The uptake consisted of nonsaturable diffusion and one saturable energy- and sodium-dependent component. GABA,l-DABA and nipecotate were strong and hypotaurine and homotaurine moderate inhibitors of the uptake. The inhibition by GABA was shown to be competitive. GABA uptake contained two

  15. Interaction of uridine with GABA binding sites in cerebellar membranes of the rat

    Microsoft Academic Search

    Patrizia Guarneri; Rosa Guarneri; Carmela Mocciaro; Federico Piccoli

    1983-01-01

    The effect of uridine, a postulated anticonvulsant agent, on GABA receptors has been investigated. Uridine inhibits [3H]GABA binding to rat cerebellar bufferwashed membranes. Pretreatment of the membranes with Triton X-100 increases the effect of uridine on GABA-binding. The Scatchard analysis reveals that both high and low affinities of GABA for its receptors are affected by 1 mM uridine, while the

  16. Allosteric Modulation by Benzodiazepine Receptor Ligands of the GABA, Receptor Channel Expressed in Xenopus Oocytes

    Microsoft Academic Search

    E. Sigel

    Chick brain mRNA was isolated and injected into Xenopus oocytes. This led to the expression in the surface membrane of functional GABA-activated channels with properties rem- iniscent of vertebrate GABA, channels. The GABA-induced current was analyzed quantitatively under voltage-clamp conditions. Picrotoxin inhibited this current in a concentra- tion-dependent manner with IC,, = 0.6 PM. The allosteric modulation of GABA currents

  17. Glutamate and GABA imbalance promotes neuronal apoptosis in hippocampus after stress

    PubMed Central

    Gao, Jie; Wang, He; Liu, Yuan; Li, Ying-yu; Chen, Can; Liu, Liang-ming; Wu, Ya-min; Li, Sen; Yang, Ce

    2014-01-01

    Background People who experience traumatic events have an increased risk of post-traumatic stress disorder (PTSD). However, PTSD-related pathological changes in the hippocampus and prefrontal cortex remain poorly understood. Material/Methods We investigated the effect of a PTSD-like animal model induced by severe stress. The experimental rats received 20 inescapable electric foot shocks in an enclosed box for a total of 6 times in 3 days. The physiological state (body weight and plasma corticosterone concentrations), emotion, cognitive behavior, brain morphology, apoptosis, and balance of gamma-aminobutyric acid (GABA) and glutamate in the hippocampus and prefrontal cortex were observed. Cell damages were examined with histological staining (HE, Nissl, and silver impregnation), while apoptosis was analyzed with flow cytometry using an Annexin V and propidium iodide (PI) binding and terminal deoxynucleotidyl transferase mediated-dUTP nick end labeling (TUNEL) method. Results In comparison with the sham litter-mates, the stressed rats showed decreased body weight, inhibition of hypothalamic-pituitary-adrenal (HPA) axis activation, increase in freezing response to trauma reminder, hypoactivity and anxiety-like behaviors in elevated plus maze and open field test, poor learning in Morris water maze, and shortened latency in hot-plate test. There were significant damages in the hippocampus but not in the prefrontal cortex. Imbalance between glutamate and GABA was more evident in the hippocampus than in the prefrontal cortex. Conclusions These results suggest that neuronal apoptosis in the hippocampus after severe traumatic stress is related to the imbalance between glutamate and GABA. Such modifications may resemble the profound changes observed in PTSD patients. PMID:24675061

  18. Refuting the challenges of the developmental shift of polarity of GABA actions: GABA more exciting than ever!

    PubMed Central

    Ben-Ari, Yehezkel; Woodin, Melanie A.; Sernagor, Evelyne; Cancedda, Laura; Vinay, Laurent; Rivera, Claudio; Legendre, Pascal; Luhmann, Heiko J.; Bordey, Angelique; Wenner, Peter; Fukuda, Atsuo; van den Pol, Anthony N.; Gaiarsa, Jean-Luc; Cherubini, Enrico

    2012-01-01

    During brain development, there is a progressive reduction of intracellular chloride associated with a shift in GABA polarity: GABA depolarizes and occasionally excites immature neurons, subsequently hyperpolarizing them at later stages of development. This sequence, which has been observed in a wide range of animal species, brain structures and preparations, is thought to play an important role in activity-dependent formation and modulation of functional circuits. This sequence has also been considerably reinforced recently with new data pointing to an evolutionary preserved rule. In a recent “Hypothesis and Theory Article,” the excitatory action of GABA in early brain development is suggested to be “an experimental artefact” (Bregestovski and Bernard, 2012). The authors suggest that the excitatory action of GABA is due to an inadequate/insufficient energy supply in glucose-perfused slices and/or to the damage produced by the slicing procedure. However, these observations have been repeatedly contradicted by many groups and are inconsistent with a large body of evidence including the fact that the developmental shift is neither restricted to slices nor to rodents. We summarize the overwhelming evidence in support of both excitatory GABA during development, and the implications this has in developmental neurobiology. PMID:22973192

  19. Refuting the challenges of the developmental shift of polarity of GABA actions: GABA more exciting than ever!

    PubMed

    Ben-Ari, Yehezkel; Woodin, Melanie A; Sernagor, Evelyne; Cancedda, Laura; Vinay, Laurent; Rivera, Claudio; Legendre, Pascal; Luhmann, Heiko J; Bordey, Angelique; Wenner, Peter; Fukuda, Atsuo; van den Pol, Anthony N; Gaiarsa, Jean-Luc; Cherubini, Enrico

    2012-01-01

    DURING BRAIN DEVELOPMENT, THERE IS A PROGRESSIVE REDUCTION OF INTRACELLULAR CHLORIDE ASSOCIATED WITH A SHIFT IN GABA POLARITY: GABA depolarizes and occasionally excites immature neurons, subsequently hyperpolarizing them at later stages of development. This sequence, which has been observed in a wide range of animal species, brain structures and preparations, is thought to play an important role in activity-dependent formation and modulation of functional circuits. This sequence has also been considerably reinforced recently with new data pointing to an evolutionary preserved rule. In a recent "Hypothesis and Theory Article," the excitatory action of GABA in early brain development is suggested to be "an experimental artefact" (Bregestovski and Bernard, 2012). The authors suggest that the excitatory action of GABA is due to an inadequate/insufficient energy supply in glucose-perfused slices and/or to the damage produced by the slicing procedure. However, these observations have been repeatedly contradicted by many groups and are inconsistent with a large body of evidence including the fact that the developmental shift is neither restricted to slices nor to rodents. We summarize the overwhelming evidence in support of both excitatory GABA during development, and the implications this has in developmental neurobiology. PMID:22973192

  20. GABA-B receptor activation and conflict behavior

    SciTech Connect

    Ketelaars, C.E.J.; Bollen, E.L.; Rigter, H.; Bruinvels, J.

    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 it 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.

  1. Effect of antioxidant treatment on spinal GABA neurons in a neuropathic pain model in the mouse

    PubMed Central

    Yowtak, June; Wang, Jigong; Kim, Hee Young; Lu, Ying; Chung, Kyungsoon; Chung, Jin Mo

    2013-01-01

    One feature of neuropathic pain is a reduced spinal GABAergic inhibitory function. However, the mechanisms behind this attenuation remain to be elucidated. This study investigated the involvement of reactive oxygen species in the spinal GABA neuron loss and reduced GABA neuron excitability in spinal nerve ligation (SNL) model of neuropathic pain in mice. The importance of spinal GABAergic inhibition in neuropathic pain was tested by examining the effects of intrathecally administered GABA receptor agonists and antagonists in SNL and naïve mice, respectively. The effects of SNL and antioxidant treatment on GABA neuron loss and functional changes were examined in transgenic GAD67-EGFP mice. GABA receptor agonists transiently reversed mechanical hypersensitivity of the hind paw in SNL mice. On the other hand, GABA receptor antagonists made naïve mice mechanically hypersensitive. Stereological analysis showed that the numbers of enhanced green fluorescent protein positive (EGFP+) GABA neurons were significantly decreased in the lateral superficial laminae (I-II) on the ipsilateral L5 spinal cord after SNL. Repeated antioxidant treatments significantly reduced the pain behaviors and prevented the reduction in EGFP+ GABA neurons. The response rate of the tonic firing GABA neurons recorded from SNL mice increased with antioxidant treatment, whereas no change was seen in those recorded from naïve mice, which suggested that oxidative stress impaired some spinal GABA neuron activity in the neuropathic pain condition. Together the data suggest that neuropathic pain, at least partially, is attributed to oxidative stress which induces both a GABA neuron loss and dysfunction of surviving GABA neurons. PMID:23880056

  2. Modulation of the GABA-benzodiazepine receptor complex by taurine in rat brain membranes

    Microsoft Academic Search

    Outi Malminen; Pirjo Kontro

    1986-01-01

    The interactions of taurine and its precursor hypotaurine with the GABA-benzodiazepine receptor complex were studied by investigating their effects on GABA and flunitrazepam binding in rat brain membranes. Taurine, and to a lesser degree also hypotaurine, displaced the high- and low-affinity GABA binding. The maximal binding capacities of both sites were decreased in the presence of taurine, while the binding

  3. Modulation of GABA-A receptors of astrocytes and STC-1 cells by taurine structural analogs.

    PubMed

    Reyes-Haro, Daniel; Cabrera-Ruíz, Elizabeth; Estrada-Mondragón, Argel; Miledi, Ricardo; Martínez-Torres, Ataúlfo

    2014-11-01

    Taurine activates and modulates GABA receptors in vivo as well as those expressed in heterologous systems. This study aimed to determine whether the structural analogs of taurine: homotaurine and hypotaurine, have the ability to activate GABA-A receptors that include GABA? subunits. The expression of GABA-A receptors containing GABA? has been reported in the STC-1 cells and astrocytes. In both cell types, taurine, homo-, and hypotaurine gated with low efficiency a picrotoxin-sensitive GABA-A receptor. The known bimodal modulatory effect of taurine on GABA? receptors was not observed; however, differences between the activation and deactivation rates were detected when they were perfused together with GABA. In silico docking simulations suggested that taurine, hypo-, and homotaurine do not form a cation-? interaction such as that generated by GABA in the agonist-binding site of GABA?. This observation complements the electrophysiological data suggesting that taurine and its analogs act as partial agonists of GABA-A receptors. All the observations above suggest that the structural analogs of taurine are partial agonists of GABA-A receptors that occupy the agonist-binding site, but their structures do not allow the proper interaction with the receptor to fully gate its Cl(-) channel. PMID:25119985

  4. RAPID COMMUNICATION Adrenoceptor-Mediated Elevation of Ambient GABA Levels Activates

    E-print Network

    Huguenard, John R.

    -aminobutyric The circumstances that normally lead to such elevations inacid (GABA) activates postsynaptic GABAA receptors but not pre- extracellular GABA and recruitment of presynaptic GABABor postsynaptic GABAB receptors. Elevation of synaptic GABA receptors in cortical circuits are unclear. One candidatelevels with pharmacological agents

  5. Activation of neurokinin-1 receptors promotes GABA release at synapses in the rat entorhinal cortex

    Microsoft Academic Search

    A. E. Stacey; G. L. Woodhall; R. S. G. Jones

    2002-01-01

    We have previously shown that activation of neurokinin-1 receptors reduces acutely provoked epileptiform activity in rat entorhinal cortex in vitro, and suggested that this may result from an increase in GABA release from inhibitory interneurones. In the present study we have made whole cell patch clamp recordings of spontaneous GABA-mediated inhibitory postsynaptic currents as an indicator of GABA release in

  6. GABA-receptor complex in monkeys treated with MPTP

    SciTech Connect

    Huffman, R.D.; Ticku, M.K.

    1986-03-01

    Tissue samples from the brains of monkeys made parkinsonian by the depletion of dopamine (DA) with dopaminergic neurotoxin (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (1.4-3.4 mg/kg, i.v.) were assayed for changed in GABA ((/sup 3/H)-GABA), benzodiazepine ((/sup 3/H)-flunitrazepam) and picrotoxin ((/sup 35/S)-TBPS) binding sites. One point binding assays were performed on globus pallidus (GP), substantia nigra reticulata (SN/sub R/) and VA-VL thalamic samples. GABA binding was markedly increased in the SN/sub R/ (129 +/- 12%, n = 2) and GP (108 +/- 33%, n = 4) and not altered in the striatum or thalamus. However, benzodiazepine binding was increased in the striatum (170%; 257 fm/mg, control; 692 fm/mg, treated) and GP (28%; 317 fm/mg, control, 405 fm/mg, treated) and (/sup 35/S)-TBPS binding was also increased in GP (100%; 32.5 fm/mg, control; 65.5 fm/mg, treated). atScatchard analysis of (/sup 3/H)-GABA binding was also performed on tissue samples of motor cortex, cerebellar vermis and striatum pooled from half brains of 4 parkinsonian and 2 control monkeys. Depletion of DA (92 +/- 5%) in the striatum of these monkeys was not associated with any change in the K/sub D/ or B/sub max/ for the high or low affinity GABA binding sites in the striatum, motor cortex or cerebellum. Thus, in the basal ganglia, DA depletion is associated with an increase in GABA binding sites in GP and SN/sub R/, an increase in picrotoxin binding sites in GP and an increase in benzodiazepine binding sites in the striatum.

  7. Differential distribution of glutamate- and GABA-gated chloride channels in the housefly Musca domestica.

    PubMed

    Kita, Tomo; Ozoe, Fumiyo; Azuma, Masaaki; Ozoe, Yoshihisa

    2013-09-01

    l-Glutamic acid (glutamate) mediates fast inhibitory neurotransmission by affecting glutamate-gated chloride channels (GluCls) in invertebrates. The molecular function and pharmacological properties of GluCls have been well studied, but not much is known about their physiological role and localization in the insect body. The distribution of GluCls in the housefly (Musca domestica L.) was thus compared with the distribution of ?-aminobutyric acid (GABA)-gated chloride channels (GABACls). Quantitative PCR and ligand-binding experiments indicate that the GluCl and GABACl transcripts and proteins are predominantly expressed in the adult head. Intense GluCl immunostaining was detected in the lamina, leg motor neurons, and legs of adult houseflies. The GABACl (Rdl) immunostaining was more widely distributed, and was found in the medulla, lobula, lobula plate, mushroom body, antennal lobe, and ellipsoid body. The present findings suggest that GluCls have physiological roles in different tissues than GABACls. PMID:23806605

  8. Trial of Zolpidem, Eszopiclone, and Other GABA Agonists in a Patient with Progressive Supranuclear Palsy

    PubMed Central

    Chang, Andrew Young; Weirich, Erica

    2014-01-01

    Progressive supranuclear palsy (PSP) is a progressive, debilitating neurodegenerative disease of the Parkinson-plus family of syndromes. Unfortunately, there are no pharmacologic treatments for this condition, as most sufferers of the classic variant respond poorly to Parkinson medications such as levodopa. Zolpidem, a gamma aminobutyric acid (GABA) agonist specific to the ?-1 receptor subtype, has been reported to show improvements in symptoms of PSP patients, including motor dysfunction, dysarthria, and ocular disturbances. We observed a 73-year-old woman with a six-year history of PSP, who, upon administration of a single 12.5?mg dose of sustained-release zolpidem, exhibited marked enhancements in speech, facial expressions, and fine motor skills for five hours. These results were reproduced upon subsequent clinic visits. In an effort to find a sustainable medication that maximized these beneficial effects while minimizing side effects and addressing some of her comorbid neuropsychological conditions, a trial of five other GABA receptor agonists was performed with the patient's consent, while she and her caregivers were blinded to the specific medications. She and her caretakers subsequently reported improvements, especially visual, while on eszopiclone, and, to a lesser degree, temazepam and flurazepam. PMID:25371679

  9. Structural mechanism of ligand activation in human GABA(B) receptor.

    PubMed

    Geng, Yong; Bush, Martin; Mosyak, Lidia; Wang, Feng; Fan, Qing R

    2013-12-12

    Human GABA(B) (?-aminobutyric acid class B) receptor is a G-protein-coupled receptor central to inhibitory neurotransmission in the brain. It functions as an obligatory heterodimer of the subunits GBR1 and GBR2. Here we present the crystal structures of a heterodimeric complex between the extracellular domains of GBR1 and GBR2 in the apo, agonist-bound and antagonist-bound forms. The apo and antagonist-bound structures represent the resting state of the receptor; the agonist-bound complex corresponds to the active state. Both subunits adopt an open conformation at rest, and only GBR1 closes on agonist-induced receptor activation. The agonists and antagonists are anchored in the interdomain crevice of GBR1 by an overlapping set of residues. An antagonist confines GBR1 to the open conformation of the inactive state, whereas an agonist induces its domain closure for activation. Our data reveal a unique activation mechanism for GABA(B) receptor that involves the formation of a novel heterodimer interface between subunits. PMID:24305054

  10. [Study of the GABA-benzodiazepine receptor system of the human myometrium].

    PubMed

    Sergeev, P V; Sizov, P I; Dukhanin, A S; Mineeva, E N

    1990-10-01

    A specific [3H] GABA and [14C] flunitrazepam binding sites have been identified in a membrane fraction of human myometrium. The specific binding of [14C] GABA was displaced by unlabelled GABA and bicuculline. It was shown that the binding of [3H] flunitrazepam to membrane preparations is enhanced in the presence of GABA. A similar reciprocal effect of benzodiazepines to enhance [14C] GABA binding has been demonstrated. The present results indicate that GABAA-BD receptors complexes may have a functional significance in human ovary. PMID:2177668

  11. [The GABA-ergic system of the myometrium: a basis for the clinical study of GABA-positive substances as pregnancy protectors].

    PubMed

    Sergeev, P V; Sizov, P I; Dukhanin, A S

    1993-12-01

    Radioligand method was used to show 14C-GABA, 3H-flunitrazepam binding sites in human, rat, rabbit myometrium. We have used muscimol, bicucullin, picrotoxin, baclofen, thiosemicarbazide for identification of GABA-benzodiazepine receptor complexes and in pharmacologic analysis of uterine contractility. Receptor affinity depended on pregnancy term (early or late). A conclusion is drawn that GABAA, GABAB, and benzodiazepine receptors of the peripheral nervous system mediate the inhibitory effect of GABA-positive substances on mammalian uterine contractility. PMID:8123815

  12. WNK1-regulated inhibitory phosphorylation of the KCC2 cotransporter maintains the depolarizing action of GABA in immature neurons.

    PubMed

    Friedel, Perrine; Kahle, Kristopher T; Zhang, Jinwei; Hertz, Nicholas; Pisella, Lucie I; Buhler, Emmanuelle; Schaller, Fabienne; Duan, JingJing; Khanna, Arjun R; Bishop, Paul N; Shokat, Kevan M; Medina, Igor

    2015-01-01

    Activation of Cl(-)-permeable ?-aminobutyric acid type A (GABAA) receptors elicits synaptic inhibition in mature neurons but excitation in immature neurons. This developmental "switch" in the GABA function depends on a postnatal decrease in intraneuronal Cl(-) concentration mediated by KCC2, a Cl(-)-extruding K(+)-Cl(-) cotransporter. We showed that the serine-threonine kinase WNK1 [with no lysine (K)] forms a physical complex with KCC2 in the developing mouse brain. Dominant-negative mutation, genetic depletion, or chemical inhibition of WNK1 in immature neurons triggered a hyperpolarizing shift in GABA activity by enhancing KCC2-mediated Cl(-) extrusion. This increase in KCC2 activity resulted from reduced inhibitory phosphorylation of KCC2 at two C-terminal threonines, Thr(906) and Thr(1007). Phosphorylation of both Thr(906) and Thr(1007) was increased in immature versus mature neurons. Together, these data provide insight into the mechanism regulating Cl(-) homeostasis in immature neurons, and suggest that WNK1-regulated changes in KCC2 phosphorylation contribute to the developmental excitatory-to-inhibitory GABA sequence. PMID:26126716

  13. Amantadine attenuates levodopa-induced dyskinesia in mice and rats preventing the accompanying rise in nigral GABA levels.

    PubMed

    Bido, Simone; Marti, Matteo; Morari, Michele

    2011-09-01

    Amantadine is the only drug marketed for treating levodopa-induced dyskinesia. However, its impact on basal ganglia circuitry in the dyskinetic brain, particularly on the activity of striatofugal pathways, has not been evaluated. We therefore used dual probe microdialysis to investigate the effect of amantadine on behavioral and neurochemical changes in the globus pallidus and substantia nigra reticulata of 6-hydroxydopamine hemi-lesioned dyskinetic mice and rats. Levodopa evoked abnormal involuntary movements (AIMs) in dyskinetic mice, and simultaneously elevated GABA release in substantia nigra reticulata (?3-fold) but not globus pallidus. Glutamate levels were unaffected in both areas. Amantadine (40 mg/kg, i.p.), ineffective alone, attenuated (?50%) AIMs expression and prevented the GABA rise. Moreover, it unraveled a facilitatory effect of levodopa on pallidal glutamate levels. Levodopa also evoked AIMs expression and a GABA surge (?2-fold) selectively in the substantia nigra of dyskinetic rats. However, different from mice, glutamate levels rose simultaneously. Amantadine, ineffective alone, attenuated (?50%) AIMs expression preventing amino acid increase and leaving unaffected pallidal glutamate. Overall, the data provide neurochemical evidence that levodopa-induced dyskinesia is accompanied by activation of the striato-nigral pathway in both mice and rats, and that the anti-dyskinetic effect of amantadine partly relies on the modulation of this pathway. PMID:21740438

  14. Spectral editing of weakly coupled spins using variable flip angles in PRESS constant echo time difference spectroscopy: Application to GABA

    NASA Astrophysics Data System (ADS)

    Snyder, Jeff; Hanstock, Chris C.; Wilman, Alan H.

    2009-10-01

    A general in vivo magnetic resonance spectroscopy editing technique is presented to detect weakly coupled spin systems through subtraction, while preserving singlets through addition, and is applied to the specific brain metabolite ?-aminobutyric acid (GABA) at 4.7 T. The new method uses double spin echo localization (PRESS) and is based on a constant echo time difference spectroscopy approach employing subtraction of two asymmetric echo timings, which is normally only applicable to strongly coupled spin systems. By utilizing flip angle reduction of one of the two refocusing pulses in the PRESS sequence, we demonstrate that this difference method may be extended to weakly coupled systems, thereby providing a very simple yet effective editing process. The difference method is first illustrated analytically using a simple two spin weakly coupled spin system. The technique was then demonstrated for the 3.01 ppm resonance of GABA, which is obscured by the strong singlet peak of creatine in vivo. Full numerical simulations, as well as phantom and in vivo experiments were performed. The difference method used two asymmetric PRESS timings with a constant total echo time of 131 ms and a reduced 120° final pulse, providing 25% GABA yield upon subtraction compared to two short echo standard PRESS experiments. Phantom and in vivo results from human brain demonstrate efficacy of this method in agreement with numerical simulations.

  15. Glutamate and GABA receptor signalling in the developing brain

    Microsoft Academic Search

    R. Luján; R. Shigemoto; G. López-Bendito

    2005-01-01

    Our understanding of the role played by neurotransmitter receptors in the developing brain has advanced in recent years. The major excitatory and inhibitory neurotransmitters in the brain, glutamate and GABA, activate both ionotropic (ligand-gated ion channels) and metabotropic (G protein-coupled) receptors, and are generally associated with neuronal communication in the mature brain. However, before the emergence of their role in

  16. Neurofibromin regulation of ERK signaling modulates GABA release and learning

    PubMed Central

    Cui, Yijun; Costa, Rui M; Murphy, Geoffrey G; Elgersma, Ype; Zhu, Yuan; Gutmann, David H.; Parada, Luis F.; Mody, Istvan; Silva, Alcino J

    2008-01-01

    Summary We uncovered a new role for ERK signaling in GABA release, long-term potentiation (LTP) and learning, and show that disruption of this mechanism accounts for the learning deficits in a mouse model for Neurofibromatosis type I (NF1), a common genetic cause for learning disabilities. Genetic, pharmacological, electrophysiological and behavioral data demonstrate that neurofibromin modulates ERK/synapsin I dependent GABA release, which in turn modulate hippocampal LTP and learning. An Nf1 heterozygous null mutation, which results in enhanced ERK and synapsin I phosphorylation, increased pre-synaptic GABA release in the hippocampus which was reversed by pharmacologically down-regulating ERK signaling. Importantly, the learning deficits associated with the Nf1 mutation were rescued by a sub-threshold dose of a GABAA antagonist. Accordingly, Cre-deletions of the Nf1 gene showed that only those deletions involving inhibitory neurons caused hippocampal inhibition, LTP and learning abnormalities. Importantly, our results also revealed lasting increases in GABA release triggered by learning, indicating that the mechanisms uncovered here are of general importance for learning and memory. PMID:18984165

  17. Caenorhabditis elegans Neuromuscular Junction: GABA Receptors and Ivermectin Action

    PubMed Central

    Hernando, Guillermina; Bouzat, Cecilia

    2014-01-01

    The prevalence of human and animal helminth infections remains staggeringly high, thus urging the need for concerted efforts towards this area of research. GABA receptors, encoded by the unc-49 gene, mediate body muscle inhibition in Caenorhabditis elegans and parasitic nematodes and are targets of anthelmintic drugs. Thus, the characterization of nematode GABA receptors provides a foundation for rational anti-parasitic drug design. We therefore explored UNC-49 channels from C. elegans muscle cultured cells of the first larval stage at the electrophysiological and behavioral levels. Whole-cell recordings reveal that GABA, muscimol and the anthelmintic piperazine elicit macroscopic currents from UNC-49 receptors that decay in their sustained presence, indicating full desensitization. Single-channel recordings show that all drugs elicit openings of ?2.5 pA (+100 mV), which appear either as brief isolated events or in short bursts. The comparison of the lowest concentration required for detectable channel opening, the frequency of openings and the amplitude of macroscopic currents suggest that piperazine is the least efficacious of the three drugs. Macroscopic and single-channel GABA-activated currents are profoundly and apparently irreversibly inhibited by ivermectin. To gain further insight into ivermectin action at C. elegans muscle, we analyzed its effect on single-channel activity of the levamisol-sensitive nicotinic receptor (L-AChR), the excitatory receptor involved in neuromuscular transmission. Ivermectin produces a profound inhibition of the frequency of channel opening without significant changes in channel properties. By revealing that ivermectin inhibits C. elegans muscle GABA and L-AChR receptors, our study adds two receptors to the already known ivermectin targets, thus contributing to the elucidation of its pleiotropic effects. Behavioral assays in worms show that ivermectin potentiates piperazine-induced paralysis, thus suggesting that their combination is a good strategy to overcome the increasing resistance of parasites, an issue of global concern for human and animal health. PMID:24743647

  18. Postsynaptic clustering of -aminobutyric acid type A receptors by the 3 subunit in vivo

    E-print Network

    Luscher, Bernhard

    neurons. This is particularly evident for fast neurotransmission mediated by receptors of the ligand (GABA) acting at heteropentameric GABA type A (GABAA) receptor chloride channels. GABAA receptorsPostsynaptic clustering of -aminobutyric acid type A receptors by the 3 subunit in vivo Kristin

  19. Passiflora incarnata L. (Passionflower) extracts elicit GABA currents in hippocampal neurons in vitro, and show anxiogenic and anticonvulsant effects in vivo, varying with extraction method.

    PubMed

    Elsas, S-M; Rossi, D J; Raber, J; White, G; Seeley, C-A; Gregory, W L; Mohr, C; Pfankuch, T; Soumyanath, A

    2010-10-01

    Potential mechanisms of Passiflora incarnata extracts and the effect of extraction methods on ingredients and biological effects were explored. Using the same batch of plant material, total flavonoid yields as measured by high-performance liquid chromatography coupled to diode array detection (HPLC-DAD) increased substantially with hot versus cold extraction methods. Whole Passiflora extract induced prominent, dose-dependent direct GABA(A) currents in hippocampal slices, but the expected modulation of synaptic GABA(A) currents was not seen. GABA was found to be a prominent ingredient of Passiflora extract, and GABA currents were absent when amino acids were removed from the extract. Five different extracts, prepared from a single batch of Passiflora incarnata, were administered to CF-1 mice for 1 week in their drinking water prior to evaluation of their behavioral effects. Anticonvulsant effects against PTZ-induced seizures were seen in mice that received 2 of the 5 Passiflora extracts. Instead of the anxiolytic effects described by others, anxiogenic effects in the elevated plus maze were seen in mice receiving any of the 5 Passiflora extracts. PMID:20382514

  20. Electrophysiological study of SR 42641, a novel aminopyridazine derivative of GABA: antagonist properties and receptor selectivity of GABAA versus GABAB responses.

    PubMed Central

    Desarmenien, M.; Desaulles, E.; Feltz, P.; Hamann, M.

    1987-01-01

    A new arylamino-pyridazine gamma-aminobutyric acid (GABA) derivative, SR 42641, has been tested for its ability to antagonize the actions of GABA on mammalian sensory neurones. SR 42641 and bicuculline reversibly decreased GABAA-induced depolarizations and currents recorded intracellularly from dorsal root ganglion neurons (DRG). Dose-response curves were shifted to the right in a parallel fashion. KB values (determined under voltage clamp conditions) were respectively 0.12 +/- 0.05 and 0.38 +/- 0.08 microM. Similar values were obtained with current clamp recording conditions. The study of the GABA-induced Cl- current under voltage-clamp conditions did not show any voltage-dependency of the antagonist effect of SR 42641. In nodose ganglion neurones, SR 42641 (0.4-4.5 microM) did not alter the (-)-baclofen-induced shortening of the calcium component of action potentials. At concentrations higher than 10 microM, SR 42641 itself prolonged calcium-dependent action potentials. Patch-clamp recordings from DRG cultured neurones indicated that SR 42641 did not affect the calcium current responsible for sustained calcium entry into cells. We conclude that SR 42641 is a potent competitive GABA antagonist, specific for the GABAA receptor. It does not act at the level of the chloride ionophore. PMID:2435350

  1. Release of endogenous dopamine, 3,4-dihydroxyphenylacetic acid, and amino acid transmitters from rat striatal slices

    Microsoft Academic Search

    R. S. Flint; J. M. Murphy; W. J. McBride

    1985-01-01

    The release of endogenous dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) was measured in superfused striatal slices of the rat and the results compared with data obtained for the release of endogenous (a) DA and DOPAC in the cerebral cortex, nucleus accumbens and thalamus; (b) 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), GABA, and glutamate in the striatum; and (c) GABA, glutamate and

  2. Local inhibition of GABA affects precedence effect in the inferior colliculus

    PubMed Central

    Wang, Yanjun; Wang, Ningyu; Wang, Dan; Jia, Jun; Liu, Jinfeng; Xie, Yan; Wen, Xiaohui; Li, Xiaoting

    2014-01-01

    The precedence effect is a prerequisite for faithful sound localization in a complex auditory environment, and is a physiological phenomenon in which the auditory system selectively suppresses the directional information from echoes. Here we investigated how neurons in the inferior colliculus respond to the paired sounds that produce precedence-effect illusions, and whether their firing behavior can be modulated through inhibition with gamma-aminobutyric acid (GABA). We recorded extracellularly from 36 neurons in rat inferior colliculus under three conditions: no injection, injection with saline, and injection with gamma-aminobutyric acid. The paired sounds that produced precedence effects were two identical 4-ms noise bursts, which were delivered contralaterally or ipsilaterally to the recording site. The normalized neural responses were measured as a function of different inter-stimulus delays and half-maximal interstimulus delays were acquired. Neuronal responses to the lagging sounds were weak when the inter-stimulus delay was short, but increased gradually as the delay was lengthened. Saline injection produced no changes in neural responses, but after local gamma-aminobutyric acid application, responses to the lagging stimulus were suppressed. Application of gamma-aminobutyric acid affected the normalized response to lagging sounds, independently of whether they or the paired sounds were contralateral or ipsilateral to the recording site. These observations suggest that local inhibition by gamma-aminobutyric acid in the rat inferior colliculus shapes the neural responses to lagging sounds, and modulates the precedence effect. PMID:25206830

  3. Expression of gamma-aminobutyric acid and gonadotropin-releasing hormone during neuronal migration through the olfactory system.

    PubMed

    Tobet, S A; Chickering, T W; King, J C; Stopa, E G; Kim, K; Kuo-Leblank, V; Schwarting, G A

    1996-12-01

    Neurons containing the decapeptide GnRH originate in the olfactory placodes and migrate into the central nervous system during fetal development. The neurotransmitter gamma-aminobutyric acid (GABA) has been proposed as a trophic factor and may also influence neuronal migration. Immunocytochemical analyses were conducted in fetal rats, mice, and humans to identify potential developmental relationships between cells containing GABA, and GnRH neurons. Cells containing GABA were found along the nasal portion of the GnRH migration pathway in rats, mice, and humans during development. A peak number of cells containing immunoreactive GABA was observed in the nasal compartment of rats at embryonic day 15. At this time (E15), a majority of GnRH neurons were clustered in the region of the cribriform plate. By postnatal day 1, all GnRH neurons had migrated into the CNS and GABA cells were virtually absent from the nasal compartment. Double-label and confocal analyses of GABA and GnRH in mice and rats demonstrated that some olfactory GABAergic neurons coexpress GnRH. This implies that neurons that transiently express GABA originate in olfactory placodes and migrate into the forebrain. Based on the transient dual-label and adjacent relationships between GABA and GnRH containing cells in the nasal compartment, and other data showing migrational and trophic roles for GABA in development, we suggest that GABA may directly influence GnRH neuronal migration and development. PMID:8940365

  4. Localization of glycine, GABA and neuropeptide containing neurons in tiger salamander retina

    SciTech Connect

    Yang, C.Y.

    1988-01-01

    Putative glycinergic and GABAergic neurons in the salamander retina were localized by a parallel analysis of high affinity {sup 3}H-glycine uptake and glycine-like immunoreactivity (Gly-IR) and a comparative analysis of high affinity {sup 3}H-GABA uptake, GABA, like immunoreactivity (GABA-IR), and glutamate decarboxylase immunoreactivity (GAD-IR) at the light microscopic level. Good correspondence of labeling of {sup 3}H-glycine uptake and Gly-IR as well as that of {sup 3}H-GABA uptake and GABA-IR were observed. In addition, GAD immunoreactive neurons contained GABA-IR as well. Extensive colocalization of {sup 3}H-glycine uptake and Gly-IR and that of {sup 3}H-GABA uptake, GABA-IR and perhaps GAD-IR were indicated by the similarities in the distribution, morphology and labeling frequency of neurons and lamination in the inner plexiform layer (IPL). However, the Gly-IR and the GABA-IR probes appeared to be more sensitive and can thus be a reliable marker for glycine and GABA containing neurons respectively.

  5. Calcium Current Block by (-)Pentobarbital, Phenobarbital, and CHEB but not (+)Pentobarbital in Acutely Isolated Hippocampal CA1 Neurons: Comparison with Effects on GABA-activated Cl Current

    Microsoft Academic Search

    Jeffery L. Barker; Michael A. Rogawski

    1993-01-01

    Block of a voltage-activated Ca*+ channel current by pheno- barbital (PHB), 5-(2-cyclohexylideneethyl)-5-ethyl barbituric acid (CHEB), and the optical R(-)- and S(+)-enantiomers of pentobarbital (PB) was examined in freshly dissociated adult guinea pig hippocampal CA1 neurons; the effects of the barbiturates on GABA-activated Cl- current were also char- acterized in the same preparation. (-)-PB, PHB, and CHEB produced a reversible, concentration-dependent

  6. Symbiosis between in vivo and in vitro NMR spectroscopy: The creatine, N-acetylaspartate, glutamate, and GABA content of the epileptic human brain

    Microsoft Academic Search

    Ognen A. C. Petroff; Lisa A. Pleban; Dennis D. Spencer

    1995-01-01

    High resolution 1H NMR spectroscopy was used to analyze temporal lobe biopsies obtained from patients with epilepsy. Heat-stabilized cerebrum, dialyzed cytosolic macromolecules, and perchloric acid extracts were studied using one- and two dimensional spectroscopy. Anterior temporal lobe neocortex was enriched in GABA, glutamate, alanine, N-acetylaspartate, and creatine. Subjacent white matter was enriched in aspartate, glutamine, and inositol. The N-acetylaspartate\\/creatine mole

  7. Fatty acid enhancement of human serum albumin binding properties. A spin label study.

    PubMed

    Soltys, B J; Hsia, J C

    1977-06-25

    The introduction of a new spin-labeled anionic ligand, 1-gamma-aminobutyrate-5-N-(1-oxyl-2,2,6,6-tetramethyl-4-aminopiperidinyl)-2,4-dinitrobenzene, is reported. Under the experimental conditions, the first molar equivalent of this ligand is 93% bound to human serum albumin. With the addition of palmitate, the free spin label concentration decreases greatly, by almost 80%, in the presence of a fatty acid:albumin ratio of 3:1 to 4:1. The spectral characteristics of the bound spin label are also affected. The changes seen in the intensity of and the splitting between the high and low field extrema are indicative of perturbations of the protein molecule. It is seen then that the binding of each molar equivalent of fatty acid effects the conformation state of albumin and allosterically affects albumin binding properties. Computer spectral subtractions, furthermore, suggest that the binding of the first molar equivalent of palmitate specifically increases the affinity of the first two 1-gamma-amino-butyrate-5-N-(1-oxyl-2,2,6,6-tetramethyl-4-aminopiperidinyl)-2,4-dinitrobenzene binding sites. The present results indicate that fluctuations in serum free fatty acid levels within the physiological range may have a major modulatory effect on the free serum levels of certain drugs and/or physiological substances that bind to albumin. PMID:193852

  8. gamma-Aminobutyric Acid is an Inhibitory Neurotransmitter Restricting the Release of Luteinizing Hormone-Releasing Hormone before the Onset of Puberty

    Microsoft Academic Search

    Dai Mitsushima; David L. Hei; Ei Terasawa

    1994-01-01

    To test the hypothesis that the pubertal increase in luteinizing hormone-releasing hormone (LHRH) release is withheld by a dominant inhibitory neuronal system, the role of gamma-aminobutyric acid (GABA), a known inhibitory neurotransmitter, in the control of LHRH release was examined in conscious female monkeys at the prepubertal and pubertal stages using a push-pull perfusion method. GABA, bicuculline (a GABA_A receptor

  9. Early depolarizing GABA controls critical period plasticity in the rat visual cortex

    PubMed Central

    Deidda, Gabriele; Allegra, Manuela; Cerri, Chiara; Naskar, Shovan; Bony, Guillaume; Zunino, Giulia; Bozzi, Yuri; Caleo, Matteo; Cancedda, Laura

    2014-01-01

    SUMMARY Hyperpolarizing and inhibitory GABA regulates “critical periods” for plasticity in sensory cortices. Here, we examine the role of early, depolarizing GABA in controlling plasticity mechanisms. We report that brief interference with depolarizing GABA during early development prolonged critical period plasticity in visual cortical circuits, without affecting overall development of the visual system. The effects on plasticity were accompanied by dampened inhibitory neurotransmission, down-regulation of BDNF expression, and reduced density of extracellular matrix-perineuronal nets. Early interference with depolarizing GABA decreased perinatal BDNF signaling, and pharmacological increase of BDNF signaling during GABA interference rescued the effects on plasticity and its regulators later in life. We conclude that depolarizing GABA exerts a long-lasting, selective modulation of plasticity of cortical circuits by a strong crosstalk with BDNF. PMID:25485756

  10. Early depolarizing GABA controls critical-period plasticity in the rat visual cortex.

    PubMed

    Deidda, Gabriele; Allegra, Manuela; Cerri, Chiara; Naskar, Shovan; Bony, Guillaume; Zunino, Giulia; Bozzi, Yuri; Caleo, Matteo; Cancedda, Laura

    2015-01-01

    Hyperpolarizing and inhibitory GABA regulates critical periods for plasticity in sensory cortices. Here we examine the role of early, depolarizing GABA in the control of plasticity mechanisms. We report that brief interference with depolarizing GABA during early development prolonged critical-period plasticity in visual cortical circuits without affecting the overall development of the visual system. The effects on plasticity were accompanied by dampened inhibitory neurotransmission, downregulation of brain-derived neurotrophic factor (BDNF) expression and reduced density of extracellular matrix perineuronal nets. Early interference with depolarizing GABA decreased perinatal BDNF signaling, and a pharmacological increase of BDNF signaling during GABA interference rescued the effects on plasticity and its regulators later in life. We conclude that depolarizing GABA exerts a long-lasting, selective modulation of plasticity of cortical circuits by a strong crosstalk with BDNF. PMID:25485756

  11. GABA Not Only a Neurotransmitter: Osmotic Regulation by GABAAR Signaling

    PubMed Central

    Cesetti, Tiziana; Ciccolini, Francesca; Li, Yuting

    2012-01-01

    Mature macroglia and almost all neural progenitor types express ?-aminobutyric (GABA) A receptors (GABAARs), whose activation by ambient or synaptic GABA, leads to influx or efflux of chloride (Cl?) depending on its electro-chemical gradient (ECl). Since the flux of Cl? is indissolubly associated to that of osmotically obliged water, GABAARs regulate water movements by modulating ion gradients. In addition, since water movements also occur through specialized water channels and transporters, GABAAR signaling could affect the movement of water by regulating the function of the channels and transporters involved, thereby affecting not only the direction of the water fluxes but also their dynamics. We will here review recent observations indicating that in neural cells GABAAR-mediated osmotic regulation affects the cellular volume thereby activating multiple intracellular signaling mechanisms important for cell proliferation, maturation, and survival. In addition, we will discuss evidence that the osmotic regulation exerted by GABA may contribute to brain water homeostasis in physiological and in pathological conditions causing brain edema, in which the GABAergic transmission is often altered. PMID:22319472

  12. GABA and Central Neuropathic Pain following Spinal Cord Injury

    PubMed Central

    Gwak, Young S.; Hulsebosch, Claire E.

    2012-01-01

    Spinal cord injury induces maladaptive synaptic transmission in the somatosensory system that results in chronic central neuropathic pain. Recent literature suggests that glial-neuronal interactions are important modulators in synaptic transmission following spinal cord injury. Neuronal hyperexcitability is one of the predominant phenomenon caused by maladaptive synaptic transmission via altered glial-neuronal interactions after spinal cord injury. In the somatosensory system, spinal inhibitory neurons counter balance the enhanced synaptic transmission from peripheral input. For a decade, the literature suggests that hypofunction of GABAergic inhibitory tone is an important factor in the enhanced synaptic transmission that often results in neuronal hyperexcitability in dorsal horn neurons following spinal cord injury. Neurons and glial cells synergistically control intracellular chloride ion gradients via modulation of chloride transporters, extracellular glutamate and GABA concentrations via uptake mechanisms. Thus, the intracellular “GABA-glutamate-glutamine cycle” is maintained for normal physiological homeostasis. However, hyperexcitable neurons and glial activation after spinal cord injury disrupts the balance of chloride ions, glutamate and GABA distribution in the spinal dorsal horn and results in chronic neuropathic pain. In this review, we address spinal cord injury induced mechanisms in hypofunction of GABAergic tone that results in chronic central neuropathic pain. PMID:21216257

  13. Discovery of novel insomnia leads from screening traditional Chinese medicine database.

    PubMed

    Chen, Hsin-Yi; Chang, Su-sen; Chan, Yueh-Chiu; Chen, Calvin Yu-Chian

    2014-01-01

    Insomnia is a prominent modern disease that affects an increasing population. Undesirable side effects of commercial drugs highlight the need to develop novel insomnia drugs. Virtual screening of traditional chinese medicine Database@Taiwan (TCM Database@Taiwan) identified 2-O-Caffeoyl tartaric acid (1), 2-O-Feruloyl tartaric acid (2), and Mumefural (3) as potential agonists for both gamma-amino butyric acid (GABA) or benzodiazepine (BZ) binding sites. The TCM candidates exhibited higher affinity than GABA and Zolpidem, a phenomenon that could be attributed to higher quantity of stabilizing H-bonds. Efficacy profiles using support vector machines and pharmacophore contour also suggest drug potential of the TCM candidates. Fragments added to the de novo derivatives 3a, 3b, 3c for GABA binding site, and 1a, 2a, and 3d for BZ binding site contributed to new binding sites and structural stability, further optimizing binding to GABA or BZ binding sites. Increased opening of the ion channel by candidate ligands provide strong support for their potential biological functions. The dual binding properties of the TCM candidates present a unique opportunity to develop twin-targeting drugs with less side effects. Derivative structures can be used as starting points for developing high affinity GABAA receptor agonists with specificity towards GABA binding site and BZ binding site. PMID:23730798

  14. Sodium dependency of GABA uptake into glial cells in bullfrog sympathetic ganglia

    Microsoft Academic Search

    Saeko Sakai; Junko Tasaka; Tsuneo Tosaka I

    1990-01-01

    The kinetics of sodium dependency of GABA uptake by satellite glial cells was studied in bullfrog sympathetic ganglia. GABA uptake followed simple Michaelis-Menten kinetics at all sodium concentrations tested. Increasing external sodium concentration increased bothKm andVmax for GABA uptake, with an increase in theVmax\\/Km ratio. The initial rate of uptake as a function of the sodium concentration exhibited sigmoid shape

  15. Expression of specific ionotropic glutamate and GABA-A receptor subunits is decreased in central amygdala of alcoholics

    PubMed Central

    Jin, Zhe; Bhandage, Amol K.; Bazov, Igor; Kononenko, Olga; Bakalkin, Georgy; Korpi, Esa R.; Birnir, Bryndis

    2014-01-01

    The central amygdala (CeA) has a role for mediating fear and anxiety responses. It is also involved in emotional imbalance caused by alcohol abuse and dependence and in regulating relapse to alcohol abuse. Growing evidences suggest that excitatory glutamatergic and inhibitory ?-aminobutyric acid-ergic (GABAergic) transmissions in the CeA are affected by chronic alcohol exposure. Human post-mortem CeA samples from male alcoholics (n = 9) and matched controls (n = 9) were assayed for the expression level of ionotropic glutamate and GABA-A receptors subunit mRNAs using quantitative real-time reverse transcription-PCR (RT-qPCR). Our data revealed that out of the 16 ionotropic glutamate receptor subunits, mRNAs encoding two AMPA [2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid] receptor subunits GluA1 and GluA4; one kainate receptor subunit GluK2; one NMDA (N-methyl-D-aspartate) receptor subunit GluN2D and one delta receptor subunit GluD2 were significantly decreased in the CeA of alcoholics. In contrast, of the 19 GABA-A receptor subunits, only the mRNA encoding the ?2 subunit was significantly down-regulated in the CeA of the alcoholics as compared with control subjects. Our findings imply that the down-regulation of specific ionotropic glutamate and GABA-A receptor subunits in the CeA of alcoholics may represent one of the molecular substrates underlying the new balance between excitatory and inhibitory neurotransmission in alcohol dependence. PMID:25278838

  16. Aminobutyric acid modulation of acetylcholine-induced contractions of a smooth muscle from an echinoderm ( Sclerodactyla briareus )

    Microsoft Academic Search

    C. Leah Devlin; Walter Schlosser

    1999-01-01

    This study provides pharmacological evidence for the presence of GABAergic neurons innervating the longitudinal muscle of the body wall (LMBW) of holothurians. %-Aminobutyric acid (GABA) A and B receptor subtypes were both present in this system and regulated spontaneous contractions as well as responses to acetylcholine (ACh) that stimulated contraction of the LMBW. GABA dose-dependently relaxed the resting tone of

  17. Identification of Benzodiazepine Binding Site Residues in the 2 Subunit of the -Aminobutyric AcidA Receptor

    E-print Network

    Kemnitz, Joseph

    of these compounds. -Aminobutyric acid (GABA) receptors are the major inhib- itory neurotransmitter receptors). The receptor contains an integral chloride-selective channel with specific binding sites for GABA and a variety., 1998). Depending on the ligand and the subunit composition of the GABAA receptor, the modulatory

  18. Synaptic inhibition and ?-aminobutyric acid in the mammalian central nervous system

    PubMed Central

    OBATA, Kunihiko

    2013-01-01

    Signal transmission through synapses connecting two neurons is mediated by release of neurotransmitter from the presynaptic axon terminals and activation of its receptor at the postsynaptic neurons. ?-Aminobutyric acid (GABA), non-protein amino acid formed by decarboxylation of glutamic acid, is a principal neurotransmitter at inhibitory synapses of vertebrate and invertebrate nervous system. On one hand glutamic acid serves as a principal excitatory neurotransmitter. This article reviews GABA researches on; (1) synaptic inhibition by membrane hyperpolarization, (2) exclusive localization in inhibitory neurons, (3) release from inhibitory neurons, (4) excitatory action at developmental stage, (5) phenotype of GABA-deficient mouse produced by gene-targeting, (6) developmental adjustment of neural network and (7) neurological/psychiatric disorder. In the end, GABA functions in simple nervous system and plants, and non-amino acid neurotransmitters were supplemented. PMID:23574805

  19. Optimization of ?-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

    2015-01-01

    Dominant strains of lactic acid bacteria (LAB) isolated from honey bees were evaluated for their ?-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. PMID:25884548

  20. Tectorotundal connections in turtles: an electron microscopic tracing and GABA-immunocytochemical study.

    PubMed

    Kenigfest, Natalia B; Rio, Jean Paul; Belekhova, Margarita G; Repérant, Jacques; Ward, Roger; Jay, Bruno; Vesselkin, Nikolai P

    2007-12-01

    The nucleus rotundus of the turtles Emys orbicularis and Testudo horsfieldi was analysed by axonal tracing methods and post-embedding GABA immunocytochemistry. After injections of horseradish peroxidase or biotinylated dextran amine into the optic tectum, electron microscopic observations showed that the vast majority of ipsilateral tectorotundal axon terminals were small in size, had smooth contours and contained small, round, densely packed synaptic vesicles. These terminals were GABA-immunonegative, often gathered in clusters, and established asymmetrical synaptic contacts with either small- or medium-sized GABA-negative dendritic profiles and with GABA-immunoreactive (GABA-ir) dendrites, which did not contain synaptic vesicles. Occasional GABA-ir-labelled axon terminals were observed; these may arise from the rare GABAergic neurons in the central tectal layer, or from neurons in the ventral pretectal nucleus, which projects both to the optic tectum and nucleus rotundus. In addition to tracer-labelled axon terminals, we observed both GABA-negative and GABA-ir cell bodies and dendrites also labelled by the tracer. No GABA-ir presynaptic dendritic profiles containing synaptic vesicles were observed. The existence in reptiles of reciprocal connections between the nucleus rotundus and the optic tectum as a phylogenetically ancient feedback system is discussed. PMID:17996857

  1. Excitatory GABA: How a Correct Observation May Turn Out to be an Experimental Artifact

    PubMed Central

    Bregestovski, Piotr; Bernard, Christophe

    2012-01-01

    The concept of the excitatory action of GABA during early development is based on data obtained mainly in brain slice recordings. However, in vivo measurements as well as observations made in intact hippocampal preparations indicate that GABA is in fact inhibitory in rodents at early neonatal stages. The apparent excitatory action of GABA seems to stem from cellular injury due to the slicing procedure, which leads to accumulation of intracellular Cl? in injured neurons. This procedural artifact was shown to be attenuated through various manipulations such as addition of energy substrates more relevant to the in vivo situation. These observations question the very concept of excitatory GABA in immature neuronal networks. PMID:22529813

  2. GABA transporter function, oligomerization state, and anchoring: correlates with subcellularly resolved FRET

    PubMed Central

    Moss, Fraser J.; Imoukhuede, P.I.; Scott, Kimberly; Hu, Jia; Jankowsky, Joanna L.; Quick, Michael W.

    2009-01-01

    The mouse ?-aminobutyric acid (GABA) transporter mGAT1 was expressed in neuroblastoma 2a cells. 19 mGAT1 designs incorporating fluorescent proteins were functionally characterized by [3H]GABA uptake in assays that responded to several experimental variables, including the mutations and pharmacological manipulation of the cytoskeleton. Oligomerization and subsequent trafficking of mGAT1 were studied in several subcellular regions of live cells using localized fluorescence, acceptor photobleach Förster resonance energy transfer (FRET), and pixel-by-pixel analysis of normalized FRET (NFRET) images. Nine constructs were functionally indistinguishable from wild-type mGAT1 and provided information about normal mGAT1 assembly and trafficking. The remainder had compromised [3H]GABA uptake due to observable oligomerization and/or trafficking deficits; the data help to determine regions of mGAT1 sequence involved in these processes. Acceptor photobleach FRET detected mGAT1 oligomerization, but richer information was obtained from analyzing the distribution of all-pixel NFRET amplitudes. We also analyzed such distributions restricted to cellular subregions. Distributions were fit to either two or three Gaussian components. Two of the components, present for all mGAT1 constructs that oligomerized, may represent dimers and high-order oligomers (probably tetramers), respectively. Only wild-type functioning constructs displayed three components; the additional component apparently had the highest mean NFRET amplitude. Near the cell periphery, wild-type functioning constructs displayed the highest NFRET. In this subregion, the highest NFRET component represented ?30% of all pixels, similar to the percentage of mGAT1 from the acutely recycling pool resident in the plasma membrane in the basal state. Blocking the mGAT1 C terminus postsynaptic density 95/discs large/zona occludens 1 (PDZ)-interacting domain abolished the highest amplitude component from the NFRET distributions. Disrupting the actin cytoskeleton in cells expressing wild-type functioning transporters moved the highest amplitude component from the cell periphery to perinuclear regions. Thus, pixel-by-pixel NFRET analysis resolved three distinct forms of GAT1: dimers, high-order oligomers, and transporters associated via PDZ-mediated interactions with the actin cytoskeleton and/or with the exocyst. PMID:19948998

  3. Biodiversity and ?-Aminobutyric Acid Production by Lactic Acid Bacteria Isolated from Traditional Alpine Raw Cow's Milk Cheeses

    PubMed Central

    Nardin, Tiziana; Schiavon, Silvia; Cavazza, Agostino; Larcher, Roberto; Tuohy, Kieran M.

    2015-01-01

    “Nostrano-cheeses” are traditional alpine cheeses made from raw cow's milk in Trentino-Alto Adige, Italy. This study identified lactic acid bacteria (LAB) developing during maturation of “Nostrano-cheeses” and evaluated their potential to produce ?-aminobutyric acid (GABA), an immunologically active compound and neurotransmitter. Cheese samples were collected on six cheese-making days, in three dairy factories located in different areas of Trentino and at different stages of cheese ripening (24?h, 15 days, and 1, 2, 3, 6, and 8 months). A total of 1,059 LAB isolates were screened using Random Amplified Polymorphic DNA-PCR (RAPD-PCR) and differentiated into 583 clusters. LAB strains from dominant clusters (n = 97) were genetically identified to species level by partial 16S rRNA gene sequencing. LAB species most frequently isolated were Lactobacillus paracasei, Streptococcus thermophilus, and Leuconostoc mesenteroides. The 97 dominant clusters were also characterized for their ability in producing GABA by high-performance liquid chromatography (HPLC). About 71% of the dominant bacteria clusters evolving during cheeses ripening were able to produce GABA. Most GABA producers were Lactobacillus paracasei but other GABA producing species included Lactococcus lactis, Lactobacillus plantarum, Lactobacillus rhamnosus, Pediococcus pentosaceus, and Streptococcus thermophilus. No Enterococcus faecalis or Sc. macedonicus isolates produced GABA. The isolate producing the highest amount of GABA (80.0±2.7?mg/kg) was a Sc. thermophilus. PMID:25802859

  4. Embryonic development of GABAergic signaling in the mouse spinal trigeminal nucleus interpolaris.

    PubMed

    Kin, Hidemichi; Kim, Jeongtae; Shimizu-Okabe, Chigusa; Okabe, Akihito; Takayama, Chitoshi

    2014-04-30

    In the mature central nervous system, ?-amino butyric acid (GABA) is an inhibitory neurotransmitter, whereas during development, GABA induces depolarization. To examine the embryonic development of GABAergic transmission in the mouse spinal trigeminal nucleus interpolaris (SpVi), which receives sensory input from the face and is important in survival of rodents, we performed immunohistochemistry for three related molecules: glutamic acid decarboxylase (GAD), a marker of GABAergic neurons; vesicular GABA transporter (VGAT), a marker of GABAergic and glycinergic vesicles; and potassium chloride co-transporter 2 (KCC2), which shifts GABA action from excitatory to inhibitory. GAD-positive longitudinal projection fibers, where VGAT-positive dots were localized, were clearly discernible until embryonic day (E)17, and were markedly decreased in number on postnatal day 0. GAD-positive neurons were detected after E15, and GAD- and VGAT-positive axon varicosities were observed after E17. KCC2 immunolabeling was first localized in the dendrites and cell bodies of several neurons in the lateral part of the SpVi on E13 and throughout the nucleus on E17. These results suggest that the SpVi may first receive GABAergic projection fibers from extra-nuclear area before birth, and GABAergic interneurons may form synapses within the SpVi after E17. In addition, GABA action may gradually shift from excitatory to inhibitory between E13 and E17. PMID:24607929

  5. Cocaine dysregulates opioid gating of GABA neurotransmission in the ventral pallidum.

    PubMed

    Kupchik, Yonatan M; Scofield, Michael D; Rice, Kenner C; Cheng, Kejun; Roques, Bernard P; Kalivas, Peter W

    2014-01-15

    The ventral pallidum (VP) is a target of dense nucleus accumbens projections. Many of these projections coexpress GABA and the neuropeptide enkephalin, a ? and ? 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

  6. Differential changes of neuroactive amino acids in samples obtained from discrete rat brain regions after systemic administration of saxitoxin

    Microsoft Academic Search

    Rosa Carmina Cervantes Cianca; Rafael Durán Barbosa; Lilian Rosana Ferreira Faro; Lucia Vidal Adan; Ana Gago-Martínez; Miguel Alfonso Pallares

    2009-01-01

    Aspartic acid, glutamic acid, ?-amino-n-butyric acid (GABA) and 2-aminoethanesulfonic acid are neuroactive amino acids. They are found in the central rat nervous system. Here, we have studied if a relationship exists between the presence of saxitoxin (STX) a paralytic poisoning shellfish (PSP) and the neuroactive amino acids. Samples of striatum (S), hypothalamus (H), mid brain (MB), frontal cortex (FC), brain

  7. Production of gamma-aminobutyric acid from glucose by introduction of synthetic scaffolds between isocitrate dehydrogenase, glutamate synthase and glutamate decarboxylase in recombinant Escherichia coli.

    PubMed

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

    2015-08-10

    Escherichia coli were engineered for the direct production of gamma-aminobutyric acid from glucose by introduction of synthetic protein scaffold. In this study, three enzymes consisting GABA pathway (isocitrate dehydrogenase, glutamate synthase and glutamate decarboxylase) were connected via synthetic protein scaffold. By introduction of scaffold, 0.92g/L of GABA was produced from 10g/L of glucose while no GABA was produced in wild type E. coli. The optimum pH and temperature for GABA production were 4.5 and 30°C, respectively. When competing metabolic network was inactivated by knockout mutation, maximum GABA concentration of 1.3g/L was obtained from 10g/L glucose. The recombinant E. coli strain which produces GABA directly from glucose was successfully constructed by introduction of protein scaffold. PMID:25997833

  8. Differences between GABA Receptor Binding to Membranes from Cerebellum during Postnatal Development and from Cultured Cerebellar Granule Cells

    Microsoft Academic Search

    Eddi Meier; Arne Schousboe

    1982-01-01

    GABA receptor binding sites were determined in membranes from cerebella of 7-, 15- and 60-day-old rats and cerebellar granule cells derived from 7-day-old rats and cultured for 8 days using [3H]GABA as the ligand and nonradioactive GABA to measure non-specific binding. Membranes from cerebellum at all postnatal stages exhibited at least two binding sites for GABA with binding constants around

  9. Pharmacological and biochemical properties of the benzodiazepine-GABA receptor in codfish brain in comparison with mammalian brain

    Microsoft Academic Search

    Deng

    1989-01-01

    The GABA receptor of codfish brain is encoded by an ancestral gene of the mammalian GABA receptor based on phylogenetic studies. The mammalian GABA receptor consists of at least two subunits (β and α) which could be photoaffinity labeled by the GABA agonist (³H)muscimol (57 kDa) and the benzodiazepine (BZ) agonist (³H)flunitrazepam (52 kDa), respectively. In contrast, electrophoresis of codfish

  10. Reduced ?-aminobutyric acid in occipital and anterior cingulate cortices in primary insomnia: a link to major depressive disorder?

    PubMed

    Plante, David T; Jensen, J Eric; Schoerning, Laura; Winkelman, John W

    2012-05-01

    Insomnia is closely related to major depressive disorder (MDD) both cross-sectionally and longitudinally, and as such, offers potential opportunities to refine our understanding of the neurobiology of both sleep and mood disorders. Clinical and basic science data suggest a role for reduced ?-aminobutyric acid (GABA) in both MDD and primary insomnia (PI). Here, we have utilized single-voxel proton magnetic spectroscopy (1H-MRS) at 4 Tesla to examine GABA relative to total creatine (GABA/Cr) in the occipital cortex (OC), anterior cingulate cortex (ACC), and thalamus in 20 non-medicated adults with PI (12 women) and 20 age- and sex-matched healthy sleeper comparison subjects. PI subjects had significantly lower GABA/Cr in the OC (p=0.0005) and ACC (p=0.03) compared with healthy sleepers. There was no significant difference in thalamic GABA/Cr between groups. After correction for multiple comparisons, GABA/Cr did not correlate significantly with insomnia severity measures among PI subjects. This study is the first to demonstrate regional reductions of GABA in PI in the OC and ACC. Reductions in GABA in similar brain regions in MDD using 1H-MRS suggest a common reduction in cortical GABA among PI and mood disorders. PMID:22318195

  11. Phasic, Nonsynaptic GABA-A Receptor-Mediated Inhibition Entrains Thalamocortical Oscillations

    PubMed Central

    Rovó, Zita; Mátyás, Ferenc; Barthó, Péter; Slézia, Andrea; Lecci, Sandro; Pellegrini, Chiara; Astori, Simone; Dávid, Csaba; Hangya, Balázs

    2014-01-01

    GABA-A receptors (GABA-ARs) are typically expressed at synaptic or nonsynaptic sites mediating phasic and tonic inhibition, respectively. These two forms of inhibition conjointly control various network oscillations. To disentangle their roles in thalamocortical rhythms, we focally deleted synaptic, ?2 subunit-containing GABA-ARs in the thalamus using viral intervention in mice. After successful removal of ?2 subunit clusters, spontaneous and evoked GABAergic synaptic currents disappeared in thalamocortical cells when the presynaptic, reticular thalamic (nRT) neurons fired in tonic mode. However, when nRT cells fired in burst mode, slow phasic GABA-AR-mediated events persisted, indicating a dynamic, burst-specific recruitment of nonsynaptic GABA-ARs. In vivo, removal of synaptic GABA-ARs reduced the firing of individual thalamocortical cells but did not abolish slow oscillations or sleep spindles. We conclude that nonsynaptic GABA-ARs are recruited in a phasic manner specifically during burst firing of nRT cells and provide sufficient GABA-AR activation to control major thalamocortical oscillations. PMID:24849349

  12. 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. PMID:25131315

  13. Homotaurine and muscimol mimic taurine and gaba effects on muscle tone and temperature regulation

    Microsoft Academic Search

    G. P. Sgaragli; V. Carlà; M. Magnani; A. Giotti

    1978-01-01

    Taurine, homotaurine, GABA and muscimol, given intraventricularly to the conscious, unrestrained rabbit cause hypothermia and a reduction in skeletal muscle tone. Taurine and homotaurine desynchronize areas of the motor and limbic cortices, while GABA and muscimol synchronize both tracings and markedly depress the arousal reaction following external stimuli.

  14. Combining Membrane Potential Imaging with L-Glutamate or GABA Photorelease

    E-print Network

    Boyer, Edmond

    Combining Membrane Potential Imaging with L-Glutamate or GABA Photorelease Kaspar E. Vogt1, BP 170, Grenoble, France Abstract Combining membrane potential imaging using voltage sensitive dyes sensitive dyes in terms of membrane potential changes (in mV) and how GABA photorelease can be used

  15. Fructose-fused ?-butyrolactones and lactams, synthesis and biological evaluation as GABA receptor ligands

    Microsoft Academic Search

    Ana C. Araújo; Francesco Nicotra; Barbara Costa; Gabriella Giagnoni; Laura Cipolla

    2008-01-01

    We describe the synthesis of sugar-fused ?-disubstituted ?-butyrolactones, ?-butyrolactams and a lipophilic ?-disubstituted GABA analogue as potential GABA receptor ligands, where the pharmacophore is engineered into the carbohydrate scaffold in the form of a C-fructoside. The products were characterized for receptor binding studies of GABAA receptors.

  16. Evidence That Different Cation Chloride Cotransporters in Retinal Neurons Allow Opposite Responses to GABA

    E-print Network

    Pennsylvania, University of

    responses for the surround has been a mystery. Both bipolar classes express ionotropic GABA receptors of the receptor. GABA would evoke opposite responses if chloride equilibrium potential (ECl) in the two bipolar terminals, which all intensely express ligand-gated anion channels (GABAA, GABAC, and glycine receptor

  17. Effects of GABA A receptor ligands on noradrenaline concentration and ?-adrenoceptor binding in mouse cerebral cortex

    Microsoft Academic Search

    D. Gettins; N. Goldsack; V. Ibegbuna; S. C. Stanford

    1990-01-01

    The present experiments investigated changes in ?-adrenoceptor binding and noradrenaline stores in mouse cerebral cortex after single treatments with drugs which bind to the GABAA receptor but which attenuate the actions of GABA. Neither the GABA antagonist, securinine, nor the picrotoxin\\/Cl? channel ligand, picrotoxin, affected noradrenaline levels or ?-adrenoceptor binding. However, both the benzodiazepine inverse agonist, DMCM, and pentylenetetrazole increased

  18. GABA Increases Electrical Excitability in a Subset of Human Unmyelinated Peripheral Axons

    Microsoft Academic Search

    Richard W. Carr; Ruth Sittl; Johannes Fleckenstein; Peter Grafe; Fabien Tell

    2010-01-01

    BackgroundA proportion of small diameter primary sensory neurones innervating human skin are chemosensitive. They respond in a receptor dependent manner to chemical mediators of inflammation as well as naturally occurring algogens, thermogens and pruritogens. The neurotransmitter GABA is interesting in this respect because in animal models of neuropathic pain GABA pre-synaptically regulates nociceptive input to the spinal cord. However, the

  19. Elevated Endogenous GABA Concentration Attenuates Glutamate-Glutamine Cycling between Neurons and Astroglia

    PubMed Central

    Yang, Jehoon; Shen, Jun

    2010-01-01

    In this study, the relationship between endogenous brain GABA concentration and glutamate-glutamine cycling flux (Vcyc) was investigated using in vivo 1H and 1H{13C} magnetic resonance spectroscopy techniques. Graded elevations of brain GABA levels were induced in rat brain after administration of the highly specific GABA-transaminase inhibitor vigabatrin (?-vinyl-GABA). The glial-specific substrate [2-13C]acetate and 1H{13C} magnetic resonance spectroscopy were used to measure Vcyc at different GABA levels. Significantly reduced Vcyc was found in rats pretreated with vigabatrin. The reduction in group mean Vcyc over the range of GABA concentrations investigated in this study (1.0 ± 0.3 ~ 5.1 ± 0.5 ?mol/g) was found to be nonlinear: ?Vcyc/Vcyc = [GABA (?mol/g)]?0.35 ? 1.0 (r2 = 0.98). The results demonstrate that Vcyc is modulated by endogenous GABA levels, and that glutamatergic and GABAergic interactions can be studied in vivo using noninvasive magnetic resonance spectroscopy techniques. PMID:19184333

  20. Utilization of Glutamine and of TCA Cycle Constituents as Precursors for Transmitter Glutamate and GABA

    Microsoft Academic Search

    Liang Peng; Leif Hertz; Rong Huang; Ursula Sonnewald; Steffen B. Petersen; Niels Westergaard; Orla Larsson; Arne Schousboe

    1993-01-01

    In the present review evidence is presented that (1) glutamine synthesis in astrocytes is essential for synthesis of GABA in neurons; (2) ?-ketoglutarate in the presence of alanine (as an amino group donor) can replace glutamine as a precursor for synthesis of transmitter glutamate, but maybe not as a precursor for transmitter GABA; (3) differences exist in the intraneuronal metabolic

  1. The influence of GABA on the synthesis of N-acetylserotonin, melatonin, O-acetyl-5-hydroxytryptophol and

    E-print Network

    Paris-Sud XI, Université de

    -hydroxytryptophol and O-acetyl-5-methoxytryptophol in the pineal gland of the male Wistar rat. M. G. M. BALEMANS D occurs. GABA is metabolized by GABA-T and this enzyme has also been demonstrated in the pineal gland shown by Schon et al. (1975) that GABA is taken up exclusively in glial cells of the pineal gland

  2. Altered ?-aminobutyric acid neurotransmission in major depressive disorder: a critical review of the supporting evidence and the influence of serotonergic antidepressants

    PubMed Central

    Pehrson, Alan L; Sanchez, Connie

    2015-01-01

    Evidence suggesting that central nervous system ?-aminobutyric acid (GABA) concentrations are reduced in patients with major depressive disorder (MDD) has been present since at least 1980, and this idea has recently gained support from more recent magnetic resonance spectroscopy data. These observations have led to the assumption that MDD’s underlying etiology is tied to an overall reduction in GABA-mediated inhibitory neurotransmission. In this paper, we review the mechanisms that govern GABA and glutamate concentrations in the brain, and provide a comprehensive and critical evaluation of the clinical data supporting reduced GABA neurotransmission in MDD. This review includes an evaluation of magnetic resonance spectroscopy data, as well as data on the expression and function of the GABA-synthesizing enzyme glutamic acid decarboxylase, GABA neuron-specific cell markers, such as parvalbumin, calretinin and calbindin, and the GABAA and GABAB receptors in clinical MDD populations. We explore a potential role for glial pathology in MDD-related reductions in GABA concentrations, and evidence of a connection between neurosteroids, GABA neurotransmission, and hormone-related mood disorders. Additionally, we investigate the effects of GABAergic pharmacological agents on mood, and demonstrate that these compounds have complex effects that do not universally support the idea that reduced GABA neurotransmission is at the root of MDD. Finally, we discuss the connections between serotonergic and GABAergic neurotransmission, and show that two serotonin-focused antidepressants – the selective serotonin-reuptake inhibitor fluoxetine and the multimodal antidepressant vortioxetine – modulate GABA neurotransmission in opposing ways, despite both being effective MDD treatments. Altogether, this review demonstrates that there are large gaps in our understanding of the relationship between GABA physiology and MDD, which must be remedied with more data from well-controlled empirical studies. In conclusion, this review suggests that the simplistic notion that MDD is caused by reduced GABA neurotransmission must be discarded in favor of a more nuanced and complex model of the role of inhibitory neurotransmission in MDD. PMID:25653499

  3. Altered ?-aminobutyric acid neurotransmission in major depressive disorder: a critical review of the supporting evidence and the influence of serotonergic antidepressants.

    PubMed

    Pehrson, Alan L; Sanchez, Connie

    2015-01-01

    Evidence suggesting that central nervous system ?-aminobutyric acid (GABA) concentrations are reduced in patients with major depressive disorder (MDD) has been present since at least 1980, and this idea has recently gained support from more recent magnetic resonance spectroscopy data. These observations have led to the assumption that MDD's underlying etiology is tied to an overall reduction in GABA-mediated inhibitory neurotransmission. In this paper, we review the mechanisms that govern GABA and glutamate concentrations in the brain, and provide a comprehensive and critical evaluation of the clinical data supporting reduced GABA neurotransmission in MDD. This review includes an evaluation of magnetic resonance spectroscopy data, as well as data on the expression and function of the GABA-synthesizing enzyme glutamic acid decarboxylase, GABA neuron-specific cell markers, such as parvalbumin, calretinin and calbindin, and the GABAA and GABAB receptors in clinical MDD populations. We explore a potential role for glial pathology in MDD-related reductions in GABA concentrations, and evidence of a connection between neurosteroids, GABA neurotransmission, and hormone-related mood disorders. Additionally, we investigate the effects of GABAergic pharmacological agents on mood, and demonstrate that these compounds have complex effects that do not universally support the idea that reduced GABA neurotransmission is at the root of MDD. Finally, we discuss the connections between serotonergic and GABAergic neurotransmission, and show that two serotonin-focused antidepressants - the selective serotonin-reuptake inhibitor fluoxetine and the multimodal antidepressant vortioxetine - modulate GABA neurotransmission in opposing ways, despite both being effective MDD treatments. Altogether, this review demonstrates that there are large gaps in our understanding of the relationship between GABA physiology and MDD, which must be remedied with more data from well-controlled empirical studies. In conclusion, this review suggests that the simplistic notion that MDD is caused by reduced GABA neurotransmission must be discarded in favor of a more nuanced and complex model of the role of inhibitory neurotransmission in MDD. PMID:25653499

  4. Characterization of the Production of Biogenic Amines and Gamma-Aminobutyric Acid in the Soybean Pastes Fermented by Aspergillus oryzae and Lactobacillus brevis.

    PubMed

    Kim, Nam Yeun; Ji, Geun Eog

    2015-04-28

    The production of gamma-aminobutyric acid (GABA) using GABA-producing lactic acid bacteria (LAB) has been considered to be an attractive strategy. However, some LAB may produce biogenic amines (BA), which may be of concern from the safety viewpoint. The aim of the present study was to characterize the production of GABA and BA in the soybean pastes fermented by Aspergillus oryzae (A. oryzae) FMB S46471 and GABA-producing Lactobacillus brevis (L. brevis) GABA 100. After a ripening period of 90 days, the levels of BA (putrescine, cadaverine, histamine, and tyramine) and GABA in the fermented soybean were assessed by highperformance liquid chromatography. The soybean pastes fermented by A. oryzae and L. brevis showed a range of 7,130-11,592 mg/kg for GABA, 178-305 mg/kg for tyramine, 139-163 mg/kg for putrescine, 7.4-10.8 mg/kg for histamine, and 7.1-7.9 mg/kg for cadaverine, whereas the soybean pastes fermented by A. oryzae only showed a range of 30-1,671 mg/kg for GABA, 0.8-189 mg/kg for tyramine, 1.3-85 mg/kg for putrescine, up to 3.6 mg/kg for histamine, and 0.2-2.4 mg/kg for cadaverine. The results showed that the production of GABA was accompanied by the increase in the production of BA, even though the production levels of histamine and cadaverine were very low. This is the first study to simultaneously characterize the production of BA and GABA in GABA-enriched fermented soybean pastes, and warrants further study to minimize the production of BA while optimizing the production of GABA. PMID:25341471

  5. [Distribution of GABA-immunoreactive elements in the reptile amygdaloid complex].

    PubMed

    Belekhova, M G; Chkheidze, D D; Veselkin, N P; Kenigfest, N B; Kratskin, I L; P'err, Zh; Reperan, Zh

    1992-01-01

    GABA-immunoreactive (GABA-I) elements (neuronal somata and neuropile) are detected in turtle Emys orbicularis and lizard Ophysaurus spodus in all structures of ventral and dorsal parts of amygdaloid complex (AC) considered as phylogenetic more ancient and younger, respectively by means of the immunohistochemical method. Their maximal quantity in the ventral section of AC is found in the lateral region, lesser--in the ventral, central and medial regions. Besides in lizards a specialized laminar distribution of GABA-I elements in n. sphaericus is observed. GABA-I neurons are also detected in structures of dorsal part in turtles and lizards against the background of the immunopositive neuropile of a moderate density. It is supposed that GABA-ergic innervation of AC is liable to considerable variations in connection with taxonomic, ecological and other factors. PMID:1584309

  6. GABA/glutamate co-release controls habenula output and is modified by antidepressant treatment

    PubMed Central

    Shabel, Steven J.; Proulx, Christophe D.; Piriz, Joaquin; Malinow, Roberto

    2015-01-01

    The lateral habenula (LHb), a key regulator of monoaminergic brain regions, is activated by negatively-valenced events. Its hyperactivity is associated with depression. While enhanced excitatory input to the LHb has been linked to depression, little is known about inhibitory transmission. We discovered that GABA is co-released with its functional opponent, glutamate, from long-range basal ganglia inputs (which signal negative events) to limit LHb activity in rodents. At this synapse, the balance of GABA/glutamate signaling is shifted towards reduced GABA in a model of depression and increased GABA by antidepressant treatment. GABA and glutamate co-release therefore controls LHb activity, and regulation of this remarkable form of transmission may be important for determining the impact of negative life events on mood and behavior. PMID:25237099

  7. Colocalization of choline acetyltransferase and ?-aminobutyric acid in the developing and adult turtle retinas

    Microsoft Academic Search

    Lynette T. Nguyen; Norberto M. Grzywacz

    2000-01-01

    Acetylcholine and g -aminobutyric acid (GABA) are putative neurotransmitters in the adult vertebrate retina. In this study, cells that coexpress choline acetyltransferase (ChAT) and GABA or glutamic acid decarboxylase (GAD) were investigated in turtle retinas from stage 14 (S14) to adulthood by using a double-labeling immunofluorescence technique. ChAT immunoreactivity was observed at S15 and included not only the presumptive starburst

  8. 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. PMID:25756551

  9. Extrasynaptic GABA(A) receptors couple presynaptic activity to postsynaptic inhibition in the somatosensory thalamus.

    PubMed

    Herd, Murray B; Brown, Adam R; Lambert, Jeremy J; Belelli, Delia

    2013-09-11

    Thalamocortical circuits govern cognitive, sensorimotor, and sleep-related network processes, and generate pathological activities during absence epilepsy. Inhibitory control of thalamocortical (TC) relay neurons is partially mediated by GABA released from neurons of the thalamic reticular nucleus (nRT), acting predominantly via synaptic ?1?2?2 GABA(A) receptors (GABA(A)Rs). Importantly, TC neurons also express extrasynaptic ?4?2? GABA(A)Rs, although how they cooperate with synaptic GABA(A)Rs to influence relay cell inhibition, particularly during physiologically relevant nRT output, is unknown. To address this question, we performed paired whole-cell recordings from synaptically coupled nRT and TC neurons of the ventrobasal (VB) complex in brain slices derived from wild-type and extrasynaptic GABA(A)R-lacking, ?4 "knock-out" (?4(0/0)) mice. We demonstrate that the duration of VB phasic inhibition generated in response to nRT burst firing is greatly reduced in ?4(0/0) pairs, suggesting that action potential-dependent phasic inhibition is prolonged by recruitment of extrasynaptic GABA(A)Rs. Furthermore, the influence of nRT tonic firing frequency on VB holding current is also greatly reduced in ?4(0/0) pairs, implying that the ?4-GABA(A)R-mediated tonic conductance of relay neurons is dynamically influenced, in an activity-dependent manner, by nRT tonic firing intensity. Collectively, our data reveal that extrasynaptic GABA(A)Rs of the somatosensory thalamus do not merely provide static tonic inhibition but can also be dynamically engaged to couple presynaptic activity to postsynaptic excitability. Moreover, these processes are highly sensitive to the ?-selective allosteric modulator, DS2 and manipulation of GABA transport systems, revealing novel opportunities for therapeutic intervention in thalamocortical network disorders. PMID:24027285

  10. Enhanced GABA action on the substantia gelatinosa neurons of the medullary dorsal horn in the offspring of streptozotocin-injected mice.

    PubMed

    Nguyen, Hoang Thi Thanh; Bhattarai, Janardhan Prasad; Park, Soo Joung; Lee, Jeong Chae; Cho, Dong Hyu; Han, Seong Kyu

    2015-07-01

    Peripheral neuropathy is a frequent complication of diabetes mellitus and a common symptom of neuropathic pain, the mechanism of which is complex and involves both peripheral and central components of the sensory system. The lamina II of the medullary dorsal horn, called the substantia gelatinosa (SG), is well known to be a critical site for processing of orofacial nociceptive information. Although there have been a number of studies done on diabetic neuropathy related to the orofacial region, the action of neurotransmitter receptors on SG neurons in the diabetic state is not yet fully understood. Therefore, we used the whole-cell patch clamp technique to investigate this alteration on SG neurons in both streptozotocin (STZ)-induced diabetic mice and offspring from diabetic female mice. STZ (200mg/kg)-injected mice showed a small decrease in body weight and a significant increase in blood glucose level when compared with their respective control group. However, application of different concentrations of glycine, gamma-aminobutyric acid (GABA) and glutamate on SG neurons from STZ-injected mice did not induce any significant differences in inward currents when compared to their control counterparts. On the other hand, the offspring of diabetic female mice (induced by multiple injections of STZ (40mg/kg) for 5 consecutive days) led to a significant decrease in both body weight and blood glucose level compared to the control offspring. Glycine and glutamate responses in the SG neurons of the offspring from diabetic female mice were similar to those of control offspring. However, the GABA response in SG neurons of offspring from diabetic female mice was greater than that of control offspring. Furthermore, the GABA-mediated responses in offspring from diabetic and control mice were examined at different concentrations ranging from 3 to 1,000?M. At each concentration, the GABA-induced mean inward currents in the SG neurons of offspring from diabetic female mice were larger than those of control mice. These results demonstrate that SG neurons in offspring from diabetic mice are more sensitive to GABA compared to control mice, suggesting that GABA sensitivity may alter orofacial pain processing in offspring from diabetic female mice. PMID:25891974

  11. Insecticidal 3-benzamido-N-phenylbenzamides specifically bind with high affinity to a novel allosteric site in housefly GABA receptors.

    PubMed

    Ozoe, Yoshihisa; Kita, Tomo; Ozoe, Fumiyo; Nakao, Toshifumi; Sato, Kazuyuki; Hirase, Kangetsu

    2013-11-01

    ?-Aminobutyric acid (GABA) receptors (GABARs) are an important target for existing insecticides such as fiproles. These insecticides act as noncompetitive antagonists (channel blockers) for insect GABARs by binding to a site within the intrinsic channel of the GABAR. Recently, a novel class of insecticides, 3-benzamido-N-phenylbenzamides (BPBs), was shown to inhibit GABARs by binding to a site distinct from the site for fiproles. We examined the binding site of BPBs in the adult housefly by means of radioligand-binding and electrophysiological experiments. 3-Benzamido-N-(2,6-dimethyl-4-perfluoroisopropylphenyl)-2-fluorobenzamide (BPB 1) (the N-demethyl BPB) was a partial, but potent, inhibitor of [(3)H]4'-ethynyl-4-n-propylbicycloorthobenzoate (GABA channel blocker) binding to housefly head membranes, whereas the 3-(N-methyl)benzamido congener (the N-methyl BPB) had low or little activity. A total of 15 BPB analogs were tested for their abilities to inhibit [(3)H]BPB 1 binding to the head membranes. The N-demethyl analogs, known to be highly effective insecticides, potently inhibited the [(3)H]BPB 1 binding, but the N-methyl analogs did not even though they, too, are considered highly effective. [(3)H]BPB 1 equally bound to the head membranes from wild-type and dieldrin-resistant (rdl mutant) houseflies. GABA allosterically inhibited [(3)H]BPB 1 binding. By contrast, channel blocker-type antagonists enhanced [(3)H]BPB 1 binding to housefly head membranes by increasing the affinity of BPB 1. Antiparasitic macrolides, such as ivermectin B1a, were potent inhibitors of [(3)H]BPB 1 binding. BPB 1 inhibited GABA-induced currents in housefly GABARs expressed in Xenopus oocytes, whereas it failed to inhibit l-glutamate-induced currents in inhibitory l-glutamate receptors. Overall, these findings indicate that BPBs act at a novel allosteric site that is different from the site for channel blocker-type antagonists and that is probably overlapped with the site for macrolides in insect GABARs. PMID:24267689

  12. Presynaptic GABA(B) receptors decrease neurotransmitter release in vestibular nuclei neurons during vestibular compensation.

    PubMed

    Shao, M; Reddaway, R; Hirsch, J C; Peusner, K D

    2012-10-25

    Unilateral damage to the peripheral vestibular receptors precipitates a debilitating syndrome of oculomotor and balance deficits at rest, which extensively normalize during the first week after the lesion due to vestibular compensation. In vivo studies suggest that GABA(B) receptor activation facilitates recovery. However, the presynaptic or postsynaptic sites of action of GABA(B) receptors in vestibular nuclei neurons after lesions have not been determined. Accordingly, here presynaptic and postsynaptic GABA(B) receptor activity in principal cells of the tangential nucleus, a major avian vestibular nucleus, was investigated using patch-clamp recordings correlated with immunolabeling and confocal imaging of the GABA(B) receptor subunit-2 (GABA(B)R2) in controls and operated chickens shortly after unilateral vestibular ganglionectomy (UVG). Baclofen, a GABA(B) agonist, generated no postsynaptic currents in principal cells in controls, which correlated with weak GABA(B)R2 immunolabeling on principal cell surfaces. However, baclofen decreased miniature excitatory postsynaptic current (mEPSC) and GABAergic miniature inhibitory postsynaptic current (mIPSC) events in principal cells in controls, compensating and uncompensated chickens three days after UVG, indicating the presence of functional GABA(B) receptors on presynaptic terminals. Baclofen decreased GABAergic mIPSC frequency to the greatest extent in principal cells on the intact side of compensating chickens, with concurrent increases in GABA(B)R2 pixel brightness and percentage overlap in synaptotagmin 2-labeled terminals. In uncompensated chickens, baclofen decreased mEPSC frequency to the greatest extent in principal cells on the intact side, with concurrent increases in GABA(B)R2 pixel brightness and percentage overlap in synaptotagmin 1-labeled terminals. Altogether, these results revealed changes in presynaptic GABA(B) receptor function and expression which differed in compensating and uncompensated chickens shortly after UVG. This work supports an important role for GABA(B) autoreceptor-mediated inhibition in vestibular nuclei neurons on the intact side during early stages of vestibular compensation, and a role for GABA(B) heteroreceptor-mediated inhibition of glutamatergic terminals on the intact side in the failure to recover function. PMID:22871524

  13. A gain-of-function mutation in the GABA receptor produces synaptic and behavioral abnormalities in the mouse.

    PubMed

    Homanics, G E; Elsen, F P; Ying, S-W; Jenkins, A; Ferguson, C; Sloat, B; Yuditskaya, S; Goldstein, P A; Kralic, J E; Morrow, A L; Harrison, N L

    2005-02-01

    In mammalian species, inhibition in the brain is mediated predominantly by the activation of GABAA receptors. We report here changes in inhibitory synaptic function and behavior in a mouse line harboring a gain-of-function mutation at Serine 270 (S270) in the GABAA receptor alpha1 subunit. In recombinant alpha1beta2gamma2 receptors, replacement of S270 by Histidine (H) results in an increase in sensitivity to gamma-aminobutyric acid (GABA), and slowing of deactivation following transient activation by saturating concentrations of GABA. Heterozygous mice expressing the S270H mutation are hyper-responsive to human contact, exhibit intention tremor, smaller body size and reduced viability. These mice also displayed reduced motor coordination, were hypoactive in the home cage, but paradoxically were hyperactive in a novel open field environment. Heterozygous knockin mice of both sexes were fertile but females failed to care for offspring. This deficit in maternal behavior prevented production of homozygous animals. Recordings from brain slices prepared from these animals revealed a substantial prolongation of miniature inhibitory postsynaptic currents (IPSCs) and a loss of sensitivity to the anesthetic isoflurane, in neurons that express a substantial amount of the alpha1 subunit. The results suggest that the biophysical properties of GABAA receptors are important in determining the time-course of inhibition in vivo, and suggest that the duration of synaptic inhibition is a critical determinant that influences a variety of behaviors in the mouse. PMID:15660664

  14. Serotonin and gamma-aminobutyric acid turnover after injection into the median raphe of substance P and D-ala-met-enkephalin amide.

    PubMed

    Forchetti, C M; Marco, E J; Meek, J L

    1982-05-01

    The raphe nuclei [which contain serotonin (5-HT) cell bodies] are also known to contain axons that store substance P, met-enkephalin, and gamma-aminobutyric acid (GABA). We have previously shown that GABA has a tonic inhibitory action on 5-HT turnover. To examine other possible interactions of these neuronal systems, we assessed the effect on 5-HT turnover of injecting substance P and 2-D-ala-met-enkephalin into the median raphe nucleus, and the effects of substance P on GABA turnover. Serotonin turnover was increased by 30% in the hippocampus after the injection of substance P (4 micrograms) into the median raphe, indicating an excitatory effect of substance P on the raphe-hippocampal system. Local injection of the metabolically stable metenkephalin analog 2-D-ala-met-enkephalin amide (10 micrograms) increased the hippocampal steady state content of 5-hydroxyindoleacetic acid (5-HIAA) by 60%. The data suggest an excitatory effect of met-enkephalin within the raphe nucleus. We attempted to estimate GABA turnover from the rate of disappearance of GABA after inhibition of glutamic acid decarboxylase by isoniazid and by the rate of accumulation of GABA after inhibition of GABA transaminase by gabaculine. Isoniazid, which is a competitive inhibitor, had too short and incomplete an action to be of use when injected intranuclearly. Gabaculine, which is an irreversible inhibitor, induced a rapid-onset increase in GABA content. This accumulation was linear up to 90 min. The injection fo gabaculine (80 ng) into the raphe increased GABA content by five times the control values, but hippocampal 5-HT and 5-HIAA contents were not significantly changed. Substance P injection increased the GABA turnover by 30%. Gabaculine seems a promising tool for detecting changes in GABA turnover. PMID:6174697

  15. Discovery of a subtype selective inhibitor of the human betaine/GABA transporter 1 (BGT-1) with a non-competitive pharmacological profile.

    PubMed

    Kragholm, Bolette; Kvist, Trine; Madsen, Karsten K; Jørgensen, Lars; Vogensen, Stine B; Schousboe, Arne; Clausen, Rasmus P; Jensen, Anders A; Bräuner-Osborne, Hans

    2013-08-15

    The ?-aminobutyric acid (GABA) transporters (GATs) are essential regulators of the activity in the GABAergic system through their continuous uptake of the neurotransmitter from the synaptic cleft and extrasynaptic space. Four GAT subtypes have been identified to date, each displaying different pharmacological properties and expression patterns. The present study focus on the human betaine/GABA transporter 1 (BGT-1), which has recently emerged as a new target for treatment of epilepsy. However, the lack of selective inhibitors of this transporter has impaired the exploration of this potential considerably. With the objective of identifying novel compounds displaying selectivity for BGT-1, we performed a screening of a small compound library at cells expressing BGT-1 using a [(3)H]GABA uptake assay. The screening resulted in the identification of the compound N-(1-benzyl-4-piperidinyl)-2,4-dichlorobenzamide (BPDBA), a selective inhibitor of the human BGT-1 transporter with a non-competitive profile exhibiting no significant inhibitory activity at the other three human GAT subtypes. The selectivity profile of the compound was subsequently confirmed at cells expressing the four mouse GAT subtypes. Thus, BPDBA constitutes a potential useful pharmacological tool compound for future explorations of the function of the BGT-1 subtype. PMID:23792119

  16. Quantitative changes of GABA-immunoreactive cells in the hindlimb representation of the rat somatosensory cortex after 14-day hindlimb unloading by tail suspension

    NASA Technical Reports Server (NTRS)

    D'Amelio, F.; Fox, R. A.; Wu, L. C.; Daunton, N. G.

    1996-01-01

    The present study was aimed at evaluating quantitatively gamma-aminobutyric acid (GABA) immunoreactivity in the hindlimb representation of the rat somatosensory cortex after 14 days of hindlimb unloading by tail suspension. A reduction in the number of GABA-immunoreactive cells with respect to the control animals was observed in layer Va and Vb. GABA-containing terminals were also reduced in the same layers, particularly those terminals surrounding the soma and apical dendrites of pyramidal cells in layer Vb. On the basis of previous morphological and behavioral studies of the neuromuscular system of hindlimb-suspended animals, it is suggested that the unloading due to hindlimb suspension alters afferent signaling and feedback information from intramuscular receptors to the cerebral cortex due to modifications in the reflex organization of hindlimb muscle groups. We propose that the reduction in immunoreactivity of local circuit GABAergic neurons and terminals is an expression of changes in their modulatory activity to compensate for the alterations in the afferent information.

  17. Effect of the 'antidementia drug' pantoyl-GABA on high affinity transport of choline and on the contents of choline and acetylcholine in rat brain.

    PubMed Central

    Nakahiro, M.; Mochizuki, D.; Uchida, S.; Yoshida, H.

    1988-01-01

    1. Effect of pantoyl-gamma-aminobutyric acid (pantoyl-GABA) on high affinity transport of choline into synaptosomes and on the choline (Ch) and acetylcholine (ACh) concentrations of rat brain were studied. 2. Pantoyl-GABA was injected intraperitoneally four times at a dose of 500 mg kg-1 at intervals of 30 min. One hour after the last injection, rats were killed by decapitation for measurement of high affinity transport of Ch into synaptosomes or by microwave irradiation for the measurement of Ch and ACh concentrations. 3. Transport of Ch was increased into synaptosomes prepared from the cerebral cortex and hippocampus, but not into those from the striatum. 4. In the cerebral cortex and hippocampus, Ch concentration was increased and ACh concentration decreased. 5. Since treatments that enhance the activity of cholinergic neurones in vivo are reported to increase high affinity transport of Ch measured in vitro, the present results suggest that pantoyl-GABA may increase cholinergic activity in vivo. This action of the drug may be related to changes in the Ch and ACh concentrations. PMID:3219489

  18. Retinal and cortical afferents to the dorsal lateral geniculate nucleus of the turtle, Emys orbicularis: a combined axonal tracing, glutamate, and GABA immunocytochemical electron microscopic study.

    PubMed

    Kenigfest, N B; Repérant, J; Rio, J P; Belekhova, M G; Ward, R; Vesselkin, N P; Miceli, D; Herbin, M

    1998-02-22

    The dorsal lateral geniculate nucleus (GLd) of the turtle Emys orbicularis has been analyzed with axonal tracing methods and immunocytochemical techniques for glutamate (GLU) and gamma-aminobutyric acid (GABA), in combination with a quantitative study of the morphologic characteristics, distribution, and synaptology of the retinofugal and corticofugal terminals. Ultrastructural observations show that the vast majority of retinal terminals (Rtr) have clear, rounded synaptic vesicles and account for 16% of all profiles containing synaptic vesicles (PCSV). Their synaptic index (0.5) is low, and they make three times more contacts with the dendrites of projection cells than with those of interneurons. A low proportion of retinal terminals of a second category contain pleomorphic synaptic vesicles and are highly GABA immunoreactive. Axon terminals, unlabeled after intraocular injection of the tracer (SR), smaller in size and with more rounded clear synaptic vesicles, longer synaptic differentiations, and higher synaptic index than Rtr terminals, account for 19.7% of all PCSV and make asymmetric synaptic contacts with large dendrites of projection cells and less with the dendrites of interneurons. Some SR have been unambiguously identified as corticofugal terminals (Cg), either after cortical injection of the tracer (16%) or cortical lesion (37%). Retinal and Cg/SR terminals are spatially segregated within the GLd. Both are highly GLU immunoreactive, with the highest density of labeling over synaptic vesicles, suggesting that these terminals may use GLU as neurotransmitter. The level of GLU immunoreactivity of GABA-positive profiles is half that of Rtr and Cg/SR terminals and is greatest over mitochondria, possibly reflecting the 'metabolic' pool of GLU that serves as a precursor in the formation of GABA. PMID:9486826

  19. Understanding your inhibitions: effects of GABA and GABAA receptor modulation on brain cortical metabolism.

    PubMed

    Nasrallah, Fatima A; Griffin, Julian L; Balcar, Vladimir J; Rae, Caroline

    2009-01-01

    A targeted neuropharmacological, (1)H/(13)C NMR spectroscopy and multivariate statistical approach was used to examine the effects of exogenous GABA and ligands at the GABA(A) receptor family on brain metabolism in the Guinea pig cortical tissue slice. All ligands at GABA(A) receptors generated metabolic patterns which were distinct from one another with the major variance in the data arising because of metabolic work (shown by net flux into Krebs cycle byproducts and increased metabolic pool sizes). Three major clusters of metabolic signatures were identified which corresponded to: (i) activity at phasic (synaptic) GABA(A) receptors, dominated by alpha1-containing receptors and responsive to GABA at 10 micromol/L; (ii) activity at perisynaptic receptors, dominated by response to high (40 micromol/L) GABA and the superagonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol hydrochloride, and C, activity at extrasynaptic receptors, dominated by response to low (0.1-1.0 micromol/L) GABA, zolpidem (400 nmol/L) and the non-specific allosteric modulator RO19-4603 (1 nmol/L). These results highlight the utility of a different but robust approach to study of the GABAergic system using metabolic systems analysis. PMID:19014380

  20. Modulation of GABA-stimulated chloride influx into membrane vesicles from rat cerebral cortex by triazolobenzodiazepines

    SciTech Connect

    Obata, T.; Yamamura, H.I.

    1988-01-01

    The effects of triazolobenzodiazepines of GABA-stimulated /sup 36/Cl/sup -/ uptake by membrane vesicles from rat cerebral cortex were examined. Triazolam and alprazolam showed a significant enhancement of GABA-stimulated /sup 36/Cl/sup -/ uptake at 0.01-10 uM. On the other hand, adinazolam showed a small enhancement at 0.1-1 uM followed by a significant inhibition of GABA-stimulated /sup 36/Cl/sup -/ uptake at 100 uM. The enhancement of GABA-stimulated /sup 36/Cl/sup -/ uptake by 1 uM alprazolam was antagonized by Ro15-1788, a benzodiazepine antagonist, but the inhibition of this response by 30 uM adinazolam was not antagonized by Ro15-1788. These results indicate that triazolobenzodiazepines enhanced GABA-stimulated /sup 36/Cl/sup -/ uptake through benzodiazepine receptors. High concentrations of adinazolam inhibit GABA-stimulated /sup 36/Cl/sup -/ uptake which may be due to the direct blockade of GABA-gated chloride channel. 23 references, 4 figures.

  1. An epilepsy-related region in the GABA(A) receptor mediates long-distance effects on GABA and benzodiazepine binding sites.

    PubMed

    Goldschen-Ohm, Marcel P; Wagner, David A; Petrou, Steven; Jones, Mathew V

    2010-01-01

    The GABA(A) receptor mutation gamma(2)R43Q causes absence epilepsy in humans. Homology modeling suggests that gamma(2)Arg43, gamma(2)Glu178, and beta(2)Arg117 participate in a salt-bridge network linking the gamma(2) and beta(2) subunits. Here we show that several mutations at these locations exert similar long-distance effects on other intersubunit interfaces involved in GABA and benzodiazepine binding. These mutations alter GABA-evoked receptor kinetics by slowing deactivation, enhancing desensitization, or both. Kinetic modeling and nonstationary noise analysis for gamma(2)R43Q reveal that these effects are due to slowed GABA unbinding and slowed recovery from desensitization. Both gamma(2)R43Q and beta(2)R117K also speed diazepam dissociation from the receptor's benzodiazepine binding interface, as assayed by the rate of decay of diazepam-induced potentiation of GABA-evoked currents. These data demonstrate that gamma(2)Arg43 and beta(2)Arg117 similarly regulate the stability of both the GABA and benzodiazepine binding sites at the distant beta/alpha and alpha/gamma intersubunit interfaces, respectively. A simple explanation for these results is that gamma(2)Arg43 and beta(2)Arg117 participate in interactions between the gamma(2) and beta(2) subunits, disruptions of which alter the neighboring intersubunit binding sites in a similar fashion. In addition, gamma(2)Arg43 and gamma(2)Glu178 regulate desensitization, probably mediated within the transmembrane domains near the pore. Therefore, mutations at the gamma/beta intersubunit interface have specific long-distance effects that are propagated widely throughout the GABA(A) receptor protein. PMID:19846749

  2. Significance of GABA(A) receptor heterogeneity: clues from developing neurons.

    PubMed

    Fritschy, Jean-Marc

    2015-01-01

    Briefly after the landmark discovery by Hanns Möhler that GABA(A) receptors (GABA(A)R) are the site of action of benzodiazepine site ligands, their distribution in the rodent CNS during development was mapped by autoradiography, demonstrating early and widespread expression of GABA(A)R in the brain and spinal cord. Ten years later, the first studies using subunit-specific antibodies revealed unsuspected heterogeneity in the subunit composition of GABA(A)R in developing brain, with striking regional specificity and rapid changes in expression and subcellular localization correlating with the maturation of neuronal circuits. These data contributed to the wealth of evidence that GABAergic neurotransmission, acting both synaptically and extrasynaptically, modulates major steps of neuronal development (proliferation, migration, differentiation, and circuit formation). In immature neurons, GABA(A)R activation leads to neuronal depolarization and activation of Ca(2+) signals, which mediate many of the developmental effects of GABA. Therefore, GABA(A)R heterogeneity might be essential to fine-tune GABA actions in the dynamics of CNS maturation. Furthermore, since a disturbance of GABAergic function during ontogeny can potentially affect many aspects of CNS maturation and contribute to the etiology of major brain disorders, GABA(A)R heterogeneity provides a substrate for the development of a tailored pharmacology targeting specific receptor subtypes. This chapter provides a brief overview of these issues with a special focus on the seminal contributions of Hanns Möhler to the emergence of these concepts of fundamental relevance in today's neuroscience research and pharmacological developments. PMID:25637436

  3. Analysis of cerebrospinal fluid ?-aminobutyric acid by capillary electrophoresis with laser-induced fluorescence detection.

    PubMed

    Casado, Mercedes; Molero, Marta; Sierra, Cristina; García-Cazorla, Angels; Ormazabal, Aida; Artuch, Rafael

    2014-04-01

    The measurement of ?-aminobutyric acid (GABA) is suitable for investigating various neurological disorders. In this study, a sensitive and selective method for free GABA quantification in cerebrospinal fluid (CSF) has been standardised. This method is based on CE with LIF detection using 4-fluoro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-F) as a derivatisating agent. The reaction conditions (NBD-F concentration, pH, temperature and reaction time) and the electrophoretic parameters (run buffer composition and pH and separation voltage) were optimised to obtain the maximum derivatisation efficiency and electrophoretic resolution. The best resolution was obtained using 200 mM sodium borate, 10 mM SDS, 8.5 mM ?-CD, pH 10 and 20 kV voltage. The method was linear in the concentration range of 2.5-1000 nM with good inter- and intra-assay precision values. The effects of CSF handling on free GABA concentrations were also evaluated. Our results show that the time delay between CSF collection and freezing strongly increases the CSF GABA values. Age-related reference values were established in 55 paediatric controls. The influence of antiepileptic therapy on free CSF GABA was studied in 38 neuropaediatric patients. Significantly, higher GABA values were obtained in patients taking valproic acid or vigabatrin therapy, which are antiepileptic drugs that modulate GABA metabolism. PMID:24338894

  4. Chronic stress shifts the GABA reversal potential in the hippocampus and increases seizure susceptibility.

    PubMed

    MacKenzie, Georgina; Maguire, Jamie

    2015-01-01

    The most commonly reported precipitating factor for seizures is stress. However, the underlying mechanisms whereby stress triggers seizures are not yet fully understood. Here we demonstrate a potential mechanism underlying changes in neuronal excitability in the hippocampus following chronic stress, involving a shift in the reversal potential for GABA (EGABA) associated with a dephosphorylation of the potassium chloride co-transporter, KCC2. Mice subjected to chronic restraint stress (30min/day for 14 consecutive days) exhibit an increase in serum corticosterone levels which is associated with increased susceptibility to seizures induced with kainic acid (20mg/kg). Following chronic stress, but not acute stress, we observe a dephosphorylation of KCC2 residue S940, which regulates KCC2 cell surface expression and function, in the hippocampus. To determine the impact of alterations in KCC2 expression following chronic stress, we performed gramicidin perforated patch recordings to measure changes in EGABA and neuronal excitability of principal hippocampal neurons. We observe a depolarizing shift in EGABA in hippocampal CA1 pyramidal neurons after chronic stress. In addition, there is an increase in the intrinsic excitability of CA1 pyramidal neurons, evident by a shift in the input-output curve which could be reversed with the NKCC1 inhibitor, bumetanide. These data uncover a potential mechanism involving chronic stress-induced plasticity in chloride homeostasis which may contribute to stress-induced seizure susceptibility. PMID:25524838

  5. GABA and benzodiazepine receptors in the gerbil brain after transient ischemia: demonstration by quantitative receptor autoradiography

    SciTech Connect

    Onodera, H.; Sato, G.; Kogure, K.

    1987-02-01

    Quantitative receptor autoradiography was used to measure the binding of gamma-aminobutyric acid (GABA) and benzodiazepine receptors after ischemia by means of transient occlusion of bilateral common carotid arteries in the gerbil. (/sup 3/H)Muscimol was used to label the GABAA receptors and (/sup 3/H)flunitrazepam to label central type benzodiazepine receptors. In the superolateral convexities of the frontal cortices, (/sup 3/H)muscimol binding was increased in 60% of the animals killed 3 days after ischemia, and decreased in 67% of the animals killed 27 days after ischemia. Twenty-seven days after ischemia, (/sup 3/H)flunitrazepam binding in the substantia nigra pars reticulata increased to 252% of the control, though the increase in (/sup 3/H)muscimol binding was not significant. In the dorsolateral region of the caudate putamen, marked neuronal necrosis and depletion of both (/sup 3/H)muscimol and (/sup 3/H)flunitrazepam binding sites were observed 27 days after ischemia, the ventromedial region being left intact. In spite of the depletion of pyramidal cells in the CA1 region of the hippocampus, both (/sup 3/H)muscimol and (/sup 3/H)flunitrazepam binding sites were preserved 27 days after ischemia. Since our previous study revealed that adenosine A1 binding sites were depleted in the CA1 subfield of the hippocampus after ischemia correlating with neuronal damage, GABAA and benzodiazepine receptors may not be distributed predominantly on the pyramidal cells in the CA1 region.

  6. Two-step production of gamma-aminobutyric acid from cassava powder using Corynebacterium glutamicum and Lactobacillus plantarum.

    PubMed

    Yang, Taowei; Rao, Zhiming; Kimani, Bernard Gitura; Xu, Meijuan; Zhang, Xian; Yang, Shang-Tian

    2015-08-01

    Production of gamma-aminobutyric acid (GABA) from crop biomass such as cassava in high concentration is desirable, but difficult to achieve. A safe biotechnological route was investigated to produce GABA from cassava powder by C. glutamicum G01 and L. plantarum GB01-21. Liquefied cassava powder was first transformed to glutamic acid by simultaneous saccharification and fermentation with C. glutamicum G01, followed by biotransformation of glutamic acid to GABA with resting cells of L. plantarum GB01-21 in the reaction medium. After optimizing the reaction conditions, the maximum concentration of GABA reached 80.5 g/L with a GABA productivity of 2.68 g/L/h. This is the highest yield ever reported of GABA production from cassava-derived glucose. The bioprocess provides the added advantage of employing nonpathogenic microorganisms, C. glutamicum and L. plantarum, in microbial production of GABA from cassava biomass, which can be used in the food and pharmaceutical industries. PMID:26115763

  7. Effect of microbial fermentation on content of statin, GABA, and polyphenols in Pu-Erh tea.

    PubMed

    Jeng, Kee-Ching; Chen, Chin-Shuh; Fang, Yu-Pun; Hou, Rolis Chien-Wei; Chen, Yuh-Shuen

    2007-10-17

    Besides cancer prevention, the hypolipidemic effects of tea have been well studied in animals and humans. Recently, statin has been identified in Pu-erh tea extract. Clinical trials have confirmed that statin decreases the incidence of major coronary and cerebrovascular events and this may be due to its hypolipidemic and antiinflammatory effects. Since a good Pu-erh tea needs longer storage (10 years or more) of fermentation to enhance the flavor and fragrance, we screened microorganisms from two Pu-erh teas, 20 and 25 years old. Species of fungi and bacteria strains that contributed to a good taste of Pu-erh tea were isolated. The effect of fermentation was investigated by inoculating fresh tea leaves with individual strains of isolated microorganisms. Results showed that statin, total polyphenol content, and the scavenging activities of alpha,alpha-diphenyl-beta-picrylhydrazyl (DPPH) radicals increased during fermentation. Tea leaves inoculated with Streptomyces bacillaris strain R9 had the highest polyphenol content (3.3 mg/100 g) and scavenging ability to DPPH radicals (92%). Streptomyces cinereus strain Y11 was equally good for polyphenol content but yielded the highest amount of statin (1012 ng/g) after 42 days of fermentation. Interestingly, the statin content of fresh tea leaves fermented with strain R9 or Y11 after 180 days was much higher (4- and 8-fold, respectively) than that of the 25-year-old Pu-erh tea (513 ng/g) as measured by the HPLC method. Similarly, these two strains also increased the content of gamma-aminobutyric acid (GABA) 5.7- and 4.7-fold in tea fermented for 180 days as compared with the fresh leaves (1270 microg/g) and that were higher than that of the Pu-erh tea (4900 microg/g). Taken together, the present results indicate that tea short-term fermented with S. bacillaris or S. cinereus enhances the color and content of statin, GABA, and polyphenols. PMID:17880152

  8. Multiple Forms of Endocannabinoid and Endovanilloid Signaling Regulate the Tonic Control of GABA Release

    PubMed Central

    Lee, Sang-Hun; Ledri, Marco; Tóth, Blanka; Marchionni, Ivan; Henstridge, Christopher M.; Dudok, Barna; Kenesei, Kata; Barna, László; Szabó, Szilárd I.; Renkecz, Tibor; Oberoi, Michelle; Watanabe, Masahiko; Limoli, Charles L.; Horvai, George; Soltesz, Ivan

    2015-01-01

    Persistent CB1 cannabinoid receptor activity limits neurotransmitter release at various synapses throughout the brain. However, it is not fully understood how constitutively active CB1 receptors, tonic endocannabinoid signaling, and its regulation by multiple serine hydrolases contribute to the synapse-specific calibration of neurotransmitter release probability. To address this question at perisomatic and dendritic GABAergic synapses in the mouse hippocampus, we used a combination of paired whole-cell patch-clamp recording, liquid chromatography/tandem mass spectrometry, stochastic optical reconstruction microscopy super-resolution imaging, and immunogold electron microscopy. Unexpectedly, application of the CB1 antagonist and inverse agonist AM251 [N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide], but not the neutral antagonist NESS0327 [8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-5,6-dihydro-4H-benzo[2,3]cyclohepta[2,4-b]pyrazole-3-carboxamine], significantly increased synaptic transmission between CB1-positive perisomatic interneurons and CA1 pyramidal neurons. JZL184 (4-nitrophenyl 4-[bis(1,3-benzodioxol-5-yl)(hydroxy)methyl]piperidine-1-carboxylate), a selective inhibitor of monoacylglycerol lipase (MGL), the presynaptic degrading enzyme of the endocannabinoid 2-arachidonoylglycerol (2-AG), elicited a robust increase in 2-AG levels and concomitantly decreased GABAergic transmission. In contrast, inhibition of fatty acid amide hydrolase (FAAH) by PF3845 (N-pyridin-3-yl-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide) elevated endocannabinoid/endovanilloid anandamide levels but did not change GABAergic synaptic activity. However, FAAH inhibitors attenuated tonic 2-AG increase and also decreased its synaptic effects. This antagonistic interaction required the activation of the transient receptor potential vanilloid receptor TRPV1, which was concentrated on postsynaptic intracellular membrane cisternae at perisomatic GABAergic symmetrical synapses. Interestingly, neither AM251, JZL184, nor PF3845 affected CB1-positive dendritic interneuron synapses. Together, these findings are consistent with the possibility that constitutively active CB1 receptors substantially influence perisomatic GABA release probability and indicate that the synaptic effects of tonic 2-AG release are tightly controlled by presynaptic MGL activity and also by postsynaptic endovanilloid signaling and FAAH activity. SIGNIFICANCE STATEMENT Tonic cannabinoid signaling plays a critical role in the regulation of synaptic transmission. However, the mechanistic details of how persistent CB1 cannabinoid receptor activity inhibits neurotransmitter release have remained elusive. Therefore, electrophysiological recordings, lipid measurements, and super-resolution imaging were combined to elucidate those signaling molecules and mechanisms that underlie tonic cannabinoid signaling. The findings indicate that constitutive CB1 activity has pivotal function in the tonic control of hippocampal GABA release. Moreover, the endocannabinoid 2-arachidonoylglycerol (2-AG) is continuously generated postsynaptically, but its synaptic effect is regulated strictly by presynaptic monoacylglycerol lipase activity. Finally, anandamide signaling antagonizes tonic 2-AG signaling via activation of postsynaptic transient receptor potential vanilloid TRPV1 receptors. This unexpected mechanistic diversity may be necessary to fine-tune GABA release probability under various physiological and pathophysiological conditions. PMID:26157003

  9. Nutriepigenetic regulation by folate-homocysteine-methionine axis: a review.

    PubMed

    Bhargava, Seema; Tyagi, S C

    2014-02-01

    Although normally folic acid is given during pregnancy, presumably to prevent neural tube defects, the mechanisms of this protection are unknown. More importantly it is unclear whether folic acid has other function during development. It is known that folic acid re-methylates homocysteine (Hcy) to methionine by methylene tetrahydrofolate reductase-dependent pathways. Folic acid also generates high-energy phosphates, behaves as an antioxidant and improves nitric oxide (NO) production by endothelial NO synthase. Interestingly, during epigenetic modification, methylation of DNA/RNA generate homocysteine unequivocally. The enhanced overexpression of methyl transferase lead to increased yield of Hcy. The accumulation of Hcy causes vascular dysfunction, reduces perfusion in the muscles thereby causing musculopathy. Another interesting fact is that children with severe hyperhomocysteinaemia (HHcy) have skeletal deformities, and do not live past teenage. HHcy is also associated with the progeria syndrome. Epilepsy is primarily caused by inhibition of gamma-amino-butyric-acid (GABA) receptor, an inhibitory neurotransmitter in the neuronal synapse. Folate deficiency leads to HHcy which then competes with GABA for binding on the GABA receptors. With so many genetic and clinical manifestations associated with folate deficiency, we propose that folate deficiency induces epigenetic alterations in the genes and thereby results in disease. PMID:24213682

  10. [Fenibut and fenazepam as potential protectors of pregnancy with a GABA-ergic mechanism of action].

    PubMed

    Sergeev, P V; Sizov, P I; Dukhanin, A S

    1997-01-01

    It has been shown that the GABAergic system of the myometrium takes part in regulation of uterine contractility during the development of pregnancy Fenibut and phenazepam exhibit a specific uterotropic effect. The uterodepressant effect of fenibut is realized via the inhibiting GABA-receptors of the myometrium. The uteroinhibiting effect of phenazepam is mediated through the interaction with the postsynaptic GABA-benzodiazepin-C1-receptor complex of the myometrium. PMID:9206566

  11. Activation of GABAA receptors containing the  4 subunit by GABA and pentobarbital

    Microsoft Academic Search

    Gustav Akk; John Bracamontes; Joe Henry Steinbach

    2004-01-01

    The activation properties of GABAA receptors containing ?4?2?2 and ?4?2? subunits were examined in the presence of GABA or pentobarbital. The receptors were expressed trans- iently in HEK 293 cells, and the electrophysiological experiments were carried out using cell- attached single-channel patch clamp or whole-cell macroscopic recordings. The data show that GABA is a stronger activator of ?4?2?2 receptors than

  12. Distribution of two GABA receptor-like subunits in the Drosophila CNS

    Microsoft Academic Search

    K. Aronstein; V. Auld; R. Ffrench-Constant

    1996-01-01

    Previously we have described the distribution of theRdl GABA receptor subunit in theDrosophila CNS. Knowing thatRdl can coassemble with LCCH3 (aDrosophila GABA receptor-like subunit showing sequence similarity to vertebrate ? subunit GABAA receptors) in baculovirus infected insect cells, we compared the localization of these two receptor subunits in order to identify any potential overlap in their spatial or temporal distribution.

  13. Ligand-binding studies on GABA receptors—Relation to physiology and behavior

    Microsoft Academic Search

    F. V. DeFeudis

    1984-01-01

    Some studies that have been conducted with ligand-binding methods support the contention that activation of cerebral GABA-receptors is involved in the control of certain behaviors. Further study of the changes in GABA-receptors that are associated with altered physiology and behavior in experimental animals and in man might lead to the development of new therapies for certain neuropsychiatric, cardiovascular, and endocrinological

  14. Midbrain dopamine neurons sustain inhibitory transmission using plasma membrane uptake of GABA, not synthesis

    PubMed Central

    Tritsch, Nicolas X; Oh, Won-Jong; Gu, Chenghua; Sabatini, Bernardo L

    2014-01-01

    Synaptic transmission between midbrain dopamine neurons and target neurons in the striatum is essential for the selection and reinforcement of movements. Recent evidence indicates that nigrostriatal dopamine neurons inhibit striatal projection neurons by releasing a neurotransmitter that activates GABAA receptors. Here, we demonstrate that this phenomenon extends to mesolimbic afferents, and confirm that the released neurotransmitter is GABA. However, the GABA synthetic enzymes GAD65 and GAD67 are not detected in midbrain dopamine neurons. Instead, these cells express the membrane GABA transporters mGAT1 (Slc6a1) and mGAT4 (Slc6a11) and inhibition of these transporters prevents GABA co-release. These findings therefore indicate that GABA co-release is a general feature of midbrain dopaminergic neurons that relies on GABA uptake from the extracellular milieu as opposed to de novo synthesis. This atypical mechanism may confer dopaminergic neurons the flexibility to differentially control GABAergic transmission in a target-dependent manner across their extensive axonal arbors. DOI: http://dx.doi.org/10.7554/eLife.01936.001 PMID:24843012

  15. GABA abnormalities in schizophrenia: A methodological review of in vivo studies.

    PubMed

    Taylor, Stephan F; Tso, Ivy F

    2014-10-25

    Abnormalities of GABAergic interneurons are some of the most consistent findings from post-mortem studies of schizophrenia. However, linking these molecular deficits with in vivo observations in patients - a critical goal in order to evaluate interventions that would target GABAergic deficits - presents a challenge. Explanatory models have been developed based on animal work and the emerging experimental literature in schizophrenia patients. This literature includes: neuroimaging ligands to GABA receptors, magnetic resonance spectroscopy (MRS) of GABA concentration, transcranial magnetic stimulation of cortical inhibitory circuits and pharmacologic probes of GABA receptors to dynamically challenge the GABA system, usually in combination with neuroimaging studies. Pharmacologic challenges have elicited behavioral changes, and preliminary studies of therapeutic GABAergic interventions have been conducted. This article critically reviews the evidence for GABAergic dysfunction from each of these areas. These methods remain indirect measures of GABAergic function, and a broad array of dysfunction is linked with the putative GABAergic measures, including positive symptoms, cognition, emotion, motor processing and sensory processing, covering diverse brain areas. Measures of receptor binding have not shown replicable group differences in binding, and MRS assays of GABA concentration have yielded equivocal evidence of large-scale alteration in GABA concentration. Overall, the experimental base remains sparse, and much remains to be learned about the role of GABAergic interneurons in healthy brains. Challenges with pharmacologic and functional probes show promise, and may yet enable a better characterization of GABAergic deficits in schizophrenia. PMID:25458856

  16. A hydrophobic area of the GABA ?? receptor containing phenylalanine 124 influences both receptor activation and deactivation.

    PubMed

    Carland, J E; Yamamoto, I; Hanrahan, J R; Abdel-Halim, H; Lewis, T M; Absalom, N; Chebib, M

    2015-02-01

    Experimental evidence suggests that GABA ?1 receptors are potential therapeutic targets for the treatment of a range of neurological conditions, including anxiety and sleep disorders. Homology modelling of the GABA ?1 extracellular N-terminal domain has revealed a novel hydrophobic area that extends beyond, but not including the GABA-binding site. Phenylalanine 124 (F124) is predicted to be involved in maintaining the structural integrity of the orthosteric-binding site. We have assessed the activity of a series of GABA ?1 receptors that incorporate a mutation at F124. Wild-type and mutant human GABA ?1 subunits were expressed in Xenopus laevis oocytes and AD293 cells, and the pharmacology and kinetic properties of the receptors were measured using electrophysiological analysis. Mutation of F124 had minimal effect on receptor pharmacology. However, the rate of deactivation was significantly increased compared to wild type. This study provides further information about the role of residues within a novel hydrophobic area of the GABA ?1 receptor. This knowledge can help future studies into the design of potent and subtype-selective ligands with therapeutic value. PMID:24816654

  17. Effects of [3H]-BIDN, a novel bicyclic dinitrile radioligand for GABA-gated chloride channels of insects and vertebrates

    PubMed Central

    Rauh, James J; Benner, Eric; Schnee, Michael E; Cordova, Daniel; Holyoke, Caleb W; Howard, Michael H; Bai, Donglin; Buckingham, Steven D; Hutton, Michael L; Hamon, Alain; Roush, Richard T; Sattelle, David B

    1997-01-01

    The radiolabelled bicyclic dinitrile, [3H]-3,3-bis-trifluoromethyl-bicyclo[2.2.1]heptane-2,2-dicarbonitrile ([3H]-BIDN), exhibited, specific binding of high affinity to membranes of the southern corn rootworm (Diabrotica undecimpunctata howardi) and other insects. A variety of ?-aminobutyric acid (GABA) receptor convulsants, including the insecticides heptachlor (IC50, 35±3?nM) and dieldrin (IC50, 93±7?nM), displaced [3H]-BIDN from rootworm membranes. When tested at 100??M, 1-(4-ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane(EBOB), 4-t-butyl-2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane-1-thione (TBPS), 1-phenyl-4-t-butyl-2,6,7-trioxabicyclo[2.2.2]octane (TBOB) and picrotoxin failed to displace 50% of [3H]-BIDN binding to rootworm membranes indicating that the bicyclic dinitrile radioligand probes a site distinct from those identified by other convulsant radioligands. Dissociation studies showed that dieldrin, ketoendrin, toxaphene, heptachlor epoxide and ? and ? endosulphan displace bound [3H]-BIDN from rootworm membranes by a competitive mechanism. Rat brain membranes were also shown to possess a population of saturable, specific [3H]-BIDN binding sites, though of lower affinity than in rootworm and with a different pharmacological profile. Of the insecticidal GABAergic convulsants that displaced [3H]-BIDN from rootworm, cockroach (Periplaneta americana) and rat brain membranes, many were more effective in rootworm. Functional GABA-gated chloride channels of rootworm nervous system and of cockroach nerve and muscle were blocked by BIDN, whereas cockroach neuronal GABAB receptors were unaffected. Expression in Xenopus oocytes of either rat brain mRNA, or cDNA-derived RNA encoding a GABA receptor subunit (Rdl) that is expressed widely in the nervous system of Drosophila melanogaster resulted in functional, homo-oligomeric GABA receptors that were blocked by BIDN. Thus, BIDN probes a novel site on GABA-gated Cl? channels to which a number of insecticidally-active molecules bind. PMID:9257933

  18. EFFECT OF TYPE 2 DIABETES MELLITUS ON BRAIN METABOLITES BY USING PROTON MAGNETIC RESONANCE SPECTROSCOPY-A SYSTEMATIC REVIEW

    PubMed Central

    Santhakumari, Rajani; Reddy, Indla Yogananda; Archana, R

    2014-01-01

    Cerebral metabolism will be affected in T2DM either by chronic hyperglycemia or by chronic hypoxia. Proton magnetic resonance spectroscopy (1H-MRS) of the brain provides detailed information about the structure, dynamics, reaction state and chemical environment of molecules. It also measures the levels of brain metabolites such as myo-inositol (mI), N acetyl aspartate (NAA), creatine (Cr), choline (Cho), glutamate (Glu), glutamine (Gln) and gamma amino butyric acid (GABA). Several studies suggest that people with type 2 diabetes mellitus (T2DM) are at an increased risk of cognitive impairment in comparison with the general population. The altered metabolites may cause cognitive dysfunction in T2DM. This review article concludes that in T2DM, metabolite levels were altered in different regions of brain. PMID:25568610

  19. Determining the relative efficacy of positive allosteric modulators of the GABAA receptor: design of a screening approach.

    PubMed

    Ghisdal, Philippe; Noel, Nadine; Pacico, Nathalie; Martini, Murielle; Foerch, Patrik; Hanon, Etienne; Wolff, Christian

    2014-03-01

    Gamma amino butyric acid receptors (GABA) are major therapeutic targets for the development of drugs in neurological and psychiatric disorders. The new generation of GABAA modulators is targeting subtype selectivity and low/partial efficacy on the receptor to potentially overcome the adverse effects described for drugs with full agonist profile. We evaluated a screening approach to measure the relative efficacy of GABAA positive allosteric modulators (PAM) using automated patch clamp and fluorescence membrane potential assays. We determined that the use of an internal comparator (zolpidem), tested on each cell in parallel to the test compound, provides a reliable approach to measure and compare the relative efficacy of PAM ligands. Patch clamp recordings on recombinant GABAA receptors, using a multiple drug addition protocol, allows us to rank PAM ligands with different levels of efficacies. We observed that fluorescence membrane potential assays are not predictive of the relative efficacies of GABAA PAM ligands. PMID:23989455

  20. Inhibition of radical reactions for an improved potassium tert-butoxide-promoted (11) C-methylation strategy for the synthesis of ?-(11) C-methyl amino acids.

    PubMed

    Suzuki, Chie; Kato, Koichi; Tsuji, Atsushi B; Zhang, Ming-Rong; Arano, Yasushi; Saga, Tsuneo

    2015-03-01

    ?-(11) C-Methyl amino acids are useful tools for biological imaging studies. However, a robust procedure for the labeling of amino acids has not yet been established. In this study, the (11) C-methylation of Schiff-base-activated ?-amino acid derivatives has been optimized for the radiosynthesis of various ?-(11) C-methyl amino acids. The benzophenone imine analog of methyl 2-amino butyrate was (11) C-methylated with [(11) C]methyl iodide following its initial deprotonation with potassium tert-butoxide (KOtBu). The use of an alternative base such as tetrabutylammonium fluoride, triethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene did not result in the (11) C-methylated product. Furthermore, the KOtBu-promoted (11) C-methylation of the Schiff-base-activated amino acid analog was enhanced by the addition of 1,2,4,5-tetramethoxybenzene or 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and inhibited by the addition of 1,10-phenanthroline. These results suggest that inhibition of radical generation induced by KOtBu improves the ?-(11) C-methylation of the Schiff-base-activated amino acids. The addition of a mixture of KOtBu and TEMPO to a solution of Schiff-base-activated amino acid ester and [(11) C]methyl iodide provided optimal results, and the tert-butyl ester and benzophenone imine groups could be readily hydrolyzed to give the desired ?-(11) C-methyl amino acids with a high radiochemical conversion. This strategy could be readily applied to the synthesis of other ?-(11) C-methyl amino acids. PMID:25690316

  1. Relation of exocytotic release of ? -aminobutyric acid to Ca 2+ entry through Ca 2+ channels or by reversal of the Na + \\/Ca 2+ exchanger in synaptosomes

    Microsoft Academic Search

    Carlos B. Duarte; Ildete L. Ferreira; Arsélio P. Carvalho; Caetana M. Carvalho

    1993-01-01

    The specific inhibitor of the ?-aminobutyric acid (GABA) carrier, NNC-711, {1-[(2-diphenylmethylene) amino]oxyethyl}-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride, blocks the Ca2+-independent release of [3H]GABA from rat brain synaptosomes induced by 50 mM K+ depolarization. Thus, in the presence of this inhibitor, it was possible to study the Ca2+-dependent release of [3H]GABA in the total absence of carrier-mediated release. Reversal of the Na+\\/Ca2+ exchanger was

  2. Comparison of gamma-aminobutyric acid production in Thai rice grains

    Microsoft Academic Search

    Panatda Jannoey; Hataichanoke Niamsup; Saisamorn Lumyong; Toshisada Suzuki; Takeshi Katayama; Griangsak Chairote

    2010-01-01

    Gamma-aminobutyric acid (GABA) has many pharmacological functions including being a major inhibitory neurotransmitter. Two\\u000a comparative methods for GABA production in rice grains as main food source in Thailand were investigated in this study. Fermentation\\u000a and germination method were separately carried out using seven selected local grain cultivars in northern Thailand. Red yeast\\u000a rice, obtained from the fermentation method, gave the

  3. Enhanced ?-aminobutyric acid-forming activity of recombinant glutamate decarboxylase (gadA) from Escherichia coli

    Microsoft Academic Search

    Qi WangYinqiang; Yinqiang Xin; Feng Zhang; Zhiyong Feng; Jin Fu; Lan Luo; Zhimin Yin

    2011-01-01

    ?-aminobutyric acid (GABA) is an important bioactive regulator, and its biosynthesis is primarily through the ?-decarboxylation of glutamate by glutamate decarboxylase (GAD). The procedures to obtain GABA by bioconvertion with high activity\\u000a recombinant Escherichia coli GAD have been seldom understood. In this study, Escherichia coli GAD (gadA) was highly expressed (about 70–75% of total protein) as soluble protein in Escherichia

  4. Rat gastroduodenal motility in vivo: interaction of GABA and VIP in control of spontaneous relaxations.

    PubMed

    Krantis, A; Mattar, K; Glasgow, I

    1998-11-01

    Spontaneous relaxations occurring within motor activity in the rat gastroduodenum in vivo can be distinguished by their dependence on either nitric oxide (NO) or ATP. We examined the interaction of gamma-aminobutyric acid (GABA) and vasoactive intestinal peptide (VIP) within pathways controlling this activity in the antrum (S) and duodenum (D) of anesthetized Sprague-Dawley rats, using miniaturized extraluminal foil strain gauges oriented perpendicular to (S1, D1) or in the axis of (S2) the circular smooth muscle. The NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg iv) attenuated (P < 0.05) antral relaxations and, in the duodenum, nonpropagating "intergroup" relaxations. The GABAA receptor antagonist bicuculline (350 micrograms/kg sc) had similar effects. The GABAA agonist 3-amino-1-propanesulfonic acid stimulated L-NAME-sensitive relaxations at S1 and D1. Propagating "grouped" responses were unchanged. VIP (6 micrograms/kg iv) always induced a relaxation of the duodenum, which was attenuated by bicuculline and L-NAME. VIP caused simultaneous responses at S1 and S2; however, the antrum displayed either contraction or relaxation in response to VIP. All antral relaxations in response to VIP were attenuated (P < 0. 05) by L-NAME; however, only VIP-induced relaxations at S1 were sensitive to bicuculline. VIP-induced contractions were also unaffected. GABAA receptors mediate the pathway(s) controlling NO-related spontaneous relaxations of the antrum and duodenal circular muscle. All VIP-induced relaxations are mediated by NO. Spontaneous relaxations of the rat gastroduodenum include responses that involve a GABAAergic NO-related pathway, which is targeted by VIP. In addition, VIP can target NO relaxations of the antrum via other pathways. PMID:9815017

  5. Tonic Control of Kisspeptin Release in Prepubertal Monkeys: Implications to the Mechanism of Puberty Onset

    PubMed Central

    Kurian, Joseph R.; Keen, Kim L.; Guerriero, Kathryn A.

    2012-01-01

    Previously we have shown that a reduction in ?-amino butyric acid (GABA) inhibition is critical for the mechanism initiating puberty onset because chronic infusion of the GABAA receptor antagonist, bicuculline, significantly increased GnRH release and accelerated the timing of menarche and first ovulation in female rhesus monkeys. Because previous studies in our laboratory indicate that in prepubertal female monkeys, kisspeptin release in the medial basal hypothalamus is low, whereas kisspeptin-10 can stimulate GnRH release, we hypothesized that a low level of kisspeptin release prior to puberty onset is due to tonic GABA inhibition. To test this hypothesis we examined the effects of bicuculline infusion on kisspeptin release using a microdialysis method. We found that bicuculline at 1 ?m dramatically stimulates kisspeptin release in the medial basal hypothalamus of prepubertal monkeys but had little effect on kisspeptin release in midpubertal monkeys. We further examined whether bicuculline-induced GnRH release is blocked by the presence of the kisspeptin antagonist, peptide 234. We found that inhibition of kisspeptin signaling blocked the bicuculline-induced stimulation of GnRH release, suggesting that kisspeptin neurons may relay inhibitory GABA signals to GnRH neurons. This implies that a reduction in tonic GABA inhibition of GnRH release is, at least in part, mediated through kisspeptin neurons. PMID:22585828

  6. GAT1, a High-Affinity GABA Plasma Membrane Transporter, Localized to Neurons and Astroglia in the Cerebral Cortex

    Microsoft Academic Search

    Andrea Minelli; Nicholas C. Brecha; Christine Karschiq; Silvia DeBiasi; Fiorenzo Conti

    1995-01-01

    High affinity, GABA plasma membrane transporters influ- ence the action of GABA, the main inhibitory neurotrans- mitter. The cellular expression of GAT-1, a prominent GABA transporter, has been investigated in the cerebral cortex of adult rats using in situ hybridizaton with %-la- beled RNA probes and immunocytochemistry with affinity purified polyclonal antibodies directed to the C-terminus of rat GAT-1. GAT-1

  7. In vivo modulation of extracellular hippocampal glutamate and GABA levels and limbic seizures by group I and II metabotropic glutamate receptor ligands.

    PubMed

    Smolders, Ilse; Lindekens, Hilde; Clinckers, Ralph; Meurs, Alfred; O'Neill, Michael J; Lodge, David; Ebinger, Guy; Michotte, Yvette

    2004-03-01

    The effects of several metabotropic receptor (mGluR) ligands on baseline hippocampal glutamate and GABA overflow in conscious rats and the modulation of limbic seizure activity by these ligands were investigated. Intrahippocampal mGluR group I agonist perfusion via a microdialysis probe [1 mm (R,S)-3,5-dihydroxyphenylglycine] induced seizures and concomitant augmentations in amino acid dialysate levels. The mGlu1a receptor antagonist LY367385 (1 mm) decreased baseline glutamate but not GABA concentrations, suggesting that mGlu1a receptors, which regulate hippocampal glutamate levels, are tonically activated by endogenous glutamate. This decrease in glutamate may contribute to the reported LY367385-mediated anticonvulsant effect. The mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (50 mg/kg) also clearly abolished pilocarpine-induced seizures. Agonist-mediated actions at mGlu2/3 receptors by LY379268 (100 microm, 10 mg/kg intraperitoneally) decreased basal hippocampal GABA but not glutamate levels. This may partly explain the increased excitation following systemic LY379268 administration and the lack of complete anticonvulsant protection within our epilepsy model with the mGlu2/3 receptor agonist. Group II selective mGluR receptor blockade with LY341495 (1-10 microm) did not alter the rats' behaviour or hippocampal amino acid levels. These data provide a neurochemical basis for the full anticonvulsant effects of mGlu1a and mGlu5 antagonists and the partial effects observed with mGlu2/3 agonists in vivo. PMID:15009663

  8. The GABA excitatory/inhibitory developmental sequence: a personal journey.

    PubMed

    Ben-Ari, Y

    2014-10-24

    The developing brain is talkative but its language is not that of the adult. Most if not all voltage and transmitter-gated ionic currents follow a developmental sequence and network-driven patterns differ in immature and adult brains. This is best illustrated in studies engaged almost three decades ago in which we observed elevated intracellular chloride (Cl(-))i levels and excitatory GABA early during development and a perinatal excitatory/inhibitory shift. This sequence is observed in a wide range of brain structures and animal species suggesting that it has been conserved throughout evolution. It is mediated primarily by a developmentally regulated expression of the NKCC1 and KCC2 chloride importer and exporter respectively. The GABAergic depolarization acts in synergy with N-methyl-d-aspartate (NMDA) receptor-mediated and voltage-gated calcium currents to enhance intracellular calcium exerting trophic effects on neuritic growth, migration and synapse formation. These sequences can be deviated in utero by genetic or environmental insults leading to a persistence of immature features in the adult brain. This "neuroarcheology" concept paves the way to novel therapeutic perspectives based on the use of drugs that block immature but not adult currents. This is illustrated notably with the return to immature high levels of chloride and excitatory actions of GABA observed in many pathological conditions. This is due to the fact that in the immature brain a down regulation of KCC2 and an up regulation of NKCC1 are seen. Here, I present a personal history of how an unexpected observation led to novel concepts in developmental neurobiology and putative treatments of autism and other developmental disorders. Being a personal account, this review is neither exhaustive nor provides an update of this topic with all the studies that have contributed to this evolution. We all rely on previous inventors to allow science to advance. Here, I present a personal summary of this topic primarily to illustrate why we often fail to comprehend the implications of our own observations. They remind us - and policy deciders - why Science cannot be programed, requiring time, and risky investigations that raise interesting questions before being translated from bench to bed. Discoveries are always on sideways, never on highways. PMID:25168736

  9. From the street to the brain: neurobiology of the recreational drug ?-hydroxybutyric acid

    Microsoft Academic Search

    C. Guin Ting Wong; K. Michael Gibson; O. Carter Snead

    2004-01-01

    ?-Hydroxybutyric acid (GHB) is a short-chain fatty acid that occurs naturally in the mammalian brain and is formed primarily from the precursor ?-aminobutyric acid (GABA). The properties of GHB suggest that it has a neuromodulatory role in the brain and has the ability to induce several pharmacological and behavioral effects. GHB has been used clinically as an anesthetic and to

  10. Structural insights into Cys-loop receptor function and ligand recognition.

    PubMed

    Nys, Mieke; Kesters, Divya; Ulens, Chris

    2013-10-15

    This review outlines recent insights into ligand recognition, channel gating and ion permeation for the family of pentameric ligand-gated ion channels (pLGICs). These receptors are involved in the fast inhibitory and excitatory neurotransmission. Prototypical anion-selective members are the ?-amino butyric acid type A (GABA(A)), ?-amino butyric acid type C (GABA(C)) and glycine receptor. The cation-selective members are the 5-HT3 serotonin and nicotinic acetylcholine (nACh) receptors. They are the target for a wide variety of drugs and dysfunction in these receptors is associated with several diseases. We summarize recent structural knowledge in combination with electrophysiological data and molecular dynamic simulations, thereby describing key features of ligand binding, channel gating and ion permeation. A conserved cation-? interaction between ligand and aromatic residues of the ligand binding site critically contributes to ligand recognition, as revealed by X-ray crystal structures of acetylcholine binding proteins, as well as the integral pLGICs, ELIC and GluCl. In addition, we summarize the possible downstream effects on gating of structural rearrangements in the extracellular ligand-binding domain, which mainly occur in loop C and loop F. These data are discussed in the context of different conformational states of the pore-forming domain observed in crystal structures of GLIC and GluCl, which likely represent the open pore conformation, and ELIC, which likely corresponds to a closed pore conformation. We conclude with a current structural view on the determinants of ion selection and permeation. PMID:23850718

  11. Glutamic acid decarboxylase 67 expression by a distinct population of mouse vestibular supporting cells

    PubMed Central

    Tavazzani, Elisa; Tritto, Simona; Spaiardi, Paolo; Botta, Laura; Manca, Marco; Prigioni, Ivo; Masetto, Sergio; Russo, Giancarlo

    2014-01-01

    The function of the enzyme glutamate decarboxylase (GAD) is to convert glutamate in ?-aminobutyric acid (GABA). Glutamate decarboxylase exists as two major isoforms, termed GAD65 and GAD67, that are usually expressed in GABA-containing neurons in the central nervous system. GAD65 has been proposed to be associated with GABA exocytosis whereas GAD67 with GABA metabolism. In the present immunofluorescence study, we have investigated the presence of the two GAD isoforms in the semicircular canal cristae of wild type and GAD67-GFP knock-in mice. While no evidence for GAD65 expression was found, GAD67 was detected in a distinct population of peripherally-located supporting cells, but not in hair cells or in centrally-located supporting cells. GABA, on the other hand, was found in all supporting cells. The present result indicate that only a discrete population of supporting cells use GAD67 to synthesize GABA. This is the first report of a marker that allows to distinguish two populations of supporting cells in the vestibular epithelium. On the other hand, the lack of GABA and GAD enzymes in hair cells excludes its involvement in afferent transmission. PMID:25565962

  12. Differences in GABA-induced chloride ion influx in brain of inbred mouse strains

    SciTech Connect

    Yu, O.; Chiu, T.H.; Rosenberg, H.C.

    1986-03-01

    Audiogenic seizure-susceptible (AS) mice (DBA2J) are a widely used model of epilepsy. The precise pathophysiology of this mouse strain is not fully understood. One of the proposed mechanisms was a difference in GABA/BZ receptor affinity and population from that of audiogenic seizure resistant (ASR) mice. This study attempted to determine the difference in function of GABA/BZ receptor between DBA2J (AS) and C57BL6J (ASR) mice by directly measuring the GABA-induced chloride ion (/sup 36/Cl/sup -/) influx in twice washed crude brain homogenates. /sup 36/Cl/sup -/ influx was terminated by ice-cold buffer and collected by filtration. A concentration range of 2-1000 ..mu..M GABA and two age-matched groups (20-22 days and 40-42 days) were used. GABA-induced /sup 36/Cl/sup -/ influx was dose-dependent, and brain homogenates from DBA2J mice (20-22 days) were less sensitive to GABA-induced Cl/sup -/ ion influx than C57BL6J mice at both age groups. However, in older DBA2J mice (40-42 days), the sensitivity to GABA was intermediate between that of the younger AS mice and the control ASR mice. No significant difference in basal influx of Cl/sup -/ was observed between age groups and mouse strains, nor was there any significant difference between 20-22 days old and 40-42 days old C57BL6J mice. In conclusion, this study had demonstrated a malfunction may recover with age.

  13. A common variant in ERBB4 regulates GABA concentrations in human cerebrospinal fluid.

    PubMed

    Luykx, Jurjen J; Vinkers, Christiaan H; Bakker, Steven C; Visser, Wouter F; van Boxmeer, Loes; Strengman, Eric; van Eijk, Kristel R; Lens, Judith A; Borgdorff, Paul; Keijzers, Peter; Kappen, Teus H; van Dongen, Eric P A; Bruins, Peter; Verhoeven, Nanda M; de Koning, Tom J; Kahn, René S; Ophoff, Roel A

    2012-08-01

    The neuregulin 1 (NRG1) receptor ErbB4 is involved in the development of cortical inhibitory GABAergic circuits and NRG1-ErbB4 signaling has been implicated in schizophrenia (SCZ). A magnetic resonance spectroscopy ((1)H-MRS) study has demonstrated that a single-nucleotide polymorphism in ERBB4, rs7598440, influences human cortical GABA concentrations. Other work has highlighted the significant impact of this genetic variant on expression of ERBB4 in the hippocampus and dorsolateral prefrontal cortex in human post mortem tissue. Our aim was to examine the association of rs7598440 with cerebrospinal fluid (CSF) GABA levels in healthy volunteers (n=155). We detected a significant dose-dependent association of the rs7598440 genotype with CSF GABA levels (G-allele standardized ?=-0.23; 95% CIs: -0.39 to -0.07; P=0.0066). GABA concentrations were highest in A homozygous, intermediate in heterozygous, and lowest in G homozygous subjects. When excluding subjects on psychotropic medication (three subjects using antidepressants), the results did not change (G-allele standardized ?=-0.23; 95% CIs: -0.40 to -0.07; P=0.0051). The explained variance in CSF GABA by rs7598440 in our model is 5.2% (P=0.004). The directionality of our findings agrees with the aforementioned (1)H-MRS and gene expression studies. Our observation therefore strengthens the evidence that the A-allele of rs7598440 in ERBB4 is associated with increased GABA concentrations in the human central nervous system (CNS). To our knowledge, our finding constitutes the first confirmation that CSF can be used to study genotype-phenotype correlations of GABA levels in the CNS. Such quantitative genetic analyses may be extrapolated to other CSF constituents relevant to SCZ in future studies. PMID:22549119

  14. A Common Variant in ERBB4 Regulates GABA Concentrations in Human Cerebrospinal Fluid

    PubMed Central

    Luykx, Jurjen J; Vinkers, Christiaan H; Bakker, Steven C; Visser, Wouter F; van Boxmeer, Loes; Strengman, Eric; van Eijk, Kristel R; Lens, Judith A; Borgdorff, Paul; Keijzers, Peter; Kappen, Teus H; van Dongen, Eric P A; Bruins, Peter; Verhoeven, Nanda M; de Koning, Tom J; Kahn, René S; Ophoff, Roel A

    2012-01-01

    The neuregulin 1 (NRG1) receptor ErbB4 is involved in the development of cortical inhibitory GABAergic circuits and NRG1-ErbB4 signaling has been implicated in schizophrenia (SCZ). A magnetic resonance spectroscopy (1H-MRS) study has demonstrated that a single-nucleotide polymorphism in ERBB4, rs7598440, influences human cortical GABA concentrations. Other work has highlighted the significant impact of this genetic variant on expression of ERBB4 in the hippocampus and dorsolateral prefrontal cortex in human post mortem tissue. Our aim was to examine the association of rs7598440 with cerebrospinal fluid (CSF) GABA levels in healthy volunteers (n=155). We detected a significant dose-dependent association of the rs7598440 genotype with CSF GABA levels (G-allele standardized ?=?0.23; 95% CIs: ?0.39 to ?0.07; P=0.0066). GABA concentrations were highest in A homozygous, intermediate in heterozygous, and lowest in G homozygous subjects. When excluding subjects on psychotropic medication (three subjects using antidepressants), the results did not change (G-allele standardized ?=?0.23; 95% CIs: ?0.40 to ?0.07; P=0.0051). The explained variance in CSF GABA by rs7598440 in our model is 5.2% (P=0.004). The directionality of our findings agrees with the aforementioned 1H-MRS and gene expression studies. Our observation therefore strengthens the evidence that the A-allele of rs7598440 in ERBB4 is associated with increased GABA concentrations in the human central nervous system (CNS). To our knowledge, our finding constitutes the first confirmation that CSF can be used to study genotype–phenotype correlations of GABA levels in the CNS. Such quantitative genetic analyses may be extrapolated to other CSF constituents relevant to SCZ in future studies. PMID:22549119

  15. Effects of ethanol on GABA(A) receptors in GABAergic and glutamatergic presynaptic nerve terminals.

    PubMed

    Wakita, Masahito; Shin, Min-Chul; Iwata, Satomi; Nonaka, Kiku; Akaike, Norio

    2012-06-01

    Ethanol (EtOH) has a number of behavioral effects, including intoxication, amnesia, and/or sedation, that are thought to relate to the activation of GABA(A) receptors. However, GABA(A) receptors at different cellular locations have different sensitivities to EtOH. The present study used the "synaptic bouton" preparation where we could stimulate nerve endings on mechanically dissociated single rat hippocampal CA1 and CA3 pyramidal neurons and investigate the effects of EtOH on presynaptic and postsynaptic GABA(A) receptors. Low concentrations of EtOH (10 mM) had no effect on postsynaptic GABA(A) and glutamate receptors or voltage-dependent Na(+) and Ca(2+) channels. Higher concentrations (?100 mM) could significantly inhibit these current responses. EtOH at 10 mM had no direct effect on inhibitory postsynaptic currents (IPSCs) and excitatory postsynaptic currents (EPSCs) evoked by focal stimulation of single boutons [evoked IPSCs (eIPSCs) and evoked EPSCs (eEPSCs)]. However, coapplication of 10 mM EtOH with muscimol decreased the amplitude of eIPSCs and eEPSCs and increased their paired-pulse ratio. The effects on eEPSCs were reversed by bicuculline. Coapplication of muscimol and EtOH significantly increased the frequency of spontaneous IPSCs and EPSCs. The EtOH effects on the postsynaptic responses and eEPSCs were similar in neurons from neonatal and mature rats. These results revealed that low concentrations of EtOH can potentiate the activation of presynaptic GABA(A) receptors to inhibit evoked GABA and glutamate release. These results indicate a high sensitivity of presynaptic GABA(A) receptor to EtOH, which needs to be accounted for when considering the cellular mechanisms of EtOH's physiological responses. PMID:22434676

  16. Rapid adaptation of rat brain and liver metabolism to a ketogenic diet: an integrated study using (1)H- and (13)C-NMR spectroscopy.

    PubMed

    Roy, Maggie; Beauvieux, Marie-Christine; Naulin, Jérôme; El Hamrani, Dounia; Gallis, Jean-Louis; Cunnane, Stephen C; Bouzier-Sore, Anne-Karine

    2015-07-01

    The ketogenic diet (KD) is an effective alternative treatment for refractory epilepsy in children, but the mechanisms by which it reduces seizures are poorly understood. To investigate how the KD modifies brain metabolism, we infused control (CT) and 7-day KD rats with either [1-(13)C]glucose (Glc) or [2,4-(13)C2]?-hydroxybutyrate (?-HB). Specific enrichments of amino acids (AAs) measured by (1)H- and (13)C-NMR in total brain perchloric acid extracts were similar between CT and KD rats after [1-(13)C]Glc infusion whereas they were higher in KD rats after [2,4-(13)C2]?-HB infusion. This suggests better metabolic efficiency of ketone body utilization on the KD. The relative rapid metabolic adaptation to the KD included (1) 11%-higher brain ?-amino butyric acid (GABA)/glutamate (Glu) ratio versus CT, (2) liver accumulation of the ketogenic branched-chain AAs (BCAAs) leucine (Leu) and isoleucine (ILeu), which were never detected in CT, and (3) higher brain Leu and ILeu contents. Since Glu and GABA are excitatory and inhibitory neurotransmitters, respectively, higher brain GABA/Glu ratio could contribute to the mechanism by which the KD reduces seizures in epilepsy. Increased BCAA on the KD may also contribute to better seizure control. PMID:25785828

  17. Plasticity-related binding of GABA and muscarinic receptor sites in piriform cortex of rat: An autoradiographic study

    SciTech Connect

    Thomas, A.P.; Westrum, L.E. (Univ. of Washington, Seattle (USA))

    1989-09-01

    This study has used the recently developed in vitro quantitative autoradiographic technique to examine the effects of olfactory bulb (OB) removal on receptor-binding sites in the deafferented piriform cortex (PC) of the rat. The gamma-aminobutyric acid-benzodiazepine receptor (GABA-BZR)- and muscarinic cholinergic receptor (MChR)-binding sites in layer I of PC were localized using (3H)flunitrazepam and (3H)quinuclidinyl benzilate as ligands, respectively. From the resultant autoradiograms the optical densities were measured using a Drexel-DUMAS image analysis system. The densities of BZR and MChR-binding sites were markedly increased in the PC ipsilateral to the lesion as compared to the contralateral side in those subjects that were operated in adulthood (Postnatal Day 100, PN 100). Comparisons between the unoperated and PN 100 operated animals also showed significant increases in the deafferented PC. In the animals operated on the day of birth (PN 0) no significant differences were seen between the operated and the contralateral PC. The difference between the PN 0 deafferented PC and the unoperated controls shows a slight decrease in BZR density in the former group; however, in case of the MChR there is a slight increase on the side of the lesion. These results demonstrate that deafferentation of PC by OB removal appears to modulate both the BZR-binding sites that are coupled with the GABA-A receptor complex and the MChR-binding sites. The results also suggest that possibility of a role for these neurotransmitter receptor-binding sites in plasticity following deafferentation.

  18. Rapid, activity-independent turnover of vesicular transmitter content at a mixed glycine/GABA synapse

    PubMed Central

    Apostolides, Pierre F.; Trussell, Laurence O.

    2013-01-01

    The release of neurotransmitter via the fusion of transmitter-filled, presynaptic vesicles is the primary means by which neurons relay information. However, little is known regarding the molecular mechanisms that supply neurotransmitter destined for vesicle filling, the endogenous transmitter concentrations inside presynaptic nerve terminals or the dynamics of vesicle refilling after exocytosis. We addressed these issues by recording from synaptically-coupled pairs of glycine/GABA co-releasing interneurons (cartwheel cells) of the mouse dorsal cochlear nucleus. We find that the plasma membrane transporter GlyT2 and the intracellular enzyme glutamate decarboxylase supply the majority of glycine and GABA, respectively. Pharmacological block of GlyT2 or glutamate decarboxylase led to rapid and complete rundown of transmission, whereas increasing GABA synthesis via intracellular glutamate uncaging dramatically potentiated GABA release within one minute. These effects were surprisingly independent of exocytosis, indicating that pre-filled vesicles re-equilibrated upon acute changes in cytosolic transmitter. Titration of cytosolic transmitter with postsynaptic responses indicated that endogenous, non-vesicular glycine/GABA levels in nerve terminals are 5 to 7 mM, and that vesicular transport mechanisms are not saturated under basal conditions. Thus, cytosolic transmitter levels dynamically set the strength of inhibitory synapses in a release-independent manner. PMID:23486948

  19. Effect of GABA(B) receptor agonist SKF97541 on cortical and hippocampal epileptic afterdischarges.

    PubMed

    Fábera, P; Mareš, P

    2014-09-01

    Activation of GABA(B) receptors leads to longer inhibitory postsynaptic potentials than activation of GABA(A) receptors. Therefore GABA(B) receptors may be a target for anticonvulsant therapy. The present study examined possible effects of GABA(B) receptor agonist SKF97541 on cortical and hippocampal epileptic afterdischarges (ADs). Epileptic ADs elicited by electrical stimulation of sensorimotor cortex or dorsal hippocampus were studied in adult male Wistar rats. Stimulation series were applied 6 times with 10- or 20-min interval. Either interval was efficient for reliable elicitation of cortical ADs but stimulation at 10-min intervals did not reliably elicit hippocampal ADs, many stimulations were without effect. SKF97541 in dose 1 mg/kg significantly prolonged cortical ADs. Duration of hippocampal ADs was not significantly changed by either dose of SKF97541 in spite of a marked myorelaxant effect of the higher dose. Our present data demonstrated that neither cortical nor hippocampal ADs in adult rats were suppressed by GABA(B) receptor agonist SKF97541. Proconvulsant effect on cortical ADs indicates a different role in these two brain structures. In addition, duration of refractory period for electrically-induced ADs in these two structures in adult rats is different. PMID:24702499

  20. Individual differences in subconscious motor control predicted by GABA concentration in SMA.

    PubMed

    Boy, Frederic; Evans, C John; Edden, Richard A E; Singh, Krish D; Husain, Masud; Sumner, Petroc

    2010-10-12

    Subliminal visual stimuli affect motor planning, but the size of such effects differs greatly between individuals. Here, we investigated whether such variation may be related to neurochemical differences between people. Cortical responsiveness is expected to be lower under the influence of more of the main inhibitory neurotransmitter, GABA. Thus, we hypothesized that, if an individual has more GABA in the supplementary motor area (SMA)--a region previously associated with automatic motor control--this would result in smaller subliminal effects. We measured the reversed masked prime--or negative compatibility--effect, and found that it correlated strongly with GABA concentration, measured with magnetic resonance spectroscopy. This occurred specifically in the SMA region, and not in other regions from which spectroscopy measurements were taken. We replicated these results in an independent cohort: more GABA in the SMA region is reliably associated with smaller effect size. These findings suggest that, across individuals, the responsiveness of subconscious motor mechanisms is related to GABA concentration in the SMA. PMID:20888227

  1. Simultaneous Spectral Editing for ?-Aminobutyric Acid and Taurine Using Double Quantum Coherence Transfer

    NASA Astrophysics Data System (ADS)

    Lei, Hao; Peeling, James

    2000-03-01

    Conventional double quantum (DQ) editing techniques recover resonances of one metabolite at a time and are thus inefficient for monitoring metabolic changes involving several metabolites. A DQ coherence transfer double editing sequence using a dual-band DQ coherence read pulse is described here. The sequence permits simultaneous spectral editing for two metabolites with similar J coupling constants in a single scan. Simultaneous editing for taurine and ?-aminobutyric acid (GABA) is demonstrated using solution phantoms and rat brain tissue. Selectivity of the double editing sequence for the target metabolites is as good as that achieved using conventional DQ editing which selects each metabolite individually. With experimental parameters of the double editing sequence chosen to optimize GABA editing, the sensitivity for GABA detection is the same as that with GABA editing only, while the sensitivity for taurine detection is decreased slightly compared to that with taurine editing only.

  2. [The participation of the GABA-A and GABA-B receptors in the mechanism of the inhibition of the contractile activity in the rabbit myometrium under the influence of GABA, AOAA and fenibut].

    PubMed

    Sizov, P I; Iasnetsov, V S

    1990-11-01

    Experiments on isolated strips of the rabbit uterus showed the stimulating effects of small doses of GABA, AOAA and phenibut on uterine contractility, while large doses exerted the reverse (suppressing) effects. Administration of bicuculline and picrotoxin before or after the above-mentioned drugs reduced their suppressing effects on uterine muscle contractility. The data postulate the involvement of GABAA and GABAB receptors in the drugs action on the rabbit uterus. PMID:1964606

  3. Blockade of GABA(B) Receptors Completely Reverses Age-related Learning Impairment

    PubMed Central

    LaSarge, Candi L.; Bañuelos, Cristina; Mayse, Jeffrey D.; Bizon, Jennifer L.

    2010-01-01

    Impaired cognitive functions are well-described in the aging process. GABA(B) antagonists can facilitate learning and memory in young subjects, but these agents have not been well-characterized in aging. Here we show a complete reversal of olfactory discrimination learning deficits in cognitively-impaired aged Fischer 344 rats using the GABA(B) antagonist CGP55845, such that drug treatment restored performance to that on par with young and cognitively-unimpaired aged subjects. There was no evidence that this improved learning was due to enhanced olfactory detection abilities produced by the drug. These results highlight the potential of targeting GABA(B) receptors to ameliorate age-related cognitive deficits and demonstrate the utility of olfactory discrimination learning as a preclinical model for testing novel therapies to improve cognitive functions in aging. PMID:19723562

  4. ( )A.A. Roberts, C.K. KelloggrDeelopmental Brain Research 119 2000 2132 GABA receptor subtypes that differ in subunit combina-A

    E-print Network

    Kellogg, Carol K.

    #12;( )A.A. Roberts, C.K. KelloggrDeelopmental Brain Research 119 2000 21­32 GABA receptor subtypes that differ in subunit combina-A tion and in sensitivity to GABA and non-competitive . modulatory ligands the GABA binding site and bindingsites for non-competitive modulatory ligands. For example,BZD augmentation

  5. Cl- uptake promoting depolarizing GABA actions in immature rat neocortical neurones is mediated by NKCC1.

    PubMed

    Yamada, Junko; Okabe, Akihito; Toyoda, Hiroki; Kilb, Werner; Luhmann, Heiko J; Fukuda, Atsuo

    2004-06-15

    GABA is the principal inhibitory neurotransmitter in the mature brain, but during early postnatal development the elevated [Cl(-)](i) in immature neocortical neurones causes GABA(A) receptor activation to be depolarizing. The molecular mechanisms underlying this intracellular Cl(-) accumulation remain controversial. Therefore, the GABA reversal potential (E(GABA)) or [Cl(-)](i) in early postnatal rat neocortical neurones was measured by the gramicidin-perforated patch-clamp method, and the relative expression levels of the cation-Cl(-) cotransporter mRNAs (in the same cells) were examined by semiquantitative single-cell multiplex RT-PCR to look for statistical correlations with [Cl(-)](i). The mRNA expression levels were positively (the Cl(-) accumulating Na(+),K(+)-2Cl(-) cotransporter NKCC1) or negatively (the Cl(-) extruding K(+)-Cl(-) cotransporter KCC2) correlated with [Cl(-)](i). NKCC1 mRNA expression was high in early postnatal days, but decreased during postnatal development, whereas KCC2 mRNA expression displayed the opposite pattern. [Cl(-)](i) and NKCC1 mRNA expression were each higher in cortical plate (CP) neurones than in the presumably older layer V/VI pyramidal neurones in a given slice. The pharmacological effects of bumetanide on E(GABA) were consistent with the different expression levels of NKCC1 mRNA. These data suggest that NKCC1 may play a pivotal role in the generation of GABA-mediated depolarization in immature CP cells, while KCC2 promotes the later maturation of GABAergic inhibition in the rat neocortex. PMID:15090604

  6. GABA and glutamate in schizophrenia: A 7 T 1H-MRS study

    PubMed Central

    Marsman, Anouk; Mandl, René C.W.; Klomp, Dennis W.J.; Bohlken, Marc M.; Boer, Vincent O.; Andreychenko, Anna; Cahn, Wiepke; Kahn, René S.; Luijten, Peter R.; Hulshoff Pol, Hilleke E.

    2014-01-01

    Schizophrenia is characterized by loss of brain volume, which may represent an ongoing pathophysiological process. This loss of brain volume may be explained by reduced neuropil rather than neuronal loss, suggesting abnormal synaptic plasticity and cortical microcircuitry. A possible mechanism is hypofunction of the NMDA-type of glutamate receptor, which reduces the excitation of inhibitory GABAergic interneurons, resulting in a disinhibition of glutamatergic pyramidal neurons. Disinhibition of pyramidal cells may result in excessive stimulation by glutamate, which in turn could cause neuronal damage or death through excitotoxicity. In this study, GABA/creatine ratios, and glutamate, NAA, creatine and choline concentrations in the prefrontal and parieto-occipital cortices were measured in 17 patients with schizophrenia and 23 healthy controls using proton magnetic resonance spectroscopy at an ultra-high magnetic field strength of 7 T. Significantly lower GABA/Cr ratios were found in patients with schizophrenia in the prefrontal cortex as compared to healthy controls, with GABA/Cr ratios inversely correlated with cognitive functioning in the patients. No significant change in the GABA/Cr ratio was found between patients and controls in the parieto-occipital cortex, nor were levels of glutamate, NAA, creatine, and choline differed in patients and controls in the prefrontal and parieto-occipital cortices. Our findings support a mechanism involving altered GABA levels distinguished from glutamate levels in the medial prefrontal cortex in schizophrenia, particularly in high functioning patients. A (compensatory) role for GABA through altered inhibitory neurotransmission in the prefrontal cortex may be ongoing in (higher functioning) patients with schizophrenia. PMID:25379453

  7. Streptozotocin-induced Diabetes Modulates GABA Receptor Activity in Rat Retinal Neurons

    PubMed Central

    Ramsey, David J.; Ripps, Harris; Qian, Haohua

    2007-01-01

    Neural deficits suggestive of involvement of the GABA signaling pathway can often be detected early in the course of diabetic retinopathy, a leading cause of blindness in the United States. To examine in greater detail the nature of the neuronal changes associated with hyperglycemia, we investigated GABA receptor activity on retinal bipolar cells in streptozotocin-induced diabetic rats; cells from age-matched normal rats served as controls. Patch-clamp recordings from isolated rod-bipolar cells revealed that diabetes enhanced the whole cell currents elicited by GABA. Responses of the GABAC receptor, the predominant GABA receptor on rat rod bipolar cells, exhibited a greater sensitivity to GABA, larger maximum current responses, slower response kinetics, and a smaller single channel conductance among diabetic cells relative to those recorded from normal controls. Compared with the properties of homomeric ?1 and heteromeric ?1?2 receptors formed in a heterologous expression system, these results suggested that there was a greater contribution from the ?1 subunit in the GABAC receptor-mediated response of diabetic cells. The levels of mRNA, measured with real-time RT-PCR, were consistent with this finding. There was a significant enhancement in the ratio of ?1/?2 subunit expression in the retina of diabetic animals, although the levels of GABA ?1 subunit expression were comparable in diabetic and normal retinas. Taken together, the results suggest that diabetes modifies the subunit composition of the GABAC receptor on retinal neurons, most likely through its effect on the efficacy of gene transcription. PMID:17662714

  8. 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. PMID:25437375

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

    SciTech Connect

    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 hr 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.

  10. Use of 3h-. gamma. -aminobutyric acid for transport studies with isolated nerve-terminals from rat brain

    SciTech Connect

    Halvarsson, G.B.; Karlsson, I.; Sellstroem, A.

    1985-07-22

    Isolated synaptosomes were used to study the problem of net accumulation of neurotransmitters. The time-course and the kinetics of exogenous and endogenous GABA transport were studied by liquid-scintillation counting and HPLC-amino acid analysis respectively. Different pools of GABA were suggested by a 6-fold difference in tissue-to-medium-ratio of endogenous vs. exogenous GABA. Net accumulation, exchange and net efflux of GABA was found to be a function of the GABA concentration in the incubation medium. The K/sub m/s for net accumulation and for /sup 3/H-GABA accumulation were 2.68 +/- 1.16 and 6.19 +/- 1.26 ..mu..M respectively, whereas the V/sub max/s were 5.9 +/- 4.9 and 134 +/- 13 pmol/mg w.w min respectively. This means that the transport studies which use exogenous substances (e.g. /sup 3/H-GABA) considerably overestimate the transport by overlooking the magnitude of the counter transport. 22 references, 5 figures, 2 tables.

  11. BIDN, a bicyclic dinitrile convulsant, selectively blocks GABA-gated Cl ? channels

    Microsoft Academic Search

    Alain Hamon; Hervé Le Corronc; Bernard Hue; James J Rauh; David B Sattelle

    1998-01-01

    BIDN (3,3-bis(trifluoromethyl)bicyclo[2,2,1]heptane-2,2-dicarbonitrile) at 10?5 M blocked GABA-induced inhibitory postsynaptic potentials (IPSPs) recorded from an identified, giant interneurone (G12) of the cockroach (Periplaneta americana). The same concentration of this bicyclic dinitrile also blocked Cl?-mediated responses of G12 to GABA applied by pressure microinjection into the terminal abdominal ganglion neuropile containing dendrites of G12. BIDN (10?5 M) was without effect on a

  12. Reversed synaptic effects of hypocretin and NPY mediated by excitatory GABA-dependent synaptic activity in developing MCH neurons

    PubMed Central

    Li, Ying; Xu, Youfen

    2013-01-01

    In mature neurons, GABA is the primary inhibitory neurotransmitter. In contrast, in developing neurons, GABA exerts excitatory actions, and in some neurons GABA-mediated excitatory synaptic activity is more prevalent than glutamate-mediated excitation. Hypothalamic neuropeptides that modulate cognitive arousal and energy homeostasis, hypocretin/orexin and neuropeptide Y (NPY), evoked reversed effects on synaptic actions that were dependent on presynaptic GABA release onto melanin-concentrating hormone (MCH) neurons. MCH neurons were identified by selective green fluorescent protein (GFP) expression in transgenic mice. In adults, hypocretin increased GABA release leading to reduced excitation. In contrast, in the developing brain as studied here with analysis of miniature excitatory postsynaptic currents, paired-pulse ratios, and evoked potentials, hypocretin acted presynaptically to enhance the excitatory actions of GABA. The ability of hypocretin to enhance GABA release increases inhibition in adult neurons but paradoxically enhances excitation in developing MCH neurons. In contrast, NPY attenuation of GABA release reduced inhibition in mature neurons but enhanced inhibition during development by attenuating GABA excitation. Both hypocretin and NPY also evoked direct actions on developing MCH neurons. Hypocretin excited MCH cells by activating a sodium-calcium exchanger and by reducing potassium currents; NPY reduced activity by increasing an inwardly rectifying potassium current. These data for the first time show that both hypocretin and NPY receptors are functional presynaptically during early postnatal hypothalamic development and that both neuropeptides modulate GABA actions during development with a valence of enhanced excitation or inhibition opposite to that of the adult state, potentially allowing neuropeptide modulation of use-dependent synapse stabilization. PMID:23255725

  13. Hippocampal Betaine/GABA Transporter mRNA Expression is not Regulated by Inflammation or Dehydration Post-Status Epilepticus

    PubMed Central

    Rowley, Nicole M.; Smith, Misty; Lamb, John G.; Schousboe, Arne; White, H. Steve

    2011-01-01

    Seizure activity can alter GABA transporter and osmoprotective gene expression, which may be involved in the pathogenesis of epilepsy. However, the response of the betaine/GABA transporter is unknown. The goal of the present study was to compare the expression of betaine/GABA transporter mRNA to that of other osmoprotective genes and GABA transporters following status epilepticus (SE). The possible contributory role of dehydration and inflammation was also investigated because both have been shown to be involved in the regulation of GABA transporter and/or osmoprotective gene expression. BGT1 mRNA was increased 24 h post-SE, as were osmoprotective genes. BGT1 was decreased 72 h and 4 weeks post-SE, as were the GABA transporter mRNAs. The mRNA values for osmoprotective genes following 24-hour water withdrawal were significantly lower than the values obtained 24 h post-SE despite similarities in their plasma osmolality values. Betaine/GABA transporter mRNA was not altered by lipopolysaccharide-induced inflammation while the transcription factor TonEBP and the GABA transporters (GAT1 and 3) were. These results suggest that neither plasma osmolality nor inflammation fully account for the changes seen in betaine/GABA transporter mRNA expression post-SE. However, it is evident that BGT1 mRNA expression is altered by SE and displays a temporal pattern with similarities to both GABA and osmolyte transporters. Further investigation of BGT1 regulation in the brain is warranted. PMID:21219332

  14. Dopamine and ?-aminobutyric acid are colocalized in restricted groups of neurons in the sea lamprey brain: insights into the early evolution of neurotransmitter colocalization in vertebrates

    PubMed Central

    Barreiro-Iglesias, Antón; Villar-Cerviño, Verona; Anadón, Ramón; Rodicio, María Celina

    2009-01-01

    Since its discovery, the possible corelease of classic neurotransmitters from neurons has received much attention. Colocalization of monoamines and amino acidergic neurotransmitters [mainly glutamate and dopamine (DA) or serotonin] in mammalian neurons has been reported. However, few studies have dealt with the colocalization of DA and ?-aminobutyric acid (GABA) in neurons. With the aim of providing some insight into the colocalization of neurotransmitters during early vertebrate phylogeny, we studied GABA expression in dopaminergic neurons in the sea lamprey brain by using double-immunofluorescence methods with anti-DA and anti-GABA antibodies. Different degrees of colocalization of DA and GABA were observed in different dopaminergic brain nuclei. A high degree of colocalization (GABA in at least 25% of DA-immunoreactive neurons) was observed in populations of the caudal rhombencephalon, ventral isthmus, postoptic commissure nucleus, preoptic nucleus and in granule-like cells of the olfactory bulb. A new DA-immunoreactive striatal population that showed colocalization with GABA in about a quarter of its neurons was observed. In the periventricular hypothalamus, colocalization was observed in only a few cells, despite the abundance of DA- and GABA-immunoreactive neurons, and no double-labelled cells were observed in the paratubercular nucleus. The frequent colocalization of DA and GABA reveals that the dopaminergic populations of lampreys are more complex than previously reported. Double-labelled fibres or terminals were observed in different brain regions, suggesting possible corelease of DA and GABA by these lamprey neurons. The present results suggest that colocalization of DA and GABA in neurons appeared early in vertebrate evolution. PMID:19840024

  15. GABA and non-GABA immunostained neurones in the nucleus prepositus and the periparabigeminal area projecting to the guinea pig superior colliculus.

    PubMed

    Hardy, O; Corvisier, J

    1991-06-10

    We have investigated the possibility that GABAergic neurones may be involved in two ascending projections to the superior colliculus, originating in the nucleus prepositus hypoglossi and in the periparabigeminal area of the mesencephalon, respectively. The projecting neurones of both structures were identified using gold-WGA-apoHRP, a retrogradely transported tracer, injected unilaterally into the superior colliculus. GABA was detected in these neurones by means of immunocytochemical staining. The results show that 25% of the projecting neurones in the prepositus hypoglossi are indeed GABA-immunoreactive. They could exert a direct inhibitory influence on the colliculus. By contrast, only a few (7%) gold-filled-GABAergic cells were detected in the periparabigeminal area, which suggests that this region cannot participate in an important inhibitory afferent system to the colliculus. PMID:1715539

  16. Embryonic cerebellar neurons accumulate (/sup 3/H-gamma-aminobutyric acid: visualization of developing gamma-aminobutyric acid-utilizing neurons in vitro and in vivo

    SciTech Connect

    Hatten, M.E.; Francois, A.M.; Napolitano, E.; Roffler-Tarlov, S.

    1984-05-01

    gamma-Aminobutyric acid (GABA) is the proposed neurotransmitter for four types of cerebellar neurons-Purkinje, Golgi, basket, and stellate neurons. With this investigation we have begun studies to establish when these neurons acquire their neurotransmitter ''identification''. Autoradiographic studies of both cultured embryonic (embryonic day 13) cerebellar cells and of intact embryonic cerebellum (embryonic day 13) were conducted with tritiated GABA. Two to 5% of the embryonic cerebellar cells accumulated (/sup 3/H)GABA in vitro. By morphological and immunocytochemical criteria, labeled cells were large neurons with either a thick, apical process, a multipolar shape, or were bipolar with longer processes. The identification of cells which accumulated (/sup 3/H)GABA as neuronal precursors was supported by the differential sensitivity to drugs that preferentially inhibit accumulation of (/sup 3/H)GABA by neurons and glia. The results of the in vitro experiments were confirmed and extended with in vivo experiments. When intact cerebellar tissue was removed at embryonic day 13, stripped of meninges and choroid plexus, exposed to low concentrations of (/sup 3/H)GABA, and processed for light microscopic autoradiography, heavily labeled cells were seen in the middle of the cerebellar anlage. Labeled cells were not seen in the ventricular zone of proliferating neuroblasts lining the fourth ventricle or in the external granular layer emerging at the lateral aspect of the pial surface. The accumulation of (/sup 3/H)GABA by these cells also showed the pharmacological characteristics of uptake by neurons. This study shows that among migrating, immature forms of the larger neurons of the embryonic cerebellum, there is a select group which accumulates (/sup 3/H)GABA and other classes of cells which do not. These results indicate very early acquisition of transmitter expression by cerebellar neurons, far in advance of their final positioning and establishment of synapses.

  17. Effect of timing and duration of salt treatment during growth of a fragrant rice variety on yield and 2-acetyl-1-pyrroline, proline, and GABA Levels.

    PubMed

    Poonlaphdecha, Janchai; Maraval, Isabelle; Roques, Sandrine; Audebert, Alain; Boulanger, Renaud; Bry, Xavier; Gunata, Ziya

    2012-04-18

    In greenhouse experiments, Aychade, a fragrant rice variety, was grown under one level of salt solution (EC of 3800 ± 400 ?S·cm(-1)) sufficient to induce salt stress in rice. Timing and duration of salt solution application varied according to the growth stages. 2-Acetyl-1-pyrroline (2AP), a characteristic flavor compound of fragrant rice as well as biogenetically related compounds, proline, and ?-aminobutyric acid (GABA) were quantified. Salt treatments induced 2AP synthesis in the leaves, but the increase was often higher in the vegetative phase. This increase was correlated with proline level but not with that of GABA. Interestingly the grains from all the salt treated plants contained significantly higher levels of 2AP (733-998 ?g·kg(-1)) than those from the control (592 ?g·kg(-1)). The highest 2AP synthesis occurred when the plants were subjected to salt treatment during whole vegetative or reproductive phases. However in the latter case crop yield decreased significantly. PMID:22404867

  18. GABAergic Alterations in Neocortex of Patients with Pharmacoresistant Temporal Lobe Epilepsy Can Explain the Comorbidity of Anxiety and Depression: The Potential Impact of Clinical Factors

    PubMed Central

    Rocha, Luisa; Alonso-Vanegas, Mario; Martínez-Juárez, Iris E.; Orozco-Suárez, Sandra; Escalante-Santiago, David; Feria-Romero, Iris Angélica; Zavala-Tecuapetla, Cecilia; Cisneros-Franco, José Miguel; Buentello-García, Ricardo Masao; Cienfuegos, Jesús

    2015-01-01

    Temporal lobe epilepsy (TLE) is a chronic neurodegenerative disease with a high prevalence of psychiatric disorders. Temporal neocortex contributes to either seizure propagation or generation in TLE, a situation that has been associated with alterations of the ?-amino-butyric acid (GABA) system. On the other hand, an impaired neurotransmission mediated by GABA in temporal neocortex has also been involved with the pathophysiology of psychiatric disorders. In spite of these situations, the role of the necortical GABA system in the comorbidity of TLE and mood disorders has not been investigated. The present study was designed to identify alterations in the GABA system such as binding to GABAA and GABAB receptors and benzodiazepine site, the tissue content of GABA and the expression of the mRNA encoding the ?1–6, ?1–3, and ? GABAA subunits, in the temporal neocortex of surgically treated patients with TLE with and without anxiety, and/or depression. Neocortex of patients with TLE and comorbid anxiety and/or depression showed increased expression of the mRNA encoding the ?2-subunit, reduced GABAB-induced G-protein activation in spite of elevated GABAB binding, and lower tissue content of GABA when compared to autopsy controls. Some of these changes significantly correlated with seizure frequency and duration of epilepsy. The results obtained suggest a dysfunction of the GABAergic neurotransmission in temporal neocortex of patients with TLE and comorbid anxiety and/or depression that could be also influenced by clinical factors such as seizure frequency and duration of illness. PMID:25601827

  19. Uptake of gamma-aminobutyric acid by a synaptic vesicle fraction isolated from rat brain.

    PubMed

    Fykse, E M; Fonnum, F

    1988-04-01

    Gamma-Aminobutyric acid (GABA) was taken up by a MgATP-dependent mechanism into synaptic vesicles isolated by hypoosmotic shock and density gradient centrifugation. The properties of the vesicular uptake differed clearly from those of synaptosomal and glial uptake, both with respect to Na+, Mg2+, and ATP dependence and with respect to response to general GABA uptake inhibitors such as nipecotic acid, diaminobutyric acid, and beta-alanine. The uptake showed a Km of 5.6 mM and a net uptake rate of 1,500 pmol/min/mg of protein. It is suggested that the vesicular uptake of GABA is driven by an electrochemical proton gradient generated by a Mg2+-ATPase. PMID:2964510

  20. GABA in the insula — a predictor of the neural response to interoceptive awareness

    PubMed Central

    Wiebking, Christine; Duncan, Niall W.; Tiret, Brice; Hayes, David J.; Marja?ska, Malgorzata; Doyon, Julien; Bajbouj, Malek; Northoff, Georg

    2015-01-01

    The insula has been identified as a key region involved in interoceptive awareness. Whilst imaging studies have investigated the neural activation patterns in this region involved in intero- and exteroceptive awareness, the underlying biochemical mechanisms still remain unclear. In order to investigate these, a well-established fMRI task targeting interoceptive awareness (heartbeat counting) and exteroceptive awareness (tone counting) was combined with magnetic resonance spectroscopy (MRS). Controlling for physiological noise, neural activity in the insula during intero- and exteroceptive awareness was confirmed in an independent data sample using the same fMRI design. Focussing on MRS values from the left insula and combining them with neural activity during intero- and exteroceptive awareness in the same healthy individuals, we demonstrated that GABA concentration in a region highly involved in interoceptive processing is correlated with neural responses to interoceptive stimuli, as opposed to exteroceptive stimuli. In addition, both GABA and interoceptive signal changes in the insula predicted the degree of depressed affect, as measured by the Beck Hopelessness Scale. On the one hand, the association between GABA concentration and neural activity during interoceptive awareness provides novel insight into the biochemical underpinnings of insula function and interoception. On the other, through the additional association of both GABA and neural activity during interoception with depressed affect, these data also bear potentially important implications for psychiatric disorders like depression and anxiety, where GABAergic deficits, altered insula function and abnormal affect coincide. PMID:23618604

  1. 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

  2. Fluorescence measurements of anion transport by the GABA receptor in reconstituted membrane preparations

    SciTech Connect

    Dunn, S.M.J.; Shelman, R.A.; Agey, M.W. (Univ. of Iowa, Iowa City (USA))

    1989-03-21

    A fluorescence assay for measuring the functional properties of the GABA{sub A} receptor in reconstituted membrane vesicles is described. This assay is based on a method previously described to measure monovalent cation transport mediated by the nicotinic acetylcholine receptor in membranes from Torpedo electric organ. The GABA{sub A} receptor has been solubilized from bovine brain membranes and reconstituted into phospholipid vesicles. Influx of chloride or iodide into the vesicles has been measured in stopped-flow experiments by monitoring the fluorescence quench of an anion-sensitive fluorophore trapped within the vesicles. Muscimol, a GABA{sub A} receptor agonist, stimulated a rapid uptake of either chloride or iodide. Stimulation of chloride influx was dependent on the concentration of muscimol, and the midpoint of the dose-response curve occurred at approximately 0.3 {mu}M. Agonist-stimulated uptake was enhanced by diazepam and blocked by desensitization and by the antagonists bicuculline and picrotoxin. These receptor-mediated effects are shown to be qualitatively similar to measurements of {sup 36}Cl{sup {minus}} and {sup 125}I{sup {minus}} efflux using synaptoneurosomes prepared from rat cerebral cortex. The advantages of the fluorescence method in terms of its improved time resolution, sensitivity, and suitability for quantitating GABA{sub A} receptor function are discussed.

  3. GABA[subscript A] Receptors Determine the Temporal Dynamics of Memory Retention

    ERIC Educational Resources Information Center

    McNally, Gavan P.; Augustyn, Katarzyna A.; Richardson, Rick

    2008-01-01

    Four experiments studied the role of GABA[subscript A] receptors in the temporal dynamics of memory retention. Memory for an active avoidance response was a nonmonotonic function of the retention interval. When rats were tested shortly (2 min) or some time (24 h) after training, retention was excellent, but when they were tested at intermediate…

  4. GABA and 5-HT chitosan nanoparticles decrease striatal neuronal degeneration and motor deficits during liver injury.

    PubMed

    Shilpa, J; Paulose, C S

    2014-07-01

    The metabolic alterations resulted from hepatic injury and cell loss lead to synaptic defects and neurodegeneration that undoubtedly contribute motor deficits. In the present study, GABA and 5-HT chitosan nanoparticles mediated liver cell proliferation influenced by growth factor and cytokines and neuronal survival in corpus striatum of partially hepatectomised rats was evaluated. Liver cell proliferation was initiated and progressed by the combined effect of increased expression of growth factor, insulin like growth factor-1 and decreased expressions of cytokines, tumor necrosis factor-? and Akt-1. This was confirmed by the extent of incorporation of thymidine analogue, BrdU, in the DNA of rapidly dividing cells. Inappropriate influx of compounds to corpus striatum resulting from incomplete metabolism elevated GABAB and 5-HT2A neurotransmissions compared to those treated with nanoparticles. This directly influenced cyclic AMP response element binding protein, glial cell derived neurotrophic factor and brain derived neurotrophic factor in the corpus striatum that facilitate neurogenesis, neuronal survival, development, differentiation and neuroprotection. Motor deficits due to liver injury followed striatal neuronal damage were scored by grid walk and rotarod studies, which confirmed the regain of motor activity by GABA and 5-HT chitosan nanoparticle treatment. The present study revealed the therapeutic significance of GABA and 5-HT chitosan nanoparticles in liver based diseases and related striatal neuronal damage that influenced by GABA and 5-HT. PMID:24682906

  5. Cellular/Molecular An Arginine Involved in GABA Binding and Unbinding But

    E-print Network

    Kemnitz, Joseph

    into interactions between ligand and receptor (binding) and the opening and closing of the ligand-bound channelCellular/Molecular An Arginine Involved in GABA Binding and Unbinding But Not Gating of the GABAA Receptor David A. Wagner,1,2 Cynthia Czajkowski,1 and Mathew V. Jones1 1Department of Physiology

  6. ORIGINAL ARTICLE Co-activation of VTA DA and GABA neurons mediates

    E-print Network

    Gutkin, Boris

    on nicotinic acetylcholine receptors (nAChRs), a heterogeneous family of pentameric, ligand-gated ion channelsORIGINAL ARTICLE Co-activation of VTA DA and GABA neurons mediates nicotine reinforcement S Tolu1 acetylcholine receptor (nAChR), expressed on most neurons, and also many other organs in the body. Even within

  7. GABAA Receptor 2 Tyr97 Line the GABA-binding Site

    E-print Network

    Kemnitz, Joseph

    GABAA Receptor 2 Tyr97 and Leu99 Line the GABA-binding Site INSIGHTS INTO MECHANISMS OF AGONIST of ligand recognition is based on the nicotinic acetylcholine receptor (nAChR) (10). The ligand-binding site and catalyze allosteric transitions that result in channel gating is crucial for understanding ligand-gated ion

  8. GABA is not elevated during neuroprotective neuronal depression in the hypoxic epaulette shark ( Hemiscyllium ocellatum)

    Microsoft Academic Search

    Jamin M. Mulvey; Gillian M. C. Renshaw

    2009-01-01

    Prolonged hypoxic exposure results in cell failure, glutamate excitotoxicity and apoptosis in the brain. The epaulette shark can withstand prolonged hypoxic exposure without brain injury, while maintaining normal function and activity at tropical temperatures. We examined whether the inhibitory neurotransmitter GABA was involved in hypoxia tolerance and neuroprotection during hypoxic preconditioning. Sharks were exposed to either cyclic hypoxic preconditioning or

  9. Calcium Influx through NMDA Receptors Directly Evokes GABA Release in Olfactory Bulb Granule Cells

    E-print Network

    Strowbridge, Ben

    Calcium Influx through NMDA Receptors Directly Evokes GABA Release in Olfactory Bulb Granule Cells, Case Western Reserve University, Cleveland, Ohio 44106-4975 Recurrent inhibition in olfactory bulb on the activation of NMDA receptors. Using whole-cell recordings from rat olfactory bulb slices, we now show

  10. Surgical Model of Menopause Symptoms: GABA'S Role in Anxiety and Hot Flashes Anna Frink1

    E-print Network

    Zhou, Yaoqi

    Surgical Model of Menopause Symptoms: GABA'S Role in Anxiety and Hot Flashes Anna Frink1 1-being; symptoms include vasomotor instability (hot flashes and night sweats), anxiety, and sleep disruption rats or the extent of activation of the same neural sites. To test this hypothesis, female rats were

  11. DOSE RESPONSE DEETERMINATION OF NMDA ANTAGONISTS AND GABA AGONIST ON SUSTAINED ATTENTION.

    EPA Science Inventory

    We have shown that acute inhalation of toluene impairs sustained attention as assessed with a visual signal detection task (SDT). In vitro studies indicate that the NMDA and GABA systems are primary targets of anesthetic agents and organic solvents such as toluene. Pharmacologica...

  12. J-difference editing of GABA: simulated and experimental multiplet patterns

    PubMed Central

    Near, Jamie; Evans, C. John; Puts, Nicolaas AJ.; Barker, Peter B.; Edden, Richard AE.

    2012-01-01

    Purpose To investigate factors that influence the multiplet pattern observed in J-difference editing of GABA. Theory and Methods Density matrix simulations were applied to investigate the shape of the 3 ppm GABA multiplet as a function of the editing sequence’s slice selective refocusing pulse properties, in particular bandwidth, transition width, and flip angle. For comparison to the calculations, experimental measurements were also made at 3T on a 10 mM GABA solution using the MEGA-PRESS sequence at various refocusing pulse flip angles. Results Good agreement was found between experiments and simulations. The edited multiplet consists of 2 outer lines of slightly unequal intensity due to strong coupling, and a smaller central line, the result of the unequal J-couplings between the C4 and C3 protons. The size of the center peak increases with increasing slice selective refocusing pulse transition width, and deviation of the flip angle from 180°. Conclusion The 3 ppm GABA multiplet pattern observed in the MEGA-PRESS experiment depends quite strongly on the properties of the slice selective refocusing pulses used. Under some circumstance the central peak can be quite large; this does not necessarily indicate inefficient editing, or a subtraction artifact, but should be recognized as a property of the pulse sequence itself. PMID:23213033

  13. GABA potentiation: a logical pharmacological approach for the treatment of acute ischaemic stroke

    Microsoft Academic Search

    A. Richard Green; Atticus H. Hainsworth; David M. Jackson

    2000-01-01

    It has been shown that enhancing the function of the major inhibitory neurotransmitter GABA decreases glutamatergic activity in the brain. Since increased glutamatergic activity is the major primary event that results in cell death following an acute hypoxic–ischaemic stroke, GABAmimetic drugs might therefore be expected to be neuroprotective. This review examines the evidence that GABAergic function is acutely depressed following

  14. GABA-A Receptor Inhibition of Local Calcium Signaling in Spines and Dendrites

    PubMed Central

    Marlin, Joseph J.

    2014-01-01

    Cortical interneurons activate GABA-A receptors to rapidly control electrical and biochemical signaling at pyramidal neurons. Different populations of interneurons are known to uniquely target the soma and dendrites of pyramidal neurons. However, the ability of these interneurons to inhibit Ca2+ signaling at spines and dendrites is largely unexplored. Here we use whole-cell recordings, two-photon microscopy, GABA uncaging and optogenetics to study dendritic inhibition at layer 5 (L5) pyramidal neurons in slices of mouse PFC. We first show that GABA-A receptors strongly inhibit action potential (AP)-evoked Ca2+ signals at both spines and dendrites. We find robust inhibition over tens of milliseconds that spreads along the dendritic branch. However, we observe no difference in the amount of inhibition at neighboring spines and dendrites. We then examine the influence of interneurons expressing parvalbumin (PV), somatostatin (SOM), or 5HT3a receptors. We determine that these populations of interneurons make unique contacts onto the apical and basal dendrites of L5 pyramidal neurons. We also show that SOM and 5HT3a but not PV interneurons potently inhibit AP Ca2+ signals via GABA-A receptors at both spines and dendrites. These findings reveal how multiple interneurons regulate local Ca2+ signaling in pyramidal neurons, with implications for cortical function and disease. PMID:25429132

  15. Selective homonuclear polarization transfer for spectroscopic imaging of GABA at 7T.

    PubMed

    Pan, J W; Duckrow, R B; Spencer, D D; Avdievich, N I; Hetherington, H P

    2013-02-01

    We develop and implement a selective homonuclear polarization transfer method for the detection of 3.0 ppm C-4 GABA resonance by spectroscopic imaging in the human brain at 7T. This single shot method is demonstrated with simulations and phantoms, which achieves comparable efficiency of detection to that of J-difference editing. The macromolecule resonance that commonly co-edits with GABA is suppressed at 7T through use of a narrow band preacquisition suppression pulse. This technique is implemented in humans with an eight channel transceiver array and high degree B(0) shimming to measure supplementary motor area and thalamic GABA in controls (n = 8) and epilepsy patients (n = 8 total). We find that the GABA/N-acetyl aspartate ratio in the thalamus of control volunteers, well controlled and poorly controlled epilepsy patients are 0.053 ± 0.012 (n = 8), 0.090 ± 0.012 (n = 2), and 0.038 ± 0.009 (n = 6), respectively. PMID:22505305

  16. Circadian Modulation of the Cl? Equilibrium Potential in the Rat Suprachiasmatic Nuclei

    PubMed Central

    Perez-Burgos, Azucena; Quinto, Daniel; Aguilar-Roblero, Raúl

    2014-01-01

    The suprachiasmatic nuclei (SCN) constitute a circadian clock in mammals, where ?-amino-butyric acid (GABA) neurotransmission prevails and participates in different aspects of circadian regulation. Evidence suggests that GABA has an excitatory function in the SCN in addition to its typical inhibitory role. To examine this possibility further, we determined the equilibrium potential of GABAergic postsynaptic currents (EGABA) at different times of the day and in different regions of the SCN, using either perforated or whole cell patch clamp. Our results indicate that during the day most neurons in the dorsal SCN have an EGABA close to ?30 mV while in the ventral SCN they have an EGABA close to ?60 mV; this difference reverses during the night, in the dorsal SCN neurons have an EGABA of ?60 mV and in the ventral SCN they have an EGABA of ?30 mV. The depolarized equilibrium potential can be attributed to the activity of the Na(+)-K(+)-2Cl(?) (NKCC) cotransporter since the equilibrium potential becomes more negative following addition of the NKCC blocker bumetanide. Our results suggest an excitatory role for GABA in the SCN and further indicate both time (day versus night) and regional (dorsal versus ventral) modulation of EGABA in the SCN. PMID:24949446

  17. Benzodiazepines in the treatment of epilepsy in people with intellectual disability.

    PubMed

    Isojärvi, J I; Tokola, R A

    1998-12-01

    All the benzodiazepines (BZDs) in clinical use have the capacity to promote the binding of the major inhibitory neurotransmitter, gamma-amino-butyric acid (GABA), to sub-types of GABA receptors which exist as multi-subunit ligand-gated chloride channels. Thus, the BZDs facilitate the actions of GABA in the brain. The BZDs in use as antiepileptic drugs are diazepam, clonazepam, clobazam, nitrazepam, and lately, also lorazepam and midazolam as emergency therapy. The BZDs have a wide-spectrum of proven clinical efficacy in the prevention of different kind of seizures. Clonazepam and clobazam, as well as nitrazepam in some cases, can be useful as an adjunct treatment in refractory epilepsies. However, the clinical use of BZDs for the prophylactic treatment of epilepsy is associated with two major problems which have limited the long-term use of these drugs: the potential for side-effects, especially sedative effects, and the high risk of development of tolerance. Despite the limitations of BZDs in the prophylactic treatment of epilepsies, these drugs play a prominent role in clinical practice in the emergency management of acute seizures and status epilepticus. Diazepam, clonazepam and lorazepam are all considered first-line agents in the emergency management of acute seizures and status epilepticus. Furthermore, the value of midazolam as an emergency therapy in epilepsy has been increasingly recognized in recent years. PMID:10030438

  18. Amino acid derivatives are substrates or non-transported inhibitors of the amino acid transporter PAT2 (slc36a2)

    Microsoft Academic Search

    Noel Edwards; Catriona M. H. Anderson; Kelly M. Gatfield; Mark P. Jevons; Vadivel Ganapathy; David T. Thwaites

    2011-01-01

    The H+-coupled amino acid transporter PAT2 (SLC36A2) transports the amino acids proline, glycine, alanine and hydroxyproline. A physiological role played by PAT2 in amino acid reabsorption in the renal proximal tubule is demonstrated by mutations in SLC36A2 that lead to an iminoglycinuric phenotype (imino acid and glycine uria) in humans. A number of proline, GABA and tryptophan derivatives were examined

  19. Enhanced Tonic GABA Current in Normotopic and Hilar Ectopic Dentate Granule Cells After Pilocarpine-Induced Status Epilepticus

    PubMed Central

    Zhan, Ren-Zhi; Nadler, J. Victor

    2009-01-01

    In temporal lobe epilepsy, loss of inhibitory neurons and circuit changes in the dentate gyrus promote hyperexcitability. This hyperexcitability is compensated to the point that dentate granule cells exhibit normal or even subnormal excitability under some conditions. This study explored the possibility that compensation involves enhanced tonic GABA inhibition. Whole cell patch-clamp recordings were made from normotopic granule cells in hippocampal slices from control rats and from both normotopic and hilar ectopic granule cells in slices from rats subjected to pilocarpine-induced status epilepticus. After status epilepticus, tonic GABA current was an order of magnitude greater than control in normotopic granule cells and was significantly greater in hilar ectopic than in normotopic granule cells. These differences could be observed whether or not the extracellular GABA concentration was increased by adding GABA to the superfusion medium or blocking plasma membrane transport. The enhanced tonic GABA current had both action potential–dependent and action potential–independent components. Pharmacological studies suggested that the small tonic GABA current of granule cells in control rats was mediated largely by high-affinity ?4?x? GABAA receptors but that the much larger current recorded after status epilepticus was mediated largely by the lower-affinity ?5?x?2 GABAA receptors. A large ?5?x?2-mediated tonic current could be recorded from controls only when the extracellular GABA concentration was increased. Status epilepticus seemed not to impair the control of extracellular GABA concentration by plasma membrane transport substantially. Upregulated tonic GABA inhibition may account for the unexpectedly modest excitability of the dentate gyrus in epileptic brain. PMID:19474175

  20. Experimental Status Epilepticus Alters ?-Aminobutyric Acid Type A Receptor Function in CA1 Pyramidal Neurons

    PubMed Central

    Kapur, Jaideep; Coulter, Douglas A.

    2010-01-01

    There is a reduction of ?-aminobutyric acid (GABA)-mediated inhibition in the CA1 pyramidal region of the hippocampus during status epilepticus (SE). The cellular basis of this loss of GABA-mediated inhibition is not known. This study tested the possibility that GABA type A (GABAA) receptor function in CA1 pyramidal neurons was reduced or blocked during SE, at least in part by postsynaptic cellular mechanisms. GABAA, receptor currents (IGABA) were studied by whole-cell patch-clamp techniques in CA1 pyramidal neurons acutely dissociated from rats undergoing lithium/pilocarpine-induced limbic status epilepticus (SE neurons) and from naive rats (naive neurons). SE neurons had more depolarized resting membrane potential (?17.3 mV) compared with naive neurons (?56 mV). IGABA was absent in 47% of SE neurons and reduced in 55% of the remainder, compared with naive neurons. The reduction in IGABA in SE neurons resulted from a combination of factors, including reduced potency and reduced efficacy of GABA in activating chloride channels, and diminished driving force for the GABA-induced chloride currents once activated. These postsynaptic cellular mechanisms resulted in a net reduction or loss in GABA-mediated inhibition and may explain previous in vivo findings reporting a loss of inhibition in hippocampus during limbic SE. PMID:8526461

  1. GABA shunt mediates thermotolerance in Saccharomyces cerevisiae by reducing reactive oxygen production.

    PubMed

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

    2013-04-01

    The GABA shunt pathway involves three enzymes, glutamate decarboxylase (GAD), GABA aminotransferase (GAT) and succinate semialdehyde dehydrogenase (SSADH). These enzymes act in concert to convert glutamate (?-ketoglutarate) to succinate. Deletion mutations in each of these genes in Saccharomyces cerevisiae resulted in growth defects at 45°C. Double and triple mutation constructs were compared for thermotolerance with the wild-type and single mutant strains. Although wild-type and all mutant strains were highly susceptible to brief heat stress at 50°C, a non-lethal 30 min at 40°C temperature pretreatment induced tolerance of the wild-type and all of the mutants to 50°C. The mutant strains collectively exhibited similar susceptibility at 45°C to the induced 50°C treatments. Intracellular reactive oxygen intermediate (ROI) accumulation was measured in wild-type and each of the mutant strains. ROI accumulation in each of the mutants and in various stress conditions was correlated to heat susceptibility of the mutant strains. The addition of ROI scavenger N-tert-butyl-?-phenylnitrone (PBN) enhanced survival of the mutants and strongly inhibited the accumulation of ROI, but did not have significant effect on the wild-type. Measurement of intracellular GABA, glutamate and ?-ketoglutarate during lethal heat exposure at 45°C showed higher levels of accumulation of GABA and ?-ketoglutarate in the uga1 and uga2 mutants, while glutamate accumulated at higher level in the gad1 mutant. These results suggest that the GABA shunt pathway plays a crucial role in protecting yeast cells from heat damage by restricting ROI production involving the flux of carbon from ?-ketoglutarate to succinate during heat stress. PMID:23447388

  2. Opposite effects of KCTD subunit domains on GABA(B) receptor-mediated desensitization.

    PubMed

    Seddik, Riad; Jungblut, Stefan P; Silander, Olin K; Rajalu, Mathieu; Fritzius, Thorsten; Besseyrias, Valérie; Jacquier, Valérie; Fakler, Bernd; Gassmann, Martin; Bettler, Bernhard

    2012-11-16

    GABA(B) receptors assemble from principle and auxiliary subunits. The principle subunits GABA(B1) and GABA(B2) form functional heteromeric GABA(B(1,2)) receptors that associate with homotetramers of auxiliary KCTD8, -12, -12b, or -16 (named after their K(+) channel tetramerization domain) subunits. These auxiliary subunits constitute receptor subtypes with distinct functional properties. KCTD12 and -12b generate desensitizing receptor responses while KCTD8 and -16 generate largely non-desensitizing receptor responses. The structural elements of the KCTDs underlying these differences in desensitization are unknown. KCTDs are modular proteins comprising a T1 tetramerization domain, which binds to GABA(B2), and a H1 homology domain. KCTD8 and -16 contain an additional C-terminal H2 homology domain that is not sequence-related to the H1 domains. No functions are known for the H1 and H2 domains. Here we addressed which domains and sequence motifs in KCTD proteins regulate desensitization of the receptor response. We found that the H1 domains in KCTD12 and -12b mediate desensitization through a particular sequence motif, T/NFLEQ, which is not present in the H1 domains of KCTD8 and -16. In addition, the H2 domains in KCTD8 and -16 inhibit desensitization when expressed C-terminal to the H1 domains but not when expressed as a separate protein in trans. Intriguingly, the inhibitory effect of the H2 domain is sequence-independent, suggesting that the H2 domain sterically hinders desensitization by the H1 domain. Evolutionary analysis supports that KCTD12 and -12b evolved desensitizing properties by liberating their H1 domains from antagonistic H2 domains and acquisition of the T/NFLEQ motif. PMID:23035119

  3. Ethanol, not metabolized in brain, significantly reduces brain metabolism, probably via specific GABA(A) receptors

    PubMed Central

    Rae, Caroline D.; Davidson, Joanne E.; Maher, Anthony D.; Rowlands, Benjamin D.; Kashem, Mohammed A.; Nasrallah, Fatima A.; Rallapalli, Sundari K.; Cook, James M; Balcar, Vladimir J.

    2014-01-01

    Ethanol is a known neuromodulatory agent with reported actions at a range of neurotransmitter receptors. Here, we used an indirect approach, measuring the effect of alcohol on metabolism of [3-13C]pyruvate in the adult Guinea pig brain cortical tissue slice and comparing the outcomes to those from a library of ligands active in the GABAergic system as well as studying the metabolic fate of [1,2-13C]ethanol. Ethanol (10, 30 and 60 mM) significantly reduced metabolic flux into all measured isotopomers and reduced all metabolic pool sizes. The metabolic profiles of these three concentrations of ethanol were similar and clustered with that of the ?4?3? positive allosteric modulator DS2 (4-Chloro-N-[2-(2-thienyl)imidazo[1,2a]-pyridin-3-yl]benzamide). Ethanol at a very low concentration (0.1 mM) produced a metabolic profile which clustered with those from inhibitors of GABA uptake, and ligands showing affinity for ?5, and to a lesser extent, ?1-containing GABA(A)R. There was no measureable metabolism of [1,2-13C]ethanol with no significant incorporation of 13C from [1,2-13C]ethanol into any measured metabolite above natural abundance, although there were measurable effects on total metabolite sizes similar to those seen with unlabeled ethanol. The reduction in metabolism seen in the presence of ethanol is therefore likely to be due to its actions at neurotransmitter receptors, particularly ?4?3? receptors, and not because ethanol is substituting as a substrate or because of the effects of ethanol catabolites acetaldehyde or acetate. We suggest that the stimulatory effects of very low concentrations of ethanol are due to release of GABA via GAT1 and the subsequent interaction of this GABA with local ?5-containing, and to a lesser extent, ?1-containing GABA(A)R. PMID:24313287

  4. An ionotropic GABA receptor in cultured mushroom body Kenyon cells of the honeybee and its modulation by intracellular calcium

    Microsoft Academic Search

    Bernd Grünewald; Anna Wersing

    2008-01-01

    GABAergic inhibitory transmission is very abundant within the insect brain. We, therefore, studied the functional properties\\u000a of the ionotropic GABA receptor of honeybee mushroom body Kenyon cells in vitro. GABA applications elicit rapidly activating\\u000a and desensitizing currents, which are concentration-dependent between 10 and 500 ?M. The mean peak amplitude induced by 500 ?M\\u000a GABA at a holding potential of ?110 mV is ?1.55 ± 0.23 nA

  5. New developments in the treatment of partial-onset epilepsy

    PubMed Central

    Besag, Frank MC; Patsalos, Philip N

    2012-01-01

    Although most people presenting with partial-onset seizures will achieve control with antiepileptic medication, a considerable minority will have difficult-to-treat epilepsy that is resistant to existing medication. Over the last few years, a large number of new antiepileptic drugs have been developed. Some of these have a novel mode of action. Many of the older antiepileptic drugs act through sodium channels or by enhancement of gamma amino butyric acid (GABA). Lamotrigine has sodium-channel blocking properties but also has other important modes of action, indicated by efficacy in treating not only partial-onset but also generalized seizures. Vigabatrin and tiagabine both increase GABA activity, by inhibiting GABA transaminase and limiting GABA reuptake, respectively. The main mode of action of gabapentin and pregabalin is not via GABA but through a selective inhibitory effect on voltage-gated calcium channels containing the ?2?-1 subunit. Levetiracetam inhibits the recycling of SV2A (synaptic vesicle protein 2A) neurotransmitter vesicles but also has other effects, including inhibition of voltage-dependent calcium channels. Some drugs, eg, felbamate, zonisamide, and topiramate, have multiple modes of action. In many cases, although the main mode of action may have been identified, other modes of action also play a role. Two recently developed antiepileptic drugs appear to have completely novel primary modes of action; retigabine (ezogabine) and perampanel act on the potassium channel and on AMPA (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, respectively. The hope is that antiepileptic drugs with a novel mode of action will be effective where previous drugs have failed and will not have unacceptable adverse effects. However, experience with these medications is too limited to allow any conclusions to be drawn at present. PMID:23093905

  6. The role of the serotonergic and GABA system in translational approaches in drug discovery for anxiety disorders

    PubMed Central

    Olivier, Jocelien D. A.; Vinkers, Christiaan H.; Olivier, Berend

    2013-01-01

    There is ample evidence that genetic factors play an important role in anxiety disorders. In support, human genome-wide association studies have implicated several novel candidate genes. However, illumination of such genetic factors involved in anxiety disorders has not resulted in novel drugs over the past decades. A complicating factor is the heterogeneous classification of anxiety disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) and diverging operationalization of anxiety used in preclinical and clinical studies. Currently, there is an increasing focus on the gene × environment (G × E) interaction in anxiety as genes do not operate in isolation and environmental factors have been found to significantly contribute to the development of anxiety disorders in at-risk individuals. Nevertheless, extensive research on G × E mechanisms in anxiety has not resulted in major breakthroughs in drug discovery. Modification of individual genes in rodent models has enabled the specific study of anxiety in preclinical studies. In this context, two extensively studied neurotransmitters involved in anxiety are the gamma-aminobutyric acid (GABA) and 5-HT (5-hydroxytryptamine) system. In this review, we illustrate the complex interplay between genes and environment in anxiety processes by reviewing preclinical and clinical studies on the serotonin transporter (5-HTT), 5-HT1A receptor, 5-HT2 receptor, and GABAA receptor. Even though targets from the serotonin and GABA system have yielded drugs with known anxiolytic efficacy, the relation between the genetic background of these targets and anxiety symptoms and development of anxiety disorders is largely unknown. The aim of this review is to show the vast complexity of genetic and environmental factors in anxiety disorders. In light of the difficulty with which common genetic variants are identified in anxiety disorders, animal models with translational validity may aid in elucidating the neurobiological background of these genes and their possible role in anxiety. We argue that, in addition to human genetic studies, translational models are essential to map anxiety-related genes and to enhance our understanding of anxiety disorders in order to develop potentially novel treatment strategies. PMID:23781201

  7. Localization of a GABA transporter to glial cells in the developing and adult olfactory pathway of the moth Manduca sexta1

    PubMed Central

    Oland, Lynne A; Gibson, Nicholas J; Tolbert, Leslie P

    2010-01-01

    Glial cells have several critical roles in the developing and adult olfactory (antennal) lobe of the moth Manduca sexta. Early in development, glial cells occupy discrete regions of the developing olfactory pathway and processes of GABAergic neurons extend into some of these regions. Because GABA is known to have developmental effects in a variety of systems, we explored the possibility that the glial cells express a GABA transporter that could regulate GABA levels to which olfactory neurons and glial cells are exposed. Using an antibody raised against a characterized high-affinity M. sexta GABA transporter with high sequence homology to known mammalian GABA transporters (Mbungu et al., 1995; Umesh and Gill, 2002), we found that the GABA transporter is localized to subsets of centrally derived glial cells during metamorphic adult development. The transporter persists into adulthood in a subset of the neuropil-associated glial cells, but its distribution pattern as determined by light- and electron-microscopic-level immunocytochemistry indicates that it could not serve to regulate GABA concentration in the synaptic cleft. Rather its role is more likely to regulate extracellular GABA levels within the glomerular neuropil. Expression in the sorting zone glial cells disappears after the period of olfactory receptor axon ingrowth, but may be important during ingrowth if GABA regulates axon growth. Glial cells take up GABA, and that uptake can be blocked by DABA. This is the first molecular evidence that the central glial cell population in this pathway is heterogeneous. PMID:20058309

  8. DIPLOMA PROJECT 2014/2015 The Cys-loop ligand-gated ion channel family includes the GABA-, glycine-,

    E-print Network

    Uppsala Universitet

    DIPLOMA PROJECT 2014/2015 The Cys-loop ligand-gated ion channel family includes the GABA-, glycine-, serotonin-, and nicotinergic acetylcholine receptors, which all play important roles in the nervous signal transduction pathway

  9. Structural analogues of the natural products magnolol and honokiol as potent allosteric potentiators of GABA(A) receptors.

    PubMed

    Fuchs, Alexander; Baur, Roland; Schoeder, Clara; Sigel, Erwin; Müller, Christa E

    2014-12-15

    Biphenylic compounds related to the natural products magnolol and 4'-O-methylhonokiol were synthesized, evaluated and optimized as positive allosteric modulators (PAMs) of GABA(A) receptors. The most efficacious compounds were the magnolol analog 5-ethyl-5'-hexylbiphenyl-2,2'-diol (45) and the honokiol analogs 4'-methoxy-5-propylbiphenyl-2-ol (61), 5-butyl-4'-methoxybiphenyl-2-ol (62) and 5-hexyl-4'-methoxybiphenyl-2-ol (64), which showed a most powerful potentiation of GABA-induced currents (up to 20-fold at a GABA concentration of 3?M). They were found not to interfere with the allosteric sites occupied by known allosteric modulators, such as benzodiazepines and N-arachidonoylglycerol. These new PAMs will be useful as pharmacological tools and may have therapeutic potential for mono-therapy, or in combination, for example, with GABA(A) receptor agonists. PMID:25456080

  10. Overexpression and optimization of glutamate decarboxylase in Lactobacillus plantarum?Taj-Apis362 for high gamma-aminobutyric acid production.

    PubMed

    Tajabadi, Naser; Baradaran, Ali; Ebrahimpour, Afshin; Rahim, Raha A; Bakar, Fatimah A; Manap, Mohd Yazid A; Mohammed, Abdulkarim S; Saari, Nazamid

    2015-07-01

    Gamma-aminobutyric acid (GABA) is an important bioactive compound biosynthesized by microorganisms through decarboxylation of glutamate by glutamate decarboxylase (GAD). In this study, a full-length GAD gene was obtained by cloning the template deoxyribonucleic acid to pTZ57R/T vector. The open reading frame of the GAD gene showed the cloned gene was composed of 1410 nucleotides and encoded a 469 amino acids protein. To improve the GABA-production, the GAD gene was cloned into pMG36e-LbGAD, and then expressed in Lactobacillus plantarum?Taj-Apis362 cells. The overexpression was confirmed by SDS-PAGE and GAD activity, showing a 53?KDa protein with the enzyme activity increased by sevenfold compared with the original GAD activity. The optimal fermentation conditions for GABA production established using response surface methodology were at glutamic acid concentration of 497.973?mM, temperature 36°C, pH 5.31 and time 60?h. Under the conditions, maximum GABA concentration obtained (11.09?mM) was comparable with the predicted value by the model at 11.23?mM. To our knowledge, this is the first report of successful cloning (clone-back) and overexpression of the LbGAD gene from L.?plantarum to L.?plantarum cells. The recombinant Lactobacillus could be used as a starter culture for direct incorporation into a food system during fermentation for production of GABA-rich products. PMID:25757029

  11. Overexpression and optimization of glutamate decarboxylase in Lactobacillus plantarum Taj-Apis362 for high gamma-aminobutyric acid production

    PubMed Central

    Tajabadi, Naser; Baradaran, Ali; Ebrahimpour, Afshin; Rahim, Raha A; Bakar, Fatimah A; Manap, Mohd Yazid A; Mohammed, Abdulkarim S; Saari, Nazamid

    2015-01-01

    Gamma-aminobutyric acid (GABA) is an important bioactive compound biosynthesized by microorganisms through decarboxylation of glutamate by glutamate decarboxylase (GAD). In this study, a full-length GAD gene was obtained by cloning the template deoxyribonucleic acid to pTZ57R/T vector. The open reading frame of the GAD gene showed the cloned gene was composed of 1410 nucleotides and encoded a 469 amino acids protein. To improve the GABA-production, the GAD gene was cloned into pMG36e-LbGAD, and then expressed in Lactobacillus plantarum?Taj-Apis362 cells. The overexpression was confirmed by SDS-PAGE and GAD activity, showing a 53?KDa protein with the enzyme activity increased by sevenfold compared with the original GAD activity. The optimal fermentation conditions for GABA production established using response surface methodology were at glutamic acid concentration of 497.973?mM, temperature 36°C, pH 5.31 and time 60?h. Under the conditions, maximum GABA concentration obtained (11.09?mM) was comparable with the predicted value by the model at 11.23?mM. To our knowledge, this is the first report of successful cloning (clone-back) and overexpression of the LbGAD gene from L.?plantarum to L.?plantarum cells. The recombinant Lactobacillus could be used as a starter culture for direct incorporation into a food system during fermentation for production of GABA-rich products. PMID:25757029

  12. GABA(B) receptor agonist only reduces ethanol drinking in light-drinking mice.

    PubMed

    Villas Boas, Gustavo Roberto; Zamboni, Camila Gadens; Peretti, Murilo Calvo; Correia, Diego; Rueda, André Veloso Lima; Camarini, Rosana; Brunialti-Godard, Ana Lucia; Boerngen-Lacerda, Roseli

    2012-08-01

    Baclofen, a GABA(B) agonist, reduces ethanol intake in animals and humans, but the contrary or no effect was also reported. Our previous study demonstrated that mice characterized as "loss of control over ethanol intake" had different Gabbr1 and Gabbr2 transcription levels, which express, respectively, the GABA(B1) and GABA(B2) subunits in brain areas related to addictive behavior. In the present study, we tested baclofen on ethanol intake in mice exposed to the free-choice paradigm. Adult male Swiss mice, individually housed, had free access to three bottles: ethanol (5% and 10%) and water. The protocol had four phases: acquisition (AC, 10 weeks), withdrawal (W, 4 cycles during 2 weeks of 2 day-free-choice and 2 day-only-water), reexposure (RE, 2 weeks), and adulteration of ethanol solutions with quinine (AD, 2 weeks). Mice characterized as "loss of control" (A, n=11, preference for ethanol in AC and maintenance of ethanol intake levels in AD), heavy (H, n=11, preference for ethanol in AC and reduction of ethanol intake levels in AD), and light (L, n=16, preference for water in all phases) drinkers were randomly distributed into two subgroups receiving either intraperitoneal injections of all doses of baclofen (1.25, 2.5, and 5.0mg/kg, given each dose twice in consecutive days) or saline, being exposed to free-choice. Fluid consumption was measured 24h later. Baclofen reduced ethanol intake in group L. In group H a reduction compared to AC was observed. Group A maintained their high ethanol intake even after baclofen treatment. Activation of the GABA(B) receptor depends on the precise balance between the GABA(B1) and GABA(B2) subunits, so the disproportionate transcription levels, we reported in group A, could explain this lack of response to baclofen. These data highlight the importance to test baclofen in individuals with different ethanol drinking profiles, including humans. PMID:22579911

  13. Genetic inactivation of midkine modulates behavioural responses to ethanol possibly by enhancing GABA(A) receptor sensitivity to GABA(A) acting drugs.

    PubMed

    Vicente-Rodríguez, Marta; Pérez-García, Carmen; Haro, María; Ramos, María P; Herradón, Gonzalo

    2014-11-01

    Midkine (MK) is a cytokine with important functions in dopaminergic neurons that is found upregulated in the prefrontal cortex of alcoholics. We have studied the behavioural effects of ethanol in MK genetically deficient (MK-/-) and wild type (MK+/+) mice. A low dose of ethanol (1.0g/kg), unable to cause conditioned place preference (CPP) in MK+/+ mice, induced a significant CPP in MK-/- mice, suggesting that MK prevents the rewarding effects of low doses of ethanol. However, this difference between genotypes is lost when a higher, rewarding, dose of ethanol (2.0g/kg) is used. Accordingly, the anxiolytic effects of 1.0mg/kg diazepam, other GABA(A) acting drug, were significantly enhanced in MK-/- mice compared to MK+/+ mice; however, 2.0mg/kg diazepam caused increased anxiolytic effects in MK+/+ mice. In addition, MK-/- mice showed a significant delayed recovery from ethanol (2.0g/kg)-induced ataxia whereas the sedative effects induced by ethanol (3.6g/kg), tested in a loss of righting reflex paradigm, were found to be similar in MK-/- and MK+/+ mice. The data indicate that MK differentially regulates the behavioural responses to ethanol. The results suggest that differences in the sensitivity of GABA(A) receptors to GABA(A) acting drugs caused by genetic inactivation of MK could underlie the different behavioural responses to ethanol in MK-/- mice. Overall, these results suggest that MK may be a novel genetic factor of importance in alcohol use disorders, and that potentiation of MK signalling pathway may be a promising therapeutic strategy in the treatment of these disorders. PMID:25149366

  14. Locally infused taurine, GABA and homotaurine alter differently the striatal extracellular concentrations of dopamine and its metabolites in rats

    Microsoft Academic Search

    M. Ruotsalainen; M. Majasaari; J. Salimäki; L. Ahtee

    1998-01-01

    Summary We studiedin vivo the effects of locally infused taurine (50, 150, and 450 mM) on the striatal dopamine and its metabolites in comparison with those of GABA and homotaurine, a GABAA receptor agonist, in freely moving rats. The extracellular dopamine concentration was elevated maximally 2.5-, 2- and 4-fold by taurine, GABA and homotaurine, respectively. At 150 mM concentration, at

  15. GABA and Glutamate Pathways Are Spatially and Developmentally Affected in the Brain of Mecp2-Deficient Mice

    PubMed Central

    Matagne, Valérie; Ghata, Adeline; Villard, Laurent; Roux, Jean-Christophe

    2014-01-01

    Proper brain functioning requires a fine-tuning between excitatory and inhibitory neurotransmission, a balance maintained through the regulation and release of glutamate and GABA. Rett syndrome (RTT) is a rare genetic disorder caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene affecting the postnatal brain development. Dysfunctions in the GABAergic and glutamatergic systems have been implicated in the neuropathology of RTT and a disruption of the balance between excitation and inhibition, together with a perturbation of the electrophysiological properties of GABA and glutamate neurons, were reported in the brain of the Mecp2-deficient mouse. However, to date, the extent and the nature of the GABA/glutamate deficit affecting the Mecp2-deficient mouse brain are unclear. In order to better characterize these deficits, we simultaneously analyzed the GABA and glutamate levels in Mecp2-deficient mice at 2 different ages (P35 and P55) and in several brain areas. We used a multilevel approach including the quantification of GABA and glutamate levels, as well as the quantification of the mRNA and protein expression levels of key genes involved in the GABAergic and glutamatergic pathways. Our results show that Mecp2-deficient mice displayed regional- and age-dependent variations in the GABA pathway and, to a lesser extent, in the glutamate pathway. The implication of the GABA pathway in the RTT neuropathology was further confirmed using an in vivo treatment with a GABA reuptake inhibitor that significantly improved the lifespan of Mecp2-deficient mice. Our results confirm that RTT mouse present a deficit in the GABAergic pathway and suggest that GABAergic modulators could be interesting therapeutic agents for this severe neurological disorder. PMID:24667344

  16. The Anaphase-Promoting Complex (APC) ubiquitin ligase regulates GABA transmission at the C. elegans neuromuscular junction

    PubMed Central

    Kowalski, Jennifer R.; Dube, Hitesh; Touroutine, Denis; Rush, Kristen M.; Goodwin, Patricia R.; Carozza, Marc; Didier, Zachary; Francis, Michael M.; Juo, Peter

    2014-01-01

    Regulation of both excitatory and inhibitory synaptic transmission is critical for proper nervous system function. Aberrant synaptic signaling, including altered excitatory to inhibitory balance, is observed innumerous neurological diseases. The ubiquitin enzyme system controls the abundance of many synaptic proteins and thus plays a key role in regulating synaptic transmission. The Anaphase-Promoting Complex (APC) is a multi-subunit ubiquitin ligase that was originally discovered as a key regulator of protein turnover during the cell cycle. More recently, the APC has been shown to function in postmitotic neurons, where it regulates diverse processes such as synapse development and synaptic transmission at glutamatergic synapses. Here we report that the APC regulates synaptic GABA signaling by acting in motor neurons to control the balance of excitatory (acetylcholine) to inhibitory (GABA) transmission at the Caenorhabditis elegans neuromuscular junction (NMJ). Loss-of-function mutants in multiple APC subunits have increased muscle excitation at the NMJ; this phenotype is rescued by expression of the missing subunit in GABA neurons. Quantitative imaging and electrophysiological analyses indicate that APC mutants have decreased GABA release but normal cholinergic transmission. Consistent with this, APC mutants exhibit convulsions in a seizure assay sensitive to reductions in GABA signaling. Previous studies in other systems showed that the APC can negatively regulate the levels of the active zone protein SYD-2 Liprin-?. Similarly, we found that SYD-2 accumulates in APC mutants at GABAergic presynaptic sites. Finally, we found that the APC subunit EMB-27 CDC16 can localize to presynapses in GABA neurons. Together, our data suggest a model in which the APC acts at GABAergic presynapses to promote GABA release and inhibit muscle excitation. These findings are the first evidence that the APC regulates transmission at inhibitory synapses and have implications for understanding nervous system pathologies, such as epilepsy, that are characterized by misregulated GABA signaling. PMID:24321454

  17. Effects of the Nootropic Drug Nefiracetam on the GABA A Receptor-channel Complex in Dorsal Root Ganglion Neurons

    Microsoft Academic Search

    CHAO-SHENG HUANG; JENNY YAN MA; W MARSZALEC; T NARAHASHI

    1996-01-01

    The effects of nefiracetam on GABA-induced chloride currents were studied with rat dorsal root ganglion neurons in primary culture using the whole-cell patch-clamp technique. The dose-response curve for GABA-induced currents was shifted by 16 ?M to lower concentrations by 10 ?M nefiracetam while the maximal response was reduced by 22.84 ± 0.68%. Thus at a low concentration (10 ?M) of

  18. Molecular motor KIF5A is essential for GABA(A) receptor transport, and KIF5A deletion causes epilepsy.

    PubMed

    Nakajima, Kazuo; Yin, Xiling; Takei, Yosuke; Seog, Dae-Hyun; Homma, Noriko; Hirokawa, Nobutaka

    2012-12-01

    KIF5 (also known as kinesin-1) family members, consisting of KIF5A, KIF5B, and KIF5C, are microtubule-dependent molecular motors that are important for neuronal function. Among the KIF5s, KIF5A is neuron specific and highly expressed in the central nervous system. However, the specific roles of KIF5A remain unknown. Here, we established conditional Kif5a-knockout mice in which KIF5A protein expression was postnatally suppressed in neurons. Epileptic phenotypes were observed by electroencephalogram abnormalities in knockout mice because of impaired GABA(A) receptor (GABA(A)R)-mediated synaptic transmission. We also identified reduced cell surface expression of GABA(A)R in knockout neurons. Importantly, we identified that KIF5A specifically interacted with GABA(A)R-associated protein (GABARAP) that is known to be involved in GABA(A)R trafficking. KIF5A regulated neuronal surface expression of GABA(A)Rs via an interaction with GABARAP. These results provide an insight into the molecular mechanisms of KIF5A, which regulate inhibitory neural transmission. PMID:23217743

  19. GABA promotes the competitive selection of dendritic spines by controlling local Ca2+ signaling

    PubMed Central

    Hayama, Tatsuya; Noguchi, Jun; Watanabe, Satoshi; Takahashi, Noriko; Hayashi-Takagi, Akiko; Ellis-Davies, Graham C R; Matsuzaki, Masanori; Kasai, Haruo

    2014-01-01

    Activity-dependent competition of synapses plays a key role in neural organization and is often promoted by GABA; however, its cellular bases are poorly understood. Excitatory synapses of cortical pyramidal neurons are formed on small protrusions known as dendritic spines, which exhibit structural plasticity. We used two-color uncaging of glutamate and GABA in rat hippocampal CA1 pyramidal neurons and found that spine shrinkage and elimination were markedly promoted by the activation of GABAA receptors shortly before action potentials. GABAergic inhibition suppressed bulk increases in cytosolic Ca2+ concentrations, whereas it preserved the Ca2+ nanodomains generated by NMDA-type receptors, both of which were necessary for spine shrinkage. Unlike spine enlargement, spine shrinkage spread to neighboring spines (<15 ?m) and competed with their enlargement, and this process involved the actin-depolymerizing factor ADF/cofilin. Thus, GABAergic inhibition directly suppresses local dendritic Ca2+ transients and strongly promotes the competitive selection of dendritic spines. PMID:23974706

  20. Interactions between modulators of the GABA(A) receptor: Stiripentol and benzodiazepines.

    PubMed

    Fisher, Janet L

    2011-03-01

    Many patients with refractory epilepsy are treated with polytherapy, and nearly 15% of epilepsy patients receive two or more anti-convulsant agents. The anti-convulsant stiripentol is used as an add-on treatment for the childhood epilepsy syndrome known as severe myoclonic epilepsy in infancy (Dravet syndrome). Stiripentol has multiple mechanisms of action, both enhancing GABA(A) receptors and reducing activity of metabolic enzymes that break down other drugs. Stiripentol is typically co-administered with other anti-convulsants such as benzodiazepines which also act through GABA(A) receptor modulation. Stiripentol slows the metabolism of some of these drugs through inhibition of a variety of cytochrome P450 enzymes, but could also influence their effects on GABAergic neurotransmission. Is it rational to co-administer drugs which can act through the same target? To examine the potential interaction between these modulators, we transiently transfected HEK-293T cells to produce ?3?3?2L or ?3?3? recombinant GABA(A) receptors. Using whole-cell patch clamp recordings, we measured the response to each benzodiazepine alone and in combination with a maximally effective concentration of stiripentol. We compared the responses to four different benzodiazepines: diazepam, clonazepam, clobazam and norclobazam. In all cases we found that these modulators were equally effective in the presence and absence of stiripentol. The ?-containing receptors were insensitive to modulation by the benzodiazepines, which did not affect potentiation by stiripentol. These data suggest that stiripentol and the benzodiazepines act independently at GABA(A) receptors and that polytherapy could be expected to increase the maximum effect beyond either drug alone, even without consideration of changes in metabolism. PMID:21237147

  1. The GABA uptake inhibitor tiagabine promotes slow wave sleep in normal elderly subjects

    Microsoft Academic Search

    Stefan Mathias; Thomas C. Wetter; Axel Steiger; Marike Lancel

    2001-01-01

    Aging is associated with a dramatic decrease in slow wave sleep (SWS) and sleep consolidation. Previous studies revealed that various GABAA agonists and the GABA uptake inhibitor tiagabine augment slow frequency components in the EEG within non-REM sleep, and thus promote deep sleep in young individuals and\\/or rats. In the present double-blind, placebo-controlled study, we assessed the effect of a

  2. Perinatal exposure to GABA-transaminase inhibitor impaired psychomotor function in the developing and adult mouse

    Microsoft Academic Search

    T. Levav; T. Saar; L. Berkovich; H. Golan

    2004-01-01

    Antiepileptic drugs acting through the potentiation of GABA-ergic pathways have harmful effects on brain development. Increased risk of impaired intellectual development was reported in children born to women treated for epilepsy during pregnancy. Here we examined the vulnerability of the developing brain to treatment with one of the new antiepileptic drugs—vigabatrin—during two time periods in newborn mice (postnatal days 1–7

  3. Effects of continuous diazepam administration on GABA A subunit mRNA in rat brain

    Microsoft Academic Search

    C. Heninger; N. Saito; J. F. Tallman; K. M. Garrett; M. P. Vitek; R. S. Duman; D. W. Gallager

    1990-01-01

    Rats treated chronically with diazepam develop tolerance to diazepam effects and show changes in sensitivity of GABAergic\\u000a systems. In order to investigate possible molecular mechanisms associated with these changes, we have evaluated the effects\\u000a of acute and chronic diazepam treatment on levels of mRNA for the ?1 and ?1 subunits of the GABAA receptor. Northern blots were hybridized with32P-labeled GABA

  4. Short-Term Monocular Deprivation Alters GABA in the Adult Human Visual Cortex.

    PubMed

    Lunghi, Claudia; Emir, Uzay E; Morrone, Maria Concetta; Bridge, Holly

    2015-06-01

    Neuroplasticity is a fundamental property of the nervous system that is maximal early in life, within the critical period [1-3]. Resting GABAergic inhibition is necessary to trigger ocular dominance plasticity and to modulate the onset and offset of the critical period [4, 5]. GABAergic inhibition also plays a crucial role in neuroplasticity of adult animals: the balance between excitation and inhibition in the primary visual cortex (V1), measured at rest, modulates the susceptibility of ocular dominance to deprivation [6-10]. In adult humans, short-term monocular deprivation strongly modifies ocular balance, unexpectedly boosting the deprived eye, reflecting homeostatic plasticity [11, 12]. There is no direct evidence, however, to support resting GABAergic inhibition in homeostatic plasticity induced by visual deprivation. Here, we tested the hypothesis that GABAergic inhibition, measured at rest, is reduced by deprivation, as demonstrated by animal studies. GABA concentration in V1 of adult humans was measured using ultra-high-field 7T magnetic resonance spectroscopy before and after short-term monocular deprivation. After monocular deprivation, resting GABA concentration decreased in V1 but was unaltered in a control parietal area. Importantly, across participants, the decrease in GABA strongly correlated with the deprived eye perceptual boost measured by binocular rivalry. Furthermore, after deprivation, GABA concentration measured during monocular stimulation correlated with the deprived eye dominance. We suggest that reduction in resting GABAergic inhibition triggers homeostatic plasticity in adult human V1 after a brief period of abnormal visual experience. These results are potentially useful for developing new therapeutic strategies that could exploit the intrinsic residual plasticity of the adult human visual cortex. PMID:26004760

  5. Modeling Starburst Cells’ GABA B Receptors and Their Putative Role in Motion Sensitivity

    Microsoft Academic Search

    Norberto M. Grzywacz; Charles L. Zucker

    2006-01-01

    Neal and Cunningham (Neal, M. J., and J. R. Cunningham. 1995. J. Physiol. (Lond.). 482:363–372) showed that GABAB agonists and glycinergic antagonists enhance the light-evoked release of retinal acetylcholine. They proposed that glycinergic cells inhibit the cholinergic Starburst amacrine cells and are in turn inhibited by GABA through GABAB receptors. However, as recently shown, glycinergic cells do not appear to

  6. Reduced GABA Content in the Motor Thalamus during Effective Deep Brain Stimulation of the Subthalamic Nucleus

    PubMed Central

    Stefani, Alessandro; Fedele, Ernesto; Pierantozzi, Mariangela; Galati, Salvatore; Marzetti, Francesco; Peppe, Antonella; Pastore, Francesco Saverio; Bernardi, Giorgio; Stanzione, Paolo

    2011-01-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN), in Parkinson's disease (PD) patients, is a well established therapeutic option, but its mechanisms of action are only partially known. In our previous study, the clinical transitions from OFF- to ON-state were not correlated with significant changes of GABA content inside GPi or substantia nigra reticulata. Here, biochemical effects of STN-DBS have been assessed in putamen (PUT), internal pallidus (GPi), and inside the antero-ventral thalamus (VA), the key station receiving pallidothalamic fibers. In 10 advanced PD patients undergoing surgery, microdialysis samples were collected before and during STN-DBS. cGMP, an index of glutamatergic transmission, was measured in GPi and PUT by radioimmunoassay, whereas GABA from VA was measured by HPLC. During clinically effective STN-DBS, we found a significant decrease in GABA extracellular concentrations in VA (?30%). Simultaneously, cGMP extracellular concentrations were enhanced in PUT (+200%) and GPi (+481%). These findings support a thalamic dis-inhibition, in turn re-establishing a more physiological corticostriatal transmission, as the source of motor improvement. They indirectly confirm the relevance of patterning (instead of mere changes of excitability) and suggest that a rigid interpretation of the standard model, at least when it indicates the hyperactive indirect pathway as key feature of hypokinetic signs, is unlikely to be correct. Finally, given the demonstration of a key role of VA in inducing clinical relief, locally administration of drugs modulating GABA transmission in thalamic nuclei could become an innovative therapeutic strategy. PMID:21519387

  7. Fragment of GABA(A) receptor containing key ligand-binding residues overexpressed in Escherichia coli.

    PubMed Central

    Xue, H.; Chu, R.; Hang, J.; Lee, P.; Zheng, H.

    1998-01-01

    GABA(A) receptor plays a major role in inhibitory synaptic transmission in the central nervous system and is the target of drugs such as the benzodiazepine tranquilizers. The polymeric membrane protein nature of GABA(A) receptor has rendered structural elucidation of the receptor a formidable task, greatly hampering structure-based drug design. We report here the first expression in Escherichia coli of a fragment of GABA(A) receptor. This 131-residue fragment, spanning Cys166 to Leu296 of human GABAA receptor alpha1 subunit, contains residues previously suggested to be involved in benzodiazepine binding. The overexpressed non-fusion recombinant protein was purified to near homogeneity and characterized by circular dichroism (CD), which showed that the recombinant protein has well defined secondary structures where beta-strands are dominant. The stability of the secondary structures was demonstrated by CD spectra at high pH and elevated temperature. Excluding part of the sequences from the carboxyl terminal of the fragment resulted in dramatic changes in the secondary structures comparable to the effects caused by SDS denaturation. Our results therefore suggest that the 131-residue fragment harbors an integral structural domain of the receptor. The overexpression of the recombinant protein fragment thus opens the way to the biochemical and structural studies of a functionally important region of the receptor, and exemplifies an effective approach of expression and characterization that potentially may be extended to other members of the ligand gated channel receptor superfamily, to which the GABA(A) receptor belongs. PMID:9514278

  8. Species dependent dual modulation of the benzodiazepine/GABA receptor chloride channel by dihydroergosine

    SciTech Connect

    Pericic, D.; Tvrdeic, A. (Rudjer Boskovic Institute, Zagreb (Yugoslavia))

    1990-01-01

    Dihydroergosine enhanced the incidence of bicuculline induced convulsions in female rats, while 100 mg/kg of dihydroergosine given to female mice made 45% convulsive dose of bicuculline to be subconvulsive. The same dose of dihydroergosine enhanced in mice the latency of bicuculline-induced convulsions. Although, in in vitro experiments dihydroergosine showed very weak ability to prevent the binding of {sup 3}H-muscimol, the drug was able to diminish and to augment the IC{sub 50} of bicuculline and GABA when added to crude synaptosomal pellet of the rat and mouse brain respectively. Lower concentrations of dihydroergosine stimulated and higher inhibited {sup 3}H-TBOB binding to the crude synaptosomal pellet of the rat brain. In the preparation of mouse brain dihydroergosine produced only inhibition of {sup 3}H-TBOB binding. Only slight quantitative differences were observed in bicuculline-induced stimulation and in GABA- and diazepam-induced inhibition of {sup 3}H-TBOB binding between the two species. The results suggest that the opposite species-dependent effects of dihydroergosine on bicuculline-induced convulsions are due to the ability of this drug to modulate species-dependently the benzodiazepine/GABA receptor chloride channel complex.

  9. Target-specific suppression of GABA release from parvalbumin interneurons in the basolateral amygdala by dopamine.

    PubMed

    Chu, Hong-Yuan; Ito, Wataru; Li, Jiayang; Morozov, Alexei

    2012-10-17

    Dopamine (DA) in the basolateral amygdala (BLA) promotes fear learning by disinhibiting principal neurons (PNs) and enabling synaptic plasticity in their sensory inputs. While BLA interneurons (INs) are heterogeneous, it is unclear which interneuron subtypes decrease GABAergic input to PNs in the presence of DA. Here, using cell type-selective photostimulation by channelrhodopsin 2 in BLA slices from mouse brain, we examined the role of parvalbumin-positive INs (PV-INs), the major interneuronal subpopulation in BLA, in the disinhibitory effect of DA. We found that DA selectively suppressed GABAergic transmission from PV-INs to PNs by acting on presynaptic D(2) receptors, and this effect was mimicked by Rp-cAMP, an inhibitor of cAMP-dependent signaling. In contrast, DA did not alter GABA release from PV-INs to INs. Furthermore, neither suppressing cAMP-dependent signaling by Rp-cAMP nor enhancing it by forskolin altered GABA release from PV-INs to BLA INs. Overall, DA disinhibits BLA, at least in part, by suppressing GABA release from PV-INs in the target cell-specific manner that results from differential control of this release by cAMP-dependent signaling. PMID:23077066

  10. Nerve regenerative effects of GABA-B ligands in a model of neuropathic pain.

    PubMed

    Magnaghi, Valerio; Castelnovo, Luca Franco; Faroni, Alessandro; Cavalli, Erica; Caffino, Lucia; Colciago, Alessandra; Procacci, Patrizia; Pajardi, Giorgio

    2014-01-01

    Neuropathic pain arises as a direct consequence of a lesion or disease affecting the peripheral somatosensory system. It may be associated with allodynia and increased pain sensitivity. Few studies correlated neuropathic pain with nerve morphology and myelin proteins expression. Our aim was to test if neuropathic pain is related to nerve degeneration, speculating whether the modulation of peripheral GABA-B receptors may promote nerve regeneration and decrease neuropathic pain. We used the partial sciatic ligation- (PSL-) induced neuropathic model. The biochemical, morphological, and behavioural outcomes of sciatic nerve were analysed following GABA-B ligands treatments. Simultaneous 7-days coadministration of baclofen (10 mg/kg) and CGP56433 (3 mg/kg) alters tactile hypersensitivity. Concomitantly, specific changes of peripheral nerve morphology, nerve structure, and myelin proteins (P0 and PMP22) expression were observed. Nerve macrophage recruitment decreased and step coordination was improved. The PSL-induced changes in nociception correlate with altered nerve morphology and myelin protein expression. Peripheral synergic effects, via GABA-B receptor activation, promote nerve regeneration and likely ameliorate neuropathic pain. PMID:25165701

  11. Traumatic alterations in GABA signaling disrupt hippocampal network activity in the developing brain

    PubMed Central

    Dzhala, Volodymyr; Valeeva, Guzel; Glykys, Joseph; Khazipov, Rustem; Staley, Kevin

    2012-01-01

    Severe head trauma causes widespread neuronal shear injuries and acute seizures. Shearing of neural processes might contribute to seizures by disrupting the transmembrane ion gradients that subserve normal synaptic signaling. To test this possibility, we investigated changes in intracellular chloride concentration ([Cl?]i) associated with the widespread neural shear injury induced during preparation of acute brain slices. In hippocampal slices and intact hippocampal preparations from immature CLM-1 mice, increases in [Cl?]i correlated with disruption of neural processes and biomarkers of cell injury. Traumatized neurons with higher [Cl?]i demonstrated excitatory GABA signaling, remained synaptically active, and facilitated network activity as assayed by the frequency of extracellular action potentials and spontaneous network-driven oscillations. These data support a more inhibitory role for GABA in the unperturbed immature brain, demonstrate the utility of the acute brain slice preparation for the study of the consequences of trauma, and provide potential mechanisms for both GABA-mediated excitatory network events in the slice preparation and early post-traumatic seizures. PMID:22442068

  12. Nerve Regenerative Effects of GABA-B Ligands in a Model of Neuropathic Pain

    PubMed Central

    Cavalli, Erica; Pajardi, Giorgio

    2014-01-01

    Neuropathic pain arises as a direct consequence of a lesion or disease affecting the peripheral somatosensory system. It may be associated with allodynia and increased pain sensitivity. Few studies correlated neuropathic pain with nerve morphology and myelin proteins expression. Our aim was to test if neuropathic pain is related to nerve degeneration, speculating whether the modulation of peripheral GABA-B receptors may promote nerve regeneration and decrease neuropathic pain. We used the partial sciatic ligation- (PSL-) induced neuropathic model. The biochemical, morphological, and behavioural outcomes of sciatic nerve were analysed following GABA-B ligands treatments. Simultaneous 7-days coadministration of baclofen (10?mg/kg) and CGP56433 (3?mg/kg) alters tactile hypersensitivity. Concomitantly, specific changes of peripheral nerve morphology, nerve structure, and myelin proteins (P0 and PMP22) expression were observed. Nerve macrophage recruitment decreased and step coordination was improved. The PSL-induced changes in nociception correlate with altered nerve morphology and myelin protein expression. Peripheral synergic effects, via GABA-B receptor activation, promote nerve regeneration and likely ameliorate neuropathic pain. PMID:25165701

  13. The development of potential new fluorine-18 labelled radiotracers for imaging the GABA(A) receptor.

    PubMed

    Jackson, Alexander; Guilbert, Benedicte B; Plant, Stuart D; Goggi, Julian; Battle, Mark R; Woodcraft, John L; Gaeta, Alessandra; Jones, Clare L; Bouvet, Denis R; Jones, Paul A; O'Shea, Dennis M; Zheng, Penny Hao; Brown, Samantha L; Ewan, Amanda L; Trigg, William

    2013-02-01

    Positron emission tomography (PET) using the tracer [(11)C]Flumazenil has shown changes in the distribution and expression of the GABA(A) receptor in a range of neurological conditions and injury states. We aim to develop a fluorine-18 labelled PET agent with comparable properties to [(11)C]Flumazenil. In this study we make a direct comparison between the currently known fluorine-18 labelled GABA(A) radiotracers and novel imidazobenzodiazepine ligands. A focussed library of novel compound was designed and synthesised where the fluorine containing moiety and the position of attachment is varied. The in vitro affinity of twenty-two compounds for the GABA(A) receptor was measured. Compounds containing a fluoroalkyl amide or a longer chain ester group were eliminated due to low potency. The fluorine-18 radiochemistry of one compound from each structural type was assessed to confirm that an automated radiosynthesis in good yield was feasible. Eleven of the novel compounds assessed appeared suitable for in vivo assessment as PET tracers. PMID:23265897

  14. Dopamine Excites Nucleus Accumbens Neurons through the Differential Modulation of Glutamate and GABA Release

    PubMed Central

    Hjelmstad, Gregory O.

    2007-01-01

    Afferent activity into the nucleus accumbens (NAc) occurs in bursts of action potentials. However, it is unclear how synapses in this nucleus respond to such bursts, or how these responses are altered by dopamine (DA). I examined the effects of DA on excitatory and inhibitory responses to trains of stimuli in rat NAc slices. Both EPSCs and IPSCs showed use-dependent depression during trains. Although DA inhibited both glutamate and GABA release in the NAc, it differentially inhibited release during trains. The inhibition of IPSCs persisted throughout the train of stimuli, whereas the inhibition of EPSCs progressively diminished. This differential modulation may be explained by a calcium-dependent change in the recovery from depression at the GABA synapses, where DA acts by decreasing Ca2+ entry. Thus, at later stages of sustained stimulation, DA preferentially inhibits GABA release, producing a net excitatory effect during bursts suggesting a mechanism for enhancing the contrast between competing inputs into the NAc, as well as for affecting long-term plasticity in this structure. PMID:15456835

  15. Effects of ?-Aminobutyric acid transporter 1 inhibition by tiagabine on brain glutamate and ?-Aminobutyric acid metabolism in the anesthetized rat In vivo.

    PubMed

    Patel, Anant B; de Graaf, Robin A; Rothman, Douglas L; Behar, Kevin L

    2015-07-01

    ?-Aminobutyric acid (GABA) clearance from the extracellular space after release from neurons involves reuptake into terminals and astrocytes through GABA transporters (GATs). The relative flows through these two pathways for GABA released from neurons remains unclear. This study determines the effect of tiagabine, a selective inhibitor of neuronal GAT-1, on the rates of glutamate (Glu) and GABA metabolism and GABA resynthesis via the GABA-glutamine (Gln) cycle. Halothane-anesthetized rats were administered tiagabine (30 mg/kg, i.p.) and 45 min later received an intravenous infusion of either [1,6-(13) C2 ]glucose (in vivo) or [2-(13) C]acetate (ex vivo). Nontreated rats served as controls. Metabolites and (13) C enrichments were measured with (1) H-[(13) C]-nuclear magnetic resonance spectroscopy and referenced to their corresponding endpoint values measured in extracts from in situ frozen brain. Metabolic flux estimates of GABAergic and glutamatergic neurons were determined by fitting a metabolic model to the (13) C turnover data measured in vivo during [1,6-(13) C2 ]glucose infusion. Tiagabine-treated rats were indistinguishable (P?>?0.05) from controls in tissue amino acid levels and in (13) C enrichments from [2-(13) C]acetate. Tiagabine reduced average rates of glucose oxidation and neurotransmitter cycling in both glutamatergic neurons (?18%, CMRglc(ox)Glu : control, 0.27?±?0.05 vs. tiagabine, 0.22?±?0.04 µmol/g/min; ?11%, Vcyc(Glu-Gln) : control 0.23?±?0.05 vs. tiagabine 0.21?±?0.04 µmol/g/min) and GABAergic neurons (?18-25%, CMRglc(ox)GABA : control 0.09?±?0.02 vs. tiagabine 0.07?±?0.03 µmol/g/min; Vcyc(GABA-Gln) : control 0.08?±?0.02 vs. tiagabine 0.07?±?0.03 µmol/g/min), but the changes in glutamatergic and GABAergic fluxes were not significant (P?>?0.10). The results suggest that any reduction in GABA metabolism by tiagabine might be an indirect response to reduced glutamatergic drive rather than direct compensatory effects. © 2015 Wiley Periodicals, Inc. PMID:25663257

  16. Membrane transporters mediating root signalling and adaptive responses to oxygen deprivation and soil flooding.

    PubMed

    Shabala, Sergey; Shabala, Lana; Barcelo, Juan; Poschenrieder, Charlotte

    2014-10-01

    This review provides a comprehensive assessment of a previously unexplored topic: elucidating the role that plasma- and organelle-based membrane transporters play in plant-adaptive responses to flooding. We show that energy availability and metabolic shifts under hypoxia and anoxia are critical in regulating membrane-transport activity. We illustrate the high tissue and time dependence of this regulation, reveal the molecular identity of transporters involved and discuss the modes of their regulation. We show that both reduced oxygen availability and accumulation of transition metals in flooded roots result in a reduction in the cytosolic K(+) pool, ultimately determining the cell's fate and transition to programmed cell death (PCD). This process can be strongly affected by hypoxia-induced changes in the amino acid pool profile and, specifically, ?-amino butyric acid (GABA) accumulation. It is suggested that GABA plays an important regulatory role, allowing plants to proceed with H2 O2 signalling to activate a cascade of genes that mediate plant adaptation to flooding while at the same time, preventing the cell from entering a 'suicide program'. We conclude that progress in crop breeding for flooding tolerance can only be achieved by pyramiding the numerous physiological traits that confer efficient energy maintenance, cytosolic ion homeostasis, and reactive oxygen species (ROS) control and detoxification. PMID:24689809

  17. GABAergic dysfunction mediates autism-like stereotypies and Rett syndrome phenotypes

    PubMed Central

    Chao, Hsiao-Tuan; Chen, Hongmei; Samaco, Rodney C.; Xue, Mingshan; Chahrour, Maria; Yoo, Jong; Neul, Jeffrey L.; Gong, Shiaoching; Lu, Hui-Chen; Heintz, Nathaniel; Ekker, Marc; Rubenstein, John L.R.; Noebels, Jeffrey L.; Rosenmund, Christian; Zoghbi, Huda Y.

    2010-01-01

    Summary Mutations in the X-linked MECP2, which encodes the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome (RTT) and several neurodevelopmental disorders including cognitive disorders, autism, juvenile-onset schizophrenia, and encephalopathy with early lethality. RTT is characterized by apparently normal early development followed by regression, motor abnormalities, seizures, and features of autism, especially stereotyped behaviors. The mechanisms mediating these striking features are poorly understood. Here we show that mice lacking Mecp2 from ?-amino-butyric-acid-(GABA)-ergic neurons recapitulate numerous RTT and autistic features, including repetitive behaviors. Loss of MeCP2 from a subset of forebrain GABAergic neurons also recapitulates many features of RTT. MeCP2-deficient GABAergic neurons show reduced inhibitory quantal size consistent with presynaptic reduction in glutamic acid decarboxylase-1 and -2 levels and GABA immunoreactivity. These data demonstrate that MeCP2 is critical for normal GABAergic neuronal function and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes. PMID:21068835

  18. The GAD65 knock out mouse - a model for GABAergic processes in fear- and stress-induced psychopathology.

    PubMed

    Müller, Iris; Çal??kan, Gürsel; Stork, Oliver

    2015-01-01

    The ?-amino butyric acid (GABA) synthetic enzyme glutamic acid decarboxylase (GAD)65 is critically involved in the activity-dependent regulation of GABAergic inhibition in the central nervous system. It is also required for the maturation of the GABAergic system during adolescence, a phase that is critical for the development of several neuropsychiatric diseases. Mice bearing a null mutation of the GAD65 gene develop hyperexcitability of the amygdala and hippocampus, and a phenotype of increased anxiety and pathological fear memory reminiscent of posttraumatic stress disorder. Although genetic association of GAD65 in human has not yet been reported, these findings are in line with observations of reduced GABAergic function in these brain regions of anxiety disorder patients. The particular value of GAD65(-/-) mice thus lies in modeling the effects of reduced GABAergic function in the mature nervous system. The expression of GAD65 and a second GAD isozyme, GAD67, are differentially regulated in response to stress in limbic brain areas suggesting that by controlling GABAergic inhibition these enzymes determine the vulnerability for the development of pathological anxiety and other stress-induced phenotypes. In fact, we could recently show that GAD65 haplodeficiency, which results in delayed postnatal increase of GABA levels, provides resilience to juvenile-stress-induced anxiety to GAD65(+/-) mice thus foiling the increased fear and anxiety in homozygous GAD65(-/-) mice. PMID:25470336

  19. Characterization of the carrier-mediated [3H]GABA release from isolated synaptic plasma membrane vesicles.

    PubMed

    Gonçalves, P P; Carvalho, A P

    1995-02-01

    Synaptic plasma membrane (SPM) vesicles were isolated under conditions which preserve most of their biochemical properties. Therefore, they appeared particularly useful to study the cytoplasmic GABA release mechanism through its neuronal transporter without interference of the exocytotic mechanism. In this work, we utilized SPM vesicles isolated from sheep brain cortex to investigate the process of [3H]GABA release induced by ouabain, veratridine and Na+ substitution by other monovalent cations (K+, Rb+, Li+, and choline). We observed that ouabain is unable to release [3H]GABA previously accumulated in the vesicles and, in our experimental conditions, it does not act as a depolarizing agent. In contrast, synaptic plasma membrane vesicles release [3H]GABA when veratridine is present in the external medium, and this process is sensitive to extravesicular Na+ and it is inhibited by extravesicular Ca2+ (1mM) under conditions which appear to permit its entry. However, veratridine-induced [3H]GABA release does not require membrane depolarization, since this drug does not induce any significant alteration in the membrane potential, which is determined by the magnitude of the ionic gradients artificially imposed to the vesicles. The substitution of Na+ by other monovalent cations promotes [3H]GABA release by altering the Na+ concentration gradient and the membrane potential of SPM vesicles. In the case of choline and Li+, we observed that the fraction of [3H]GABA released relatively to the total amount of neurotransmitter released by K+ or Rb+ is about 28% and 68%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7783842

  20. Zebrafish larvae exposed to ginkgotoxin exhibit seizure-like behavior that is relieved by pyridoxal-5'-phosphate, GABA and anti-epileptic drugs.

    PubMed

    Lee, Gang-Hui; Sung, Shian-Ying; Chang, Wen-Ni; Kao, Tseng-Ting; Du, Hung-Chi; Hsiao, Tsun-Hsien; Safo, Martin K; Fu, Tzu-Fun

    2012-11-01

    The etiology of epilepsy is a very complicated, multifactorial process that is not completely understood. Therefore, the availability of epilepsy animal models induced by different mechanisms is crucial in advancing our knowledge and developing new therapeutic regimens for this disorder. Considering the advantages of zebrafish, we have developed a seizure model in zebrafish larvae using ginkgotoxin, a neurotoxin naturally occurring in Ginkgo biloba and hypothesized to inhibit the formation of the neurotransmitter ?-aminobutyric acid (GABA). We found that a 2-hour exposure to ginkgotoxin induced a seizure-like behavior in zebrafish larvae. This seizure-like swimming pattern was alleviated by the addition of either pyridoxal-5'-phosphate (PLP) or GABA and responded quickly to the anti-convulsing activity of gabapentin and phenytoin, two commonly prescribed anti-epileptic drugs (AEDs). Unexpectedly, the ginkgotoxin-induced PLP depletion in our experimental setting did not affect the homeostasis of folate-mediated one-carbon metabolism, another metabolic pathway playing a crucial role in neural function that also relies on the availability of PLP. This ginkgotoxin-induced seizure behavior was also relieved by primidone, which had been tested on a pentylenetetrazole-induced zebrafish seizure model but failed to rescue the seizure phenotype, highlighting the potential use and complementarity of this ginkgotoxin-induced seizure model for AED development. Structural and morphological characterization showed that a 2-hour ginkgotoxin exposure did not cause appreciable changes in larval morphology and tissues development. In conclusion, our data suggests that this ginkgotoxin-induced seizure in zebrafish larvae could serve as an in vivo model for epileptic seizure research and potential AED screening. PMID:22736461