Subunit Arrangement and Phenylethanolamine Binding in GluN1/GluN2B NMDA Receptors

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

E Karakas; N Simorowski; H Furukawa

2011-12-31

Since it was discovered that the anti-hypertensive agent ifenprodil has neuroprotective activity through its effects on NMDA (N-methyl-D-aspartate) receptors, a determined effort has been made to understand the mechanism of action and to develop improved therapeutic compounds on the basis of this knowledge. Neurotransmission mediated by NMDA receptors.

Combination of behaviorally sub-effective doses of glutamate NMDA and dopamine D1 receptor antagonists impairs executive function.

PubMed

Desai, Sagar J; Allman, Brian L; Rajakumar, Nagalingam

2017-04-14

Impairment of executive function is a core feature of schizophrenia. Preclinical studies indicate that injections of either N-methyl d-aspartate (NMDA) or dopamine D 1 receptor blockers impair executive function. Despite the prevailing notion based on postmortem findings in schizophrenia that cortical areas have marked suppression of glutamate and dopamine, recent in vivo imaging studies suggest that abnormalities of these neurotransmitters in living patients may be quite subtle. Thus, we hypothesized that modest impairments in both glutamate and dopamine function can act synergistically to cause executive dysfunction. In the present study, we investigated the effect of combined administration of "behaviorally sub-effective" doses of NMDA and dopamine D 1 receptor antagonists on executive function. An operant conditioning-based set-shifting task was used to assess behavioral flexibility in rats that were systemically injected with NMDA and dopamine D 1 receptor antagonists individually or in combination prior to task performance. Separate injections of the NMDA receptor antagonist, MK-801, and the dopamine D 1 receptor antagonist, SCH 23390, at low doses did not impair set-shifting; however, the combined administration of these same behaviorally sub-effective doses of the antagonists significantly impaired the performance during set-shifting without affecting learning, retrieval of the memory of the initial rule, latency of responses or the number of omissions. The combined treatment also produced an increased number of perseverative errors. Our results indicate that NMDA and D 1 receptor blockade act synergistically to cause behavioral inflexibility, and as such, subtle abnormalities in glutamatergic and dopaminergic systems may act cooperatively to cause deficits in executive function. Copyright © 2017 Elsevier B.V. All rights reserved.

TAAR1 Modulates Cortical Glutamate NMDA Receptor Function

PubMed Central

Espinoza, Stefano; Lignani, Gabriele; Caffino, Lucia; Maggi, Silvia; Sukhanov, Ilya; Leo, Damiana; Mus, Liudmila; Emanuele, Marco; Ronzitti, Giuseppe; Harmeier, Anja; Medrihan, Lucian; Sotnikova, Tatyana D; Chieregatti, Evelina; Hoener, Marius C; Benfenati, Fabio; Tucci, Valter; Fumagalli, Fabio; Gainetdinov, Raul R

2015-01-01

Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled receptor expressed in the mammalian brain and known to influence subcortical monoaminergic transmission. Monoamines, such as dopamine, also play an important role within the prefrontal cortex (PFC) circuitry, which is critically involved in high-o5rder cognitive processes. TAAR1-selective ligands have shown potential antipsychotic, antidepressant, and pro-cognitive effects in experimental animal models; however, it remains unclear whether TAAR1 can affect PFC-related processes and functions. In this study, we document a distinct pattern of expression of TAAR1 in the PFC, as well as altered subunit composition and deficient functionality of the glutamate N-methyl-D-aspartate (NMDA) receptors in the pyramidal neurons of layer V of PFC in mice lacking TAAR1. The dysregulated cortical glutamate transmission in TAAR1-KO mice was associated with aberrant behaviors in several tests, indicating a perseverative and impulsive phenotype of mutants. Conversely, pharmacological activation of TAAR1 with selective agonists reduced premature impulsive responses observed in the fixed-interval conditioning schedule in normal mice. Our study indicates that TAAR1 plays an important role in the modulation of NMDA receptor-mediated glutamate transmission in the PFC and related functions. Furthermore, these data suggest that the development of TAAR1-based drugs could provide a novel therapeutic approach for the treatment of disorders related to aberrant cortical functions. PMID:25749299

Nedd4 is a Specific E3 Ubiquitin Ligase for the NMDA Receptor Subunit GluN2D

PubMed Central

Gautam, Vivek; Trinidad, Jonathan C.; Rimerman, Ronald A.; Costa, Blaise M.; Burlingame, Alma L.; Monaghan, Daniel T.

2013-01-01

NMDA receptors are a family of glutamate-gated ion channels that regulate various CNS functions such as synaptic plasticity and learning. However hypo-or hyper-activation of NMDA receptors is critically involved in many neurological and psychiatric conditions such as pain, stroke, epilepsy, neurodegeneration, schizophrenia, and depression. Thus, it is important to identify mechanisms (such as by targeted ubiquitination) that regulate the levels of individual subtypes of NMDA receptors. In this study, we used a series of tagged, carboxy terminal constructs of GluN2D to identify associating proteins from rat brain. Of seven different GluN2D C-terminal fragments used as bait, only the construct containing amino acids 983-1097 associated with an E3 ligase, Nedd4. A direct interaction between GluN2D and Nedd4 was confirmed both in vivo and in vitro. This association is mediated by an interaction between GluN2D's C-terminal PPXY motif and the 2nd and 3rd WW domains of Nedd4. Of the four GluN2 subunits, Nedd4 directly interacted with GluN2D and also weakly with GluN2A. Nedd4 coexpression with GluN2D enhances GluN2D ubiquitination and reduces GluN1/GluN2D NMDA receptor responses. These results identify Nedd4 as a novel binding partner for GluN2D and suggest a mechanism for the regulation of NMDA receptors that contains GluN2D subunit through ubiquitination-dependent downregulation. PMID:23639431

Glycine Potentiates AMPA Receptor Function through Metabotropic Activation of GluN2A-Containing NMDA Receptors

PubMed Central

Li, Li-Jun; Hu, Rong; Lujan, Brendan; Chen, Juan; Zhang, Jian-Jian; Nakano, Yasuko; Cui, Tian-Yuan; Liao, Ming-Xia; Chen, Jin-Cao; Man, Heng-Ye; Feng, Hua; Wan, Qi

2016-01-01

NMDA receptors are Ca2+-permeable ion channels. The activation of NMDA receptors requires agonist glutamate and co-agonist glycine. Recent evidence indicates that NMDA receptor also has metabotropic function. Here we report that in cultured mouse hippocampal neurons, glycine increases AMPA receptor-mediated currents independent of the channel activity of NMDA receptors and the activation of glycine receptors. The potentiation of AMPA receptor function by glycine is antagonized by the inhibition of ERK1/2. In the hippocampal neurons and in the HEK293 cells transfected with different combinations of NMDA receptors, glycine preferentially acts on GluN2A-containing NMDA receptors (GluN2ARs), but not GluN2B-containing NMDA receptors (GluN2BRs), to enhance ERK1/2 phosphorylation independent of the channel activity of GluN2ARs. Without requiring the channel activity of GluN2ARs, glycine increases AMPA receptor-mediated currents through GluN2ARs. Thus, these results reveal a metabotropic function of GluN2ARs in mediating glycine-induced potentiation of AMPA receptor function via ERK1/2 activation. PMID:27807405

Heteroreceptor Complexes Formed by Dopamine D1, Histamine H3, and N-Methyl-D-Aspartate Glutamate Receptors as Targets to Prevent Neuronal Death in Alzheimer's Disease.

PubMed

Rodríguez-Ruiz, Mar; Moreno, Estefanía; Moreno-Delgado, David; Navarro, Gemma; Mallol, Josefa; Cortés, Antonio; Lluís, Carme; Canela, Enric I; Casadó, Vicent; McCormick, Peter J; Franco, Rafael

2017-08-01

Alzheimer's disease (AD) is a neurodegenerative disorder causing progressive memory loss and cognitive dysfunction. Anti-AD strategies targeting cell receptors consider them as isolated units. However, many cell surface receptors cooperate and physically contact each other forming complexes having different biochemical properties than individual receptors. We here report the discovery of dopamine D 1 , histamine H 3 , and N-methyl-D-aspartate (NMDA) glutamate receptor heteromers in heterologous systems and in rodent brain cortex. Heteromers were detected by co-immunoprecipitation and in situ proximity ligation assays (PLA) in the rat cortex where H 3 receptor agonists, via negative cross-talk, and H 3 receptor antagonists, via cross-antagonism, decreased D 1 receptor agonist signaling determined by ERK1/2 or Akt phosphorylation, and counteracted D 1 receptor-mediated excitotoxic cell death. Both D 1 and H 3 receptor antagonists also counteracted NMDA toxicity suggesting a complex interaction between NMDA receptors and D 1 -H 3 receptor heteromer function. Likely due to heteromerization, H 3 receptors act as allosteric regulator for D 1 and NMDA receptors. By bioluminescence resonance energy transfer (BRET), we demonstrated that D 1 or H 3 receptors form heteromers with NR1A/NR2B NMDA receptor subunits. D 1 -H 3 -NMDA receptor complexes were confirmed by BRET combined with fluorescence complementation. The endogenous expression of complexes in mouse cortex was determined by PLA and similar expression was observed in wild-type and APP/PS1 mice. Consistent with allosteric receptor-receptor interactions within the complex, H 3 receptor antagonists reduced NMDA or D 1 receptor-mediated excitotoxic cell death in cortical organotypic cultures. Moreover, H 3 receptor antagonists reverted the toxicity induced by ß 1-42 -amyloid peptide. Thus, histamine H 3 receptors in D 1 -H 3 -NMDA heteroreceptor complexes arise as promising targets to prevent neurodegeneration.

Activation of µ-opioid receptors and block of KIR3 potassium channels and NMDA receptor conductance by l- and d-methadone in rat locus coeruleus

PubMed Central

Matsui, Aya; Williams, John T

2010-01-01

BACKGROUND AND PURPOSE Methadone activates opioid receptors to increase a potassium conductance mediated by G-protein-coupled, inwardly rectifying, potassium (KIR3) channels. Methadone also blocks KIR3 channels and N-methyl-D-aspartic acid (NMDA) receptors. However, the concentration dependence and stereospecificity of receptor activation and channel blockade by methadone on single neurons has not been characterized. EXPERIMENTAL APPROACH Intracellular and whole-cell recording were made from locus coeruleus neurons in brain slices and the activation of µ-opioid receptors and blockade of KIR3 and NMDA channels with l- and d-methadone was examined. KEY RESULTS The potency of l-methadone, measured by the amplitude of hyperpolarization was 16.5-fold higher than with d-methadone. A maximum hyperpolarization was caused by both enantiomers (∼30 mV); however, the maximum outward current measured with whole-cell voltage-clamp recording was smaller than the current induced by [Met]5enkephalin. The KIR3 conductance induced by activation of α2-adrenoceptors was decreased with high concentrations of l- and d-methadone (10–30 µM). In addition, methadone blocked the resting inward rectifying conductance (KIR). Both l- and d-methadone blocked the NMDA receptor-dependent current. The block of NMDA receptor-dependent current was voltage-dependent suggesting that methadone acted as a channel blocker. CONCLUSIONS AND IMPLICATIONS Methadone activated µ-opioid receptors at low concentrations in a stereospecific manner. KIR3 and NMDA receptor channel block was not stereospecific and required substantially higher concentrations. The separation in the concentration range suggests that the activation of µ-opioid receptors rather than the channel blocking properties mediate both the therapeutic and toxic actions of methadone. PMID:20659105

Genetic differences in NMDA and D1 receptor levels, and operant responding for food and morphine in Lewis and Fischer 344 rats.

PubMed

Martín, Sonsoles; Lyupina, Yulia; Crespo, José Antonio; González, Begoña; García-Lecumberri, Carmen; Ambrosio, Emilio

2003-05-30

addition, a basal higher NMDA and D(1) receptor levels of LEW rats compared to F344 rats may participate in the neurochemical background that mediates the behavioral differences between both inbred rat strains.

[The role of glycine binding site in NMDA receptor--interactions between NMDA and D-serine in artificial anoxia/agycemia rat hippocampus].

PubMed

Kawasaki, Kazuyoshi; Ogawa, Seturou

2003-01-01

NMDA receptor contributes to cause neuronal death in anoxic condition. It is not known how a part of NMDA receptors, NMDA-binding site and/or glycine-binding site, influence neuronal damage in rats' hippocampus in vitro. Rats' hippocampus, labeled with norepinephrine (3H-NE), was incubated in artificial cerebrospinal fluid (aCSF) and we measured 3H-NE in superfusion solution and remaining tissue. Glucose was eliminated from aCSF and 95% N2 + 5% CO2 produced the anoxic state. The amount of 3H-NE release increased in anoxia with NMDA (NMDA-binding site agonist), while there was no influence on NMDA receptor in non-anoxic state even after D-serine (glycine-binding site agonist) has been administered. The 3H-NE was released more when D-serine (100 mu mM) and NMDA (100 mu mM) were administered together than when only D-serine (10 mu mM, 100 mu mM, 1000 mu mM) in anoxia or NMDA (10 mu mM, 100 mu mM, 1000 mu mM) in anoxia was administered. Glycine-binding site agonist alone does not act significantly but ion channels in NMDA receptor open more and become more effective when both glycine-binding site agonist and NMDA-binding site agonist exist, suggesting that there are interactions between NMDA-binding site and glycine-binding site in NMDA-receptor during anoxia.

Basic pharmacology of NMDA receptors.

PubMed

Gonda, Xenia

2012-01-01

NMDA receptors are ionotropic receptors mediating glutamatergic neurotransmission and play a role in several basic functions in the central nervous system, from regulating neurodevelopment and synaptic plasticity, learning and memory formation, cognitive processes, rhythm generation necessary for locomotor activity and breathing, and excitotoxicity. Due to their complex involvement in the above processes, NMDA receptors have been established to play a role in the etiopathology of several neuropsychiatric disorders such as ischaemia and traumatic brain injury, neurodegenerative disorders, pain syndromes, addiction, affective disorders and such neurodevelopmental disorders as autism or schizophrenia. NMDA receptors contain multiple types of subunits with distinct functional and pharmacological properties making the picture more complex. These receptors also offer multiple binding sites to be targeted with pharmacons, however, early broad-spectrum NMDA receptor antagonists had limited clinical use due to their intolerable adverse effect profile. The discovery of several types of subunit selective NMDA receptor antagonists may offer valuable therapeutic possibilities for several disorders, with improved clinical efficacy and decreased side effects. However, in spite of our increasing knowledge concerning the involvement of NMDA receptors in pathological processes, molecules with a selective action, tolerable side effect profile and good clinical efficacy are still only in clinical development in the majority of cases. Nevertheless, NMDA receptors offer a novel opportunity in the treatment of various neuropsychiatric conditions.

Roles of NMDA and dopamine D1 and D2 receptors in the acquisition and expression of flavor preferences conditioned by oral glucose in rats.

PubMed

Dela Cruz, J A D; Coke, T; Icaza-Cukali, D; Khalifa, N; Bodnar, R J

2014-10-01

Animals learn to prefer flavors associated with the intake of sugar (sucrose, fructose, glucose) and fat (corn oil: CO) solutions. Conditioned flavor preferences (CFP) have been elicited for sugars based on orosensory (flavor-flavor: e.g., fructose-CFP) and post-ingestive (flavor-nutrient: e.g., intragastric (IG) glucose-CFP) processes. Dopamine (DA) D1, DA D2 and NMDA receptor antagonism differentially eliminate the acquisition and expression of fructose-CFP and IG glucose-CFP. However, pharmacological analysis of fat (CO)-CFP, mediated by both flavor-flavor and flavor-nutrient processes, indicated that acquisition and expression of fat-CFP were minimally affected by systemic DA D1 and D2 antagonists, and were reduced by NMDA antagonism. Therefore, the present study examined whether systemic DA D1 (SCH23390), DA D2 (raclopride) or NMDA (MK-801) receptor antagonists altered acquisition and/or expression of CFP induced by oral glucose that should be mediated by both flavor-flavor and flavor-nutrient processes. Oral glucose-CFP was elicited following by training rats to drink one novel flavor (CS+, e.g., cherry) mixed in 8% glucose and another flavor (CS-, e.g., grape) mixed in 2% glucose. In expression studies, food-restricted rats drank these solutions in one-bottle sessions (2 h) over 10 days. Subsequent two-bottle tests with the CS+ and CS- flavors mixed in 2% glucose occurred 0.5 h after systemic administration of vehicle (VEH), SCH23390 (50-800 nmol/kg), raclopride (50-800 nmol/kg) or MK-801 (50-200 μg/kg). Rats displayed a robust CS+ preference following VEH treatment (94-95%) which was significantly though marginally attenuated by SCH23390 (67-70%), raclopride (77%) or MK-801 (70%) at doses that also markedly reduced overall CS intake. In separate acquisition studies, rats received VEH, SCH23390 (50-400 nmol/kg), raclopride (50-400 nmol/kg) or MK-801 (100 μg/kg) 0.5 h prior to ten 1-bottle training trials with CS+/8%G and CS-/2%G training solutions that was

Selective enhancement of NMDA receptor-mediated locomotor hyperactivity by male sex hormones in mice.

PubMed

van den Buuse, Maarten; Low, Jac Kee; Kwek, Perrin; Martin, Sally; Gogos, Andrea

2017-09-01

Altered glutamate NMDA receptor function is implicated in schizophrenia, and gender differences have been demonstrated in this illness. This study aimed to investigate the interaction of gonadal hormones with NMDA receptor-mediated locomotor hyperactivity and PPI disruption in mice. The effect of 0.25 mg/kg of MK-801 on locomotor activity was greater in male mice than in female mice. Gonadectomy (by surgical castration) significantly reduced MK-801-induced hyperlocomotion in male mice, but no effect of gonadectomy was seen in female mice or on amphetamine-induced locomotor hyperactivity. The effect of MK-801 on prepulse inhibition of startle (PPI) was similar in intact and castrated male mice and in ovariectomized (OVX) female mice. In contrast, there was no effect of MK-801 on PPI in intact female mice. Forebrain NMDA receptor density, as measured with [ 3 H]MK-801 autoradiography, was significantly higher in male than in female mice but was not significantly altered by either castration or OVX. These results suggest that male sex hormones enhance the effect of NMDA receptor blockade on psychosis-like behaviour. This interaction was not seen in female mice and was independent of NMDA receptor density in the forebrain. Male sex hormones may be involved in psychosis by an interaction with NMDA receptor hypofunction.

Inhibition of Morphine Tolerance and Dependence by the NMDA Receptor Antagonist MK-801

NASA Astrophysics Data System (ADS)

Trujillo, Keith A.; Akil, Huda

1991-01-01

The N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor is an important mediator of several forms of neural and behavioral plasticity. The present studies examined whether NMDA receptors might be involved in the development of opiate tolerance and dependence, two examples of behavioral plasticity. The noncompetitive NMDA receptor antagonist MK-801 attenuated the development of tolerance to the analgesic effect of morphine without affecting acute morphine analgesia. In addition, MK-801 attenuated the development of morphine dependence as assessed by naloxone-precipitated withdrawal. These results suggest that NMDA receptors may be important in the development of opiate tolerance and dependence.

Gelidium amansii promotes dendritic spine morphology and synaptogenesis, and modulates NMDA receptor-mediated postsynaptic current.

PubMed

Hannan, Md Abdul; Mohibbullah, Md; Hong, Yong-Ki; Nam, Joo Hyun; Moon, Il Soo

2014-01-01

Neurotrophic factors are essential for the differentiation and maturation of developing neurons as well as providing survival support to the mature neurons. Moreover, therapeutically neurotrophic factors are promising to reconstruct partially damaged neuronal networks in neurodegenerative diseases. In the previous study, we reported that the ethanol extract of an edible marine alga, Gelidium amansii (GAE) had shown promising effects in the development and maturation of both axon and dendrites of hippocampal neurons. Here, we demonstrate that in primary culture of hippocampal neurons (1) GAE promotes a significant increase in the number of filopodia and dendritic spines; (2) promotes synaptogenesis; (3) enhances N-methyl-D-aspartic acid (NMDA) receptor recruitment; and (4) modulates NMDA-receptor-mediated postsynaptic current. Taken together these findings that GAE might be involved in both morphological and functional maturation of neurons suggest the possibility that GAE may constitute a promising candidate for novel compounds for the prevention and treatment of neurodegenerative diseases.

Involvement of N-methyl-D-aspartate receptor subunits in zinc-mediated modification of CA1 long-term potentiation in the developing hippocampus.

PubMed

Takeda, Atsushi; Itagaki, Kosuke; Ando, Masaki; Oku, Naoto

2012-03-01

Zinc is an endogenous N-methyl-D-aspartate (NMDA) receptor blocker. It is possible that zinc-mediated modification of hippocampal CA1 long-term potentiation (LTP) is linked to the expression of NMDA receptor subunits, which varies with postnatal development. In the present study, the effect of ZnCl(2) and CaEDTA, a membrane-impermeable zinc chelator, on CA1 LTP induction was examined in hippocampal slices from immature (3-week-old) and young (6-week-old) rats. Tetanus (10-100 Hz, 1 sec)-induced CA1 LTP was more greatly enhanced in 3-week-old rats. CA1 LTP was inhibited in the presence of 2-amino-5-phosphonovalerate (APV), an NMDA receptor antagonist, and CaEDTA in 3-week-old rats, as in the case of 6-week-old rats reported previously. In 3-week-old rats, on the other hand, 5 μM ZnCl(2) attenuated NMDA receptor-mediated EPSPs more than in 6-week-old rats and significantly attenuated CA1 LTP. Moreover, 5 μM ZnCl(2) significantly attenuated CA1 LTP in the presence of (2R,4S)-4-(3-phosphonopropyl)-2-piperidinecarboxylic acid (PPPA), an NR2A antagonist, in 3-week-old rats, but not that in the presence of ifenprodil, an NR2B antagonist, suggesting that zinc-mediated attenuation of CA1 LTP is associated with the preferential expression of NR2B subunit in 3-week-old rats. In 6-week-old rats, however, 5 μM ZnCl(2) significantly potentiated CA1 LTP and also CA1 LTP in the presence of PPPA. The present study demonstrates that endogenous zinc may participate in the induction of CA1 LTP. It is likely that the changes in expression of NMDA receptor subunits are involved in the zinc-mediated modification of CA1 LTP in the developing hippocampus. Copyright © 2011 Wiley Periodicals, Inc.

Non-NMDA receptor antagonist-induced drinking in rat

NASA Technical Reports Server (NTRS)

Xu, Z.; Johnson, A. K.

1998-01-01

Glutamate has been implicated in the central control of mechanisms that maintain body fluid homeostasis. The present studies demonstrate that intracerebroventricular (i.c.v.) injections of the non-N-methyl-d-aspartate (NMDA) receptor antagonists 6, 7-dinitroquinoxaline-2,3-dione (DNQX) and 6-cyano-7-nitroquinoxaline-2,3 dione (CNQX) induce drinking in rats. The dipsogenic effect of i.c.v. DNQX was antagonized by the non-NMDA receptor agonist alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). The water intake induced by DNQX was also blocked by pretreatment with a NMDA receptor antagonist, MK-801, but not by angiotensin type 1 (AT1) or acetylcholine muscarinic receptor antagonists (losartan and atropine). The results indicate that non-NMDA receptors may exert a tonic inhibitory effect within brain circuits that control dipsogenic activity and that functional integrity of NMDA receptors may be required for the non-NMDA receptor antagonists to induce water intake. Copyright 1998 Published by Elsevier Science B.V.

Interactions of Pannexin1 channels with purinergic and NMDA receptor channels.

PubMed

Li, Shuo; Bjelobaba, Ivana; Stojilkovic, Stanko S

2018-01-01

Pannexins are a three-member family of vertebrate plasma membrane spanning molecules that have homology to the invertebrate gap junction forming proteins, the innexins. However, pannexins do not form gap junctions but operate as plasma membrane channels. The best-characterized member of these proteins, Pannexin1 (Panx1) was suggested to be functionally associated with purinergic P2X and N-methyl-D-aspartate (NMDA) receptor channels. Activation of these receptor channels by their endogenous ligands leads to cross-activation of Panx1 channels. This in turn potentiates P2X and NMDA receptor channel signaling. Two potentiation concepts have been suggested: enhancement of the current responses and/or sustained receptor channel activation by ATP released through Panx1 pore and adenosine generated by ectonucleotidase-dependent dephosphorylation of ATP. Here we summarize the current knowledge and hypotheses about interactions of Panx1 channels with P2X and NMDA receptor channels. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve. Published by Elsevier B.V.

BDNF released during neuropathic pain potentiates NMDA receptors in primary afferent terminals

PubMed Central

Chen, Wenling; Walwyn, Wendy; Ennes, Helena S.; Kim, Hyeyoung; McRoberts, James A.; Marvizón, Juan Carlos G.

2014-01-01

NMDA receptors in primary afferent terminals can contribute to hyperalgesia by increasing neurotransmitter release. In rats and mice, we found that the ability of intrathecal NMDA to induce neurokinin 1 receptor (NK1R) internalization (a measure of substance P release) required a previous injection of BDNF. Selective knock-down of NMDA receptors in primary afferents decreased NMDA-induced NK1R internalization, confirming the presynaptic location of these receptors. The effect of BDNF was mediated by tropomyosin-related kinase B (trkB) receptors and not p75 neurotrophin receptors (p75NTR), because it was not produced by proBDNF and was inhibited by the trkB antagonist ANA-12 but not by the p75NTR inhibitor TAT-Pep5. These effects are probably mediated through the truncated form of the trkB receptor as there is little expression of full-length trkB in dorsal root ganglion (DRG) neurons. Src family kinase inhibitors blocked the effect of BDNF, suggesting that trkB receptors promote the activation of these NMDA receptors by Src family kinase phosphorylation. Western blots of cultured DRG neurons revealed that BDNF increased Tyr1472 phosphorylation of the NR2B subunit of the NMDA receptor, known to have a potentiating effect. Patch-clamp recordings showed that BDNF, but not proBDNF, increased NMDA receptor currents in cultured DRG neurons. NMDA-induced NK1R internalization was also enabled in a neuropathic pain model or by activating dorsal horn microglia with lipopolysaccharide. These effects were decreased by a BDNF scavenger, a trkB receptor antagonist and an Src family kinase inhibitor, indicating that BDNF released by microglia potentiates NMDA receptors in primary afferents during neuropathic pain. PMID:24611998

The Relationship Between the Renin-Angiotensin-Aldosterone System and NMDA Receptor-Mediated Signal and the Prevention of Retinal Ganglion Cell Death.

PubMed

Kobayashi, Mamoru; Hirooka, Kazuyuki; Ono, Aoi; Nakano, Yuki; Nishiyama, Akira; Tsujikawa, Akitaka

2017-03-01

Excitotoxicity, which is due to glutamate-induced toxic effects on the retinal ganglion cell (RGC), is one of several mechanisms of RGC loss. The renin-angiotensin-aldosterone system (RAAS) has also been implicated in RGC death. Therefore, it is important to determine the exact relationship between the RAAS and N-methyl-d-aspartate (NMDA) receptor-mediated signal in order to prevent RGC death. N-methyl-d-aspartate or aldosterone was injected into the vitreous body. After intravitreal injection of NMDA or aldosterone, animals were treated with spironolactone or memantine. Retinal damage was evaluated by measuring the number of RGCs at 4 weeks after local administration of aldosterone or at 2 weeks after local administration of NMDA. Vitreous humor levels of aldosterone were measured using enzyme immunoassay kits. A significantly decreased number of RGCs were observed after intravitreal injection of NMDA. Although spironolactone did not show any neuroprotective effects, memantine significantly reduced NMDA-induced degeneration in the retina. Furthermore, a significant decrease in the number of RGCs was observed after an intravitreal injection of aldosterone. While memantine did not exhibit any neuroprotective effects, spironolactone caused a significant reduction in the aldosterone-induced degeneration in the retina. There was no change in the aldosterone concentration in the vitreous humor after an NMDA injection. Our findings indirectly show that there is no relationship between the RAAS and NMDA receptor-mediated signal with regard to RGC death.

Oxidative stress upregulates the NMDA receptor on cerebrovascular endothelium.

PubMed

Betzen, Christian; White, Robin; Zehendner, Christoph M; Pietrowski, Eweline; Bender, Bianca; Luhmann, Heiko J; Kuhlmann, Christoph R W

2009-10-15

N-methyl-d-aspartate receptor (NMDA-R)-mediated oxidative stress has been implicated in blood-brain barrier (BBB) disruption in a variety of neuropathological diseases. Although some interactions between both phenomena have been elucidated, possible influences of reactive oxygen species (ROS) on the NMDA-R itself have so far been neglected. The objective of this study was to examine how the cerebroendothelial NMDA-R is affected by exposure to oxidative stress and to assess possible influences on BBB integrity. RT-PCR confirmed several NMDA-R subunits (NR1, NR2B-D) expressed in the bEnd3 cell line (murine cerebrovascular endothelial cells). NR1 protein expression after exposure to ROS was observed via in-cell Western. The functionality of the expressed NMDA-R was determined by measuring DiBAC fluorescence in ROS-preexposed cells upon stimulation with the specific agonist NMDA. Finally, the effects on barrier integrity were evaluated using the ECIS system to detect changes in monolayer impedance upon NMDA-R stimulation after exposure to ROS. The expression of NR1 significantly (p<0.001) increased 72 h after 30 min exposure to superoxide (+33.8+/-7.5%), peroxynitrite (+84.9+/-10.7%), or hydrogen peroxide (+92.8+/-7.6%), resulting in increased cellular response to NMDA-R stimulation and diminished monolayer impedance. We conclude that oxidative stress upregulates NMDA-R on cerebrovascular endothelium and thus heightens susceptibility to glutamate-induced BBB disruption.

NMDA Receptor Activity in Circulating Red Blood Cells: Methods of Detection.

PubMed

Makhro, Asya; Kaestner, Lars; Bogdanova, Anna

2017-01-01

Abundance and activity of N-methyl-D-aspartate (NMDA) in circulating red blood cells contributes to the maintenance of intracellular Ca 2+ in these cells and, by doing that, controls red cell volume, membrane stability, and O 2 carrying capacity. Detection of the NMDA receptor activity in red blood cells is challenging as the number of its copies is low and shows substantial cell-to-cell heterogeneity. Receptor abundance is reliably assessed using the radiolabeled antagonist ([ 3 H]MK-801) binding technique. Uptake of Ca 2+ following the NMDA receptor activation is detected in cells loaded with Ca 2+ -sensitive fluorescent dye Fluo-4 AM. Both microfluorescence live-cell imaging and flow cytometry may be used for fluorescence intensity detection. Automated patch clamp is currently used for recording of electric currents triggered by the stimulation of the NMDA receptor. These currents are mediated by the Ca 2+ -sensitive K + (Gardos) channels that open upon Ca 2+ uptake via the active NMDA receptor. Furthermore, K + flux through the Gardos channels induced by the NMDA receptor stimulation in red blood cells may be detected using unidirectional K + ( 86 Rb + ) influx.

NMDA receptors are involved in the antidepressant-like effects of capsaicin following amphetamine withdrawal in male mice.

PubMed

Amiri, Shayan; Alijanpour, Sakineh; Tirgar, Fatemeh; Haj-Mirzaian, Arya; Amini-Khoei, Hossein; Rahimi-Balaei, Maryam; Rastegar, Mojgan; Ghaderi, Marzieh; Ghazi-Khansari, Mahmoud; Zarrindast, Mohammad-Reza

2016-08-04

Amphetamine withdrawal (AW) is accompanied by diminished pleasure and depression which plays a key role in drug relapse and addictive behaviors. There is no efficient treatment for AW-induced depression and underpinning mechanisms were not well determined. Considering both transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and N-Methyl-d-aspartate (NMDA) receptors contribute to pathophysiology of mood and addictive disorders, in this study, we investigated the role of TRPV1 and NMDA receptors in mediating depressive-like behaviors following AW in male mice. Results revealed that administration of capsaicin, TRPV1 agonist, (100μg/mouse, i.c.v.) and MK-801, NMDA receptor antagonist (0.005mg/kg, i.p.) reversed AW-induced depressive-like behaviors in forced swimming test (FST) and splash test with no effect on animals' locomotion. Co-administration of sub-effective doses of MK-801 (0.001mg/kg, i.p.) and capsaicin (10μg/mouse, i.c.v) exerted antidepressant-like effects in behavioral tests. Capsazepine, TRPV1 antagonist, (100μg/mouse, i.c.v) and NMDA, NMDA receptor agonist (7.5mg/kg, i.p.) abolished the effects of capsaicin and MK-801, respectively. None of aforementioned treatments had any effect on behavior of control animals. Collectively, our findings showed that activation of TRPV1 and blockade of NMDA receptors produced antidepressant-like effects in male mice following AW, and these receptors are involved in AW-induced depressive-like behaviors. Further, we found that rapid antidepressant-like effects of capsaicin in FST and splash test are partly mediated by NMDA receptors. Copyright © 2016. Published by Elsevier Ltd.

Structure of the Zinc-Bound Amino-Terminal Domain of the NMDA Receptor NR2B Subunit

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

Karakas, E.; Simorowski, N; Furukawa, H

2009-01-01

N-methyl-D-aspartate (NMDA) receptors belong to the family of ionotropic glutamate receptors (iGluRs) that mediate the majority of fast excitatory synaptic transmission in the mammalian brain. One of the hallmarks for the function of NMDA receptors is that their ion channel activity is allosterically regulated by binding of modulator compounds to the extracellular amino-terminal domain (ATD) distinct from the L-glutamate-binding domain. The molecular basis for the ATD-mediated allosteric regulation has been enigmatic because of a complete lack of structural information on NMDA receptor ATDs. Here, we report the crystal structures of ATD from the NR2B NMDA receptor subunit in the zinc-freemore » and zinc-bound states. The structures reveal the overall clamshell-like architecture distinct from the non-NMDA receptor ATDs and molecular determinants for the zinc-binding site, ion-binding sites, and the architecture of the putative phenylethanolamine-binding site.« less

NMDA receptor modulators: an updated patent review (2013-2014).

PubMed

Strong, Katie L; Jing, Yao; Prosser, Anthony R; Traynelis, Stephen F; Liotta, Dennis C

2014-12-01

The NMDA receptor mediates a slow component of excitatory synaptic transmission, and NMDA receptor dysfunction has been implicated in numerous neurological disorders. Thus, interest in developing modulators that are capable of regulating the channel continues to be strong. Recent research has led to the discovery of a number of compounds that hold therapeutic and clinical value. Deeper insight into the NMDA intersubunit interactions and structural motifs gleaned from the recently solved crystal structures of the NMDA receptor should facilitate a deeper understanding of how these compounds modulate the receptor. This article discusses the known pharmacology of NMDA receptors. A discussion of the patent literature since 2012 is also included, with an emphasis on those that claimed new chemical entities as regulators of the NMDA receptor. The number of patents involving novel NMDA receptor modulators suggests a renewed interest in the NMDA receptor as a therapeutic target. Subunit-selective modulators continue to show promise, and the development of new subunit-selective NMDA receptor modulators appears poised for continued growth. Although a modest number of channel blocker patents were published, successful clinical outcomes involving ketamine have led to a resurgent interest in low-affinity channel blockers as therapeutics.

NMDA Receptor Modulators in the Treatment of Drug Addiction.

PubMed

Tomek, Seven E; Lacrosse, Amber L; Nemirovsky, Natali E; Olive, M Foster

2013-02-06

Glutamate plays a pivotal role in drug addiction, and the N-methyl-D-aspartate (NMDA) glutamate receptor subtype serves as a molecular target for several drugs of abuse. In this review, we will provide an overview of NMDA receptor structure and function, followed by a review of the mechanism of action, clinical efficacy, and side effect profile of NMDA receptor ligands that are currently in use or being explored for the treatment of drug addiction. These ligands include the NMDA receptor modulators memantine and acamprosate, as well as the partial NMDA agonist D-cycloserine. Data collected to date suggest that direct NMDA receptor modulators have relatively limited efficacy in the treatment of drug addiction, and that partial agonism of NMDA receptors may have some efficacy with regards to extinction learning during cue exposure therapy. However, the lack of consistency in results to date clearly indicates that additional studies are needed, as are studies examining novel ligands with indirect mechanisms for altering NMDA receptor function.

Rapid surface accumulation of NMDA receptors increases glutamatergic excitation during status epilepticus

PubMed Central

Naylor, David E.; Liu, Hantao; Niquet, Jerome; Wasterlain, Claude G.

2017-01-01

After 1 h of lithium-pilocarpine status epilepticus (SE), immunocytochemical labeling of NMDA receptor NR1 subunits reveals relocation of subunits from the interior to the cell surface of dentate gyrus granule cells and CA3 pyramidal cells. Simultaneously, an increase in NMDA-miniature excitatory postsynaptic currents (mEPSC) as well as an increase in NMDA receptor-mediated tonic currents is observed in hippocampal slices after SE. Mean-variance analysis of NMDA-mEPSCs estimates that the number of functional postsynaptic NMDA receptors per synapse increases 38% during SE, and antagonism by ifenprodil suggests that an increase in the surface representation of NR2B-containing NMDA receptors is responsible for the augmentation of both the phasic and tonic excitatory currents with SE. These results provide a potential mechanism for an enhancement of glutamatergic excitation that maintains SE and may contribute to excitotoxic injury during SE. Therapies that directly antagonize NMDA receptors may be a useful therapeutic strategy during refractory SE. PMID:23313318

Identification of N-methyl-D-aspartic acid (NMDA) receptor subtype-specific binding sites that mediate direct interactions with scaffold protein PSD-95.

PubMed

Cousins, Sarah L; Stephenson, F Anne

2012-04-13

N-methyl-D-aspartate (NMDA) neurotransmitter receptors and the postsynaptic density-95 (PSD-95) membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins are integral components of post-synaptic macromolecular signaling complexes that serve to propagate glutamate responses intracellularly. Classically, NMDA receptor NR2 subunits associate with PSD-95 MAGUKs via a conserved ES(E/D)V amino acid sequence located at their C termini. We previously challenged this dogma to demonstrate a second non-ES(E/D)V PSD-95-binding site in both NMDA receptor NR2A and NR2B subunits. Here, using a combination of co-immunoprecipitations from transfected mammalian cells, yeast two-hybrid interaction assays, and glutathione S-transferase (GST) pulldown assays, we show that NR2A subunits interact directly with PSD-95 via the C-terminal ESDV motif and additionally via an Src homology 3 domain-binding motif that associates with the Src homology 3 domain of PSD-95. Peptide inhibition of co-immunoprecipitations of NR2A and PSD-95 demonstrates that both the ESDV and non-ESDV sites are required for association in native brain tissue. Furthermore, we refine the non-ESDV site within NR2B to residues 1149-1157. These findings provide a molecular basis for the differential association of NMDA receptor subtypes with PSD-95 MAGUK scaffold proteins. These selective interactions may contribute to the organization, lateral mobility, and ultimately the function of NMDA receptor subtypes at synapses. Furthermore, they provide a more general molecular mechanism by which the scaffold, PSD-95, may discriminate between potential interacting partner proteins.

Subthreshold pharmacological and genetic approaches to analyzing CaV2.1-mediated NMDA receptor signaling in short-term memory.

PubMed

Takahashi, Eiki; Niimi, Kimie; Itakura, Chitoshi

2010-10-25

Ca(V)2.1 is highly expressed in the nervous system and plays an essential role in the presynaptic modulation of neurotransmitter release machinery. Recently, the antiepileptic drug levetiracetam was reported to inhibit presynaptic Ca(V)2.1 functions, reducing glutamate release in the hippocampus, although the precise physiological role of Ca(V)2.1-regulated synaptic functions in cognitive performance at the system level remains unknown. This study examined whether Ca(V)2.1 mediates hippocampus-dependent spatial short-term memory using the object location and Y-maze tests, and perirhinal cortex-dependent nonspatial short-term memory using the object recognition test, via a combined pharmacological and genetic approach. Heterozygous rolling Nagoya (rol/+) mice carrying the Ca(V)2.1alpha(1) mutation had normal spatial and nonspatial short-term memory. A 100mg/kg dose of levetiracetam, which is ineffective in wild-type controls, blocked spatial short-term memory in rol/+ mice. At 5mg/kg, the N-methyl-D-aspartate (NMDA) receptor blocker (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), which is ineffective in wild-type controls, also blocked the spatial short-term memory in rol/+ mice. Furthermore, a combination of subthreshold doses of levetiracetam (25 mg/kg) and CPP (2.5mg/kg) triggered a spatial short-term memory deficit in rol/+ mice, but not in wild-type controls. Similar patterns of nonspatial short-term memory were observed in wild-type and rol/+ mice when injected with levetiracetam (0-300 mg/kg). These results indicate that Ca(V)2.1-mediated NMDA receptor signaling is critical in hippocampus-dependent spatial short-term memory and differs in various regions. The combination subthreshold pharmacological and genetic approach presented here is easily performed and can be used to study functional signaling pathways in neuronal circuits. Copyright © 2010 Elsevier B.V. All rights reserved.

Specific Roles of NMDA Receptor Subunits in Mental Disorders.

PubMed

Yamamoto, H; Hagino, Y; Kasai, S; Ikeda, K

2015-01-01

N-methyl-D-aspartate (NMDA) receptor plays important roles in learning and memory. NMDA receptors are a tetramer that consists of two glycine-binding subunits GluN1, two glutamate-binding subunits (i.e., GluN2A, GluN2B, GluN2C, and GluN2D), a combination of a GluN2 subunit and glycine-binding GluN3 subunit (i.e., GluN3A or GluN3B), or two GluN3 subunits. Recent studies revealed that the specific expression and distribution of each subunit are deeply involved in neural excitability, plasticity, and synaptic deficits. The present article summarizes reports on the dysfunction of NMDA receptors and responsible subunits in various neurological and psychiatric disorders, including schizophrenia, autoimmune-induced glutamatergic receptor dysfunction, mood disorders, and autism. A key role for the GluN2D subunit in NMDA receptor antagonist-induced psychosis has been recently revealed.

NMDA receptor mediates proliferation and CREB phosphorylation in postnatal Müller glia-derived retinal progenitors

PubMed Central

Ramírez, Mónica

2009-01-01

Purpose Postnatal retinal Müller glia are considered to be retinal progenitors as they retain the ability to dedifferentiate, proliferate, and differentiate to new retinal glia and neurons after injury. The proliferation and differentiation processes are coordinated by several extrinsic factors and neurotransmitters, including glutamate. Thus, the appropriate numbers and proportions of the different cell types are generated to form a functional retina during development and during injury repair. Here we analyze the changes in the proliferation of postnatal Müller glia-derived progenitors after activation of the N-methyl-D-aspartate (NMDA) glutamate receptors. Methods Müller glia-derived progenitor cell cultures were characterized by immunocytochemistry with antibodies against the NR1 subunit of the NMDA receptor and the progenitor cell marker nestin. The effect of glutamate receptor agonists and antagonists on cell proliferation was analyzed by BrdU incorporation or Ki67 immunostaining, cell counting, and by immunolabeling of phosphorylated cAMP response element binding protein (P-CREB) transcription factor. The effect of NMDA receptor activation was analyzed in vivo by P-CREB immunohistochemistry in retinal sections of Long-Evans NMDA injected rats. Results We show that NMDA receptor activation significantly increases the proliferation rate of Müller-glia derived progenitor cells and that this increase can be blocked by NMDA receptor antagonists. Furthermore, we show that CREB phosphorylation is induced in NMDA-treated Müller-glia derived progenitor cells in culture and that specific pharmacological inhibition of CREB phosphorylation results in a decreased number of proliferating cells. We confirmed the relevance of these observations by the analysis of retinal sections after NMDA injection in vivo where immunoreactivity to phosphorylated CREB is also increased after treatment. Conclusions In the present study we show that NMDA receptor activation induces

Neonatal NMDA Receptor Blockade Disrupts Spike Timing and Glutamatergic Synapses in Fast Spiking Interneurons in a NMDA Receptor Hypofunction Model of Schizophrenia

PubMed Central

Jones, Kevin S.; Corbin, Joshua G.; Huntsman, Molly M.

2014-01-01

The dysfunction of parvalbumin-positive, fast-spiking interneurons (FSI) is considered a primary contributor to the pathophysiology of schizophrenia (SZ), but deficits in FSI physiology have not been explicitly characterized. We show for the first time, that a widely-employed model of schizophrenia minimizes first spike latency and increases GluN2B-mediated current in neocortical FSIs. The reduction in FSI first-spike latency coincides with reduced expression of the Kv1.1 potassium channel subunit which provides a biophysical explanation for the abnormal spiking behavior. Similarly, the increase in NMDA current coincides with enhanced expression of the GluN2B NMDA receptor subunit, specifically in FSIs. In this study mice were treated with the NMDA receptor antagonist, MK-801, during the first week of life. During adolescence, we detected reduced spike latency and increased GluN2B-mediated NMDA current in FSIs, which suggests transient disruption of NMDA signaling during neonatal development exerts lasting changes in the cellular and synaptic physiology of neocortical FSIs. Overall, we propose these physiological disturbances represent a general impairment to the physiological maturation of FSIs which may contribute to schizophrenia-like behaviors produced by this model. PMID:25290690

Evidence that NMDA-dependent limbic neural plasticity in the right hemisphere mediates pharmacological stressor (FG-7142)-induced lasting increases in anxiety-like behavior. Study 2--The effects on behavior of block of NMDA receptors prior to injection of FG-7142.

PubMed

Adamec, R E

1998-01-01

The hypothesis that N-methyl-D-aspartate (NMDA) receptors mediate initiation of lasting behavioral changes induced by the anxiogenic beta-carboline, FG-7142, was supported in this study. Behavioral changes normally induced by FG-7142 were blocked when the competitive NMDA receptor blocker, 7-amino-phosphono-heptanoic acid, was given prior to administration of FG-7142. When cats were subsequently given FG-7142 alone, the drug produced lasting behavioral changes like those reported previously. Flumazenil, a benzodiazepine receptor antagonist, reversed an increase in defensiveness produced by FG-7142 alone, replicating previous findings. The data are consistent with the hypothesis that NMDA-dependent long-term potentiation in limbic pathways subserving defensive response to threat mediates lasting increases in defensiveness produced by FG-7142.

Citrate Modulates the Regulation by Zn2+ of N-Methyl-D-Aspartate Receptor-Mediated Channel Current and Neurotransmitter Release

NASA Astrophysics Data System (ADS)

Westergaard, Niels; Banke, Tue; Wahl, Philip; Sonnewald, Ursula; Schousboe, Arne

1995-04-01

The effect of the two metal-ion chelators EDTA and citrate on the action of N-methyl-D-aspartate (NMDA) receptors was investigated by use of cultured mouse cerebellar granule neurons and Xenopus oocytes, respectively, to monitor either NMDA-evoked transmitter release or membrane currents. Transmitter release from the glutamatergic neurons was determined by superfusion of the cells after preloading with the glutamate analogue D-[^3H]aspartate. The oocytes were injected with mRNA isolated from mouse cerebellum and, after incubation to allow translation to occur, currents mediated by NMDA were recorded electrophysiologically by voltage clamp at a holding potential of -80 mV. It was found that citrate as well as EDTA could attenuate the inhibitory action of Zn2+ on NMDA receptor-mediated transmitter release from the neurons and membrane currents in the oocytes. These effects were specifically related to the NMDA receptor, since the NMDA receptor antagonist MK-801 abolished the action and no effects of Zn2+ and its chelators were observed when kainate was used to selectively activate non-NMDA receptors. Since it was additionally demonstrated that citrate (and EDTA) preferentially chelated Zn2+ rather than Ca2+, the present findings strongly suggest that endogenous citrate released specifically from astrocytes into the extracellular space in the brain may function as a modulator of NMDA receptor activity. This is yet another example of astrocytic influence on neuronal activity.

Ionotropic and metabotropic glutamate receptor mediation of glucocorticoid-induced apoptosis in hippocampal cells and the neuroprotective role of synaptic N-methyl-D-aspartate receptors.

PubMed

Lu, J; Goula, D; Sousa, N; Almeida, O F X

2003-01-01

Glutamate receptors have been proposed to mediate the apoptotic actions of glucocorticoids in hippocampal cells. To further analyze the role of glutamate receptors in this process, we pretreated primary hippocampal cells from neonatal (postnatal day 4) rats with antagonists of ionotropic glutamate receptor (iGluR) and metabotropic glutamate receptor (mGluR) antagonists before exposure to the specific glucocorticoid receptor agonist dexamethasone (DEX) at a dose of 1 microM. Dizocilpine (MK801; a general N-methyl-D-aspartic acid [NMDA] receptor antagonist, NMDAR antagonist) and ifenprodil (a specific ligand of the NMDAR 2B subunit, NR2B), were used to block iGluR; (RS)-alpha-ethyl-4-carboxyphenylglycine (E4CPG) and (RS)-alpha-cyclopropyl-4-phosphonophenyl-glycine (CPPG) were employed as I/II (E4CPG) and II/III (CPPG) mGluR antagonists. Blockade of iGluR resulted in a significant attenuation of DEX-induced cell death; the finding that ifenprodil exerted a similar potency to MK801 demonstrates the involvement of NR2B receptors in glucocorticoid-induced cell death. Apoptosis accounted for a significant amount of the cell loss observed, as detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling histochemistry for the in situ labeling of DNA breaks; apoptotic cells were distinguished from necrosis on the basis of morphological criteria, including chromatin condensation, membrane blebbing and presence of apoptotic bodies. Treatment with E4CPG and CPPG completely abolished the apoptotic response to DEX, thus showing the additional contribution of mGluR to the phenomenon. Further, dose-response studies with NMDA revealed that whereas high (10 microM) doses of NMDA themselves elicit cytotoxic responses, low (1-5 microM) concentrations of NMDA can effectively oppose DEX-induced cell death. Interestingly, the neuroprotective actions of low dose NMDA stimulation were abolished when either synaptic or extrasynaptic NMDA receptors were blocked with MK801

Identification of N-Methyl-d-aspartic Acid (NMDA) Receptor Subtype-specific Binding Sites That Mediate Direct Interactions with Scaffold Protein PSD-95*

PubMed Central

Cousins, Sarah L.; Stephenson, F. Anne

2012-01-01

N-methyl-d-aspartate (NMDA) neurotransmitter receptors and the postsynaptic density-95 (PSD-95) membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins are integral components of post-synaptic macromolecular signaling complexes that serve to propagate glutamate responses intracellularly. Classically, NMDA receptor NR2 subunits associate with PSD-95 MAGUKs via a conserved ES(E/D)V amino acid sequence located at their C termini. We previously challenged this dogma to demonstrate a second non-ES(E/D)V PSD-95-binding site in both NMDA receptor NR2A and NR2B subunits. Here, using a combination of co-immunoprecipitations from transfected mammalian cells, yeast two-hybrid interaction assays, and glutathione S-transferase (GST) pulldown assays, we show that NR2A subunits interact directly with PSD-95 via the C-terminal ESDV motif and additionally via an Src homology 3 domain-binding motif that associates with the Src homology 3 domain of PSD-95. Peptide inhibition of co-immunoprecipitations of NR2A and PSD-95 demonstrates that both the ESDV and non-ESDV sites are required for association in native brain tissue. Furthermore, we refine the non-ESDV site within NR2B to residues 1149–1157. These findings provide a molecular basis for the differential association of NMDA receptor subtypes with PSD-95 MAGUK scaffold proteins. These selective interactions may contribute to the organization, lateral mobility, and ultimately the function of NMDA receptor subtypes at synapses. Furthermore, they provide a more general molecular mechanism by which the scaffold, PSD-95, may discriminate between potential interacting partner proteins. PMID:22375001

Rapid surface accumulation of NMDA receptors increases glutamatergic excitation during status epilepticus.

PubMed

Naylor, David E; Liu, Hantao; Niquet, Jerome; Wasterlain, Claude G

2013-06-01

After 1h of lithium-pilocarpine status epilepticus (SE), immunocytochemical labeling of NMDA receptor NR1 subunits reveals relocation of subunits from the interior to the cell surface of dentate gyrus granule cells and CA3 pyramidal cells. Simultaneously, an increase in NMDA-miniature excitatory postsynaptic currents (mEPSC) as well as an increase in NMDA receptor-mediated tonic currents is observed in hippocampal slices after SE. Mean-variance analysis of NMDA-mEPSCs estimates that the number of functional postsynaptic NMDA receptors per synapse increases 38% during SE, and antagonism by ifenprodil suggests that an increase in the surface representation of NR2B-containing NMDA receptors is responsible for the augmentation of both the phasic and tonic excitatory currents with SE. These results provide a potential mechanism for an enhancement of glutamatergic excitation that maintains SE and may contribute to excitotoxic injury during SE. Therapies that directly antagonize NMDA receptors may be a useful therapeutic strategy during refractory SE. Copyright © 2013 Elsevier Inc. All rights reserved.

Stronger Dopamine D1 Receptor-Mediated Neurotransmission in Dyskinesia.

PubMed

Farré, Daniel; Muñoz, Ana; Moreno, Estefanía; Reyes-Resina, Irene; Canet-Pons, Júlia; Dopeso-Reyes, Iria G; Rico, Alberto J; Lluís, Carme; Mallol, Josefa; Navarro, Gemma; Canela, Enric I; Cortés, Antonio; Labandeira-García, José L; Casadó, Vicent; Lanciego, José L; Franco, Rafael

2015-12-01

Radioligand binding assays to rat striatal dopamine D1 receptors showed that brain lateralization of the dopaminergic system were not due to changes in expression but in agonist affinity. D1 receptor-mediated striatal imbalance resulted from a significantly higher agonist affinity in the left striatum. D1 receptors heteromerize with dopamine D3 receptors, which are considered therapeutic targets for dyskinesia in parkinsonian patients. Expression of both D3 and D1-D3 receptor heteromers were increased in samples from 6-hydroxy-dopamine-hemilesioned rats rendered dyskinetic by treatment with 3, 4-dihydroxyphenyl-L-alanine (L-DOPA). Similar findings were obtained using striatal samples from primates. Radioligand binding studies in the presence of a D3 agonist led in dyskinetic, but not in lesioned or L-DOPA-treated rats, to a higher dopamine sensitivity. Upon D3-receptor activation, the affinity of agonists for binding to the right striatal D1 receptor increased. Excess dopamine coming from L-DOPA medication likely activates D3 receptors thus making right and left striatal D1 receptors equally responsive to dopamine. These results show that dyskinesia occurs concurrently with a right/left striatal balance in D1 receptor-mediated neurotransmission.

Medial prefrontal cortex TRPV1 and CB1 receptors modulate cardiac baroreflex activity by regulating the NMDA receptor/nitric oxide pathway.

PubMed

Lagatta, Davi C; Kuntze, Luciana B; Ferreira-Junior, Nilson C; Resstel, Leonardo B M

2018-05-29

The ventral medial prefrontal cortex (vMPFC) facilitates the cardiac baroreflex response through N-methyl-D-aspartate (NMDA) receptor activation and nitric oxide (NO) formation by neuronal NO synthase (nNOS) and soluble guanylate cyclase (sGC) triggering. Glutamatergic transmission is modulated by the cannabinoid receptor type 1 (CB 1 ) and transient receptor potential vanilloid type 1 (TRPV 1 ) receptors, which may inhibit or stimulate glutamate release in the brain, respectively. Interestingly, vMPFC CB 1 receptors decrease cardiac baroreflex responses, while TRPV 1 channels facilitate them. Therefore, the hypothesis of the present study is that the vMPFC NMDA/NO pathway is regulated by both CB 1 and TRPV 1 receptors in the modulation of cardiac baroreflex activity. In order to test this assumption, we used male Wistar rats that had stainless steel guide cannulae bilaterally implanted in the vMPFC. Subsequently, a catheter was inserted into the femoral artery, for cardiovascular recordings, and into the femoral vein for assessing baroreflex activation. The increase in tachycardic and bradycardic responses observed after the microinjection of a CB 1 receptors antagonist into the vMPFC was prevented by an NMDA antagonist as well as by the nNOS and sGC inhibition. NO extracellular scavenging also abolished these responses. These same pharmacological manipulations inhibited cardiac reflex enhancement induced by TRPV 1 agonist injection into the area. Based on these results, we conclude that vMPFC CB 1 and TRPV 1 receptors inhibit or facilitate the cardiac baroreflex activity by stimulating or blocking the NMDA activation and NO synthesis.

Dopamine Modulation of Avoidance Behavior in Caenorhabditis elegans Requires the NMDA Receptor NMR-1

PubMed Central

Baidya, Melvin; Genovez, Marx; Torres, Marissa; Chao, Michael Y.

2014-01-01

The nematode C. elegans utilizes a relatively simple neural circuit to mediate avoidance responses to noxious stimuli such as the volatile odorant octanol. This avoidance behavior is modulated by dopamine. cat-2 mutant animals that are deficient in dopamine biosynthesis have an increased response latency to octanol compared to wild type animals, and this defect can be fully restored with the application of exogenous dopamine. Because this avoidance behavior is mediated by glutamatergic signaling between sensory neurons and premotor interneurons, we investigated the genetic interactions between dopaminergic signaling and ionotropic glutamate receptors. cat-2 mutant animals lacking either the GLR-1 or GLR-2 AMPA/kainate receptors displayed an increased response latency to octanol, which could be restored via exogenous dopamine. However, whereas cat-2 mutant animals lacking the NMR-1 NMDA receptor had increased response latency to octanol they were insensitive to exogenous dopamine. Mutants that lacked both AMPA/kainate and NMDA receptors were also insensitive to exogenous dopamine. Our results indicate that dopamine modulation of octanol avoidance requires NMR-1, consistent with NMR-1 as a potential downstream signaling target for dopamine. PMID:25089710

Cortical NMDA receptor expression in human chronic alcoholism: influence of the TaqIA allele of ANKK1.

PubMed

Ridge, Justin P; Dodd, Peter R

2009-10-01

Real-time RT-PCR normalized to GAPDH was used to assay N-methyl-D-aspartate (NMDA) receptor NR1, NR2A and NR2B subunit mRNA in human autopsy cortex tissue from chronic alcoholics with and without comorbid cirrhosis of the liver and matched controls. Subunit expression was influenced by the subject's genotype. The TaqIA polymorphism selectively modulated NMDA receptor mean transcript expression in cirrhotic-alcoholic superior frontal cortex, in diametrically opposite ways in male and female subjects. Genetic make-up may differentially influence vulnerability to brain damage by altering the excitation: inhibition balance, particularly in alcoholics with comorbid cirrhosis of the liver. The TaqIA polymorphism occurs within the poorly characterised ankyrin-repeat containing kinase 1 (ANKK1) gene. Using PCR, ANKK1 mRNA transcript was detected in inferior temporal, occipital, superior frontal and primary motor cortex of control human brain. ANKK1 expression may mediate the influence of the TaqIA polymorphism on phenotype.

Role of AMPA and NMDA receptors and back-propagating action potentials in spike timing-dependent plasticity.

PubMed

Fuenzalida, Marco; Fernández de Sevilla, David; Couve, Alejandro; Buño, Washington

2010-01-01

The cellular mechanisms that mediate spike timing-dependent plasticity (STDP) are largely unknown. We studied in vitro in CA1 pyramidal neurons the contribution of AMPA and N-methyl-d-aspartate (NMDA) components of Schaffer collateral (SC) excitatory postsynaptic potentials (EPSPs; EPSP(AMPA) and EPSP(NMDA)) and of the back-propagating action potential (BAP) to the long-term potentiation (LTP) induced by a STDP protocol that consisted in pairing an EPSP and a BAP. Transient blockade of EPSP(AMPA) with 7-nitro-2,3-dioxo-1,4-dihydroquinoxaline-6-carbonitrile (CNQX) during the STDP protocol prevented LTP. Contrastingly LTP was induced under transient inhibition of EPSP(AMPA) by combining SC stimulation, an imposed EPSP(AMPA)-like depolarization, and BAP or by coupling the EPSP(NMDA) evoked under sustained depolarization (approximately -40 mV) and BAP. In Mg(2+)-free solution EPSP(NMDA) and BAP also produced LTP. Suppression of EPSP(NMDA) or BAP always prevented LTP. Thus activation of NMDA receptors and BAPs are needed but not sufficient because AMPA receptor activation is also obligatory for STDP. However, a transient depolarization of another origin that unblocks NMDA receptors and a BAP may also trigger LTP.

Involvement of CRF but not NPY in the anxiety regulation via NMDA receptors.

PubMed

Wierońska, Joanna M; Szewczyk, Bernadeta; Pałucha, Agnieszka; Brański, Piotr; Smiałowska, Maria

2003-01-01

The study attempts to evaluate whether neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) are involved in anxiogenic and anxiolytic reactions induced by NMDA receptor ligands. The animals were given MK-801 (1 mg/kg, ip), a non-competitive NMDA-receptor antagonist, which acts as anxiolytic agent, or NMDA (15 mg/kg, ip), which has an anxiogenic effect. The anxiogenic or anxiolytic actions of these compounds were evaluated in the plus-maze test. The animals, which were given MK-801, were administered BIBO 3304 (130 ng/0.5 microl/site) intraamygdalarly and the animals which were given NMDA were administered alpha-helical CRF (500 ng/0.5 microl/site). BIBO 3304 did not attenuate MK-801-induced anxiolysis and alpha-helical CRF abolished NMDA-induced anxiogenesis. Our results show that anxiogenic effect of NMDA is mediated via CRF1 receptors and anxiolytic action of MK-801 is not dependent on Y1 receptors.

Central role for NMDA receptors in redox mediated impairment of synaptic function during aging and Alzheimer's disease.

PubMed

Foster, T C; Kyritsopoulos, C; Kumar, A

2017-03-30

Increased human longevity has magnified the negative impact that aging can have on cognitive integrity of older individuals experiencing some decline in cognitive function. Approximately 30% of the elderly will have cognitive problems that influence their independence. Impaired executive function and memory performance are observed in normal aging and yet can be an early sign of a progressive cognitive impairment of Alzheimer's disease (AD), the most common form of dementia. Brain regions that are vulnerable to aging exhibit the earliest pathology of AD. Senescent synaptic function is observed as a shift in Ca 2+ -dependent synaptic plasticity and similar mechanisms are thought to contribute to the early cognitive deficits associated with AD. In the case of aging, intracellular redox state mediates a shift in Ca 2+ regulation including N-methyl-d-aspartate (NMDA) receptor hypofunction and increased Ca 2+ release from intracellular stores to alter synaptic plasticity. AD can interact with these aging processes such that molecules linked to AD, β-amyloid (Aβ) and mutated presenilin 1 (PS1), can also degrade NMDA receptor function, promote Ca 2+ release from intracellular stores, and may increase oxidative stress. Thus, age is one of the most important predictors of AD and brain aging likely contributes to the onset of AD. The focus of this review article is to provide an update on mechanisms that contribute to the senescent synapse and possible interactions with AD-related molecules, with special emphasis on regulation of NMDA receptors. Copyright © 2016 Elsevier B.V. All rights reserved.

Iron Mediates N-Methyl-d-aspartate Receptor-dependent Stimulation of Calcium-induced Pathways and Hippocampal Synaptic Plasticity*

PubMed Central

Muñoz, Pablo; Humeres, Alexis; Elgueta, Claudio; Kirkwood, Alfredo; Hidalgo, Cecilia; Núñez, Marco T.

2011-01-01

Iron deficiency hinders hippocampus-dependent learning processes and impairs cognitive performance, but current knowledge on the molecular mechanisms underlying the unique role of iron in neuronal function is sparse. Here, we investigated the participation of iron on calcium signal generation and ERK1/2 stimulation induced by the glutamate agonist N-methyl-d-aspartate (NMDA), and the effects of iron addition/chelation on hippocampal basal synaptic transmission and long-term potentiation (LTP). Addition of NMDA to primary hippocampal cultures elicited persistent calcium signals that required functional NMDA receptors and were independent of calcium influx through L-type calcium channels or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; NMDA also promoted ERK1/2 phosphorylation and nuclear translocation. Iron chelation with desferrioxamine or inhibition of ryanodine receptor (RyR)-mediated calcium release with ryanodine-reduced calcium signal duration and prevented NMDA-induced ERK1/2 activation. Iron addition to hippocampal neurons readily increased the intracellular labile iron pool and stimulated reactive oxygen species production; the antioxidant N-acetylcysteine or the hydroxyl radical trapper MCI-186 prevented these responses. Iron addition to primary hippocampal cultures kept in calcium-free medium elicited calcium signals and stimulated ERK1/2 phosphorylation; RyR inhibition abolished these effects. Iron chelation decreased basal synaptic transmission in hippocampal slices, inhibited iron-induced synaptic stimulation, and impaired sustained LTP in hippocampal CA1 neurons induced by strong stimulation. In contrast, iron addition facilitated sustained LTP induction after suboptimal tetanic stimulation. Together, these results suggest that hippocampal neurons require iron to generate RyR-mediated calcium signals after NMDA receptor stimulation, which in turn promotes ERK1/2 activation, an essential step of sustained LTP. PMID:21296883

Early Use of the NMDA Receptor Antagonist Ketamine in Refractory and Superrefractory Status Epilepticus

PubMed Central

Zeiler, F. A.

2015-01-01

Refractory status epilepticus (RSE) and superrefractory status epilepticus (SRSE) pose a difficult clinical challenge. Multiple cerebral receptor and transporter changes occur with prolonged status epilepticus leading to pharmacoresistance patterns unfavorable for conventional antiepileptics. In particular, n-methyl-d-aspartate (NMDA) receptor upregulation leads to glutamate mediated excitotoxicity. Targeting these NMDA receptors may provide a novel approach to otherwise refractory seizures. Ketamine has been utilized in RSE. Recent systematic review indicates 56.5% and 63.5% cessation in seizures in adults and pediatrics, respectively. No complications were described. We should consider earlier implementation of ketamine or other NMDA receptor antagonists, for RSE. Prospective study of early implementation of ketamine should shed light on the role of such medications in RSE. PMID:25649724

Access of inhibitory neurosteroids to the NMDA receptor

PubMed Central

Borovska, Jirina; Vyklicky, Vojtech; Stastna, Eva; Kapras, Vojtech; Slavikova, Barbora; Horak, Martin; Chodounska, Hana; Vyklicky Jr, Ladislav

2012-01-01

BACKGROUND AND PURPOSE NMDA receptors are glutamatergic ionotropic receptors involved in excitatory neurotransmission, synaptic plasticity and excitotoxic cell death. Many allosteric modulators can influence the activity of these receptors positively or negatively, with behavioural consequences. 20-Oxo-5β-pregnan-3α-yl sulphate (pregnanolone sulphate; PA-6) is an endogenous neurosteroid that inhibits NMDA receptors and is neuroprotective. We tested the hypothesis that the interaction of PA-6 with the plasma membrane is critical for its inhibitory effect at NMDA receptors. EXPERIMENTAL APPROACH Electrophysiological recordings and live microscopy were performed on heterologous HEK293 cells expressing GluN1/GluN2B receptors and cultured rat hippocampal neurons. KEY RESULTS Our experiments showed that the kinetics of the steroid inhibition were slow and not typical of drug-receptor interaction in an aqueous solution. In addition, the recovery from steroid inhibition was accelerated by β- and γ-cyclodextrin. Values of IC50 assessed for novel synthetic C3 analogues of PA-6 differed by more than 30-fold and were positively correlated with the lipophilicity of the PA-6 analogues. Finally, the onset of inhibition induced by C3 analogues of PA-6 ranged from use-dependent to use-independent. The onset and offset of cell staining by fluorescent analogues of PA-6 were slower than those of steroid-induced inhibition of current responses mediated by NMDA receptors. CONCLUSION AND IMPLICATIONS We conclude that steroid accumulation in the plasma membrane is the route by which it accesses a binding site on the NMDA receptor. Thus, our results provide a possible structural framework for pharmacologically targeting the transmembrane domains of the receptor. PMID:22188257

Kinetic Contributions to Gating by Interactions Unique to N-methyl-d-aspartate (NMDA) Receptors*

PubMed Central

Borschel, William F.; Cummings, Kirstie A.; Tindell, LeeAnn K.; Popescu, Gabriela K.

2015-01-01

Among glutamate-gated channels, NMDA receptors produce currents that subside with unusually slow kinetics, and this feature is essential to the physiology of central excitatory synapses. Relative to the homologous AMPA and kainate receptors, NMDA receptors have additional intersubunit contacts in the ligand binding domain that occur at both conserved and non-conserved sites. We examined GluN1/GluN2A single-channel currents with kinetic analyses and modeling to probe these class-specific intersubunit interactions for their role in glutamate binding and receptor gating. We found that substitutions that eliminate such interactions at non-conserved sites reduced stationary gating, accelerated deactivation, and imparted sensitivity to aniracetam, an AMPA receptor-selective positive modulator. Abolishing unique contacts at conserved sites also reduced stationary gating and accelerated deactivation. These results show that contacts specific to NMDA receptors, which brace the heterodimer interface within the ligand binding domain, stabilize actively gating receptor conformations and result in longer bursts and slower deactivations. They support the view that the strength of the heterodimer interface modulates gating in both NMDA and non-NMDA receptors and that unique interactions at this interface are responsible in part for basic differences between the kinetics of NMDA and non-NMDA currents at glutamatergic synapses. PMID:26370091

Trigeminal Medullary Dorsal Horn Neurons Activated by Nasal Stimulation Coexpress AMPA, NMDA, and NK1 Receptors

PubMed Central

McCulloch, P. F.; DiNovo, K. M.; Westerhaus, D. J.; Vizinas, T. A.; Peevey, J. F.; Lach, M. A.; Czarnocki, P.

2013-01-01

Afferent information initiating the cardiorespiratory responses during nasal stimulation projects from the nasal passages to neurons within the trigeminal medullary dorsal horn (MDH) via the anterior ethmoidal nerve (AEN). Central AEN terminals are thought to release glutamate to activate the MDH neurons. This study was designed to determine which neurotransmitter receptors (AMPA, kainate, or NMDA glutamate receptor subtypes or the Substance P receptor NK1) are expressed by these activated MDH neurons. Fos was used as a neuronal marker of activated neurons, and immunohistochemistry combined with epifluorescent microscopy was used to determine which neurotransmitter receptor subunits were coexpressed by activated MDH neurons. Results indicate that, during nasal stimulation with ammonia vapors in urethane-anesthetized Sprague-Dawley rats, activated neurons within the superficial MDH coexpress the AMPA glutamate receptor subunits GluA1 (95.8%) and GluA2/3 (88.2%), the NMDA glutamate receptor subunits GluN1 (89.1%) and GluN2A (41.4%), and NK1 receptors (64.0%). It is therefore likely that during nasal stimulation the central terminals of the AEN release glutamate and substance P that then produces activation of these MDH neurons. The involvement of AMPA and NMDA receptors may mediate fast and slow neurotransmission, respectively, while NK1 receptor involvement may indicate activation of a nociceptive pathway. PMID:24967301

Aniracetam, 1-BCP and cyclothiazide differentially modulate the function of NMDA and AMPA receptors mediating enhancement of noradrenaline release in rat hippocampal slices.

PubMed

Pittaluga, A; Bonfanti, A; Arvigo, D; Raiteri, M

1999-04-01

Aniracetam, 1-(1,3-benzodioxol-5-yl-carbonyl)piperidine (1-BCP) and cyclothiazide, three compounds considered to enhance cognition through modulation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, were evaluated in the 'kynurenate test', a biochemical assay in which some nootropics have been shown to prevent the antagonism by kynurenic acid of the N-methyl-D-aspartate (NMDA)-evoked [3H]noradrenaline ([3H]NA) release from rat hippocampal slices. Aniracetam attenuated the kynurenate (100 microM) antagonism of the [3H]NA release elicited by 100 microM NMDA with high potency (EC50< or =0.1 microM). Cyclothiazide and 1-BCP were about 10 and 100 times less potent than aniracetam, respectively. The effect of aniracetam persisted in the presence of the AMPA receptor antagonist 6-nitro-7-sulphamoyl-benzo[f]quinoxaline-2,3-dione (NBQX) added at 5 microM, a concentration that did not affect NMDA receptors; in contrast, NBQX reduced the effect of 1-BCP and abolished that of cyclothiazide. The AMPA-evoked release of [3H]NA from hippocampal slices or synaptosomes was enhanced by cyclothiazide, less potently by 1-BCP and weakly by aniracetam. High concentrations of kynurenate (1 mM) antagonized the AMPA-evoked [3H]NA release in slices; this antagonism was attenuated by 1 microM cyclothiazide and reversed to an enhancement of AMPA-evoked [3H]NA release by 10 microM of the drug, but was insensitive to 1-BCP or aniracetam. It is concluded that aniracetam exerts a dual effect on glutamatergic transmission: modulation of NMDA receptor function at nanomolar concentrations, and modulation of AMPA receptors at high micromolar concentrations. As to cyclothiazide and 1-BCP, our data concur with the idea that both compounds largely act through AMPA receptors, although an NMDA component may be involved in the effect of 1-BCP.

Control of βAR- and N-methyl-D-aspartate (NMDA) Receptor-Dependent cAMP Dynamics in Hippocampal Neurons

PubMed Central

Chay, Andrew; Zamparo, Ilaria; Koschinski, Andreas; Zaccolo, Manuela; Blackwell, Kim T.

2016-01-01

Norepinephrine, a neuromodulator that activates β-adrenergic receptors (βARs), facilitates learning and memory as well as the induction of synaptic plasticity in the hippocampus. Several forms of long-term potentiation (LTP) at the Schaffer collateral CA1 synapse require stimulation of both βARs and N-methyl-D-aspartate receptors (NMDARs). To understand the mechanisms mediating the interactions between βAR and NMDAR signaling pathways, we combined FRET imaging of cAMP in hippocampal neuron cultures with spatial mechanistic modeling of signaling pathways in the CA1 pyramidal neuron. Previous work implied that cAMP is synergistically produced in the presence of the βAR agonist isoproterenol and intracellular calcium. In contrast, we show that when application of isoproterenol precedes application of NMDA by several minutes, as is typical of βAR-facilitated LTP experiments, the average amplitude of the cAMP response to NMDA is attenuated compared with the response to NMDA alone. Models simulations suggest that, although the negative feedback loop formed by cAMP, cAMP-dependent protein kinase (PKA), and type 4 phosphodiesterase may be involved in attenuating the cAMP response to NMDA, it is insufficient to explain the range of experimental observations. Instead, attenuation of the cAMP response requires mechanisms upstream of adenylyl cyclase. Our model demonstrates that Gs-to-Gi switching due to PKA phosphorylation of βARs as well as Gi inhibition of type 1 adenylyl cyclase may underlie the experimental observations. This suggests that signaling by β-adrenergic receptors depends on temporal pattern of stimulation, and that switching may represent a novel mechanism for recruiting kinases involved in synaptic plasticity and memory. PMID:26901880

Afferent specific role of NMDA receptors for the circuit integration of hippocampal neurogliaform cells.

PubMed

Chittajallu, R; Wester, J C; Craig, M T; Barksdale, E; Yuan, X Q; Akgül, G; Fang, C; Collins, D; Hunt, S; Pelkey, K A; McBain, C J

2017-07-28

Appropriate integration of GABAergic interneurons into nascent cortical circuits is critical for ensuring normal information processing within the brain. Network and cognitive deficits associated with neurological disorders, such as schizophrenia, that result from NMDA receptor-hypofunction have been mainly attributed to dysfunction of parvalbumin-expressing interneurons that paradoxically express low levels of synaptic NMDA receptors. Here, we reveal that throughout postnatal development, thalamic, and entorhinal cortical inputs onto hippocampal neurogliaform cells are characterized by a large NMDA receptor-mediated component. This NMDA receptor-signaling is prerequisite for developmental programs ultimately responsible for the appropriate long-range AMPAR-mediated recruitment of neurogliaform cells. In contrast, AMPAR-mediated input at local Schaffer-collateral synapses on neurogliaform cells remains normal following NMDA receptor-ablation. These afferent specific deficits potentially impact neurogliaform cell mediated inhibition within the hippocampus and our findings reveal circuit loci implicating this relatively understudied interneuron subtype in the etiology of neurodevelopmental disorders characterized by NMDA receptor-hypofunction.Proper brain function depends on the correct assembly of excitatory and inhibitory neurons into neural circuits. Here the authors show that during early postnatal development in mice, NMDAR signaling via activity of long-range synaptic inputs onto neurogliaform cells is required for their appropriate integration into the hippocampal circuitry.

Interplay between non-NMDA and NMDA receptor activation during oscillatory wave propagation: Analyses of caffeine-induced oscillations in the visual cortex of rats.

PubMed

Yoshimura, Hiroshi; Sugai, Tokio; Kato, Nobuo; Tominaga, Takashi; Tominaga, Yoko; Hasegawa, Takahiro; Yao, Chenjuan; Akamatsu, Tetsuya

2016-07-01

Generation and propagation of oscillatory activities in cortical networks are important features of the brain. However, many issues related to oscillatory phenomena are unclear. We previously reported neocortical oscillation following caffeine treatment of rat brain slices. Input to the primary visual cortex (Oc1) generates N-methyl-d-aspartate (NMDA) receptor-dependent oscillations, and we proposed that the oscillatory signals originate in the secondary visual cortex (Oc2). Because non-NMDA and NMDA receptors cooperate in synaptic transmission, non-NMDA receptors may also play an important role in oscillatory activities. Here we investigated how non-NMDA receptor activities contribute to NMDA receptor-dependent oscillations by using optical recording methods. After induction of stable oscillations with caffeine application, blockade of NMDA receptors abolished the late stable oscillatory phase, but elicited 'hidden' non-NMDA receptor-dependent oscillation during the early depolarizing phase. An interesting finding is that the origin of the non-NMDA receptor-dependent oscillation moved from the Oc1, during the early phase, toward the origin of the NMDA receptor-dependent oscillation that is fixed in the Oc2. In addition, the frequency of the non-NMDA receptor-dependent oscillation was higher than that of the NMDA receptor-dependent oscillation. Thus, in one course of spatiotemporal oscillatory activities, the relative balance in receptor activities between non-NMDA and NMDA receptors gradually changes, and this may be due to the different kinetics of the two receptor types. These results suggest that interplay between the two receptor types in the areas of Oc1 and Oc2 may play an important role in oscillatory signal communication. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effects of Ethanol on Phosphorylation Site Mutants of Recombinant NMDA Receptors

PubMed Central

Xu, Minfu; Smothers, Corigan T.; Woodward, John J.

2010-01-01

N-methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels activated by the neurotransmitter glutamate. These channels are highly expressed by brain neurons and are critically involved in excitatory synaptic transmission. Results from previous studies show that both native and recombinant NMDA receptors are inhibited by ethanol at concentrations associated with signs of behavioral impairment and intoxication. Given the important role that NMDA receptors play in synaptic transmission and brain function, it is important to understand the factors that regulate the ethanol inhibition of these receptors. One dynamic mechanism for regulating ethanol action may be via phosphorylation of NMDA subunits by serine-threonine and tyrosine kinases. Both NR1 and NR2 subunits contain multiple sites of phosphorylation and in the NR1 subunit, most of these are contained within the C1 domain, a carboxy-terminal cassette that is subject to alternative splicing. While results from our previous studies suggest that single phosphorylation sites do not greatly affect ethanol sensitivity of NMDA receptors, it is likely that in vivo, these subunits are phosphorylated at multiple sites by different kinases. In the present study, we constructed a series of NMDA receptor mutants at serine (S) or threonine (T) residues proposed to be sites of phosphorylation by PKA and various isoforms of PKC. Ethanol (100 mM) inhibited currents from wild-type NR1/2A and NR1/2B receptors expressed in HEK293 cells by approximately 25% and 30% respectively. This inhibition was not different in single site mutants expressing alanine (A) or aspartate/glutamate (D/E) at positions T879, S896 or T900. The mutant NR1(S890D) showed greater ethanol inhibition than NR1(890A) containing receptors although this was only observed when it was combined with the NR2A subunit. Ethanol inhibition was not altered by aspartate substitution at four serines (positions 889, 890, 896, 897) or when T879D was added to the four

Opiate and N-methyl-D-aspartate receptors in form-deprivation myopia.

PubMed

Fischer, A J; Seltner, R L; Stell, W K

1998-01-01

Pharmacological studies have implicated retinal opiate pathways in the visual regulation of ocular growth. However, the effects of opiate receptor subtype-specific compounds on form-deprivation myopia (FDM) are inconsistent (Seltner et al., 1997), and may be mediated by non-opiate receptors. The purpose of this study was to test whether opiate receptor-inactive (D-) enantiomers elicit the same FDM-suppressing effect as their opiate receptor-active (L-) counterparts. Since some opiates are thought to act at NMDA receptors, we also tested whether NMDA receptor agonists and antagonists influence ocular growth or FDM. We found that both L- and D- enantiomers of morphine-like compounds (dextrorphanol and levorphanol, and D- and L-naloxone) were equally effective in blocking FDM. The NMDA receptor antagonists dextromethorphan, MK801, and AP5 also suppressed FDM. A single toxic dose of NMDA, that destroys many subtypes of amacrine cells (including those that synthesize the opioid peptide enkephalin), induced myopia and ocular enlargement in ungoggled eyes, and eliminated the ability of form-deprivation to enhance ocular growth. The NR-1 subunit of the NMDA receptor was localized to a narrowly stratified, intense stratum at approximately 50% depth in the inner plexiform layer, diffusely throughout the proximal inner plexiform layer, and to many somata in the amacrine and ganglion cell layers. These observations suggest that most effects of opiate receptor ligands on FDM in the chick are mediated by non-opiate receptors, which are likely to include NMDA receptors. NMDA as an excitotoxin transiently enhances ocular growth, but thereafter disables retinal mechanisms that promote emmetropization and FDM. These observations are consistent with a prominent role for pathways utilizing NMDA receptors in FDM and ocular growth-control.

Reboxetine Enhances the Olanzapine-Induced Antipsychotic-Like Effect, Cortical Dopamine Outflow and NMDA Receptor-Mediated Transmission

PubMed Central

Marcus, Monica M; Jardemark, Kent; Malmerfelt, Anna; Björkholm, Carl; Svensson, Torgny H

2010-01-01

Preclinical data have shown that addition of the selective norepinephrine transporter (NET) inhibitor reboxetine increases the antipsychotic-like effect of the D2/3 antagonist raclopride and, in parallel, enhances cortical dopamine output. Subsequent clinical results suggested that adding reboxetine to stable treatments with various antipsychotic drugs (APDs) may improve positive, negative and depressive symptoms in schizophrenia. In this study, we investigated in rats the effects of adding reboxetine to the second-generation APD olanzapine on: (i) antipsychotic efficacy, using the conditioned avoidance response (CAR) test, (ii) extrapyramidal side effect (EPS) liability, using a catalepsy test, (iii) dopamine efflux in the medial prefrontal cortex and the nucleus accumbens, using in vivo microdialysis in freely moving animals and (iv) cortical N-methyl--aspartate (NMDA) receptor-mediated transmission, using intracellular electrophysiological recording in vitro. Reboxetine (6 mg/kg) enhanced the suppression of CAR induced by a suboptimal dose (1.25 mg/kg), but not an optimal (2.5 mg/kg) dose of olanzapine without any concomitant catalepsy. Addition of reboxetine to the low dose of olanzapine also markedly increased cortical dopamine outflow and facilitated prefrontal NMDA receptor-mediated transmission. Our data suggest that adjunctive treatment with a NET inhibitor may enhance the therapeutic effect of low-dose olanzapine in schizophrenia without increasing EPS liability and add an antidepressant action, thus in principle allowing for a dose reduction of olanzapine with a concomitant reduction of dose-related side effects, such as EPS and weight gain. PMID:20463659

Essential Role of NMDA Receptor Channel ε4 Subunit (GluN2D) in the Effects of Phencyclidine, but Not Methamphetamine

PubMed Central

Hagino, Yoko; Kasai, Shinya; Han, Wenhua; Yamamoto, Hideko; Nabeshima, Toshitaka; Mishina, Masayoshi; Ikeda, Kazutaka

2010-01-01

Phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, increases locomotor activity in rodents and causes schizophrenia-like symptoms in humans. Although activation of the dopamine (DA) pathway is hypothesized to mediate these effects of PCP, the precise mechanisms by which PCP induces its effects remain to be elucidated. The present study investigated the effect of PCP on extracellular levels of DA (DAex) in the striatum and prefrontal cortex (PFC) using in vivo microdialysis in mice lacking the NMDA receptor channel ε1 or ε4 subunit (GluRε1 [GluN2A] or GluRε4 [GluN2D]) and locomotor activity. PCP significantly increased DAex in wildtype and GluRε1 knockout mice, but not in GluRε4 knockout mice, in the striatum and PFC. Acute and repeated administration of PCP did not increase locomotor activity in GluRε4 knockout mice. The present results suggest that PCP enhances dopaminergic transmission and increases locomotor activity by acting at GluRε4. PMID:21060893

Control of Appetite and Food Preference by NMDA Receptor and Its Co-Agonist d-Serine

PubMed Central

Sasaki, Tsutomu; Matsui, Sho; Kitamura, Tadahiro

2016-01-01

Obesity causes a significant negative impact on health of human beings world-wide. The main reason for weight gain, which eventually leads to obesity, is excessive ingestion of energy above the body’s homeostatic needs. Therefore, the elucidation of detailed mechanisms for appetite control is necessary to prevent and treat obesity. N-methyl-d-aspartate (NMDA) receptor is a post-synaptic glutamate receptor and is important for excitatory neurotransmission. It is expressed throughout the nervous system, and is important for long-term potentiation. It requires both ligand (glutamate) and co-agonist (d-serine or glycine) for efficient opening of the channel to allow calcium influx. d-serine is contained in fermented foods and marine invertebrates, and brain d-serine level is maintained by synthesis in vivo and supply from food and gut microbiota. Although the NMDA receptor has been reported to take part in the central regulation of appetite, the role of d-serine had not been addressed. We recently reported that exogenous d-serine administration can suppress appetite and alter food preference. In this review, we will discuss how NMDA receptor and its co-agonist d-seine participate in the control of appetite and food preference, and elaborate on how this system could possibly be manipulated to suppress obesity. PMID:27399680

NMDA-receptor blockade by CPP impairs post-training consolidation of a rapidly acquired spatial representation in rat hippocampus.

PubMed

McDonald, Robert J; Hong, Nancy S; Craig, Laura A; Holahan, Matthew R; Louis, Meira; Muller, Robert U

2005-09-01

Recent evidence suggests that N-methyl-D-aspartate (NMDA)-receptor mediated plasticity in hippocampus has a more subtle role in memory-based behaviours than originally thought. One idea is that NMDA-based plasticity is essential for the consolidation of post-training memory but not for the initial encoding or for short-term memory. To further test this idea we used a three-phase variant of the hidden goal water maze task. In the first phase, rats were pre-trained to an initial location. Next, intense, massed training was done in a 2-h interval to teach the rats to go to a new location after either an injection of the NMDA receptor antagonist (6)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) or of vehicle. Finally, under drug-free conditions 24 h after new location training, a competition test was done between the original and new locations. We find that N-methyl-D-aspartate (NMDA)-receptor blockade has little or no effect on new location training. In contrast, when tested 24 h later, the strength of the trace for the new location learned during NMDA-receptor blockade was much weaker compared with the trace for the new location learned after saline injection. Further experiments showed similar effects when NMDA-receptors were blocked immediately after the new location training, suggesting that this is a memory consolidation effect. Our results therefore reinforce the notion that hippocampal NMDA-receptors participate in post-training memory consolidation but are not essential for the processes necessary to learn or retain navigational information in the short term.

Implementation of a Fluorescence-Based Screening Assay Identifies Histamine H3 Receptor Antagonists Clobenpropit and Iodophenpropit as Subunit-Selective N-Methyl-d-Aspartate Receptor Antagonists

PubMed Central

Hansen, Kasper B.; Mullasseril, Praseeda; Dawit, Sara; Kurtkaya, Natalie L.; Yuan, Hongjie; Vance, Katie M.; Orr, Anna G.; Kvist, Trine; Ogden, Kevin K.; Le, Phuong; Vellano, Kimberly M.; Lewis, Iestyn; Kurtkaya, Serdar; Du, Yuhong; Qui, Min; Murphy, T. J.; Snyder, James P.; Bräuner-Osborne, Hans

2010-01-01

N-Methyl-d-aspartate (NMDA) receptors are ligand-gated ion channels that mediate a slow, Ca2+-permeable component of excitatory synaptic transmission in the central nervous system and play a pivotal role in synaptic plasticity, neuronal development, and several neurological diseases. We describe a fluorescence-based assay that measures NMDA receptor-mediated changes in intracellular calcium in a BHK-21 cell line stably expressing NMDA receptor NR2D with NR1 under the control of a tetracycline-inducible promoter (Tet-On). The assay selectively identifies allosteric modulators by using supramaximal concentrations of glutamate and glycine to minimize detection of competitive antagonists. The assay is validated by successfully identifying known noncompetitive, but not competitive NMDA receptor antagonists among 1800 screened compounds from two small focused libraries, including the commercially available library of pharmacologically active compounds. Hits from the primary screen are validated through a secondary screen that used two-electrode voltage-clamp recordings on recombinant NMDA receptors expressed in Xenopus laevis oocytes. This strategy identified several novel modulators of NMDA receptor function, including the histamine H3 receptor antagonists clobenpropit and iodophenpropit, as well as the vanilloid receptor transient receptor potential cation channel, subfamily V, member 1 (TRPV1) antagonist capsazepine. These compounds are noncompetitive antagonists and the histamine H3 receptor ligand showed submicromolar potency at NR1/NR2B NMDA receptors, which raises the possibility that compounds can be developed that act with high potency on both glutamate and histamine receptor systems simultaneously. Furthermore, it is possible that some actions attributed to histamine H3 receptor inhibition in vivo may also involve NMDA receptor antagonism. PMID:20197375

NMDA receptor-antagonistic properties of hyperforin, a constituent of St. John's Wort.

PubMed

Kumar, Vikas; Mdzinarishvili, Alexander; Kiewert, Cornelia; Abbruscato, Thomas; Bickel, Ulrich; van der Schyf, Cornelis J; Klein, Jochen

2006-09-01

Extracts of the medicinal plant St. John's wort (Hypericum perforatum) are widely used for the treatment of affective disorders. Hyperforin, a constituent of St. John's wort, is known to modulate the release and re-uptake of various neurotransmitters, an action that likely underlies its antidepressive activity. We now report that hyperforin also has N-methyl-D-aspartate (NMDA)-antagonistic effects. Hyperforin (10 microM) was found to inhibit the NMDA-induced calcium influx into cortical neurons. In rat hippocampal slices, hyperforin inhibited the NMDA-receptor-mediated release of choline from phospholipids. Hyperforin also antagonized the increase of water content in freshly isolated hippocampal slices, and it counteracted, at 3 and 10 microM, the increase of water content induced by NMDA. Hyperforin was inactive, however, in two in vivo models of brain edema formation, middle cerebral artery occlusion and water intoxication in mice. In conclusion, hyperforin has NMDA-receptor-antagonistic and potential neuroprotective effects in vitro. This effect may contribute to the therapeutic effectiveness of St. John's wort extracts in some situations, for example, for relapse prevention in alcoholism.

Involvement of NMDA receptor in low-frequency magnetic field-induced anxiety in mice.

PubMed

Salunke, Balwant P; Umathe, Sudhir N; Chavan, Jagatpalsingh G

2014-12-01

It had been reported that exposure to extremely low-frequency magnetic field (ELFMF) induces anxiety in human and rodents. Anxiety mediates via the activation of N-methyl-d-aspartate (NMDA) receptor, whereas activation of γ-aminobutyric acid (GABA) receptor attenuates the same. Hence, the present study was carried out to understand the contribution of NMDA and/or GABA receptors modulation in ELFMF-induced anxiety for which Swiss albino mice were exposed to ELFMF (50 Hz, 10 G) by subjecting them to Helmholtz coils. The exposure was for 8 h/day for 7, 30, 60, 90 and 120 days. Anxiety level was assessed in elevated plus maze, open field test and social interaction test, on 7th, 30th, 60th, 90th and 120th exposure day, respectively. Moreover, the role of GABA and glutamate in ELFMF-induced anxiety was assessed by treating mice with muscimol [0.25 mg/kg intraperitoneally (i.p.)], bicuculline (1.0 mg/kg i.p.), NMDA (15 mg/kg i.p.) and MK-801 (0.03 mg/kg i.p.), as a GABAA and NMDA receptor agonist and antagonist, respectively. Glutamate receptor agonist exacerbated while inhibitor attenuated the ELFMF-induced anxiety. In addition, levels of GABA and glutamate were determined in regions of the brain viz, cortex, striatum, hippocampus and hypothalamus. Experiments demonstrated significant elevation of GABA and glutamate levels in the hippocampus and hypothalamus. However, GABA receptor modulators did not produce significant effect on ELFMF-induced anxiety and elevated levels of GABA at tested dose. Together, these findings suggest that ELFMF significantly induced anxiety behavior, and indicated the involvement of NMDA receptor in its effect.

[Anti-NMDA receptor encephalitis: two paediatric cases].

PubMed

González-Toro, M Cristina; Jadraque-Rodríguez, Rocío; Sempere-Pérez, Ángela; Martínez-Pastor, Pedro; Jover-Cerdá, Jenaro; Gómez-Gosálvez, Francisco

2013-12-01

Encephalitis associated to anti-N-methyl D-aspartate (NMDA) receptor antibodies is an autoimmune neurological pathology that has been reported increasingly more frequently in the paediatric population in recent years. We report two cases from our own experience with similar clinical pictures. Case 1: a 5-year-old girl who began with clinical signs and symptoms of convulsions and altered consciousness, associated to movement disorders and regression of previously acquired abilities that developed into autism. Case 2: a 13-year-old girl who presented left-side hemiparesis, abnormal movements, conduct disorder and dysautonomia. In both cases positive anti-NMDA receptor antibodies were obtained in cerebrospinal fluid and they were diagnosed with anti-NMDA receptor encephalitis. In the first case, treatment was established with intravenous perfusion of corticoids and immunoglobulins, and rituximab also had to be associated. In the second case, treatment consisted in corticoids and immunoglobulins. Progress was favourable in both cases, with a slight language disorder as a sequela in the first case and a relapse in the second case, with full resolution. Anti-NMDA receptor encephalitis is a treatable disorder and early diagnosis and treatment are crucial, since this improves the prognosis and diminishes the chances of relapses.

The role of striatal NMDA receptors in drug addiction.

PubMed

Ma, Yao-Ying; Cepeda, Carlos; Cui, Cai-Lian

2009-01-01

The past decade has witnessed an impressive accumulation of evidence indicating that the excitatory amino acid glutamate and its receptors, in particular the N-methyl-D-aspartate (NMDA) receptor subtype, play an important role in drug addiction. Various lines of research using animal models of drug addiction have demonstrated that drug-induced craving is accompanied by significant upregulation of NR2B subunit expression. Furthermore, selective blockade of NR2B-containing NMDA receptors in the striatum, especially in the nucleus accumbens (NAc) can inhibit drug craving and reinstatement. The purpose of this review is to examine the role of striatal NMDA receptors in drug addiction. After a brief description of glutamatergic innervation and NMDA receptor subunit distribution in the striatum, we discuss potential mechanisms to explain the role of striatal NMDA receptors in drug addiction by elucidating signaling cascades involved in the regulation of subunit expression and redistribution, phosphorylation of receptor subunits, as well as activation of intracellular signals triggered by drug experience. Understanding the mechanisms regulating striatal NMDA receptor changes in drug addiction will provide more specific and rational targets to counteract the deleterious effects of drug addiction.

CDKL5 controls postsynaptic localization of GluN2B-containing NMDA receptors in the hippocampus and regulates seizure susceptibility.

PubMed

Okuda, Kosuke; Kobayashi, Shizuka; Fukaya, Masahiro; Watanabe, Aya; Murakami, Takuto; Hagiwara, Mai; Sato, Tempei; Ueno, Hiroe; Ogonuki, Narumi; Komano-Inoue, Sayaka; Manabe, Hiroyuki; Yamaguchi, Masahiro; Ogura, Atsuo; Asahara, Hiroshi; Sakagami, Hiroyuki; Mizuguchi, Masashi; Manabe, Toshiya; Tanaka, Teruyuki

2017-10-01

Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders accompanied by intractable epilepsies, i.e. West syndrome or atypical Rett syndrome. Here we report generation of the Cdkl5 knockout mouse and show that CDKL5 controls postsynaptic localization of GluN2B-containing N-methyl-d-aspartate (NMDA) receptors in the hippocampus and regulates seizure susceptibility. Cdkl5 -/Y mice showed normal sensitivity to kainic acid; however, they displayed significant hyperexcitability to NMDA. In concordance with this result, electrophysiological analysis in the hippocampal CA1 region disclosed an increased ratio of NMDA/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated excitatory postsynaptic currents (EPSCs) and a significantly larger decay time constant of NMDA receptor-mediated EPSCs (NMDA-EPSCs) as well as a stronger inhibition of the NMDA-EPSCs by the GluN2B-selective antagonist ifenprodil in Cdkl5 -/Y mice. Subcellular fractionation of the hippocampus from Cdkl5 -/Y mice revealed a significant increase of GluN2B and SAP102 in the PSD (postsynaptic density)-1T fraction, without changes in the S1 (post-nuclear) fraction or mRNA transcripts, indicating an intracellular distribution shift of these proteins to the PSD. Immunoelectron microscopic analysis of the hippocampal CA1 region further confirmed postsynaptic overaccumulation of GluN2B and SAP102 in Cdkl5 -/Y mice. Furthermore, ifenprodil abrogated the NMDA-induced hyperexcitability in Cdkl5 -/Y mice, suggesting that upregulation of GluN2B accounts for the enhanced seizure susceptibility. These data indicate that CDKL5 plays an important role in controlling postsynaptic localization of the GluN2B-SAP102 complex in the hippocampus and thereby regulates seizure susceptibility, and that aberrant NMDA receptor-mediated synaptic transmission underlies the pathological mechanisms of the CDKL5 loss-of-function. Copyright © 2017 Elsevier Inc. All rights

Modeling the effect of glutamate diffusion and uptake on NMDA and non-NMDA receptor saturation.

PubMed Central

Holmes, W R

1995-01-01

One- and two-dimensional models of glutamate diffusion, uptake, and binding in the synaptic cleft were developed to determine if the release of single vesicles of glutamate would saturate NMDA and non-NMDA receptors. Ranges of parameter values were used in the simulations to determine the conditions when saturation could occur. Single vesicles of glutamate did not saturate NMDA receptors unless diffusion was very slow and the number of glutamate molecules in a vesicle was large. However, the release of eight vesicles at 400 Hz caused NMDA receptor saturation for all parameter values tested. Glutamate uptake was found to reduce NMDA receptor saturation, but the effect was smaller than that of changes in the diffusion coefficient or in the number of glutamate molecules in a vesicle. Non-NMDA receptors were not saturated unless diffusion was very slow and the number of glutamate molecules in a vesicle was large. The release of eight vesicles at 400 Hz caused significant non-NMDA receptor desensitization. The results suggest that NMDA and non-NMDA receptors are not saturated by single vesicles of glutamate under usual conditions, and that tetanic input, of the type typically used to induce long-term potentiation, will increase calcium influx by increasing receptor binding as well as by reducing voltage-dependent block of NMDA receptors. Images FIGURE 1 PMID:8580317

Modulation of NMDA Receptor Properties and Synaptic Transmission by the NR3A Subunit in Mouse Hippocampal and Cerebrocortical Neurons

PubMed Central

Tong, Gary; Takahashi, Hiroto; Tu, Shichun; Shin, Yeonsook; Talantova, Maria; Zago, Wagner; Xia, Peng; Nie, Zhiguo; Goetz, Thomas; Zhang, Dongxian; Lipton, Stuart A.; Nakanishi, Nobuki

2015-01-01

Expression of the NR3A subunit with NR1/NR2 in Xenopus oocytes or mammalian cell lines leads to a reduction in N-methyl-D-aspartate (NMDA)-induced currents and decreased Mg2+ sensitivity and Ca2+ permeability compared with NR1/NR2 receptors. Consistent with these findings, neurons from NR3A knockout (KO) mice exhibit enhanced NMDA-induced currents. Recombinant NR3A can also form excitatory glycine receptors with NR1 in the absence of NR2. However, the effects of NR3A on channel properties in neurons and synaptic transmission have not been fully elucidated. To study physiological roles of NR3A subunits, we generated NR3A transgenic (Tg) mice. Cultured NR3A Tg neurons exhibited two populations of NMDA receptor (NMDAR) channels, reduced Mg2+ sensitivity, and decreased Ca2+ permeability in response to NMDA/glycine, but glycine alone did not elicit excitatory currents. In addition, NMDAR-mediated excitatory postsynaptic currents (EPSCs) in NR3A Tg hippocampal slices showed reduced Mg2+ sensitivity, consistent with the notion that NR3A subunits incorporated into synaptic NMDARs. To study the function of endogenous NR3A subunits, we compared NMDAR-mediated EPSCs in NR3A KO and WT control mice. In NR3A KO mice, the ratio of the amplitudes of the NMDAR-mediated component to α-amino-3-hydroxy-5-methyl-4-isox-azolepropionic acid receptor-mediated component of the EPSC was significantly larger than that seen in WT littermates. This result suggests that NR3A subunits contributed to the NMDAR-mediated component of the EPSC in WT mice. Taken together, these results show that NR3A subunits contribute to NMDAR responses from both synaptic and extra-synaptic receptors, likely composed of NR1, NR2, and NR3 subunits. PMID:18003876

NMDA receptor blockade in the prelimbic cortex activates the mesolimbic system and dopamine-dependent opiate reward signaling.

PubMed

Tan, Huibing; Rosen, Laura G; Ng, Garye A; Rushlow, Walter J; Laviolette, Steven R

2014-12-01

N-Methyl-D-aspartate (NMDA) receptors in the medial prefrontal cortex (mPFC) are involved in opiate reward processing and modulate sub-cortical dopamine (DA) activity. NMDA receptor blockade in the prelimbic (PLC) division of the mPFC strongly potentiates the rewarding behavioural properties of normally sub-reward threshold doses of opiates. However, the possible functional interactions between cortical NMDA and sub-cortical DAergic motivational neural pathways underlying these effects are not understood. This study examines how NMDA receptor modulation in the PLC influences opiate reward processing via interactions with sub-cortical DAergic transmission. We further examined whether direct intra-PLC NMDA receptor modulation may activate DA-dependent opiate reward signaling via interactions with the ventral tegmental area (VTA). Using an unbiased place conditioning procedure (CPP) in rats, we performed bilateral intra-PLC microinfusions of the competitive NMDA receptor antagonist, (2R)-amino-5-phosphonovaleric acid (AP-5), prior to behavioural morphine place conditioning and challenged the rewarding effects of morphine with DA receptor blockade. We next examined the effects of intra-PLC NMDA receptor blockade on the spontaneous activity patterns of presumptive VTA DA or GABAergic neurons, using single-unit, extracellular in vivo neuronal recordings. We show that intra-PLC NMDA receptor blockade strongly activates sub-cortical DA neurons within the VTA while inhibiting presumptive non-DA GABAergic neurons. Behaviourally, NMDA receptor blockade activates a DA-dependent opiate reward system, as pharmacological blockade of DA transmission blocked morphine reward only in the presence of intra-PLC NMDA receptor antagonism. These findings demonstrate a cortical NMDA-mediated mechanism controlling mesolimbic DAergic modulation of opiate reward processing.

Activation of NMDA receptors in the brainstem, rostral ventromedial medulla, and nucleus reticularis gigantocellularis mediates mechanical hyperalgesia produced by repeated intramuscular injections of acidic saline in rats.

PubMed

Da Silva, Luis F; Desantana, Josimari M; Sluka, Kathleen A

2010-04-01

Repeated injections of acidic saline into the gastrocnemius muscle induce both muscle and cutaneous hypersensitivity. We have previously shown that microinjection of local anesthetic into either the rostral ventromedial medulla (RVM) or the nucleus reticularis gigantocellularis (NGC) reverses this muscle and cutaneous hypersensitivity. Although prior studies show that NMDA receptors in the RVM play a clear role in mediating visceral and inflammatory hypersensitivity, the role of NMDA receptors in the NGC or in noninflammatory muscle pain is unclear. Therefore, the present study evaluated involvement of the NMDA receptors in the RVM and NGC in muscle and cutaneous hypersensitivity induced by repeated intramuscular injections of acidic saline. Repeated intramuscular injections of acidic saline, 5 days apart, resulted in a bilateral decrease in the withdrawal thresholds of the paw and muscle in all groups 24 hours after the second injection. Microinjection of NMDA receptor antagonists into the RVM reversed both the muscle and cutaneous hypersensitivity. However, microinjection of NMDA receptor antagonists into the NGC only reversed cutaneous but not muscle hypersensitivity. These results suggest that NMDA receptors in the RVM mediate both muscle and cutaneous hypersensitivity, but those in the NGC mediate only cutaneous hypersensitivity after muscle insult. The current study shows that NMDA receptors in supraspinal facilitatory sites maintain noninflammatory muscle pain. Clinical studies in people with chronic widespread, noninflammatory pain, similarly, show alterations in central excitability. Thus, understanding mechanisms in an animal model could lead to improved treatment for patients with chronic muscle pain. Copyright 2010 American Pain Society. Published by Elsevier Inc. All rights reserved.

Developmental changes in NMDA receptor expression in the platyfish brain

NASA Technical Reports Server (NTRS)

Flynn, K. M.; Schreibman, M. P.; Magliulo-Cepriano, L.

1997-01-01

We have examined the distribution of the N-methyl-D-aspartate (NMDA) receptor in the brain of a freshwater teleost using an antibody against the R1 subunit of the receptor (NMDAR1). The primary site of localization was the nucleus olfactoretinalis (NOR), a significant gonadotropin releasing hormone (GnRH)-containing brain nucleus. The number of cells expressing NMDAR1 in this nucleus was dependent upon developmental stage, with pubescent and mature animals displaying significantly more stained cells than immature and senescent animals. This is the first reported observation of age- and maturity-related NMDA receptor association with GnRH-containing brain areas.

Pre-synaptic glycine GlyT1 transporter--NMDA receptor interaction: relevance to NMDA autoreceptor activation in the presence of Mg2+ ions.

PubMed

Musante, Veronica; Summa, Maria; Cunha, Rodrigo A; Raiteri, Maurizio; Pittaluga, Anna

2011-05-01

Rat hippocampal glutamatergic terminals possess NMDA autoreceptors whose activation by low micromolar NMDA elicits glutamate exocytosis in the presence of physiological Mg(2+) (1.2 mM), the release of glutamate being significantly reduced when compared to that in Mg(2+)-free condition. Both glutamate and glycine were required to evoke glutamate exocytosis in 1.2 mM Mg(2+), while dizocilpine, cis-4-[phosphomethyl]-piperidine-2-carboxylic acid and 7-Cl-kynurenic acid prevented it, indicating that occupation of both agonist sites is needed for receptor activation. D-serine mimicked glycine but also inhibited the NMDA/glycine-induced release of [(3H]D-aspartate, thus behaving as a partial agonist. The NMDA/glycine-induced release in 1.2 mM Mg(2+) strictly depended on glycine uptake through the glycine transporter type 1 (GlyT1), because the GlyT1 blocker N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl])sarcosine hydrochloride, but not the GlyT2 blocker Org 25534, prevented it. Accordingly, [(3)H]glycine was taken up during superfusion, while lowering the external concentration of Na(+), the monovalent cation co-transported with glycine by GlyT1, abrogated the NMDA-induced effect. Western blot analysis of subsynaptic fractions confirms that GlyT1 and NMDA autoreceptors co-localize at the pre-synaptic level, where GluN3A subunits immunoreactivity was also recovered. It is proposed that GlyT1s coexist with NMDA autoreceptors on rat hippocampal glutamatergic terminals and that glycine taken up by GlyT1 may permit physiological activation of NMDA pre-synaptic autoreceptors. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

The effect of the mGlu5 negative allosteric modulator MTEP and NMDA receptor partial agonist D-cycloserine on Pavlovian conditioned fear.

PubMed

Handford, Charlotte E; Tan, Shawn; Lawrence, Andrew J; Kim, Jee Hyun

2014-09-01

The metabotropic glutamate receptor 5 (mGlu5) and N-methyl-D-aspartate (NMDA) receptor are critical for processes underlying synaptic plasticity, such as long-term potentiation. mGlu5 signaling increases neuronal excitability and potentiates NMDA receptor currents in the amygdala and the hippocampus. The present study examined the involvement of mGlu5 in the acquisition and consolidation of conditioned fear to a tone and context in mice, and explored the functional relationship between mGlu5 and NMDA receptors in this regard. Experiment 1 showed that systemic administration of the mGlu5 negative allosteric modulator 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) prior to conditioning significantly attenuated cue-elicited freezing during fear conditioning, which suggests that mGlu5 is necessary for the formation of a tone-shock association. This effect was dose-related (Experiment 2) and not due to any effects of MTEP on shock sensitivity or state-dependency (Experiment 3). Post-conditioning injection of MTEP had no effects (Experiment 4). Although post-conditioning injection of the NMDA receptor partial agonist D-cycloserine (DCS) alone facilitated consolidation of conditioned fear (Experiment 6), it was not able to rescue the acquisition deficit caused by MTEP (Experiment 5). Taken together, these findings indicate a crucial role for mGlu5 signaling in acquisition and NMDA receptor signaling in consolidation of conditioned fear.

Implication of Genes for the N-Methyl-D-Aspartate (NMDA) Receptor in Substance Addictions.

PubMed

Chen, Jiali; Ma, Yunlong; Fan, Rongli; Yang, Zhongli; Li, Ming D

2018-02-10

Drug dependence is a chronic brain disease with harmful consequences for both individual users and society. Glutamate is a primary excitatory neurotransmitter in the brain, and both in vivo and in vitro experiments have implicated N-methyl-D-aspartate (NMDA) receptor, a glutamate receptor, as an element in various types of addiction. Recent findings from genetics-based approaches such as genome-wide linkage, candidate gene association, genome-wide association (GWA), and next-generation sequencing have demonstrated the significant association of NMDA receptor subunit genes such as GluN3A, GluN2B, and GluN2A with various addiction-related phenotypes. Of these genes, GluN3A has been the most studied, and it has been revealed to play crucial roles in the etiology of addictions. In this communication, we provide an updated view of the genetic effects of NMDA receptor subunit genes and their functions in the etiology of addictions based on the findings from investigation of both common and rare variants as well as SNP-SNP interactions. To better understand the molecular mechanisms underlying addiction-related behaviors and to promote the development of specific medicines for the prevention and treatment of addictions, current efforts aim not only to identify more causal variants in NMDA receptor subunits by using large independent samples but also to reveal the molecular functions of these variants in addictions.

NMDA receptor adjusted co-administration of ecstasy and cannabinoid receptor-1 agonist in the amygdala via stimulation of BDNF/Trk-B/CREB pathway in adult male rats.

PubMed

Ashabi, Ghorbangol; Sadat-Shirazi, Mitra-Sadat; Khalifeh, Solmaz; Elhampour, Laleh; Zarrindast, Mohammad-Reza

2017-04-01

Consumption of cannabinoid receptor-1 (CB-1) agonist such as cannabis is widely taken in 3,4- methylenedioxymethamphetamine (MDMA) or ecstasy users; it has been hypothesized that co-consumption of CB-1 agonist might protect neurons against MDMA toxicity. N-methyl-d-aspartate (NMDA) receptors regulate neuronal plasticity and firing rate in the brain through Tyrosine-kinase B (Trk-B) activation. The molecular and electrophysiological association among NMDA and MDMA/Arachidonylcyclopropylamide (ACPA, a selective CB-1 receptor agonist) co-consumption was not well-known. Here, neuronal spontaneous activity, Brain-derived neurotrophic factor (BDNF), Trk-B and cAMP response element binding protein (CREB) phosphorylation levels were recognized in ACPA and MDMA co-injected rats. Besides, we proved the role of NMDA receptor on MDMA and ACPA combination on neuronal spontaneous activity and Trk-B/BDNF pathway in the central amygdala (CeA). Male rats were anesthetized with intra-peritoneal injections of urethane; MDMA, D-2-amino-5-phosphonopentanoate (D-AP5, NMDA receptor antagonist) were injected into CeA. ACPA was administrated by intra-cerebroventricular injection. Thirty minutes following injections, neuronal firing rate was recorded from CeA. Two hours after drug injection, amygdala was collected from brain for molecular evaluations. Single administration of MDMA and/or ACPA reduced firing rates compared with sham group in the CeA dose-dependently. Injection of D-AP5, ACPA and MDMA reduced firing rate compared with sham group (P<0.001). Interestingly, injection of ACPA+MDMA enhanced BDNF, Trk-B and CREB phosphorylation compared with MDMA groups. D-AP5, ACPA and MDMA co-injection decreased BDNF, Trk-B and CREB phosphorylation levels compared with ACPA+MDMA in the amygdala (P<0.01). Probably, NMDA receptors are involved in the protective role of acute MDMA+ACPA co-injection via BDNF/Trk-B/CREB pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

N-methyl-d-aspartate receptors, learning and memory: chronic intraventricular infusion of the NMDA receptor antagonist d-AP5 interacts directly with the neural mechanisms of spatial learning.

PubMed

Morris, R G M; Steele, R J; Bell, J E; Martin, S J

2013-03-01

Three experiments were conducted to contrast the hypothesis that hippocampal N-methyl-d-aspartate (NMDA) receptors participate directly in the mechanisms of hippocampus-dependent learning with an alternative view that apparent impairments of learning induced by NMDA receptor antagonists arise because of drug-induced neuropathological and/or sensorimotor disturbances. In experiment 1, rats given a chronic i.c.v. infusion of d-AP5 (30 mm) at 0.5 μL/h were selectively impaired, relative to aCSF-infused animals, in place but not cued navigation learning when they were trained during the 14-day drug infusion period, but were unimpaired on both tasks if trained 11 days after the minipumps were exhausted. d-AP5 caused sensorimotor disturbances in the spatial task, but these gradually worsened as the animals failed to learn. Histological assessment of potential neuropathological changes revealed no abnormalities in d-AP5-treated rats whether killed during or after chronic drug infusion. In experiment 2, a deficit in spatial learning was also apparent in d-AP5-treated rats trained on a spatial reference memory task involving two identical but visible platforms, a task chosen and shown to minimise sensorimotor disturbances. HPLC was used to identify the presence of d-AP5 in selected brain areas. In Experiment 3, rats treated with d-AP5 showed a delay-dependent deficit in spatial memory in the delayed matching-to-place protocol for the water maze. These data are discussed with respect to the learning mechanism and sensorimotor accounts of the impact of NMDA receptor antagonists on brain function. We argue that NMDA receptor mechanisms participate directly in spatial learning. © 2013 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Effects of the NMDA receptor antagonist, D-CPPene, on sensitization to the operant decrement produced by naloxone in morphine-treated rats.

PubMed

Bespalov, A Y; Medvedev, I O; Sukhotina, I A; Zvartau, E E

2001-04-01

Sensitization to the rate-decreasing effects of opioid antagonists induced by acute pretreatment with opioid agonists has been suggested to reflect initial changes in opioid systems that underlie physical dependence. Glutamate receptors are implicated in the development and expression of opioid dependence, and antagonists acting at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors have been shown repeatedly to attenuate the severity of opioid withdrawal. The present study evaluated the ability of a competitive NMDA receptor antagonist, D-CPPene (SDZ EAA 494; 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid), to affect morphine-induced sensitization to naloxone in rats trained to lever-press on a multiple-trial, fixed-ratio 10 schedule of food reinforcement. D-CPPene (0.3-3 mg/kg) was administered either 4 h or 30 min prior to the test session. Morphine (10 mg/kg) or its vehicle was administered 4 h before naloxone challenge (0.3-3 mg/kg). D-CPPene failed to prevent morphine-induced potentiation of the naloxone-produced decrement in operant performance. Thus, these results suggest that agonist-induced sensitization to behavioral effects of opioid antagonists may be insensitive to NMDA receptor blockade.

Lipid raft integrity affects GABAA receptor, but not NMDA receptor modulation by psychopharmacological compounds.

PubMed

Nothdurfter, Caroline; Tanasic, Sascha; Di Benedetto, Barbara; Uhr, Manfred; Wagner, Eva-Maria; Gilling, Kate E; Parsons, Chris G; Rein, Theo; Holsboer, Florian; Rupprecht, Rainer; Rammes, Gerhard

2013-07-01

Lipid rafts have been shown to play an important role for G-protein mediated signal transduction and the function of ligand-gated ion channels including their modulation by psychopharmacological compounds. In this study, we investigated the functional significance of the membrane distribution of NMDA and GABAA receptor subunits in relation to the accumulation of the tricyclic antidepressant desipramine (DMI) and the benzodiazepine diazepam (Diaz). In the presence of Triton X-100, which allowed proper separation of the lipid raft marker proteins caveolin-1 and flotillin-1 from the transferrin receptor, all receptor subunits were shifted to the non-raft fractions. In contrast, under detergent-free conditions, NMDA and GABAA receptor subunits were detected both in raft and non-raft fractions. Diaz was enriched in non-raft fractions without Triton X-100 in contrast to DMI, which preferentially accumulated in lipid rafts. Impairment of lipid raft integrity by methyl-β-cyclodextrine (MβCD)-induced cholesterol depletion did not change the inhibitory effect of DMI at the NMDA receptor, whereas it enhanced the potentiating effect of Diaz at the GABAA receptor at non-saturating concentrations of GABA. These results support the hypothesis that the interaction of benzodiazepines with the GABAA receptor likely occurs outside of lipid rafts while the antidepressant DMI acts on ionotropic receptors both within and outside these membrane microdomains.

Dorsal hippocampal NMDA receptors mediate the interactive effects of arachidonylcyclopropylamide and MDMA/ecstasy on memory retrieval in rats.

PubMed

Ghaderi, Marzieh; Rezayof, Ameneh; Vousooghi, Nasim; Zarrindast, Mohammad-Reza

2016-04-03

A combination of cannabis and ecstasy may change the cognitive functions more than either drug alone. The present study was designed to investigate the possible involvement of dorsal hippocampal NMDA receptors in the interactive effects of arachidonylcyclopropylamide (ACPA) and ecstasy/MDMA on memory retrieval. Adult male Wistar rats were cannulated into the CA1 regions of the dorsal hippocampus (intra-CA1) and memory retrieval was examined using the step-through type of passive avoidance task. Intra-CA1 microinjection of a selective CB1 receptor agonist, ACPA (0.5-4ng/rat) immediately before the testing phase (pre-test), but not after the training phase (post-training), impaired memory retrieval. In addition, pre-test intra-CA1 microinjection of MDMA (0.5-1μg/rat) dose-dependently decreased step-through latency, indicating an amnesic effect of the drug by itself. Interestingly, pre-test microinjection of a higher dose of MDMA into the CA1 regions significantly improved ACPA-induced memory impairment. Moreover, pre-test intra-CA1 microinjection of a selective NMDA receptor antagonist, D-AP5 (1 and 2μg/rat) inhibited the reversal effect of MDMA on the impairment of memory retrieval induced by ACPA. Pre-test intra-CA1 microinjection of the same doses of D-AP5 had no effect on memory retrieval alone. These findings suggest that ACPA or MDMA consumption can induce memory retrieval impairment, while their co-administration improves this amnesic effect through interacting with hippocampal glutamatergic-NMDA receptor mechanism. Thus, it seems that the tendency to abuse cannabis with ecstasy may be for avoiding cognitive dysfunction. Copyright © 2015. Published by Elsevier Inc.

Salicylate enables cochlear arachidonic-acid-sensitive NMDA receptor responses.

PubMed

Ruel, Jérôme; Chabbert, Christian; Nouvian, Régis; Bendris, Rim; Eybalin, Michel; Leger, Claude Louis; Bourien, Jérôme; Mersel, Marcel; Puel, Jean-Luc

2008-07-16

Currently, many millions of people treated for various ailments receive high doses of salicylate. Consequently, understanding the mechanisms by which salicylate induces tinnitus is an important issue for the research community. Behavioral testing in rats have shown that tinnitus induced by salicylate or mefenamate (both cyclooxygenase blockers) are mediated by cochlear NMDA receptors. Here we report that the synapses between the sensory inner hair cells and the dendrites of the cochlear spiral ganglion neurons express NMDA receptors. Patch-clamp recordings and two-photon calcium imaging demonstrated that salicylate and arachidonate (a substrate of cyclooxygenase) enabled the calcium flux and the neural excitatory effects of NMDA on cochlear spiral ganglion neurons. Salicylate also increased the arachidonate content of the whole cochlea in vivo. Single-unit recordings of auditory nerve fibers in adult guinea pig confirmed the neural excitatory effect of salicylate and the blockade of this effect by NMDA antagonist. These results suggest that salicylate inhibits cochlear cyclooxygenase, which increased levels of arachidonate. The increased levels of arachidonate then act on NMDA receptors to enable NMDA responses to glutamate that inner hair cells spontaneously release. This new pharmacological profile of salicylate provides a molecular mechanism for the generation of tinnitus at the periphery of the auditory system.

Actions of Bupivacaine, a Widely Used Local Anesthetic, on NMDA Receptor Responses

PubMed Central

Paganelli, Meaghan A.

2015-01-01

NMDA receptors mediate excitatory neurotransmission in brain and spinal cord and play a pivotal role in the neurological disease state of chronic pain, which is caused by central sensitization. Bupivacaine is the indicated local anesthetic in caudal, epidural, and spinal anesthesia and is widely used clinically to manage acute and chronic pain. In addition to blocking Na+ channels, bupivacaine affects the activity of many other channels, including NMDA receptors. Importantly, bupivacaine inhibits NMDA receptor-mediated synaptic transmission in the dorsal horn of the spinal cord, an area critically involved in central sensitization. We used recombinant NMDA receptors expressed in HEK293 cells and found that increasing concentrations of bupivacaine decreased channel open probability in GluN2 subunit- and pH-independent manner by increasing the mean duration of closures and decreasing the mean duration of openings. Using kinetic modeling of one-channel currents, we attributed the observed current decrease to two main mechanisms: a voltage-dependent “foot-in-the-door” pore block and an allosteric gating effect. Further, the inhibition was state-independent because it occurred to the same degree whether the drug was applied before or after glutamate stimulation and was mediated by extracellular and intracellular inhibitory sites, via hydrophilic and hydrophobic pathways. These results predict that clinical doses of bupivacaine would decrease the peak and accelerate the decay of synaptic NMDA receptor currents during normal synaptic transmission. These quantitative predictions inform possible applications of bupivacaine as preventative and therapeutic approaches in chronic pain. PMID:25589775

Okadaic acid induces epileptic seizures and hyperphosphorylation of the NR2B subunit of the NMDA receptor in rat hippocampus in vivo.

PubMed

Arias, Clorinda; Montiel, Teresa; Peña, Fernando; Ferrera, Patricia; Tapia, Ricardo

2002-09-01

Overactivation of N-methyl-D-aspartate (NMDA) glutamate receptors is closely related to epilepsy and excitotoxicity, and the phosphorylation of these receptors may facilitate glutamate-mediated synaptic transmission. Here we show that in awake rats the microinjection into the hippocampus of okadaic acid, a potent inhibitor of protein phosphatases 1 and 2A, induces in about 20 min intense electroencephalographic and behavioral limbic-type seizures, which are suppressed by the systemic administration of the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine hydrogen maleate and by the intrahippocampal administration of 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, an inhibitor of protein kinases. Two hours after okadaic acid, when the EEG seizures were intense, an increased serine phosphorylation of some hippocampal proteins, including an enhancement of the serine phosphorylation of the NMDA receptor subunit NR2B, was detected by immunoblotting. Twenty-four hours after okadaic acid a marked destruction of hippocampal CA1 region was observed, which was not prevented by the receptor antagonists. These findings suggest that hyperphosphorylation of glutamate receptors in vivo may result in an increased sensitivity to the endogenous transmitter and therefore induce neuronal hyperexcitability and epilepsy.

Blonanserin Ameliorates Phencyclidine-Induced Visual-Recognition Memory Deficits: the Complex Mechanism of Blonanserin Action Involving D3-5-HT2A and D1-NMDA Receptors in the mPFC

PubMed Central

Hida, Hirotake; Mouri, Akihiro; Mori, Kentaro; Matsumoto, Yurie; Seki, Takeshi; Taniguchi, Masayuki; Yamada, Kiyofumi; Iwamoto, Kunihiro; Ozaki, Norio; Nabeshima, Toshitaka; Noda, Yukihiro

2015-01-01

Blonanserin differs from currently used serotonin 5-HT2A/dopamine-D2 receptor antagonists in that it exhibits higher affinity for dopamine-D2/3 receptors than for serotonin 5-HT2A receptors. We investigated the involvement of dopamine-D3 receptors in the effects of blonanserin on cognitive impairment in an animal model of schizophrenia. We also sought to elucidate the molecular mechanism underlying this involvement. Blonanserin, as well as olanzapine, significantly ameliorated phencyclidine (PCP)-induced impairment of visual-recognition memory, as demonstrated by the novel-object recognition test (NORT) and increased extracellular dopamine levels in the medial prefrontal cortex (mPFC). With blonanserin, both of these effects were antagonized by DOI (a serotonin 5-HT2A receptor agonist) and 7-OH-DPAT (a dopamine-D3 receptor agonist), whereas the effects of olanzapine were antagonized by DOI but not by 7-OH-DPAT. The ameliorating effect was also antagonized by SCH23390 (a dopamine-D1 receptor antagonist) and H-89 (a protein kinase A (PKA) inhibitor). Blonanserin significantly remediated the decrease in phosphorylation levels of PKA at Thr197 and of NR1 (an essential subunit of N-methyl-D-aspartate (NMDA) receptors) at Ser897 by PKA in the mPFC after a NORT training session in the PCP-administered mice. There were no differences in the levels of NR1 phosphorylated at Ser896 by PKC in any group. These results suggest that the ameliorating effect of blonanserin on PCP-induced cognitive impairment is associated with indirect functional stimulation of the dopamine-D1-PKA-NMDA receptor pathway following augmentation of dopaminergic neurotransmission due to inhibition of both dopamine-D3 and serotonin 5-HT2A receptors in the mPFC. PMID:25120077

Bisphenol-A rapidly promotes dynamic changes in hippocampal dendritic morphology through estrogen receptor-mediated pathway by concomitant phosphorylation of NMDA receptor subunit NR2B

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

Xu Xiaohong, E-mail: xuxh63@zjnu.cn; Ye Yinping; Li Tao

Bisphenol-A (BPA) is known to be a potent endocrine disrupter. Evidence is emerging that estrogen exerts a rapid influence on hippocampal synaptic plasticity and the dendritic spine density, which requires activation of NMDA receptors. In the present study, we investigated the effects of BPA (ranging from 1 to 1000 nM), focusing on the rapid dynamic changes in dendritic filopodia and the expressions of estrogen receptor (ER) {beta} and NMDA receptor, as well as the phosphorylation of NMDA receptor subunit NR2B in the cultured hippocampal neurons. A specific ER antagonist ICI 182,780 was used to examine the potential involvement of ERs.more » The results demonstrated that exposure to BPA (ranging from 10 to 1000 nM) for 30 min rapidly enhanced the motility and the density of dendritic filopodia in the cultured hippocampal neurons, as well as the phosphorylation of NR2B (pNR2B), though the expressions of NMDA receptor subunits NR1, NR2B, and ER{beta} were not changed. The antagonist of ERs completely inhibited the BPA-induced increases in the filopodial motility and the number of filopodia extending from dendrites. The increased pNR2B induced by BPA (100 nM) was also completely eliminated. Furthermore, BPA attenuated the effects of 17{beta}-estradiol (17{beta}-E{sub 2}) on the dendritic filopodia outgrowth and the expression of pNR2B when BPA was co-treated with 17{beta}-E{sub 2}. The present results suggest that BPA, like 17{beta}-E{sub 2}, rapidly results in the enhanced motility and density of dendritic filopodia in the cultured hippocampal neurons with the concomitant activation of NMDA receptor subunit NR2B via an ER-mediated signaling pathway. Meanwhile, BPA suppressed the enhancement effects of 17{beta}-E{sub 2} when it coexists with 17{beta}-E{sub 2}. These results provided important evidence suggesting the neurotoxicity of the low levels of BPA during the early postnatal development of the brain.« less

Genetic Demonstration of a Role for Stathmin in Adult Hippocampal Neurogenesis, Spinogenesis, and NMDA Receptor-Dependent Memory

PubMed Central

Martel, Guillaume; Uchida, Shusaku; Hevi, Charles; Chévere-Torres, Itzamarie; Fuentes, Ileana; Park, Young Jin; Hafeez, Hannah; Yamagata, Hirotaka; Watanabe, Yoshifumi

2016-01-01

Neurogenesis and memory formation are essential features of the dentate gyrus (DG) area of the hippocampus, but to what extent the mechanisms responsible for both processes overlap remains poorly understood. Stathmin protein, whose tubulin-binding and microtubule-destabilizing activity is negatively regulated by its phosphorylation, is prominently expressed in the DG. We show here that stathmin is involved in neurogenesis, spinogenesis, and memory formation in the DG. tTA/tetO-regulated bitransgenic mice, expressing the unphosphorylatable constitutively active Stathmin4A mutant (Stat4A), exhibit impaired adult hippocampal neurogenesis and reduced spine density in the DG granule neurons. Although Stat4A mice display deficient NMDA receptor-dependent memory in contextual discrimination learning, which is dependent on hippocampal neurogenesis, their NMDA receptor-independent memory is normal. Confirming NMDA receptor involvement in the memory deficits, Stat4A mutant mice have a decrease in the level of synaptic NMDA receptors and a reduction in learning-dependent CREB-mediated gene transcription. The deficits in neurogenesis, spinogenesis, and memory in Stat4A mice are not present in mice in which tTA/tetO-dependent transgene transcription is blocked by doxycycline through their life. The memory deficits are also rescued within 3 d by intrahippocampal infusion of doxycycline, further indicating a role for stathmin expressed in the DG in contextual memory. Our findings therefore point to stathmin and microtubules as a mechanistic link between neurogenesis, spinogenesis, and NMDA receptor-dependent memory formation in the DG. SIGNIFICANCE STATEMENT In the present study, we aimed to clarify the role of stathmin in neuronal and behavioral functions. We characterized the neurogenic, behavioral, and molecular consequences of the gain-of-function stathmin mutation using a bitransgenic mouse expressing a constitutively active form of stathmin. We found that stathmin plays an

Prolonged exposure of cortical neurons to oligomeric amyloid-β impairs NMDA receptor function via NADPH oxidase-mediated ROS production: protective effect of green tea (–)-epigallocatechin-3-gallate

PubMed Central

He, Yan; Cui, Jiankun; Lee, James C-M; Ding, Shinghua; Chalimoniuk, Malgorzata; Simonyi, Agnes; Sun, Albert Y; Gu, Zezong; Weisman∥, Gary A; Gibson Wood, W; Sun, Grace Y

2011-01-01

Excessive production of Aβ (amyloid β-peptide) has been shown to play an important role in the pathogenesis of AD (Alzheimer's disease). Although not yet well understood, aggregation of Aβ is known to cause toxicity to neurons. Our recent study demonstrated the ability for oligomeric Aβ to stimulate the production of ROS (reactive oxygen species) in neurons through an NMDA (N-methyl-d-aspartate)-dependent pathway. However, whether prolonged exposure of neurons to aggregated Aβ is associated with impairment of NMDA receptor function has not been extensively investigated. In the present study, we show that prolonged exposure of primary cortical neurons to Aβ oligomers caused mitochondrial dysfunction, an attenuation of NMDA receptor-mediated Ca2+ influx and inhibition of NMDA-induced AA (arachidonic acid) release. Mitochondrial dysfunction and the decrease in NMDA receptor activity due to oligomeric Aβ are associated with an increase in ROS production. Gp91ds-tat, a specific peptide inhibitor of NADPH oxidase, and Mn(III)-tetrakis(4-benzoic acid)-porphyrin chloride, an ROS scavenger, effectively abrogated Aβ-induced ROS production. Furthermore, Aβ-induced mitochondrial dysfunction, impairment of NMDA Ca2+ influx and ROS production were prevented by pre-treatment of neurons with EGCG [(−)-epigallocatechin-3-gallate], a major polyphenolic component of green tea. Taken together, these results support a role for NADPH oxidase-mediated ROS production in the cytotoxic effects of Aβ, and demonstrate the therapeutic potential of EGCG and other dietary polyphenols in delaying onset or retarding the progression of AD. PMID:21434871

Opposite modulation of brain stimulation reward by NMDA and AMPA receptors in the ventral tegmental area

PubMed Central

Ducrot, Charles; Fortier, Emmanuel; Bouchard, Claude; Rompré, Pierre-Paul

2013-01-01

Previous studies have shown that blockade of ventral tegmental area (VTA) glutamate N-Methyl-D-Aspartate (NMDA) receptors induces reward, stimulates forward locomotion and enhances brain stimulation reward. Glutamate induces two types of excitatory response on VTA neurons, a fast and short lasting depolarization mediated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors and a longer lasting depolarization mediated by NMDA receptors. A role for the two glutamate receptors in modulation of VTA neuronal activity is evidenced by the functional change in AMPA and NMDA synaptic responses that result from repeated exposure to reward. Since both receptors contribute to the action of glutamate on VTA neuronal activity, we studied the effects of VTA AMPA and NMDA receptor blockade on reward induced by electrical brain stimulation. Experiments were performed on rats trained to self-administer electrical pulses in the medial posterior mesencephalon. Reward thresholds were measured with the curve-shift paradigm before and for 2 h after bilateral VTA microinjections of the AMPA antagonist, NBQX (2,3,-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo(f)quinoxaline-7-sulfonamide, 0, 80, and 800 pmol/0.5 μl/side) and of a single dose (0.825 nmol/0.5 μl/side) of the NMDA antagonist, PPPA (2R,4S)-4-(3-Phosphonopropyl)-2-piperidinecarboxylic acid). NBQX produced a dose-dependent increase in reward threshold with no significant change in maximum rate of responding. Whereas PPPA injected at the same VTA sites produced a significant time dependent decrease in reward threshold and increase in maximum rate of responding. We found a negative correlation between the magnitude of the attenuation effect of NBQX and the enhancement effect of PPPA; moreover, NBQX and PPPA were most effective when injected, respectively, into the anterior and posterior VTA. These results suggest that glutamate acts on different receptor sub-types, most likely located on different VTA neurons, to

Opposite modulation of brain stimulation reward by NMDA and AMPA receptors in the ventral tegmental area.

PubMed

Ducrot, Charles; Fortier, Emmanuel; Bouchard, Claude; Rompré, Pierre-Paul

2013-01-01

Previous studies have shown that blockade of ventral tegmental area (VTA) glutamate N-Methyl-D-Aspartate (NMDA) receptors induces reward, stimulates forward locomotion and enhances brain stimulation reward. Glutamate induces two types of excitatory response on VTA neurons, a fast and short lasting depolarization mediated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors and a longer lasting depolarization mediated by NMDA receptors. A role for the two glutamate receptors in modulation of VTA neuronal activity is evidenced by the functional change in AMPA and NMDA synaptic responses that result from repeated exposure to reward. Since both receptors contribute to the action of glutamate on VTA neuronal activity, we studied the effects of VTA AMPA and NMDA receptor blockade on reward induced by electrical brain stimulation. Experiments were performed on rats trained to self-administer electrical pulses in the medial posterior mesencephalon. Reward thresholds were measured with the curve-shift paradigm before and for 2 h after bilateral VTA microinjections of the AMPA antagonist, NBQX (2,3,-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo(f)quinoxaline-7-sulfonamide, 0, 80, and 800 pmol/0.5 μl/side) and of a single dose (0.825 nmol/0.5 μl/side) of the NMDA antagonist, PPPA (2R,4S)-4-(3-Phosphonopropyl)-2-piperidinecarboxylic acid). NBQX produced a dose-dependent increase in reward threshold with no significant change in maximum rate of responding. Whereas PPPA injected at the same VTA sites produced a significant time dependent decrease in reward threshold and increase in maximum rate of responding. We found a negative correlation between the magnitude of the attenuation effect of NBQX and the enhancement effect of PPPA; moreover, NBQX and PPPA were most effective when injected, respectively, into the anterior and posterior VTA. These results suggest that glutamate acts on different receptor sub-types, most likely located on different VTA neurons, to

Modulation of the NMDA receptor by polyamines

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

Williams, K.; Romano, C.; Dichter, M.A.

1991-01-01

Results of recent biochemical and electrophysiological studies have suggested that a recognition site for polyamines exists as part of the NMDA receptor complex. The endogenous polyamines spermine and spermidine increase the binding of open-channel blockers and increase NMDA-elicited currents in cultured neutrons. These polyamines have been termed agonists at the polyamine recognition site. Studies of the effects of natural and synthetic polyamines on the binding of ({sup 3}H)MK-801 and on NMDA-elicited currents in cultured neurons have led to the identification of compounds classified as partial agonists, antagonists, and inverse agonists at the polyamine recognition site. Polyamines have also been foundmore » to affect the binding of ligands to the recognition sites for glutamate and glycine. However, these effects may be mediated at a site distinct from that at which polyamines act to modulate the binding of open-channel blockers. Endogenous polyamines may modulate excitatory synaptic transmission by acting at the polyamine recognition site of the NMDA receptor. This site could represent a novel therapeutic target for the treatment of ischemia-induced neurotoxicity, epilepsy, and neurodegenerative diseases.« less

Adult forebrain NMDA receptors gate social motivation and social memory.

PubMed

Jacobs, Stephanie; Tsien, Joe Z

2017-02-01

Motivation to engage in social interaction is critical to ensure normal social behaviors, whereas dysregulation in social motivation can contribute to psychiatric diseases such as schizophrenia, autism, social anxiety disorders and post-traumatic stress disorder (PTSD). While dopamine is well known to regulate motivation, its downstream targets are poorly understood. Given the fact that the dopamine 1 (D1) receptors are often physically coupled with the NMDA receptors, we hypothesize that the NMDA receptor activity in the adult forebrain principal neurons are crucial not only for learning and memory, but also for the proper gating of social motivation. Here, we tested this hypothesis by examining sociability and social memory in inducible forebrain-specific NR1 knockout mice. These mice are ideal for exploring the role of the NR1 subunit in social behavior because the NR1 subunit can be selectively knocked out after the critical developmental period, in which NR1 is required for normal development. We found that the inducible deletion of the NMDA receptors prior to behavioral assays impaired, not only object and social recognition memory tests, but also resulted in profound deficits in social motivation. Mice with ablated NR1 subunits in the forebrain demonstrated significant decreases in sociability compared to their wild type counterparts. These results suggest that in addition to its crucial role in learning and memory, the NMDA receptors in the adult forebrain principal neurons gate social motivation, independent of neuronal development. Copyright © 2016 Elsevier Inc. All rights reserved.

NMDA Receptors as Potential Therapeutic Targets in Diabetic Nephropathy: Increased Renal NMDA Receptor Subunit Expression in Akita Mice and Reduced Nephropathy Following Sustained Treatment With Memantine or MK-801.

PubMed

Roshanravan, Hila; Kim, Eun Young; Dryer, Stuart E

2016-10-01

N-methyl-d-aspartate (NMDA) receptors are expressed throughout the kidney, and the abundance of these receptors and some of their endogenous agonists are increased in diabetes. Moreover, sustained activation of podocyte NMDA receptors induces Ca(2+) influx, oxidative stress, loss of slit diaphragm proteins, and apoptosis. We observed that NMDA receptor subunits and their transcripts are increased in podocytes and mesangial cells cultured in elevated glucose compared with controls. A similar increase in NMDA subunits, especially NR1, NR2A, and NR2C, was observed in glomeruli and tubules of Akita mice. Sustained continuous treatment with the strong NMDA receptor antagonist dizocilpine (MK-801) for 28 days starting at 8 weeks of age reduced 24-h albumin excretion and mesangial matrix expansion and improved glomerular ultrastructure in Akita mice. MK-801 did not alleviate reduced Akita mouse body weight and had no effect on kidney histology or ultrastructure in DBA/2J controls. The structurally dissimilar NMDA antagonist memantine also reduced diabetic nephropathy, although it was less effective than MK-801. Inhibition of NMDA receptors may represent a valid therapeutic approach to reduce renal complications of diabetes, and it is possible to develop well-tolerated agents with minimal central nervous system effects. Two such agents, memantine and dextromethorphan, are already in widespread clinical use. © 2016 by the American Diabetes Association.

Role of motor cortex NMDA receptors in learning-dependent synaptic plasticity of behaving mice

PubMed Central

Hasan, Mazahir T.; Hernández-González, Samuel; Dogbevia, Godwin; Treviño, Mario; Bertocchi, Ilaria; Gruart, Agnès; Delgado-García, José M.

2013-01-01

The primary motor cortex has an important role in the precise execution of learned motor responses. During motor learning, synaptic efficacy between sensory and primary motor cortical neurons is enhanced, possibly involving long-term potentiation and N-methyl-D-aspartate (NMDA)-specific glutamate receptor function. To investigate whether NMDA receptor in the primary motor cortex can act as a coincidence detector for activity-dependent changes in synaptic strength and associative learning, here we generate mice with deletion of the Grin1 gene, encoding the essential NMDA receptor subunit 1 (GluN1), specifically in the primary motor cortex. The loss of NMDA receptor function impairs primary motor cortex long-term potentiation in vivo. Importantly, it impairs the synaptic efficacy between the primary somatosensory and primary motor cortices and significantly reduces classically conditioned eyeblink responses. Furthermore, compared with wild-type littermates, mice lacking primary motor cortex show slower learning in Skinner-box tasks. Thus, primary motor cortex NMDA receptors are necessary for activity-dependent synaptic strengthening and associative learning. PMID:23978820

Decrement in operant performance produced by NMDA receptor antagonists in the rat: tolerance and cross-tolerance.

PubMed

Dravolina, O A; Zvartau, E E; Bespalov, A Y

2000-04-01

Current perspectives on the clinical use of NMDA receptor antagonists infer repeated administration schedules for the management of different pathological states. The development of tolerance and cross-tolerance between different NMDA receptor antagonists may be an important factor contributing to the clinical efficacy of these drugs. The present study aimed to characterize the development of tolerance and cross-tolerance to the ability of various site-selective NMDA receptor antagonists to produce a decrement of operant responding (multiple extinction 9 s fixed-interval 1-s schedule of water reinforcement). Acute administration of D-CPPen (SDZ EAA 494; 1-5.6 mg/kg), dizocilpine (MK-801; 0.03-0.3 mg/kg), memantine (0.3-17 mg/kg), ACEA-1021 (10-56 mg/kg), and eliprodil (1-30 mg/kg) differentially affected operant responding. Both increases and decreases in response rates and accuracy of responding were observed. Repeated preexposure to D-CPPen (5.6 mg/kg, once a day for 7 days) attenuated a behavioral disruption produced by an acute challenge with D-CPPen or ACEA-1021, but potentiated the effects of dizocilpine, memantine, and eliprodil. Based on the present results, one can suggest that the repeated administration of a competitive NMDA receptor antagonist differentially affects the functional activity of various sites on NMDA receptor complex.

SETDB1 HISTONE METHYLTRANSFERASE REGULATES MOOD-RELATED BEHAVIORS AND EXPRESSION OF THE NMDA RECEPTOR SUBUNIT NR2B

PubMed Central

Jiang, Yan; Jakovcevski, Mira; Bharadwaj, Rahul; Connor, Caroline; Schroeder, Frederick A.; Lin, Cong L.; Straubhaar, Juerg; Martin, Gilles; Akbarian, Schahram

2010-01-01

Histone methyltransferases specific for the histone H3-lysine 9 (H3K9) residue, including Setdb1 (Set domain, bifurcated 1)/Eset/Kmt1e are associated with repressive chromatin remodeling and expressed in adult brain, but potential effects on neuronal function and behavior remain unexplored. Here, we report that transgenic mice with increased Setdb1 expression in adult forebrain neurons show antidepressant-like phenotypes in behavioral paradigms for anhedonia, despair and learned helplessness. Chromatin immunoprecipitation in conjunction with DNA tiling arrays (ChIP-chip) revealed that genomic occupancies of neuronal Setdb1 are limited to less than 1% of annotated genes, which include the NMDA receptor subunit NR2B/Grin2B and other ionotropic glutamate receptor genes. Chromatin conformation capture (“3C”) and Setdb1-ChIP revealed a loop formation tethering the NR2B/Grin2b promoter to the Setdb1 target site positioned 30Kb downstream of the transcription start site. In hippocampus and ventral striatum, two key structures in the neuronal circuitry regulating mood-related behaviors, Setdb1-mediated repressive histone methylation at NR2B/Grin2b was associated with decreased NR2B expression and EPSP insensitivity to pharmacological blockade of NR2B, and accelerated NMDA receptor desensitization consistent with a shift in NR2A/B subunit ratios. In wildtype mice, systemic treatment with the NR2B antagonist, Ro-256981, and hippocampal siRNA-mediated NR2B/Grin2b knockdown, resulted in behavioral changes similar to those elicited by the Setdb1 transgene. Together, these findings point to a role for neuronal Setdb1 in the regulation of affective and motivational behaviors through repressive chromatin remodeling at a select set of target genes, resulting in altered NMDA receptor subunit composition and other molecular adaptations. PMID:20505083

Neonatal (+)-methamphetamine exposure in rats alters adult locomotor responses to dopamine D1 and D2 agonists and to a glutamate NMDA receptor antagonist, but not to serotonin agonists

PubMed Central

Graham, Devon L.; Amos-Kroohs, Robyn M.; Braun, Amanda A.; Grace, Curtis E.; Schaefer, Tori L.; Skelton, Matthew R.; Williams, Michael T.; Vorhees, Charles V.

2015-01-01

Neonatal exposure to (+)-methamphetamine (Meth) results in long-term behavioural abnormalities but its developmental mechanisms are unknown. In a series of experiments, rats were treated from post-natal days (PD) 11–20 (stage that approximates human development from the second to third trimester) with Meth or saline and assessed using locomotor activity as the readout following pharmacological challenge doses with dopamine, serotonin and glutamate agonists or antagonists during adulthood. Exposure to Meth early in life resulted in an exaggerated adult locomotor hyperactivity response to the dopamine D1 agonist SKF-82958 at multiple doses, a high dose only under-response activating effect of the D2 agonist quinpirole, and an exaggerated under-response to the activating effect of the N-methyl-D-aspartic acid (NMDA) receptor antagonist, MK-801. No change in locomotor response was seen following challenge with the 5-HT releaser p-chloroamphetamine or the 5-HT2/3 receptor agonist, quipazine. These are the first data to show that PD 11-20 Meth exposure induces long-lasting alterations to dopamine D1, D2 and glutamate NMDA receptor function and may suggest how developmental Meth exposure leads to many of its long-term adverse effects. PMID:22391043

Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies

PubMed Central

Dalmau, Josep; Gleichman, Amy J; Hughes, Ethan G; Rossi, Jeffrey E; Peng, Xiaoyu; Lai, Meizan; Dessain, Scott K; Rosenfeld, Myrna R; Balice-Gordon, Rita; Lynch, David R

2008-01-01

Summary Background A severe form of encephalitis associated with antibodies against NR1–NR2 heteromers of the NMDA receptor was recently identified. We aimed to analyse the clinical and immunological features of patients with the disorder and examine the effects of antibodies against NMDA receptors in neuronal cultures. Methods We describe the clinical characteristics of 100 patients with encephalitis and NR1–NR2 antibodies. HEK293 cells ectopically expressing single or assembled NR1–NR2 subunits were used to determine the epitope targeted by the antibodies. Antibody titres were measured with ELISA. The effect of antibodies on neuronal cultures was determined by quantitative analysis of NMDA-receptor clusters. Findings Median age of patients was 23 years (range 5–76 years); 91 were women. All patients presented with psychiatric symptoms or memory problems; 76 had seizures, 88 unresponsiveness (decreased conciousness), 86 dyskinesias, 69 autonomic instability, and 66 hypoventilation. 58 (59%) of 98 patients for whom results of oncological assessments were available had tumours, most commonly ovarian teratoma. Patients who received early tumour treatment (usually with immunotherapy) had better outcome (p=0.004) and fewer neurological relapses (p=0.009) than the rest of the patients. 75 patients recovered or had mild deficits and 25 had severe deficits or died. Improvement was associated with a decrease of serum antibody titres. The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. Patients’ antibodies decreased the numbers of cell-surface NMDA receptors and NMDA-receptor clusters in postsynaptic dendrites, an effect that could be reversed by antibody removal. Interpretation A well-defined set of clinical characteristics are associated with anti-NMDA-receptor encephalitis. The pathogenesis of the disorder seems to be mediated by antibodies. PMID:18851928

Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.

PubMed

Dalmau, Josep; Gleichman, Amy J; Hughes, Ethan G; Rossi, Jeffrey E; Peng, Xiaoyu; Lai, Meizan; Dessain, Scott K; Rosenfeld, Myrna R; Balice-Gordon, Rita; Lynch, David R

2008-12-01

A severe form of encephalitis associated with antibodies against NR1-NR2 heteromers of the NMDA receptor was recently identified. We aimed to analyse the clinical and immunological features of patients with the disorder and examine the effects of antibodies against NMDA receptors in neuronal cultures. We describe the clinical characteristics of 100 patients with encephalitis and NR1-NR2 antibodies. HEK293 cells ectopically expressing single or assembled NR1-NR2 subunits were used to determine the epitope targeted by the antibodies. Antibody titres were measured with ELISA. The effect of antibodies on neuronal cultures was determined by quantitative analysis of NMDA-receptor clusters. Median age of patients was 23 years (range 5-76 years); 91 were women. All patients presented with psychiatric symptoms or memory problems; 76 had seizures, 88 unresponsiveness (decreased consciousness), 86 dyskinesias, 69 autonomic instability, and 66 hypoventilation. 58 (59%) of 98 patients for whom results of oncological assessments were available had tumours, most commonly ovarian teratoma. Patients who received early tumour treatment (usually with immunotherapy) had better outcome (p=0.004) and fewer neurological relapses (p=0.009) than the rest of the patients. 75 patients recovered or had mild deficits and 25 had severe deficits or died. Improvement was associated with a decrease of serum antibody titres. The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. Patients' antibodies decreased the numbers of cell-surface NMDA receptors and NMDA-receptor clusters in postsynaptic dendrites, an effect that could be reversed by antibody removal. A well-defined set of clinical characteristics are associated with anti-NMDA-receptor encephalitis. The pathogenesis of the disorder seems to be mediated by antibodies.

Fyn kinase-mediated phosphorylation of NMDA receptor NR2B subunit at Tyr1472 is essential for maintenance of neuropathic pain.

PubMed

Abe, Tetsuya; Matsumura, Shinji; Katano, Tayo; Mabuchi, Tamaki; Takagi, Kunio; Xu, Li; Yamamoto, Akitsugu; Hattori, Kotaro; Yagi, Takeshi; Watanabe, Masahiko; Nakazawa, Takanobu; Yamamoto, Tadashi; Mishina, Masayoshi; Nakai, Yoshihide; Ito, Seiji

2005-09-01

Despite abundant evidence implicating the importance of N-methyl-D-aspartate (NMDA) receptors in the spinal cord for pain transmission, the signal transduction coupled to NMDA receptor activation is largely unknown for the neuropathic pain state that lasts over periods of weeks. To address this, we prepared mice with neuropathic pain by transection of spinal nerve L5. Wild-type, NR2A-deficient, and NR2D-deficient mice developed neuropathic pain; in addition, phosphorylation of NR2B subunits of NMDA receptors at Tyr1472 was observed in the superficial dorsal horn of the spinal cord 1 week after nerve injury. Neuropathic pain and NR2B phosphorylation at Tyr1472 were attenuated by the NR2B-selective antagonist CP-101,606 and disappeared in mice lacking Fyn kinase, a Src-family tyrosine kinase. Concomitant with the NR2B phosphorylation, an increase in neuronal nitric oxide synthase activity was visualized in the superficial dorsal horn of neuropathic pain mice by NADPH diaphorase histochemistry. Electron microscopy showed that the phosphorylated NR2B was localized at the postsynaptic density in the spinal cord of mice with neuropathic pain. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, and PGE receptor subtype EP1-selective antagonist reduced the NR2B phosphorylation in these mice. Conversely, EP1-selective agonist stimulated Fyn kinase-dependent nitric oxide formation in the spinal cord. The present study demonstrates that Tyr1472 phosphorylation of NR2B subunits by Fyn kinase may have dual roles in the retention of NMDA receptors in the postsynaptic density and in activation of nitric oxide synthase, and suggests that PGE2 is involved in the maintenance of neuropathic pain via the EP1 subtype.

Functional characterization of α7 nicotinic acetylcholine and NMDA receptor signaling in SH-SY5Y neuroblastoma cells in an ERK phosphorylation assay.

PubMed

Elnagar, Mohamed R; Walls, Anne Byriel; Helal, Gouda K; Hamada, Farid M; Thomsen, Morten Skøtt; Jensen, Anders A

2018-05-05

In the present study, the functional properties of α7 nicotinic acetylcholine receptors (α7 nAChRs) and N-methyl-D-aspartate receptors (NMDARs) endogenously expressed in SH-SY5Y human neuroblastoma cells were characterized in an extracellular-signal regulated kinase (ERK) phosphorylation assay. Both choline and N-methyl-D-aspartate (NMDA) mediated robust concentration-dependent increases in ERK phosphorylation in the SH-SY5Y cells, exhibiting EC 50 values in good agreement with those reported for the agonists at recombinant α7 nAChRs and NMDARs, respectively. Importantly, the responses evoked by choline (10 mM) and by NMDA (50 μM) were significantly inhibited by the α7-selective antagonist α-bungarotoxin (100 nM) and by the NMDAR-selective antagonist MK-801 (50 μM), respectively. The increased ERK phosphorylation levels observed upon co-application of choline (1, 3, 10 mM) and NMDA (50 μM) compared to those produced by the two agonists on their own were fully reconcilable with additive effects and did not reveal substantial synergy between α7 nAChR and NMDAR signaling. Interestingly, however, the responses evoked by the "choline (10 mM) - NMDA (50 μM)" combination were almost completely inhibited by α-bungarotoxin (100 nM) as well as by MK-801 (50 μM), suggesting some sort of a link between α7 nAChR- and NMDAR-mediated ERK phosphorylation. Finally, oligomeric amyloid-β 1-42 peptide (1000 nM) mediated robust inhibition of the ERK phosphorylation induced by choline (10 mM), NMDA (50 μM) and the "choline (10 mM) - NMDA (50 μM)" combination. In conclusion, ERK phosphorylation measurements in SH-SY5Y cells provides a robust assay for studies of α7 nAChR- and NMDAR-mediating signaling and putative functional interactions between the receptors. Copyright © 2018 Elsevier B.V. All rights reserved.

Treatment with a Clinically-Relevant Dose of Methylphenidate Alters NMDA Receptor Composition and Synaptic Plasticity in the Juvenile Rat Prefrontal Cortex

PubMed Central

Urban, Kimberly R.; Li, Yan-Chun; Gao, Wen-Jun

2013-01-01

Methylphenidate (Ritalin, MPH) is the most commonly prescribed psychoactive drug for children. Used to treat attention-deficit/hyperactivity disorder (ADHD) and for cognitive enhancement in healthy individuals, its cellular mechanisms of action and potential long-term effects are poorly understood. We recently reported that a clinically relevant (1 mg/kg i.p., single injection) dose of MPH significantly decreased neuronal excitability in the juvenile rat prefrontal cortical neurons. Here we further explore the actions of acute treatment with MPH on the level of NMDA receptor subunits and NMDA receptor-mediated short- and long-term synaptic plasticity in the juvenile rat prefrontal cortical neurons. We found that a single dose of MPH treatment (1 mg/kg, intraperitoneal) significantly decreased the surface and total protein levels of NMDA receptor subunits NR1 and NR2B, but not NR2A, in the juvenile prefrontal cortex. In addition, the amplitude, decay time and charge transfer of NMDA receptor-mediated EPSCs were significantly decreased whereas the amplitude and short-term depression of AMPA receptor-mediated EPSCs were significantly increased in the prefrontal neurons. Furthermore, MPH treatment also significantly increased the probability and magnitude of LTP induction, but had only a small effect on LTD induction in juvenile rat prefrontal cortical neurons. Our data thus present a novel mechanism of action of MPH, i.e., changes in glutamatergic receptor-mediated synaptic plasticity following early-life treatment. Furthermore, since a single dosage resulted in significant changes in NMDA receptors, off-label usage by healthy individuals, especially children and adolescents, may result in altered potential for plastic learning. PMID:23333502

A postmortem analysis of NMDA ionotropic and group 1 metabotropic glutamate receptors in the nucleus accumbens in schizophrenia.

PubMed

Lum, Jeremy S; Millard, Samuel J; Huang, Xu-Feng; Ooi, Lezanne; Newell, Kelly A

2018-03-01

The nucleus accumbens (NAcc) has been implicated in the pathology and treatment of schizophrenia. Recent postmortem evidence suggests a hyperglutamatergic state in the NAcc. With the present study we aimed to explore possible glutamatergic alterations in the NAcc of a large schizophrenia cohort. We performed immunoblots on postmortem NAcc samples from 30 individuals who had schizophrenia and 30 matched controls. We examined the protein expression of primary glutamatergic receptors, including the N -methyl-D-aspartate (NMDA) receptor (NR1, NR2A and NR2B subunits) and the group 1 metabotropic glutamate receptor (mGluR1 and mGluR5; dimeric and monomeric forms). In addition, we measured the group 1 mGluR endogenous regulators, neurochondrin and Homer1b/c, which have recently been implicated in the pathophysiology of schizophrenia. Protein levels of glutamatergic receptors and endogenous regulators were not significantly different between the controls and individuals who had schizophrenia. Furthermore, mGluR5, but not mGluR1, showed a positive association with NMDA receptor subunits, suggesting differential interactions between these receptors in this brain region. Investigation of these proteins in antipsychotic-naive individuals, in addition to the subregions of the NAcc and subcellular fractions, will strengthen future studies. The present study does not provide evidence for glutamatergic abnormalities within the NAcc of individuals with schizophrenia. Taken together with the results of previous studies, these findings suggest NMDA receptors and group 1 mGluRs are altered in a brain region-dependent manner in individuals with schizophrenia. The differential associations between mGluR1, mGluR5 and NMDA receptors observed in this study warrant further research into the interactions of these proteins and the implications for the therapeutic and adverse effect profile of glutamatergic-based novel therapeutics.

A postmortem analysis of NMDA ionotropic and group 1 metabotropic glutamate receptors in the nucleus accumbens in schizophrenia.

PubMed

Lum, Jeremy S; Millard, Samuel J; Huang, Xu-Feng; Ooi, Lezanne; Newell, Kelly A

2017-10-06

The nucleus accumbens (NAcc) has been implicated in the pathology and treatment of schizophrenia. Recent postmortem evidence suggests a hyperglutamatergic state in the NAcc. With the present study we aimed to explore possible glutamatergic alterations in the NAcc of a large schizophrenia cohort. We performed immunoblots on postmortem NAcc samples from 30 individuals who had schizophrenia and 30 matched controls. We examined the protein expression of primary glutamatergic receptors, including the N -methyl-D-aspartate (NMDA) receptor (NR1, NR2A and NR2B subunits) and the group 1 metabotropic glutamate receptor (mGluR1 and mGluR5; dimeric and monomeric forms). In addition, we measured the group 1 mGluR endogenous regulators, neurochondrin and Homer1b/c, which have recently been implicated in the pathophysiology of schizophrenia. Protein levels of glutamatergic receptors and endogenous regulators were not significantly different between the controls and individuals who had schizophrenia. Furthermore, mGluR5, but not mGluR1, showed a positive association with NMDA receptor subunits, suggesting differential interactions between these receptors in this brain region. Investigation of these proteins in antipsychotic-naive individuals, in addition to the subregions of the NAcc and subcellular fractions, will strengthen future studies. The present study does not provide evidence for glutamatergic abnormalities within the NAcc of individuals with schizophrenia. Taken together with the results of previous studies, these findings suggest NMDA receptors and group 1 mGluRs are altered in a brain region-dependent manner in individuals with schizophrenia. The differential associations between mGluR1, mGluR5 and NMDA receptors observed in this study warrant further research into the interactions of these proteins and the implications for the therapeutic and adverse effect profile of glutamatergic-based novel therapeutics.

Regulation of dopamine D1 receptor dynamics within the postsynaptic density of hippocampal glutamate synapses.

PubMed

Ladepeche, Laurent; Yang, Luting; Bouchet, Delphine; Groc, Laurent

2013-01-01

Dopamine receptor potently modulates glutamate signalling, synaptic plasticity and neuronal network adaptations in various pathophysiological processes. Although key intracellular signalling cascades have been identified, the cellular mechanism by which dopamine and glutamate receptor-mediated signalling interplay at glutamate synapse remain poorly understood. Among the cellular mechanisms proposed to aggregate D1R in glutamate synapses, the direct interaction between D1R and the scaffold protein PSD95 or the direct interaction with the glutamate NMDA receptor (NMDAR) have been proposed. To tackle this question we here used high-resolution single nanoparticle imaging since it provides a powerful way to investigate at the sub-micron resolution the dynamic interaction between these partners in live synapses. We demonstrate in hippocampal neuronal networks that dopamine D1 receptors (D1R) laterally diffuse within glutamate synapses, in which their diffusion is reduced. Disrupting the interaction between D1R and PSD95, through genetical manipulation and competing peptide, did not affect D1R dynamics in glutamatergic synapses. However, preventing the physical interaction between D1R and the GluN1 subunit of NMDAR abolished the synaptic stabilization of diffusing D1R. Together, these data provide direct evidence that the interaction between D1R and NMDAR in synapses participate in the building of the dopamine-receptor-mediated signalling, and most likely to the glutamate-dopamine cross-talk.

Inhibition of N-methyl-D-aspartate receptors increases paraoxon-induced apoptosis in cultured neurons

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

Wu Xuan; Tian Feng; Okagaki, Peter

2005-10-01

Organophosphorus (OP) compounds, used as insecticides and chemical warfare agents, are potent neurotoxins. We examined the neurotoxic effect of paraoxon (O,O-diethyl O-p-nitrophenyl phosphate), an organophosphate compound, and the role of NMDA receptors as a mechanism of action in cultured cerebellar granule cells. Paraoxon is neurotoxic to cultured rat cerebellar granule cells in a time- and concentration-dependent manner. Cerebellar granule cells are less sensitive to the neurotoxic effects of paraoxon on day in vitro (DIV) 4 than neurons treated on DIV 8. Surprisingly, the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, enhances paraoxon-mediated neurotoxicity suggesting that NMDA receptors may play a protective role.more » Pretreatment with a subtoxic concentration of N-methyl-D-aspartate (NMDA) [100 {mu}M] protects about 40% of the vulnerable neurons that would otherwise die from paraoxon-induced neurotoxicity. Moreover, addition of a neuroprotective concentration of NMDA 3 h after treatment with paraoxon provides the same level of protection. Because paraoxon-mediated neuronal cell death is time-dependent, we hypothesized that apoptosis may be involved. Paraoxon increases apoptosis about 10-fold compared to basal levels. The broad-spectrum caspase inhibitor (Boc-D-FMK) and the caspase-9-specific inhibitor (Z-LEHD-FMK) protect against paraoxon-mediated apoptosis, paraoxon-stimulated caspase-3 activity and neuronal cell death. MK-801 increases, whereas NMDA blocks paraoxon-induced apoptosis and paraoxon-stimulated caspase-3 activity. These results suggest that activation of NMDA receptors protect neurons against paraoxon-induced neurotoxicity by blocking apoptosis initiated by paraoxon.« less

MPX-004 and MPX-007: New Pharmacological Tools to Study the Physiology of NMDA Receptors Containing the GluN2A Subunit.

PubMed

Volkmann, Robert A; Fanger, Christopher M; Anderson, David R; Sirivolu, Venkata Ramana; Paschetto, Kathy; Gordon, Earl; Virginio, Caterina; Gleyzes, Melanie; Buisson, Bruno; Steidl, Esther; Mierau, Susanna B; Fagiolini, Michela; Menniti, Frank S

2016-01-01

GluN2A is the most abundant of the GluN2 NMDA receptor subunits in the mammalian CNS. Physiological and genetic evidence implicate GluN2A-containing receptors in susceptibility to autism, schizophrenia, childhood epilepsy and neurodevelopmental disorders such as Rett Syndrome. However, GluN2A-selective pharmacological probes to explore the therapeutic potential of targeting these receptors have been lacking. Here we disclose a novel series of pyrazine-containing GluN2A antagonists exemplified by MPX-004 (5-(((3-chloro-4-fluorophenyl)sulfonamido)methyl)-N-((2-methylthiazol-5-yl)methyl)pyrazine-2-carboxamide) and MPX-007 (5-(((3-fluoro-4-fluorophenyl)sulfonamido)methyl)-N-((2-methylthiazol-5-yl)methyl)methylpyrazine-2-carboxamide). MPX-004 and MPX-007 inhibit GluN2A-containing NMDA receptors expressed in HEK cells with IC50s of 79 nM and 27 nM, respectively. In contrast, at concentrations that completely inhibited GluN2A activity these compounds have no inhibitory effect on GluN2B or GluN2D receptor-mediated responses in similar HEK cell-based assays. Potency and selectivity were confirmed in electrophysiology assays in Xenopus oocytes expressing GluN2A-D receptor subtypes. Maximal concentrations of MPX-004 and MPX-007 inhibited ~30% of the whole-cell current in rat pyramidal neurons in primary culture and MPX-004 inhibited ~60% of the total NMDA receptor-mediated EPSP in rat hippocampal slices. GluN2A-selectivity at native receptors was confirmed by the finding that MPX-004 had no inhibitory effect on NMDA receptor mediated synaptic currents in cortical slices from GRIN2A knock out mice. Thus, MPX-004 and MPX-007 offer highly selective pharmacological tools to probe GluN2A physiology and involvement in neuropsychiatric and developmental disorders.

An EP2 Agonist Facilitates NMDA-Induced Outward Currents and Inhibits Dendritic Beading through Activation of BK Channels in Mouse Cortical Neurons

PubMed Central

Hayashi, Yoshinori; Morinaga, Saori; Liu, Xia; Zhang, Jing; Wu, Zhou; Yokoyama, Takeshi; Nakanishi, Hiroshi

2016-01-01

Prostaglandin E2 (PGE2), a major metabolite of arachidonic acid produced by cyclooxygenase pathways, exerts its bioactive responses by activating four E-prostanoid receptor subtypes, EP1, EP2, EP3, and EP4. PGE2 enables modulating N-methyl-D-aspartate (NMDA) receptor-mediated responses. However, the effect of E-prostanoid receptor agonists on large-conductance Ca2+-activated K+ (BK) channels, which are functionally coupled with NMDA receptors, remains unclear. Here, we showed that EP2 receptor-mediated signaling pathways increased NMDA-induced outward currents (I NMDA-OUT), which are associated with the BK channel activation. Patch-clamp recordings from the acutely dissociated mouse cortical neurons revealed that an EP2 receptor agonist activated I NMDA-OUT, whereas an EP3 receptor agonist reduced it. Agonists of EP1 or EP4 receptors showed no significant effects on I NMDA-OUT. A direct perfusion of 3,5′-cyclic adenosine monophosphate (cAMP) through the patch pipette facilitated I NMDA-OUT, which was abolished by the presence of protein kinase A (PKA) inhibitor. Furthermore, facilitation of I NMDA-OUT caused by an EP2 receptor agonist was significantly suppressed by PKA inhibitor. Finally, the activation of BK channels through EP2 receptors facilitated the recovery phase of NMDA-induced dendritic beading in the primary cultured cortical neurons. These results suggest that a direct activation of BK channels by EP2 receptor-mediated signaling pathways plays neuroprotective roles in cortical neurons. PMID:27298516

Modulating NMDA Receptor Function with D-Amino Acid Oxidase Inhibitors: Understanding Functional Activity in PCP-Treated Mouse Model

PubMed Central

Sershen, Henry; Hashim, Audrey; Dunlop, David S.; Suckow, Raymond F.; Cooper, Tom B.; Javitt, Daniel C.

2016-01-01

Deficits in N-methyl-D-aspartate receptor (NMDAR) function are increasingly linked to persistent negative symptoms and cognitive deficits in schizophrenia. Accordingly, clinical studies have been targeting the modulatory site of the NMDA receptor, based on the decreased function of NMDA receptor, to see whether increasing NMDA function can potentially help treat the negative and cognitive deficits seen in the disease. Glycine and D-serine are endogenous ligands to the NMDA modulatory site, but since high doses are needed to affect brain levels, related compounds are being developed, for example glycine transport (GlyT) inhibitors to potentially elevate brain glycine or targeting enzymes, such as D-amino acid oxidase (DAAO) to slow the breakdown and increase the brain level of D-serine. In the present study we further evaluated the effect of DAAO inhibitors 5-chloro-benzo[d]isoxazol-3-ol (CBIO) and sodium benzoate (NaB) in a phencyclidine (PCP) rodent mouse model to see if the inhibitors affect PCP-induced locomotor activity, alter brain D-serine level, and thereby potentially enhance D-serine responses. D-Serine dose-dependently reduced the PCP-induced locomotor activity at doses above 1000 mg/kg. Acute CBIO (30 mg/kg) did not affect PCP-induced locomotor activity, but appeared to reduce locomotor activity when given with D-serine (600 mg/kg); a dose that by itself did not have an effect. However, the effect was also present when the vehicle (Trappsol®) was tested with D-serine, suggesting that the reduction in locomotor activity was not related to DAAO inhibition, but possibly reflected enhanced bioavailability of D-serine across the blood brain barrier related to the vehicle. With this acute dose of CBIO, D-serine level in brain and plasma were not increased. Another weaker DAAO inhibitor sodium benzoate (NaB) (400 mg/kg), and NaB plus D-serine also significantly reduced PCP-induced locomotor activity, but without affecting plasma or brain D-serine level

NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin

PubMed Central

Alagarsamy, Sudar; Saugstad, Julie; Warren, Lee; Mansuy, Isabelle M.; Gereau, Robert W.; Conn, P. Jeffrey

2010-01-01

Previous reports have shown that activation of N-methyl-D-aspartate (NMDA) receptors potentiates responses to activation of the group I metabotropic glutamate receptor mGluR5 by reversing PKC-mediated desensitization of this receptor. NMDA-induced reversal of mGluR5 desensitization is dependent on activation of protein phosphatases. However, the specific protein phosphatase involved and the precise mechanism by which NMDA receptor activation reduces mGluR desensitization are not known. We have performed a series of molecular, biochemical, and genetic studies to show that NMDA-induced regulation of mGluR5 is dependent on activation of calcium-dependent protein phosphatase 2B/calcineurin (PP2B/CaN). Furthermore, we report that purified calcineurin directly dephosphorylates the C-terminal tail of mGluR5 at sites that are phosphorylated by PKC. Finally, immunoprecipitation and GST fusion protein pull-down experiments reveal that calcineurin interacts with mGluR5, suggesting that these proteins could be colocalized in a signaling complex. Taken together with previous studies, these data suggest that activation of NMDA receptors leads to activation of calcineurin and that calcineurin modulates mGluR5 function by directly dephosphorylating mGluR5 at PKC sites that are involved in desensitization of this receptor. 2005 Elsevier Ltd. All rights reserved. PMID:16005030

NMDA and D1 receptors are involved in one-trial tolerance to the anxiolytic-like effects of diazepam in the elevated plus maze test in rats.

PubMed

Zhou, Heng; Yu, Cheng-Long; Wang, Li-Ping; Yang, Yue-Xiong; Mao, Rong-Rong; Zhou, Qi-Xin; Xu, Lin

2015-08-01

The elevated plus maze (EPM) test is used to examine anxiety-like behaviors in rodents. One interesting phenomenon in the EPM test is one-trial tolerance (OTT), which refers to the reduction in the anxiolytic-like effects of benzodiazepines when rodents are re-exposed to the EPM. However, the underlying mechanism of OTT is still unclear. In this study, we reported that OTT occurred when re-exposure to the EPM (trial 2) only depended on the prior experience of the EPM (trial 1) rather than diazepam treatment. This process was memory-dependent, as it was prevented by the N-methyl-D-aspartate (NMDA) receptors antagonist MK-801 1.5h before trial 2. In addition, OTT was maintained for at least one week but was partially abolished after an interval of 28 days. Furthermore, the administration of the D1-like receptors agonist SKF38393 to the bilateral dorsal hippocampus largely prevented OTT, as demonstrated by the ability of the diazepam treatment to produce significant anxiolytic-like effects in trial 2 after a one-day interval. These findings suggest that OTT to the EPM test may occur via the activation of NMDA receptors and the inactivation of D1-like receptors in certain brain regions, including the hippocampus. Copyright © 2015 Elsevier Inc. All rights reserved.

Virally mediated increased neurotensin 1 receptor in the nucleus accumbens decreases behavioral effects of mesolimbic system activation.

PubMed

Cáceda, Ricardo; Kinkead, Becky; Owens, Michael J; Nemeroff, Charles B

2005-12-14

Dopamine receptor agonist and NMDA receptor antagonist activation of the mesolimbic dopamine system increases locomotion and disrupts prepulse inhibition of the acoustic startle response (PPI), paradigms frequently used to study both the pharmacology of antipsychotic drugs and drugs of abuse. In rats, virally mediated overexpression of the neurotensin 1 (NT1) receptor in the nucleus accumbens antagonized d-amphetamine- and dizocilpine-induced PPI disruption, hyperlocomotion, and D-amphetamine-induced rearing. The NT receptor antagonist SR 142948A [2-[[5-(2,6-dimethoxyphenyl)-1-(4-N-(3-dimethylaminopropyl)-N-methylcarbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]amino] adamantane-2-carboxylic acid, hydrochloride] blocked inhibition of dizocilpine-induced hyperlocomotion mediated by overexpression of the NT1 receptor. Together, these results suggest that increased nucleus accumbens NT neurotransmission, via the NT1 receptor, can decrease the effects of activation of the mesolimbic dopamine system and disruption of the glutamatergic input from limbic cortices, resembling the action of the atypical antipsychotic drug clozapine. In contrast to clozapine, virally mediated overexpression of the NT1 receptor in the nucleus accumbens had prolonged protective effects (up to 4 weeks after viral injection) without perturbing baseline PPI and locomotor behaviors. These data further confirm the NT1 receptor as the receptor mediating the antistimulant- and antipsychotic-like properties of NT and provide rationale for the development of NT1 receptor agonists as novel antipsychotic drugs. In addition, the NT1 receptor vector might be a valuable tool for understanding the mechanism of action of antipsychotic drugs and drugs of abuse and may have potential therapeutic applications.

Dexras1 a unique ras-GTPase interacts with NMDA receptor activity and provides a novel dissociation between anxiety, working memory and sensory gating.

PubMed

Carlson, G C; Lin, R E; Chen, Y; Brookshire, B R; White, R S; Lucki, I; Siegel, S J; Kim, S F

2016-05-13

Dexras1 is a novel GTPase that acts at a confluence of signaling mechanisms associated with psychiatric and neurological disease including NMDA receptors, NOS1AP and nNOS. Recent work has shown that Dexras1 mediates iron trafficking and NMDA-dependent neurodegeneration but a role for Dexras1 in normal brain function or psychiatric disease has not been studied. To test for such a role, mice with germline knockout (KO) of Dexras1 were assayed for behavioral abnormalities as well as changes in NMDA receptor subunit protein expression. Because Dexras1 is up-regulated during stress or by dexamethasone treatment, we included measures associated with emotion including anxiety and depression. Baseline anxiety-like measures (open field and zero maze) were not altered, nor were depression-like behavior (tail suspension). Measures of memory function yielded mixed results, with no changes in episodic memory (novel object recognition) but a significant decrement on working memory (T-maze). Alternatively, there was an increase in pre-pulse inhibition (PPI), without concomitant changes in either startle amplitude or locomotor activity. PPI data are consistent with the direction of change seen following exposure to dopamine D2 antagonists. An examination of NMDA subunit expression levels revealed an increased expression of the NR2A subunit, contrary to previous studies demonstrating down-regulation of the receptor following antipsychotic exposure (Schmitt et al., 2003) and up-regulation after exposure to isolation rearing (Turnock-Jones et al., 2009). These findings suggest a potential role for Dexras1 in modulating a selective subset of psychiatric symptoms, possibly via its interaction with NMDARs and/or other disease-related binding-partners. Furthermore, data suggest that modulating Dexras1 activity has contrasting effects on emotional, sensory and cognitive domains. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Bidirectional modulation of windup by NMDA receptors in the rat spinal trigeminal nucleus.

PubMed

Woda, Alain; Blanc, Olivier; Voisin, Daniel L; Coste, Jérôme; Molat, Jean-Louis; Luccarini, Philippe

2004-04-01

Activation of afferent nociceptive pathways is subject to activity-dependent plasticity, which may manifest as windup, a progressive increase in the response of dorsal horn nociceptive neurons to repeated stimuli. At the cellular level, N-methyl-d-aspartate (NMDA) receptor activation by glutamate released from nociceptive C-afferent terminals is currently thought to generate windup. Most of the wide dynamic range nociceptive neurons that display windup, however, do not receive direct C-fibre input. It is thus unknown where the NMDA mechanisms for windup operate. Here, using the Sprague-Dawley rat trigeminal system as a model, we anatomically identify a subpopulation of interneurons that relay nociceptive information from the superficial dorsal horn where C-fibres terminate, to downstream wide dynamic range nociceptive neurons. Using in vivo electrophysiological recordings, we show that at the end of this pathway, windup was reduced (24 +/- 6%, n = 7) by the NMDA receptor antagonist AP-5 (2.0 fmol) and enhanced (62 +/- 19%, n = 12) by NMDA (1 nmol). In contrast, microinjections of AP-5 (1.0 fmol) within the superficial laminae increased windup (83 +/- 44%, n = 9), whereas NMDA dose dependently decreased windup (n = 19). These results indicate that NMDA receptor function at the segmental level depends on their precise location in nociceptive neural networks. While some NMDA receptors actually amplify pain information, the new evidence for NMDA dependent inhibition of windup we show here indicates that, simultaneously, others act in the opposite direction. Working together, the two mechanisms may provide a fine tuning of gain in pain.

Target-specific expression of presynaptic NMDA receptors in neocortical microcircuits.

PubMed

Buchanan, Katherine A; Blackman, Arne V; Moreau, Alexandre W; Elgar, Dale; Costa, Rui P; Lalanne, Txomin; Tudor Jones, Adam A; Oyrer, Julia; Sjöström, P Jesper

2012-08-09

Traditionally, NMDA receptors are located postsynaptically; yet, putatively presynaptic NMDA receptors (preNMDARs) have been reported. Although implicated in controlling synaptic plasticity, their function is not well understood and their expression patterns are debated. We demonstrate that, in layer 5 of developing mouse visual cortex, preNMDARs specifically control synaptic transmission at pyramidal cell inputs to other pyramidal cells and to Martinotti cells, while leaving those to basket cells unaffected. We also reveal a type of interneuron that mediates ascending inhibition. In agreement with synapse-specific expression, we find preNMDAR-mediated calcium signals in a subset of pyramidal cell terminals. A tuned network model predicts that preNMDARs specifically reroute information flow in local circuits during high-frequency firing, in particular by impacting frequency-dependent disynaptic inhibition mediated by Martinotti cells, a finding that we experimentally verify. We conclude that postsynaptic cell type determines presynaptic terminal molecular identity and that preNMDARs govern information processing in neocortical columns. Copyright © 2012 Elsevier Inc. All rights reserved.

Effects of NMDA receptor antagonists on probability discounting depend on the order of probability presentation.

PubMed

Yates, Justin R; Breitenstein, Kerry A; Gunkel, Benjamin T; Hughes, Mallory N; Johnson, Anthony B; Rogers, Katherine K; Shape, Sara M

Risky decision making can be measured using a probability-discounting procedure, in which animals choose between a small, certain reinforcer and a large, uncertain reinforcer. Recent evidence has identified glutamate as a mediator of risky decision making, as blocking the N-methyl-d-aspartate (NMDA) receptor with MK-801 increases preference for a large, uncertain reinforcer. Because the order in which probabilities associated with the large reinforcer can modulate the effects of drugs on choice, the current study determined if NMDA receptor ligands alter probability discounting using ascending and descending schedules. Sixteen rats were trained in a probability-discounting procedure in which the odds against obtaining the large reinforcer increased (n=8) or decreased (n=8) across blocks of trials. Following behavioral training, rats received treatments of the NMDA receptor ligands MK-801 (uncompetitive antagonist; 0, 0.003, 0.01, or 0.03mg/kg), ketamine (uncompetitive antagonist; 0, 1.0, 5.0, or 10.0mg/kg), and ifenprodil (NR2B-selective non-competitive antagonist; 0, 1.0, 3.0, or 10.0mg/kg). Results showed discounting was steeper (indicating increased risk aversion) for rats on an ascending schedule relative to rats on the descending schedule. Furthermore, the effects of MK-801, ketamine, and ifenprodil on discounting were dependent on the schedule used. Specifically, the highest dose of each drug decreased risk taking in rats in the descending schedule, but only MK-801 (0.03mg/kg) increased risk taking in rats on an ascending schedule. These results show that probability presentation order modulates the effects of NMDA receptor ligands on risky decision making. Copyright © 2016 Elsevier Inc. All rights reserved.

Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis: an unusual cause of autistic regression in a toddler.

PubMed

Scott, Ori; Richer, Lawrence; Forbes, Karen; Sonnenberg, Lyn; Currie, Angela; Eliyashevska, Myroslava; Goez, Helly R

2014-05-01

Anti N-methyl-d-aspartate (NMDA) receptor encephalitis in children is associated with psychiatric changes, seizures, and dyskinesias. We present the first report of autistic regression in a toddler caused by this entity. A 33-month-old boy presented with decreased appetite, irritability, and insomnia following an upper respiratory tract infection. Over the next few weeks he lost language and social skills, and abnormal movements of his hand developed. Within a month, this patient came to fit the diagnostic criteria for autistic spectrum disorder. Upon investigation, anti-NMDA receptor antibodies were found in the boy's cerebrospinal fluid. He was treated with intravenous immunoglobulins and steroids, resulting in reacquisition of language and social skills and resolution of movements. Our case emphasizes the significance of suspecting anti-NMDA receptor encephalitis as the cause of autistic regression, even in an age group where the diagnosis of autistic spectrum disorder is typically made, and especially when presentation follows a febrile illness.

NMDA receptor antagonism with novel indolyl, 2-(1,1-Dimethyl-1,3-dihydro-benzo[e]indol-2-ylidene)-malonaldehyde, reduces seizures duration in a rat model of epilepsy

PubMed Central

Rothan, Hussin A.; Amini, Elham; Faraj, Fadihl L.; Golpich, Mojtaba; Teoh, Teow Chong; Gholami, Khadijeh; Yusof, Rohana

2017-01-01

N-methyl-D-aspartate receptors (NMDAR) play a central role in epileptogensis and NMDAR antagonists have been shown to have antiepileptic effects in animals and humans. Despite significant progress in the development of antiepileptic therapies over the previous 3 decades, a need still exists for novel therapies. We screened an in-house library of small molecules targeting the NMDA receptor. A novel indolyl compound, 2-(1,1-Dimethyl-1,3-dihydro-benzo[e]indol-2-ylidene)-malonaldehyde, (DDBM) showed the best binding with the NMDA receptor and computational docking data showed that DDBM antagonised the binding sites of the NMDA receptor at lower docking energies compared to other molecules. Using a rat electroconvulsive shock (ECS) model of epilepsy we showed that DDBM decreased seizure duration and improved the histological outcomes. Our data show for the first time that indolyls like DDBM have robust anticonvulsive activity and have the potential to be developed as novel anticonvulsants. PMID:28358047

The role of GluN2B-containing NMDA receptors in short- and long-term fear recall.

PubMed

Mikics, Eva; Toth, Mate; Biro, Laszlo; Bruzsik, Biborka; Nagy, Boglarka; Haller, Jozsef

2017-08-01

N-methyl-d-aspartate (NMDA) receptors are crucial synaptic elements in long-term memory formation, including the associative learning of fearful events. Although NMDA blockers were consistently shown to inhibit fear memory acquisition and recall, the clinical use of general NMDA blockers is hampered by their side effects. Recent studies revealed significant heterogeneity in the distribution and neurophysiological characteristics of NMDA receptors with different GluN2 (NR2) subunit composition, which may have differential role in fear learning and recall. To investigate the specific role of NMDA receptor subpopulations with different GluN2 subunit compositions in the formation of lasting traumatic memories, we contrasted the effects of general NMDA receptor blockade with GluN2A-, GluN2B-, and GluN2C/D subunit selective antagonists (MK-801, PEAQX, Ro25-6981, PPDA, respectively). To investigate acute and lasting consequences, behavioral responses were investigated 1 and 28days after fear conditioning. We found that MK-801 (0.05 and 0.1mg/kg) decreased fear recall at both time points. GluN2B receptor subunit blockade produced highly similar effects, albeit efficacy was somewhat smaller 28days after fear conditioning. Unlike MK-801, Ro25-6981 (3 and 10mg/kg) did not affect locomotor activity in the open-field. In contrast, GluN2A and GluN2C/D blockers (6 and 20mg/kg PEAQX; 3 and 10mg/kg PPDA, respectively) had no effect on conditioned fear recall at any time point and dose. This sharp contrast between GluN2B- and other subunit-containing NMDA receptor function indicates that GluN2B receptor subunits are intimately involved in fear memory formation, and may provide a novel pharmacological target in post-traumatic stress disorder or other fear-related disorders. Copyright © 2017 Elsevier Inc. All rights reserved.

Evaluation of 11C-Me-NB1 as a Potential PET Radioligand for Measuring GluN2B-Containing NMDA Receptors, Drug Occupancy, and Receptor Cross Talk.

PubMed

Krämer, Stefanie D; Betzel, Thomas; Mu, Linjing; Haider, Ahmed; Herde, Adrienne Müller; Boninsegni, Anna K; Keller, Claudia; Szermerski, Marina; Schibli, Roger; Wünsch, Bernhard; Ametamey, Simon M

2018-04-01

Clinical and preclinical research with modulators at the N -methyl-d-aspartate (NMDA) receptor GluN2B N-terminal domain (NTD) aims for the treatment of various neurologic diseases. The interpretation of the results is hampered by the lack of a suitable NMDA PET tracer for assessing the receptor occupancy of potential drugs. We have developed 11 C-Me-NB1 as a PET tracer for imaging GluN1/GluN2B-containing NMDA receptors and used it to investigate in rats the dose-dependent receptor occupancy of eliprodil, a GluN2B NTD modulator. Methods: 11 C-Me-NB1 was synthesized and characterized by in vitro displacement binding experiments with rat brain membranes, in vitro autoradiography, and blocking and displacement experiments by PET and PET kinetic modeling. Receptor occupancy by eliprodil was studied by PET with 11 C-Me-NB1. Results: 11 C-Me-NB1 was synthesized at 290 ± 90 GBq/μmol molar activity, 7.4 ± 1.9 GBq total activity at the end of synthesis ( n = 17), and more than 99% radiochemical purity. 11 C-Me-NB1 binding in rat brain was blocked in vitro and in vivo by the NTD modulators Ro-25-6981 and eliprodil. Half-maximal receptor occupancy by eliprodil occurred at 1.5 μg/kg. At 1 mg/kg of eliprodil, a dose with reported neuroprotective effects, more than 99.5% of binding sites were occupied. In vitro, 11 C-Me-NB1 binding was independent of the σ-1 receptor (Sigma1R), and the Sigma1R agonist (+)-pentazocine did not compete for high-affinity binding. In vivo, a 2.5 mg/kg dose of (+)-pentazocine abolished 11 C-Me-NB1-specific binding, indicating an indirect effect of Sigma1R on 11 C-Me-NB1 binding. Conclusion: 11 C-Me-NB1 is suitable for the in vivo imaging of NMDA GluN1/GluN2B receptors and the assessment of receptor occupancy by NTD modulators. GluN1/GluN2B NMDA receptors are fully occupied at neuroprotective doses of eliprodil. Furthermore, 11 C-Me-NB1 enables imaging of GluN1/GluN2B NMDA receptor cross talk. © 2018 by the Society of Nuclear Medicine and

Hippocampus NMDA receptors selectively mediate latent extinction of place learning.

PubMed

Goodman, Jarid; Gabriele, Amanda; Packard, Mark G

2016-09-01

Extinction of maze learning may be achieved with or without the animal performing the previously acquired response. In typical "response extinction," animals are given the opportunity to make the previously acquired approach response toward the goal location of the maze without reinforcement. In "latent extinction," animals are not given the opportunity to make the previously acquired response and instead are confined to the previous goal location without reinforcement. Previous evidence indicates that the effectiveness of these protocols may depend on the type of memory being extinguished. Thus, one aim of the present study was to further examine the effectiveness of response and latent extinction protocols across dorsolateral striatum (DLS)-dependent response learning and hippocampus-dependent place learning tasks. In addition, previous neural inactivation experiments indicate a selective role for the hippocampus in latent extinction, but have not investigated the precise neurotransmitter mechanisms involved. Thus, the present study also examined whether latent extinction of place learning might depend on NMDA receptor activity in the hippocampus. In experiment 1, adult male Long-Evans rats were trained in a response learning task in a water plus-maze, in which animals were reinforced to make a consistent body-turn response to reach an invisible escape platform. Results indicated that response extinction, but not latent extinction, was effective at extinguishing memory in the response learning task. In experiment 2, rats were trained in a place learning task, in which animals were reinforced to approach a consistent spatial location containing the hidden escape platform. In experiment 2, animals also received intra-hippocampal infusions of the NMDA receptor antagonist 2-amino-5-phosphopentanoic acid (AP5; 5.0 or 7.5 ug/0.5 µg) or saline vehicle immediately before response or latent extinction training. Results indicated that both extinction protocols were

Role of Autoantibodies to N-Methyl-d-Aspartate (NMDA) Receptor in Relapsing Herpes Simplex Encephalitis: A Retrospective, One-Center Experience.

PubMed

Sutcu, Murat; Akturk, Hacer; Somer, Ayper; Tatli, Burak; Torun, Selda Hancerli; Yıldız, Edibe Pembegul; Şık, Guntulu; Citak, Agop; Agacfidan, Ali; Salman, Nuran

2016-03-01

Post-herpes simplex virus encephalitis relapses have been recently associated with autoimmunity driven by autoantibodies against N-methyl-d-aspartate (NMDA) receptors. Because it offers different treatment options, determination of this condition is important. Between 2011 and 2014, 7 children with proven diagnosis of herpes simplex virus encephalitis were identified in a university hospital of Istanbul. Two patients had neurologic relapse characterized mainly by movement disorders 2 to 3 weeks after initial encephalitis. The first patient received a second 14 days of acyclovir treatment together with antiepileptic drugs and left with severe neurologic sequelae. The second patient was found to be NMDA receptors antibody positive in the cerebrospinal fluid. She was treated with intravenous immunoglobulin and prednisolone. She showed substantial improvement, gradually regaining lost neurologic abilities. Post-herpes simplex virus encephalitis relapses may frequently be immune-mediated rather than a viral reactivation, particularly in children displaying movement disorders like choreoathetosis. Immunotherapy may provide benefit for this potentially devastating condition, like the case described in this report. © The Author(s) 2015.

Vinpocetine protects inner retinal neurons with functional NMDA glutamate receptors against retinal ischemia.

PubMed

Nivison-Smith, Lisa; Khoo, Pauline; Acosta, Monica L; Kalloniatis, Michael

2018-02-01

Retinal ischemia is involved in the pathogenesis of many major vision threatening diseases. Vinpocetine is a natural drug, which has a range of neuroprotective actions against retinal ischemia including modulating cation flow, improving metabolic activity and preventing apoptosis. The exact mechanism behind these actions remains unknown but may involve glutamate receptors, major components of the ischemic cascade. This study examined the effects of vinpocetine in association with specific ionotropic glutamate receptor agonists: N-methyl-D-aspartate (NMDA) and kainate. Vinpocetine's actions to improve cation channel permeability and cell marker immunoreactivity following ischemia appeared to be limited to NMDA activation with no changes observed following kainate stimulation. Vinpocetine's actions were lost in the presence of an NMDA receptor inhibitor further suggesting they may be secondary to NMDA receptor activation. NMDA receptor function was also necessary for vinpocetine's actions on glucose availability during ischemia but not lactate dehydrogenase (LDH) activity in the ischemic retina suggesting not all of vinpocetine's actions are linked to NMDA receptor function. These results may explain vinpocetine's effectiveness as a neuroprotective agent as the NMDA receptor is implicated in the pathogenesis of ischemia in a range of tissues of the central nervous system. Copyright © 2017 Elsevier Ltd. All rights reserved.

New-Onset Headache in Patients With Autoimmune Encephalitis Is Associated With anti-NMDA-Receptor Antibodies.

PubMed

Schankin, Christoph J; Kästele, Fabian; Gerdes, Lisa Ann; Winkler, Tobias; Csanadi, Endy; Högen, Tobias; Pellkofer, Hannah; Paulus, Walter; Kümpfel, Tania; Straube, Andreas

2016-06-01

We tested the hypotheses (i) that autoimmune encephalitis is associated with new-onset headache, and (ii) that the occurrence of headache is associated with the presence of anti-N-methyl-D-aspartate (NMDA)-receptor antibodies. Autoimmune encephalitis presents with cognitive dysfunction as well as neuro-psychiatric symptoms. Its pathophysiology might involve antibody-mediated dysfunction of the glutamatergic system as indicated by the presence of anti-NMDA-receptor antibodies in some patients. In this cross-sectional study, patients with autoimmune encephalitis were assessed with a standardized interview for previous headache and headache associated with autoimmune encephalitis. Headache was classified according to the International Classification of Headache Disorders, second edition. Clinical and paraclinical findings were correlated with the occurrence of headache. Of 40 patients with autoimmune encephalitis, 19 did not have a history of headache. Of those, nine suffered from encephalitis-associated headache. Seven of these nine had anti-NMDA-receptor antibodies in contrast to only two among the remaining 10 patients without new-onset headache (P = .023, odds ratio: 14, 95% confidence interval: 1.5; 127). In most patients headache occurred in attacks on more than 15 days/month, was severe, and of short duration (less than 4 hours). International Headache Society criteria for migraine were met in three patients. New-onset headache is a relevant symptom in patients with autoimmune encephalitis who have no history of previous headache, especially in the subgroup with anti-NMDA-receptor antibodies. This indicates a thorough investigation for secondary headaches including anti-NMDA-R antibodies for patients with new-onset headache and neuropsychiatric findings. Glutamatergic dysfunction might be important for the generation of head pain but may only occasionally be sufficient to trigger migraine-like attacks in nonmigraineurs. © 2016 American Headache Society.

STEP activation by Gαq coupled GPCRs opposes Src regulation of NMDA receptors containing the GluN2A subunit

PubMed Central

Tian, Meng; Xu, Jian; Lei, Gang; Lombroso, Paul J.; Jackson, Michael F.; MacDonald, John F.

2016-01-01

N-methyl-D-aspartate receptors (NMDARs) are necessary for the induction of synaptic plasticity and for the consolidation of learning and memory. NMDAR function is tightly regulated by functionally opposed families of kinases and phosphatases. Herein we show that the striatal-enriched protein tyrosine phosphatase (STEP) is recruited by Gαq-coupled receptors, including the M1 muscarinic acetylcholine receptor (M1R), and opposes the Src tyrosine kinase-mediated increase in the function of NMDARs composed of GluN2A. STEP activation by M1R stimulation requires IP3Rs and can depress NMDA-evoked currents with modest intracellular Ca2+ buffering. Src recruitment by M1R stimulation requires coincident NMDAR activation and can augment NMDA-evoked currents with high intracellular Ca2+ buffering. Our findings suggest that Src and STEP recruitment is contingent on differing intracellular Ca2+ dynamics that dictate whether NMDAR function is augmented or depressed following M1R stimulation. PMID:27857196

Neuropeptide S attenuates neuropathological, neurochemical and behavioral changes induced by the NMDA receptor antagonist MK-801

PubMed Central

Okamura, Naoe; Reinscheid, Rainer K.; Ohgake, Shintaro; Iyo, Masaomi; Hashimoto, Kenji

2009-01-01

Neuropeptide S (NPS) and its cognate receptor were reported to mediate anxiolytic-like and arousal effects. NPS receptors are predominantly expressed in the brain, especially in limbic structures, including amygdala, olfactory nucleus, subiculum and retrosplenial cortex. In contrast, the NPS precursor is expressed in only a few brainstem nuclei where it is co-expressed with various excitatory transmitters, including glutamate. The current study investigates interactions of the NPS system with glutamatergic neurotransmission. It has been suggested that dysfunctions in glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors might be involved in the pathophysiology of schizophrenia since NMDA receptor antagonists, such as MK-801, have been shown to induce psychotic-like behavior in humans and animal models. Also, MK-801 is known to produce histological changes such as cytoplasmic vacuoles in retrosplenial cortex neurons where NPS receptors are highly expressed. In this study we show that NPS is able to alleviate neuropathological, neurochemical and behavioral changes produced by NMDA receptor antagonists. NPS treatment attenuated MK-801-induced vacuolization in the rat retrosplenial cortex in a dose dependent manner that can be blocked by an NPS receptor-selective antagonist. NPS also suppressed MK-801-induced increases of extracellular acetylcholine levels in the retrosplenial cortex. In the prepulse inhibition (PPI) assay, animals pretreated with NPS recovered significantly from MK-801-induced disruption of PPI. Our study suggests that NPS may have protective effects against the neurotoxic and behavioral changes produced by NMDA receptor antagonists and that NPS receptor agonists may elicit antipsychotic effects. PMID:19576911

NMDA Receptors on Dopaminoceptive Neurons Are Essential for Drug-Induced Conditioned Place Preference.

PubMed

Sikora, Magdalena; Tokarski, Krzysztof; Bobula, Bartosz; Zajdel, Joanna; Jastrzębska, Kamila; Cieślak, Przemysław Eligiusz; Zygmunt, Magdalena; Sowa, Joanna; Smutek, Magdalena; Kamińska, Katarzyna; Gołembiowska, Krystyna; Engblom, David; Hess, Grzegorz; Przewlocki, Ryszard; Rodriguez Parkitna, Jan

2016-01-01

Plasticity of the brain's dopamine system plays a crucial role in adaptive behavior by regulating appetitive motivation and the control of reinforcement learning. In this study, we investigated drug- and natural-reward conditioned behaviors in a mouse model in which the NMDA receptor-dependent plasticity of dopaminoceptive neurons was disrupted. We generated a transgenic mouse line with inducible selective inactivation of the NR1 subunit in neurons expressing dopamine D1 receptors (the NR1(D1CreERT2) mice). Whole-cell recordings of spontaneous EPSCs on neurons in the nucleus accumbens confirmed that a population of neurons lacked the NMDA receptor-dependent component of the current. This effect was accompanied by impaired long-term potentiation in the nucleus accumbens and in the CA1 area of the ventral, but not the dorsal, hippocampus. Mutant mice did not differ from control animals when tested for pavlovian or instrumental conditioning. However, NR1(D1CreERT2) mice acquired no preference for a context associated with administration of drugs of abuse. In the conditioned place preference paradigm, mutant mice did not spend more time in the context paired with cocaine, morphine, or ethanol, although these mice acquired a preference for sucrose jelly and an aversion to naloxone injections, as normal. Thus, we observed that the selective inducible ablation of the NMDA receptors specifically blocks drug-associated context memory with no effect on positive reinforcement in general.

Tryptophanol-derived oxazolopiperidone lactams: identification of a hit compound as NMDA receptor antagonist.

PubMed

Pereira, Nuno A L; Sureda, Francesc X; Esplugas, Roser; Pérez, Maria; Amat, Mercedes; Santos, Maria M M

2014-08-01

N-Methyl-D-aspartate receptors (NMDAR) exacerbated activation leads to neuron death through a phenomenon called excitotoxicity. These receptors are implicated in several neurological diseases (e.g., Alzheimer and Parkinson) and thus represent an important therapeutic target. We herein describe the study of enantiopure tryptophanol-derived oxazolopiperidone lactams as NMDA receptor antagonists. The most active hit exhibited an IC50 of 63.4 μM in cultured rat cerebellar granule neurons thus being 1.5 fold more active than clinically approved NMDA antagonist amantadine (IC50=92 μM). Copyright © 2014 Elsevier Ltd. All rights reserved.

A new and specific non-NMDA receptor antagonist, FG 9065, blocks L-AP4-evoked depolarization in rat cerebral cortex.

PubMed

Sheardown, M J

1988-04-13

L(+)-AP4 (2-amino-4-phosphonobutyrate) depolarized slices of rat cerebral cortex, when applied following a 2 min priming application of quisqualate. This response diminishes with time and is not seen after NMDA application. A new selective non-N-methyl-D-aspartate (NMDA) antagonist, 6-cyano-7-nitro-2,3-dihydroxyquinoxaline (FG 9065), inhibits the L(+)-AP4 depolarization. It is argued that the response is mediated indirectly by postsynaptic quisqualate receptors.

Postsynaptic Synaptotagmins Mediate AMPA Receptor Exocytosis During LTP

PubMed Central

Wu, Dick; Bacaj, Taulant; Morishita, Wade; Goswami, Debanjan; Arendt, Kristin L.; Xu, Wei; Chen, Lu; Malenka, Robert C.; Südhof, Thomas C.

2017-01-01

Strengthening of synaptic connections by NMDA-receptor-dependent long-term potentiation (LTP) shapes neural circuits and mediates learning and memory. During NMDA-receptor-dependent LTP induction, Ca2+-influx stimulates recruitment of synaptic AMPA-receptors, thereby strengthening synapses. How Ca2+ induces AMPA-receptor recruitment, however, remains unclear. Here we show that, in pyramidal neurons of the hippocampal CA1-region, blocking postsynaptic expression of both synaptotagmin-1 and synaptotagmin-7, but not of synaptotagmin-1 or synaptotagmin-7 alone, abolished LTP. LTP was rescued by wild-type but not by Ca2+-binding-deficient mutant synaptotagmin-7. Blocking postsynaptic synaptotagmin-1/7 expression did not impair basal synaptic transmission, synaptic or extrasynaptic AMPA-receptor levels, or other AMPA-receptor trafficking events. Moreover, expression of dominant-negative mutant synaptotagmin-1 that inhibited Ca2+-dependent presynaptic vesicle exocytosis also blocked Ca2+-dependent postsynaptic AMPA-receptor exocytosis, thereby abolishing LTP. Our results suggest that postsynaptic synaptotagmin-1 and synaptotagmin-7 act as redundant Ca2+-sensors for Ca2+-dependent exocytosis of AMPA-receptors during LTP, thus delineating a simple mechanism for the recruitment of AMPA-receptors that mediates LTP. PMID:28355182

NMDA receptor dependent PGC-1alpha up-regulation protects the cortical neuron against oxygen-glucose deprivation/reperfusion injury.

PubMed

Luo, Yun; Zhu, Wenjing; Jia, Jia; Zhang, Chenyu; Xu, Yun

2009-09-01

The peroxisome proliferator activated receptor coactivator 1 alpha (PGC-1alpha) is a nuclear transcriptional coactivator that is widely expressed in the brain areas. Over-expression of PGC-1alpha can protect neuronal cells from oxidant-induced injury. The purpose of the current study is to investigate the role of PGC-1alpha in the oxygen (anoxia) deprivation (OGD) neurons. The PGC-1alpha mRNA and protein level between control and OGD neurons were examined by real-time PCR and Western blot. More PGC-1alpha expression was found in the OGD neurons compared with the normal group. Over-expression of PGC-1alpha suppressed cell apoptosis while inhibition of the PGC-1alpha expression induced cell apoptosis in OGD neurons. Furthermore, increase of PGC-1alpha resulted in activation of N-methyl-D-aspartate (NMDA) receptor, p38, and ERK mitogen-activated protein kinase (MAPK) pathway. The blocking of the NMDA receptor by its antagonists MK-801 reduced PGC-1alpha mRNA expression in OGD neurons, while NMDA itself can directly induce the expression of PGC-1alpha in neuronal cells. At the same time, PD98059 (ERK MAPK inhibitor) and SB203580 (P38 MAPK inhibitor) also prevented the up-regulation of PGC-1alpha in OGD neurons and MK801 can inhibit the expression of P38 and ERK MAPK. These data suggested that the expression of PGC-1alpha was up-regulated in OGD mice cortical neurons, which protected the neurons against OGD injury. Moreover, this effect was correlated to the NMDA receptor and the ERK and P38 MAPK pathway. The protective effect of PGC-1alpha on OGD cortical neurons may be useful for stroke therapy.

Modulation of inhibitory activity markers by intermittent theta-burst stimulation in rat cortex is NMDA-receptor dependent.

PubMed

Labedi, Adnan; Benali, Alia; Mix, Annika; Neubacher, Ute; Funke, Klaus

2014-01-01

Intermittent theta-burst stimulation (iTBS) applied via transcranial magnetic stimulation has been shown to increase cortical excitability in humans. In the rat brain it strongly reduced the number of neurons expressing the 67-kD isoform of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD67) and those expressing the calcium-binding proteins parvalbumin (PV) and calbindin (CB), specific markers of fast-spiking (FS) and non-FS inhibitory interneurons, respectively, an indication of modified cortical inhibition. Since iTBS effects in humans have been shown to be NMDA receptor sensitive, we wondered whether the iTBS-induced changes in the molecular phenotype of interneurons may be also sensitive to glutamatergic synaptic transmission mediated by NMDA receptors. In a sham-controlled fashion, five iTBS-blocks of 600 stimuli were applied to rats either lightly anesthetized by only urethane or by an additional low (subnarcotic) or high dose of the NMDA receptor antagonist ketamine before immunohistochemical analysis. iTBS reduced the number of neurons expressing GAD67, PV and CB. Except for CB, a low dose of ketamine partially prevented these effects while a higher dose almost completely abolished the iTBS effects. Our findings indicate that iTBS modulates the molecular, and likely also the electric, activity of cortical inhibitory interneurons and that the modulation of FS-type but less that of non-FS-type neurons is mediated by NMDA receptors. A combination of iTBS with pharmacological interventions affecting distinct receptor subtypes may thus offer options to enhance its selectivity in modulating the activity of distinct cell types and preventing others from being modulated. Copyright © 2014 Elsevier Inc. All rights reserved.

NMDA receptor agonists reverse impaired psychomotor and cognitive functions associated with hippocampal Hbegf-deficiency in mice.

PubMed

Sasaki, Keita; Omotuyi, Olaposi Idowu; Ueda, Mutsumi; Shinohara, Kazuyuki; Ueda, Hiroshi

2015-12-04

Structural and functional changes of the hippocampus are correlated with psychiatric disorders and cognitive dysfunctions. Genetic deletion of heparin-binding epidermal growth factor-like growth factor (HB-EGF), which is predominantly expressed in cortex and hippocampus, also causes similar psychiatric and cognitive dysfunctions, accompanying down-regulated NMDA receptor signaling. However, little is known of such dysfunctions in hippocampus-specific Hbegf cKO mice. We successfully developed hippocampus-specific cKO mice by crossbreeding floxed Hbegf and Gng7-Cre knock-in mice, as Gng7 promoter-driven Cre is highly expressed in hippocampal neurons as well as striatal medium spiny neurons. In mice lacking hippocampus Hbegf gene, there was a decreased neurogenesis in the subgranular zone (SGZ) of the dentate gyrus as well as down-regulation of PSD-95/NMDA-receptor-NR1/NR2B subunits and related NMDA receptor signaling. Psychiatric, social-behavioral and cognitive abnormalities were also observed in hippocampal cKO mice. Interestingly, D-cycloserine and nefiracetam, positive allosteric modulators (PAMs) of NMDA receptor reversed the apparent reduction in NMDA receptor signaling and most behavioral abnormalities. Furthermore, decreased SGZ neurogenesis in hippocampal cKO mice was reversed by nefiracetam. The present study demonstrates that PAMs of NMDA receptor have pharmacotherapeutic potentials to reverse down-regulated NMDA receptor signaling, neuro-socio-cognitive abnormalities and decreased neurogenesis in hippocampal cKO mice.

Glutamate receptor activation in the kindled dentate gyrus.

PubMed

Behr, J; Heinemann, U; Mody, I

2000-01-01

The contribution of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA), and kainate receptor activation to the enhanced seizure susceptibility of the dentate gyrus was investigated in an experimental model of temporal lobe epilepsy. Using the specific NMDA and AMPA receptor antagonists D-APV and SYM 2206, we examined alterations in glutamate receptor-dependent synaptic currents 48 hours and 28 days after kindling in field-potential and voltage-clamp recordings. Forty-eight hours after kindling, the fractions of AMPA and NMDA receptor-mediated excitatory postsynaptic current components shifted dramatically in favor of the NMDA receptor-mediated response. Four weeks after kindling, however, AMPA and NMDA receptor-mediated excitatory postsynaptic currents reverted to control-like values. Neither single nor repetitive perforant path stimuli evoked kainate receptor-mediated excitatory postsynaptic currents in dentate gyrus granule cells of control or kindled rats. The enhanced excitability of the kindled dentate gyrus 48 hours after the last seizure most likely results from transiently enhanced NMDA receptor activation. The NMDA receptor seems to play a critical role in the induction of the kindled state rather than in the persistence of the enhanced seizure susceptibility.

Cholesterol modulates open probability and desensitization of NMDA receptors

PubMed Central

Korinek, Miloslav; Vyklicky, Vojtech; Borovska, Jirina; Lichnerova, Katarina; Kaniakova, Martina; Krausova, Barbora; Krusek, Jan; Balik, Ales; Smejkalova, Tereza; Horak, Martin; Vyklicky, Ladislav

2015-01-01

NMDA receptors (NMDARs) are glutamate-gated ion channels that mediate excitatory neurotransmission in the CNS. Although these receptors are in direct contact with plasma membrane, lipid–NMDAR interactions are little understood. In the present study, we aimed at characterizing the effect of cholesterol on the ionotropic glutamate receptors. Whole-cell current responses induced by fast application of NMDA in cultured rat cerebellar granule cells (CGCs) were almost abolished (reduced to 3%) and the relative degree of receptor desensitization was increased (by seven-fold) after acute cholesterol depletion by methyl-β-cyclodextrin. Both of these effects were fully reversible by cholesterol repletion. By contrast, the responses mediated by AMPA/kainate receptors were not affected by cholesterol depletion. Similar results were obtained in CGCs after chronic inhibition of cholesterol biosynthesis by simvastatin and acute enzymatic cholesterol degradation to 4-cholesten-3-one by cholesterol oxidase. Fluorescence anisotropy measurements showed that membrane fluidity increased after methyl-β-cyclodextrin pretreatment. However, no change in fluidity was observed after cholesterol enzymatic degradation, suggesting that the effect of cholesterol on NMDARs is not mediated by changes in membrane fluidity. Our data show that diminution of NMDAR responses by cholesterol depletion is the result of a reduction of the open probability, whereas the increase in receptor desensitization is the result of an increase in the rate constant of entry into the desensitized state. Surface NMDAR population, agonist affinity, single-channel conductance and open time were not altered in cholesterol-depleted CGCs. The results of our experiments show that cholesterol is a strong endogenous modulator of NMDARs. Key points NMDA receptors (NMDARs) are tetrameric cation channels permeable to calcium; they mediate excitatory synaptic transmission in the CNS and their excessive activation can lead to

Prenatal exposure to phencyclidine produces abnormal behaviour and NMDA receptor expression in postpubertal mice.

PubMed

Lu, Lingling; Mamiya, Takayoshi; Lu, Ping; Toriumi, Kazuya; Mouri, Akihiro; Hiramatsu, Masayuki; Kim, Hyoung-Chun; Zou, Li-Bo; Nagai, Taku; Nabeshima, Toshitaka

2010-08-01

Several studies have shown the disruptive effects of non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists on neurobehavioural development. Based on the neurodevelopment hypothesis of schizophrenia, there is growing interest in animal models treated with NMDA antagonists at developing stages to investigate the pathogenesis of psychological disturbances in humans. Previous studies have reported that perinatal treatment with phencyclidine (PCP) impairs the development of neuronal systems and induces schizophrenia-like behaviour. However, the adverse effects of prenatal exposure to PCP on behaviour and the function of NMDA receptors are not well understood. This study investigated the long-term effects of prenatal exposure to PCP in mice. The prenatal PCP-treated mice showed hypersensitivity to a low dose of PCP in locomotor activity and impairment of recognition memory in the novel object recognition test at age 7 wk. Meanwhile, the prenatal exposure reduced the phosphorylation of NR1, although it increased the expression of NR1 itself. Furthermore, these behavioural changes were attenuated by atypical antipsychotic treatment. Taken together, prenatal exposure to PCP produced long-lasting behavioural deficits, accompanied by the abnormal expression and dysfunction of NMDA receptors in postpubertal mice. It is worth investigating the influences of disrupted NMDA receptors during the prenatal period on behaviour in later life.

Anti-dyskinetic mechanisms of amantadine and dextromethorphan in the 6-OHDA rat model of Parkinson’s disease: role of NMDA vs. 5-HT1A receptors

PubMed Central

Paquette, Melanie A.; Martinez, Alex A.; Macheda, Teresa; Meshul, Charles K.; Johnson, Steven W.; Berger, S. Paul; Giuffrida, Andrea

2013-01-01

Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia (LID) in patients with Parkinson’s disease (PD) and abnormal involuntary movements (AIMs) in the unilateral 6-hydroxydopamine (6-OHDA) rat model. These effects have been attributed to N-methyl-d-aspartate (NMDA) antagonism. However, amantadine and dextromethorphan are also thought to block serotonin (5-HT) uptake and cause 5-HT overflow, leading to stimulation of 5-HT1A receptors, which has been shown to reduce LID. We undertook a study in 6-OHDA rats to determine whether the anti-dyskinetic effects of these two compounds are mediated by NMDA antagonism and/or 5-HT1A agonism. In addition, we assessed the sensorimotor effects of these drugs using the Vibrissae-Stimulated Forelimb Placement and Cylinder tests. Our data show that the AIM-suppressing effect of amantadine was not affected by the 5-HT1A antagonist WAY-100635, but was partially reversed by the NMDA agonist d-cycloserine. Conversely, the AIM-suppressing effect of dextromethorphan was prevented by WAY-100635 but not by d-cycloserine. Neither amantadine nor dextromethorphan affected the therapeutic effects of L-DOPA in sensorimotor tests. We conclude that the anti-dyskinetic effect of amantadine is partially dependent on NMDA antagonism, while dextromethorphan suppresses AIMs via indirect 5-HT1A agonism. Combined with previous work from our group, our results support the investigation of 5-HT1A agonists as pharmacotherapies for LID in PD patients. PMID:22861201

Is the Acute NMDA Receptor Hypofunction a Valid Model of Schizophrenia?

PubMed Central

Adell, Albert; Jiménez-Sánchez, Laura; López-Gil, Xavier; Romón, Tamara

2012-01-01

Several genetic, neurodevelopmental, and pharmacological animal models of schizophrenia have been established. This short review examines the validity of one of the most used pharmacological model of the illness, ie, the acute administration of N-methyl-D-aspartate (NMDA) receptor antagonists in rodents. In some cases, data on chronic or prenatal NMDA receptor antagonist exposure have been introduced for comparison. The face validity of acute NMDA receptor blockade is granted inasmuch as hyperlocomotion and stereotypies induced by phencyclidine, ketamine, and MK-801 are regarded as a surrogate for the positive symptoms of schizophrenia. In addition, the loss of parvalbumin-containing cells (which is one of the most compelling finding in postmortem schizophrenia brain) following NMDA receptor blockade adds construct validity to this model. However, the lack of changes in glutamic acid decarboxylase (GAD67) is at variance with human studies. It is possible that changes in GAD67 are more reflective of the neurodevelopmental condition of schizophrenia. Finally, the model also has predictive validity, in that its behavioral and transmitter activation in rodents are responsive to antipsychotic treatment. Overall, although not devoid of drawbacks, the acute administration of NMDA receptor antagonists can be considered as a good model of schizophrenia bearing a satisfactory degree of validity. PMID:21965469

Direct involvement of sigma-1 receptors in the dopamine D1 receptor-mediated effects of cocaine.

PubMed

Navarro, Gemma; Moreno, Estefanía; Aymerich, Marisol; Marcellino, Daniel; McCormick, Peter J; Mallol, Josefa; Cortés, Antoni; Casadó, Vicent; Canela, Enric I; Ortiz, Jordi; Fuxe, Kjell; Lluís, Carmen; Ferré, Sergi; Franco, Rafael

2010-10-26

It is well known that cocaine blocks the dopamine transporter. This mechanism should lead to a general increase in dopaminergic neurotransmission, and yet dopamine D(1) receptors (D(1)Rs) play a more significant role in the behavioral effects of cocaine than the other dopamine receptor subtypes. Cocaine also binds to σ-1 receptors, the physiological role of which is largely unknown. In the present study, D(1)R and σ(1)R were found to heteromerize in transfected cells, where cocaine robustly potentiated D(1)R-mediated adenylyl cyclase activation, induced MAPK activation per se and counteracted MAPK activation induced by D(1)R stimulation in a dopamine transporter-independent and σ(1)R-dependent manner. Some of these effects were also demonstrated in murine striatal slices and were absent in σ(1)R KO mice, providing evidence for the existence of σ(1)R-D(1)R heteromers in the brain. Therefore, these results provide a molecular explanation for which D(1)R plays a more significant role in the behavioral effects of cocaine, through σ(1)R-D(1)R heteromerization, and provide a unique perspective toward understanding the molecular basis of cocaine addiction.

AMPA/Kainate, NMDA, and Dopamine D1 Receptor Function in the Nucleus Accumbens Core: A Context-Limited Role in the Encoding and Consolidation of Instrumental Memory

ERIC Educational Resources Information Center

Hernandez, Pepe J.; Andrzejewski, Matthew E.; Sadeghian, Kenneth; Panksepp, Jules B.; Kelley, Ann E.

2005-01-01

Neural integration of glutamate- and dopamine-coded signals within the nucleus accumbens (NAc) is a fundamental process governing cellular plasticity underlying reward-related learning. Intra-NAc core blockade of NMDA or D1 receptors in rats impairs instrumental learning (lever-pressing for sugar pellets), but it is not known during which phase of…

NMDA receptors regulate nicotine-enhanced brain reward function and intravenous nicotine self-administration: role of the ventral tegmental area and central nucleus of the amygdala.

PubMed

Kenny, Paul J; Chartoff, Elena; Roberto, Marisa; Carlezon, William A; Markou, Athina

2009-01-01

Nicotine is considered an important component of tobacco responsible for the smoking habit in humans. Nicotine increases glutamate-mediated transmission throughout brain reward circuitries. This action of nicotine could potentially contribute to its intrinsic rewarding and reward-enhancing properties, which motivate consumption of the drug. Here we show that the competitive N-methyl-D-aspartate (NMDA) receptor antagonist LY235959 (0.5-2.5 mg per kg) abolished nicotine-enhanced brain reward function, reflected in blockade of the lowering of intracranial self-stimulation (ICSS) thresholds usually observed after experimenter-administered (0.25 mg per kg) or intravenously self-administered (0.03 mg per kg per infusion) nicotine injections. The highest LY235959 dose (5 mg per kg) tested reversed the hedonic valence of nicotine from positive to negative, reflected in nicotine-induced elevations of ICSS thresholds. LY235959 doses that reversed nicotine-induced lowering of ICSS thresholds also markedly decreased nicotine self-administration without altering responding for food reinforcement, whereas the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist NBQX had no effects on nicotine intake. In addition, nicotine self-administration upregulated NMDA receptor subunit expression in the central nucleus of the amygdala (CeA) and ventral tegmental area (VTA), suggesting important interactions between nicotine and the NMDA receptor. Furthermore, nicotine (1 microM) increased NMDA receptor-mediated excitatory postsynaptic currents in rat CeA slices, similar to its previously described effects in the VTA. Finally, infusion of LY235959 (0.1-10 ng per side) into the CeA or VTA decreased nicotine self-administration. Taken together, these data suggest that NMDA receptors, including those in the CeA and VTA, gate the magnitude and valence of the effects of nicotine on brain reward systems, thereby regulating motivation to consume the drug.

Prenatal exposure of testosterone prevents SDN-POA neurons of postnatal male rats from apoptosis through NMDA receptor.

PubMed

Hsu, H K; Yang, R C; Shih, H C; Hsieh, Y L; Chen, U Y; Hsu, C

2001-11-01

The role of N-methyl-D-aspartate (NMDA) receptor in mediating the effect of testosterone exposure prenatally on neuronal apoptosis in the sexual dimorphic nucleus of the preoptic area (SDN-POA) of rats was studied. The endogenous testosterone was diminished by prenatal stress (PNS) or simulated by testosterone exposure (TE) to understand the effect of testosterone on NR(1) (a functional subunit protein of NMDA receptor) expression and neuronal apoptosis. To further study whether the testosterone, after being converted into estradiol, modulates NR(1) expression, 4-androstein-4-ol-3,17-dione (ATD; an aromatase inhibitor) was used to block the conversion of estradiol from testosterone. The expressions of the NR(1) mRNA and NR(1) subunit protein were quantified by RT-PCR and western blotting analysis, respectively. In addition, a noncompetitive antagonist of NMDA receptor, MK-801, was used to find out whether blockage of NMDA receptor affects the naturally occurring apoptosis in SDN-POA. The results showed the following. 1) Expression of perinatal NR(1) subunit protein in the central part of the medial preoptic area of male rats was significantly higher than that of females, especially on postnatal days 1 and 3. 2) The testosterone level of male fetuses on embryonic day 18 was significantly higher than that of females, while the testosterone level of TE females or PNS males was similar to that of intact males or intact females, respectively. 3) The apoptotic incidence of intact male rats was significantly less than that of females, and the apoptosis was stimulated by PNS in male or inhibited by TE in female. 4) The expression of NR(1) subunit protein could be inhibited by PNS or ATD-treatment in male, while stimulated by TE in female. 5) NR(1) mRNA showed no significant difference among intact male, PNS male, ATD-treated male, TE female and intact female rats. 6) The low apoptotic incidence of male rats was significantly increased when NMDA receptor was blocked by MK

Evidence for the involvement of NMDA receptors in the antidepressant-like effect of nicotine in mouse forced swimming and tail suspension tests.

PubMed

Haj-Mirzaian, Arya; Kordjazy, Nastaran; Haj-Mirzaian, Arvin; Ostadhadi, Sattar; Ghasemi, Mehdi; Amiri, Shayan; Faizi, Mehrdad; Dehpour, AhmadReza

2015-10-01

The antidepressant action of acute nicotine administration in clinical and animal studies is well recognized. But the underlying mechanism for this effect has not been carefully discovered. We attempted to evaluate the possible role of N-Methyl-D-aspartate (NMDA) receptors in the antidepressant-like effect of nicotine. After the assessment of locomotor activity in the open-field test, forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant-like effect of nicotine in mice. We performed intraperitoneal administration of nicotine at different doses and periods before the tests. To assess the possible involvement of NMDA receptors, non-effective doses of NMDA antagonists and an NMDA agonist were obtained and were administered simultaneously with the non-effective and effective doses of nicotine, respectively. Nicotine (0.2 mg/kg, 30 min before FST/TST) significantly reduced the immobility time of mice similar to fluoxetine (20 mg/kg). Nicotine did not affect the locomotor behavior of mice in open-field test. Co-administration of non-effective doses of NMDA receptor antagonists, ketamine (1 or 0.3 mg/kg), MK-801 (0.05 or 0.005 mg/kg), and magnesium sulfate (10 or 5 mg/kg) with nicotine (0.1 or 0.03 mg/kg) had remarkable synergistic antidepressant effect in both FST and TST. Also, non-effective NMDA (75 or 30 mg/kg) reversed the anti-immobility effect of nicotine (0.2 mg/kg) on mouse FST and TST. Our study has for the first time confirmed that the antidepressant-like effect of nicotine on mice is NMDA-mediated, and nicotine presumably exerts this effect by antagonizing the glutamatergic NMDA receptors.

Ion channels in EEG: isolating channel dysfunction in NMDA receptor antibody encephalitis.

PubMed

Symmonds, Mkael; Moran, Catherine H; Leite, M Isabel; Buckley, Camilla; Irani, Sarosh R; Stephan, Klaas Enno; Friston, Karl J; Moran, Rosalyn J

2018-06-01

See Roberts and Breakspear (doi:10.1093/brain/awy136) for a scientific commentary on this article.Neurological and psychiatric practice frequently lack diagnostic probes that can assess mechanisms of neuronal communication non-invasively in humans. In N-methyl-d-aspartate (NMDA) receptor antibody encephalitis, functional molecular assays are particularly important given the presence of NMDA antibodies in healthy populations, the multifarious symptomology and the lack of radiological signs. Recent advances in biophysical modelling techniques suggest that inferring cellular-level properties of neural circuits from macroscopic measures of brain activity is possible. Here, we estimated receptor function from EEG in patients with NMDA receptor antibody encephalitis (n = 29) as well as from encephalopathic and neurological patient controls (n = 36). We show that the autoimmune patients exhibit distinct fronto-parietal network changes from which ion channel estimates can be obtained using a microcircuit model. Specifically, a dynamic causal model of EEG data applied to spontaneous brain responses identifies a selective deficit in signalling at NMDA receptors in patients with NMDA receptor antibody encephalitis but not at other ionotropic receptors. Moreover, though these changes are observed across brain regions, these effects predominate at the NMDA receptors of excitatory neurons rather than at inhibitory interneurons. Given that EEG is a ubiquitously available clinical method, our findings suggest a unique re-purposing of EEG data as an assay of brain network dysfunction at the molecular level.

Activation of NMDA receptor by elevated homocysteine in chronic liver disease contributes to encephalopathy.

PubMed

Choudhury, Sabanum; Borah, Anupom

2015-07-01

Liver diseases lead to a complex syndrome characterized by neurological, neuro-psychiatric and motor complications, called hepatic encephalopathy, which is prevalent in patients and animal models of acute, sub-chronic and chronic liver failure. Although alterations in GABAergic, glutamatergic, cholinergic and serotonergic neuronal functions have been implicated in HE, the molecular mechanisms that lead to HE in chronic liver disease (CLD) is least illustrated. Due to hepatocellular failure, levels of ammonia and homocysteine (Hcy), in addition to others, are found to increase in the brain as well as plasma. Hcy, a non-protein forming amino acid and an excitotoxin, activates ionotropic glutamate (n-methyl-d-aspartate; NMDA) receptors, and thereby leads to influx of Ca(2+) into neurons, which in turn activates several pathways that trigger oxidative stress, inflammation and apoptosis, collectively called excitotoxicity. Elevated levels of Hcy in the plasma and brain, a condition called Hyperhomocysteinemia (HHcy), and the resultant NMDA receptor-mediated excitotoxicity has been implicated in several diseases, including Parkinson's disease and Alzheimer's disease. Although, hyperammonemia has been shown to cause excitotoxicity, the role of HHcy in the development of behavioral and neurochemical alterations that occur in HE has not been illustrated yet. It is hypothesized that CLD-induced HHcy plays a major role in the development of HE through activation of NMDA receptors. It is further hypothesized that HHcy synergizes with hyperammonemia to activate NMDA receptor in the brain, and thereby cause oxidative stress, inflammation and apoptosis, and neuronal loss that leads to HE. Copyright © 2015 Elsevier Ltd. All rights reserved.

Anti-dyskinetic mechanisms of amantadine and dextromethorphan in the 6-OHDA rat model of Parkinson's disease: role of NMDA vs. 5-HT1A receptors.

PubMed

Paquette, Melanie A; Martinez, Alex A; Macheda, Teresa; Meshul, Charles K; Johnson, Steven W; Berger, S Paul; Giuffrida, Andrea

2012-11-01

Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia (LID) in patients with Parkinson's disease (PD) and abnormal involuntary movements (AIMs) in the unilateral 6-hydroxydopamine (6-OHDA) rat model. These effects have been attributed to N-methyl-d-aspartate (NMDA) antagonism. However, amantadine and dextromethorphan are also thought to block serotonin (5-HT) uptake and cause 5-HT overflow, leading to stimulation of 5-HT(1A) receptors, which has been shown to reduce LID. We undertook a study in 6-OHDA rats to determine whether the anti-dyskinetic effects of these two compounds are mediated by NMDA antagonism and/or 5-HT(1A) agonism. In addition, we assessed the sensorimotor effects of these drugs using the Vibrissae-Stimulated Forelimb Placement and Cylinder tests. Our data show that the AIM-suppressing effect of amantadine was not affected by the 5-HT(1A) antagonist WAY-100635, but was partially reversed by the NMDA agonist d-cycloserine. Conversely, the AIM-suppressing effect of dextromethorphan was prevented by WAY-100635 but not by d-cycloserine. Neither amantadine nor dextromethorphan affected the therapeutic effects of L-DOPA in sensorimotor tests. We conclude that the anti-dyskinetic effect of amantadine is partially dependent on NMDA antagonism, while dextromethorphan suppresses AIMs via indirect 5-HT(1A) agonism. Combined with previous work from our group, our results support the investigation of 5-HT(1A) agonists as pharmacotherapies for LID in PD patients. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Asynchronous Movements Prior to Pore Opening in NMDA Receptors

PubMed Central

Kazi, Rashek; Gan, Quan; Talukder, Iehab; Markowitz, Michael; Salussolia, Catherine L.

2013-01-01

Glutamate-gated ion channels embedded within the neuronal membrane are the primary mediators of fast excitatory synaptic transmission in the CNS. The ion channel of these glutamate receptors contains a pore-lining transmembrane M3 helix surrounded by peripheral M1 and M4 helices. In the NMDA receptor subtype, opening of the ion channel pore, mediated by displacement of the M3 helices away from the central pore axis, occurs in a highly concerted fashion, but the associated temporal movements of the peripheral helices are unknown. To address the gating dynamics of the peripheral helices, we constrained the relative movements of the linkers that connect these helices to the ligand-binding domain using engineered cross-links, either within (intra-GluN1 or GluN2A) or between subunits. Constraining the peripheral linkers in any manner dramatically curtailed channel opening, highlighting the requirement for rearrangements of these peripheral structural elements for efficient gating to occur. However, the magnitude of this gating effect depended on the specific subunit being constrained, with the most dramatic effects occurring when the constraint was between subunits. Based on kinetic and thermodynamic analysis, our results suggest an asynchrony in the displacement of the peripheral linkers during the conformational and energetic changes leading to pore opening. Initially there are large-scale rearrangements occurring between the four subunits. Subsequently, rearrangements occur within individual subunits, mainly GluN2A, leading up to or in concert with pore opening. Thus, the conformational changes induced by agonist binding in NMDA receptors converge asynchronously to permit pore opening. PMID:23864691

Postsynaptic density levels of the NMDA receptor NR1 subunit and PSD-95 protein in prefrontal cortex from people with schizophrenia.

PubMed

Catts, Vibeke Sørensen; Derminio, Dominique Suzanne; Hahn, Chang-Gyu; Weickert, Cynthia Shannon

2015-01-01

There is converging evidence of involvement of N-methyl-d-aspartate (NMDA) receptor hypofunction in the pathophysiology of schizophrenia. Our group recently identified a decrease in total NR1 mRNA and protein expression in the dorsolateral prefrontal cortex in a case-control study of individuals with schizophrenia (n=37/group). The NR1 subunit is critical to NMDA receptor function at the postsynaptic density, a cellular structure rich in the scaffolding protein, PSD-95. The extent to which the NMDA receptor NR1 subunit is altered at the site of action, in the postsynaptic density, is not clear. To extend our previous results by measuring levels of NR1 and PSD-95 protein in postsynaptic density-enriched fractions of prefrontal cortex from the same individuals in the case-control study noted above. Postsynaptic density-enriched fractions were isolated from fresh-frozen prefrontal cortex (BA10) and subjected to western blot analysis for NR1 and PSD-95. We found a 20% decrease in NR1 protein (t(66)=-2.874, P=0.006) and a 30% decrease in PSD-95 protein (t(63)=-2.668, P=0.010) in postsynaptic density-enriched fractions from individuals with schizophrenia relative to unaffected controls. Individuals with schizophrenia have less NR1 protein, and therefore potentially fewer functional NMDA receptors, at the postsynaptic density. The associated decrease in PSD-95 protein at the postsynaptic density suggests that not only are glutamate receptors compromised in individuals with schizophrenia, but the overall spine architecture and downstream signaling supported by PSD-95 may also be deficient.

NMDA Receptors on Dopaminoceptive Neurons Are Essential for Drug-Induced Conditioned Place Preference123

PubMed Central

Tokarski, Krzysztof; Bobula, Bartosz; Zygmunt, Magdalena; Smutek, Magdalena; Kamińska, Katarzyna; Gołembiowska, Krystyna; Hess, Grzegorz; Przewlocki, Ryszard

2016-01-01

Abstract Plasticity of the brain’s dopamine system plays a crucial role in adaptive behavior by regulating appetitive motivation and the control of reinforcement learning. In this study, we investigated drug- and natural-reward conditioned behaviors in a mouse model in which the NMDA receptor-dependent plasticity of dopaminoceptive neurons was disrupted. We generated a transgenic mouse line with inducible selective inactivation of the NR1 subunit in neurons expressing dopamine D1 receptors (the NR1D1CreERT2 mice). Whole-cell recordings of spontaneous EPSCs on neurons in the nucleus accumbens confirmed that a population of neurons lacked the NMDA receptor-dependent component of the current. This effect was accompanied by impaired long-term potentiation in the nucleus accumbens and in the CA1 area of the ventral, but not the dorsal, hippocampus. Mutant mice did not differ from control animals when tested for pavlovian or instrumental conditioning. However, NR1D1CreERT2 mice acquired no preference for a context associated with administration of drugs of abuse. In the conditioned place preference paradigm, mutant mice did not spend more time in the context paired with cocaine, morphine, or ethanol, although these mice acquired a preference for sucrose jelly and an aversion to naloxone injections, as normal. Thus, we observed that the selective inducible ablation of the NMDA receptors specifically blocks drug-associated context memory with no effect on positive reinforcement in general. PMID:27294197

NMDA Receptors Are Not Required for Pattern Completion During Associative Memory Recall

PubMed Central

Gu, Yiran; Cui, Zhenzhong; Tsien, Joe Z.

2011-01-01

Pattern completion, the ability to retrieve complete memories initiated by subsets of external cues, has been a major focus of many computation models. A previously study reports that such pattern completion requires NMDA receptors in the hippocampus. However, such a claim was derived from a non-inducible gene knockout experiment in which the NMDA receptors were absent throughout all stages of memory processes as well as animal's adult life. This raises the critical question regarding whether the previously described results were truly resulting from the requirement of the NMDA receptors in retrieval. Here, we have examined the role of the NMDA receptors in pattern completion via inducible knockout of NMDA receptors limited to the memory retrieval stage. By using two independent mouse lines, we found that inducible knockout mice, lacking NMDA receptor in either forebrain or hippocampus CA1 region at the time of memory retrieval, exhibited normal recall of associative spatial reference memory regardless of whether retrievals took place under full-cue or partial-cue conditions. Moreover, systemic antagonism of NMDA receptor during retention tests also had no effect on full-cue or partial-cue recall of spatial water maze memories. Thus, both genetic and pharmacological experiments collectively demonstrate that pattern completion during spatial associative memory recall does not require the NMDA receptor in the hippocampus or forebrain. PMID:21559402

Blockade of NMDA receptors prevents analgesic tolerance to repeated transcutaneous electrical nerve stimulation (TENS) in rats

PubMed Central

Hingne, Priyanka M.; Sluka, Kathleen A.

2008-01-01

Repeated daily application transcutaneous electrical nerve stimulation (TENS) results in tolerance, at spinal opioid receptors, to the anti-hyperalgesia produced by TENS. Since N-Methyl-D-Aspartate (NMDA) receptor antagonists prevent analgesic tolerance to opioid agonists we hypothesized that blockade of NMDA receptors will prevent tolerance to TENS. In rats with knee joint inflammation, TENS was applied for 20 minute daily at high frequency (100 Hz), low frequency (4 Hz), or sham TENS. Rats were treated with the NMDA antagonist MK-801 (0.01 mg/kg-0.1 mg/kg) or vehicle daily before TENS. Paw withdrawal thresholds were tested before and after inflammation, and before and after TENS treatment for 4 days. On day 1 TENS reversed the decreased mechanical withdrawal threshold induced by joint inflammation. On day 4 TENS had no effect on the decreased withdrawal threshold in the group treated with vehicle demonstrating development of tolerance. However, in the group treated with 0.1 mg/kg MK-801, TENS significantly reversed the mechanical withdrawal thresholds on day 4 demonstrating that tolerance did not develop. Vehicle treated animals developed cross-tolerance at spinal opioid receptors. Treatment with MK-801 reversed this cross-tolerance at spinal opioid receptors. In summary, blockade of NMDA receptors prevents analgesic tolerance to daily TENS by preventing tolerance at spinal opioid receptors. Perspective Tolerance observed to the clinical treatment of TENS could be prevented by administration of pharmaceutical agents with NMDA receptors activity such as ketamine or dextromethorphan. PMID:18061543

NMDA receptor-mediated long term modulation of electrically evoked field potentials in the rat medial vestibular nuclei.

PubMed

Capocchi, G; Della Torre, G; Grassi, S; Pettorossi, V E; Zampolini, M

1992-01-01

The effect of high frequency stimulation (HFS) of the primary vestibular afferents on field potentials recorded in the ipsilateral Medial Vestibular Nuclei (MVN) was studied. Our results show that potentiation and depression can be induced in different portions of MVN, which are distinguishable by their anatomical organization. HFS induces potentiation of the monosynaptic component in the ventral portion of the MVN, whereas it provokes depression of the polysynaptic component in the dorsal portion of the same nucleus. The induction of both potentiation and depression was blocked under AP5 perfusion, thus demonstrating that NMDA receptor activation mediates both phenomena. Furthermore, the finding that the field potentials were not modified during perfusion with DL-AP5, as previously reported, supports the hypothesis that NMDA receptors are not involved in the normal synaptic transmission from the primary vestibular afferent fibres, but are only activated following hyperstimulation of this afferent system. Our results suggest that the mechanisms of long term modification of synaptic efficacy observed in MVN may underlie the plasticity phenomena occurring in vestibular nuclei.

The brain cytoplasmic RNA BC1 regulates dopamine D2 receptor-mediated transmission in the striatum.

PubMed

Centonze, Diego; Rossi, Silvia; Napoli, Ilaria; Mercaldo, Valentina; Lacoux, Caroline; Ferrari, Francesca; Ciotti, Maria Teresa; De Chiara, Valentina; Prosperetti, Chiara; Maccarrone, Mauro; Fezza, Filomena; Calabresi, Paolo; Bernardi, Giorgio; Bagni, Claudia

2007-08-15

Dopamine D(2) receptor (D(2)DR)-mediated transmission in the striatum is remarkably flexible, and changes in its efficacy have been heavily implicated in a variety of physiological and pathological conditions. Although receptor-associated proteins are clearly involved in specific forms of synaptic plasticity, the molecular mechanisms regulating the sensitivity of D(2) receptors in this brain area are essentially obscure. We have studied the physiological responses of the D(2)DR stimulations in mice lacking the brain cytoplasmic RNA BC1, a small noncoding dendritically localized RNA that is supposed to play a role in mRNA translation. We show that the efficiency of D(2)-mediated transmission regulating striatal GABA synapses is under the control of BC1 RNA, through a negative influence on D(2) receptor protein level affecting the functional pool of receptors. Ablation of the BC1 gene did not result in widespread dysregulation of synaptic transmission, because the sensitivity of cannabinoid CB(1) receptors was intact in the striatum of BC1 knock-out (KO) mice despite D(2) and CB(1) receptors mediated similar electrophysiological actions. Interestingly, the fragile X mental retardation protein FMRP, one of the multiple BC1 partners, is not involved in the BC1 effects on the D(2)-mediated transmission. Because D(2)DR mRNA is apparently equally translated in the BC1-KO and wild-type mice, whereas the protein level is higher in BC1-KO mice, we suggest that BC1 RNA controls D(2)DR indirectly, probably regulating translation of molecules involved in D(2)DR turnover and/or stability.

Involvement of pre- and postsynaptic NMDA receptors at local circuit interneuron connections in rat neocortex

PubMed Central

De-May, C.L.; Ali, A.B.

2013-01-01

To investigate the involvement of N-Methyl-D-aspartate (NMDA) receptors in local neocortical synaptic transmission, dual whole-cell recordings – combined with biocytin labelling – were obtained from bitufted adapting, multipolar adapting or multipolar non-adapting interneurons and pyramidal cells in layers II–V of rat (postnatal days 17–22) sensorimotor cortex. The voltage dependency of the amplitude of Excitatory postsynaptic potentials (EPSPs) received by the three types of interneuron appeared to coincide with the interneuron subclass; upon depolarisation, EPSPs received by multipolar non-adapting interneurons either decreased in amplitude or appeared insensitive, multipolar adapting interneuron EPSP amplitudes increased or appeared insensitive, whereas bitufted interneuron EPSP amplitudes increased or decreased. Connections were challenged with the NMDA receptor antagonist d-(−)-2-amino-5-phosphonopentanoic acid (d-AP5) (50 μM) revealing NMDA receptors to contribute to EPSPs received by all cell types, this also abolished the non-conventional voltage dependency. Reciprocal connections were frequent between pyramidal cells and multipolar interneurons, and inhibitory postsynaptic potentials (IPSPs) elicited in pyramidal cells by both multipolar adapting and multipolar non-adapting interneurons were sensitive to a significant reduction in amplitude by d-AP5. The involvement of presynaptic NMDA receptors was indicated by coefficient of variation analysis and an increase in the failures of transmission. Furthermore, by loading MK-801 into the pre- or postsynaptic neurons, we observed that a reduction in inhibition requires presynaptic and not postsynaptic NMDA receptors. These results suggest that NMDA receptors possess pre- and postsynaptic roles at selective neocortical synapses that are probably important in governing spike-timing and information flow. PMID:23079623

Approach to the Management of Pediatric-Onset Anti-N-Methyl-d-Aspartate (Anti-NMDA) Receptor Encephalitis: A Case Series.

PubMed

Brenton, J Nicholas; Kim, Joshua; Schwartz, Richard H

2016-08-01

Anti-N-methyl-d-aspartate (anti-NMDA) receptor encephalitis is a treatable cause of autoimmune encephalitis. It remains unclear if the natural history of this disease is altered by choice of acute therapy or the employment of chronic immunotherapy. Chart review was undertaken for pediatric patients diagnosed with anti-NMDA receptor encephalitis. Data obtained included patient demographics, disease manifestations, treatment course, and clinical outcomes. Ten patients with anti-NMDA receptor encephalitis were identified. All patients were treated with immunotherapy in the acute period, and all patients experienced good recovery. Neurologic relapse did not occur in any patient. All patients received varied forms of chronic immunosuppression to prevent relapses. Complications of chronic immunotherapy occurred in 50% of patients. The benefits of chronic immunotherapy and the duration of use should be carefully weighed against the risks. Complications from immunotherapy are not uncommon and can be serious. Clinical trials assessing the benefit of long-term immunotherapy in this population are needed. © The Author(s) 2016.

Pharmacological characterization of NMDA-like receptors in the single-celled organism Paramecium primaurelia.

PubMed

Ramoino, Paola; Candiani, Simona; Pittaluga, Anna Maria; Usai, Cesare; Gallus, Lorenzo; Ferrando, Sara; Milanese, Marco; Faimali, Marco; Bonanno, Giambattista

2014-02-01

Paramecium primaurelia is a unicellular eukaryote that moves in freshwater by ciliary beating and responds to environmental stimuli by altering motile behaviour. The movements of the cilia are controlled by the electrical changes of the cell membrane: when the intraciliary Ca(2+) concentration associated with plasma membrane depolarization increases, the ciliary beating reverses its direction, and consequently the swimming direction changes. The ciliary reversal duration is correlated with the amount of Ca(2+) influx. Here, we evaluated the effects due to the activation or blockade of N-methyl-d-aspartic acid (NMDA) receptors on swimming behaviour in Paramecium. Paramecia normally swim forward, drawing almost linear tracks. We observed that the simultaneous administration of NMDA and glycine induced a partial ciliary reversal (PaCR) leading to a continuous spiral-like swim. Furthermore, the duration of continuous ciliary reversal (CCR), triggered by high external KCl concentrations, was longer in NMDA+glycine-treated cells. NMDA action required the presence of Ca(2+), as the normal forward swimming was restored when the ion was omitted from the extracellular milieu. The PaCR and the enhancement of CCR duration significantly decreased when the antagonists of the glutamate site D-AP5 or CGS19755, the NMDA channel blocker MK-801 or the glycine site antagonist DCKA was added. The action of NMDA+glycine was also abolished by Zn(2+) or ifenprodil, the GluN2A and the GluN2B NMDA-containing subunit blockers, respectively. Searches of the Paramecium genome database currently available indicate that the NMDA-like receptor with ligand-binding characteristics of an NMDA receptor-like complex, purified from rat brain synaptic membranes and found in some metazoan genomes, is also present in Paramecium. These results provide evidence that functional NMDA receptors similar to those typical of mammalian neuronal cells are present in the single-celled organism Paramecium and thus

Exploring neuroprotective potential of Withania somnifera phytochemicals by inhibition of GluN2B-containing NMDA receptors: An in silico study.

PubMed

Kumar, Gaurav; Patnaik, Ranjana

2016-07-01

N-methyl-d-aspartate receptors (NMDARs) mediated excitotoxicity has been implicated in multi-neurodegenerative diseases. Due to lack of efficacy and adverse effects of NMDA receptor antagonists, search for herbal remedies that may act as therapeutic agents is an active area of research to combat these diseases. Withania somnifera (WS) is being used for centuries as a nerve tonic and Nootropic agents. The present study targets the in silico evaluation of the neuroprotective efficacy of W. somnifera phytochemicals by inhibition of NMDA receptor-mediated excitotoxicity through allosteric inhibition of the GluN2B containing NMDARs. We predict Blood Brain Barrier (BBB) penetration, mutagenicity, drug-likeness and Human Intestinal Absorption properties of 25 WS phytochemicals. Further, molecular docking was performed to know whether these phytochemicals inhibit the GluN2B containing NMDARs or not. The results suggest that Anaferine, Beta-Sitosterol, Withaferin A, Withanolide A, Withanolide B and Withanolide D inhibit GluN2B containing NMDARs through allosteric mode similar to the well-known selective antagonist Ifenprodil. These phytochemicals have potential as an essentially useful oral drug to counter NMDARs mediated excitotoxicity and to treat multi-neurodegenerative diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

A family of photoswitchable NMDA receptors

PubMed Central

Berlin, Shai; Szobota, Stephanie; Reiner, Andreas; Carroll, Elizabeth C; Kienzler, Michael A; Guyon, Alice; Xiao, Tong; Trauner, Dirk; Isacoff, Ehud Y

2016-01-01

NMDA receptors, which regulate synaptic strength and are implicated in learning and memory, consist of several subtypes with distinct subunit compositions and functional properties. To enable spatiotemporally defined, rapid and reproducible manipulation of function of specific subtypes, we engineered a set of photoswitchable GluN subunits ('LiGluNs'). Photo-agonism of GluN2A or GluN2B elicits an excitatory drive to hippocampal neurons that can be shaped in time to mimic synaptic activation. Photo-agonism of GluN2A at single dendritic spines evokes spine-specific calcium elevation and expansion, the morphological correlate of LTP. Photo-antagonism of GluN2A alone, or in combination with photo-antagonism of GluN1a, reversibly blocks excitatory synaptic currents, prevents the induction of long-term potentiation and prevents spine expansion. In addition, photo-antagonism in vivo disrupts synaptic pruning of developing retino-tectal projections in larval zebrafish. By providing precise and rapidly reversible optical control of NMDA receptor subtypes, LiGluNs should help unravel the contribution of specific NMDA receptors to synaptic transmission, integration and plasticity. DOI: http://dx.doi.org/10.7554/eLife.12040.001 PMID:26929991

Acute D2/D3 dopaminergic agonism but chronic D2/D3 antagonism prevents NMDA antagonist neurotoxicity.

PubMed

Farber, Nuri B; Nemmers, Brian; Noguchi, Kevin K

2006-09-15

Antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor, most likely by producing disinhibtion in complex circuits, acutely produce psychosis and cognitive disturbances in humans, and neurotoxicity in rodents. Studies examining NMDA Receptor Hypofunction (NRHypo) neurotoxicity in animals, therefore, may provide insights into the pathophysiology of psychotic disorders. Dopaminergic D2 and/or D3 agents can modify psychosis over days to weeks, suggesting involvement of these transmitter system(s). We studied the ability of D2/D3 agonists and antagonists to modify NRHypo neurotoxicity both after a one-time acute exposure and after chronic daily exposure. Here we report that D2/D3 dopamine agonists, probably via D3 receptors, prevent NRHypo neurotoxicity when given acutely. The protective effect with D2/D3 agonists is not seen after chronic daily dosing. In contrast, the antipsychotic haloperidol does not affect NRHypo neurotoxicity when given acutely at D2/D3 doses. However, after chronic daily dosing of 1, 3, or 5 weeks, haloperidol does prevent NRHypo neurotoxicity with longer durations producing greater protection. Understanding the changes that occur in the NRHypo circuit after chronic exposure to dopaminergic agents could provide important clues into the pathophysiology of psychotic disorders.

Glucocorticoid acts on a putative G protein-coupled receptor to rapidly regulate the activity of NMDA receptors in hippocampal neurons.

PubMed

Zhang, Yanmin; Sheng, Hui; Qi, Jinshun; Ma, Bei; Sun, Jihu; Li, Shaofeng; Ni, Xin

2012-04-01

Glucocorticoids (GCs) have been demonstrated to act through both genomic and nongenomic mechanisms. The present study demonstrated that corticosterone rapidly suppressed the activity of N-methyl-D-aspartate (NMDA) receptors in cultured hippocampal neurons. The effect was maintained with corticosterone conjugated to bovine serum albumin and blocked by inhibition of G protein activity with intracellular GDP-β-S application. Corticosterone increased GTP-bound G(s) protein and cyclic AMP (cAMP) production, activated phospholipase Cβ(3) (PLC-β(3)), and induced inositol-1,4,5-triphosphate (IP(3)) production. Blocking PLC and the downstream cascades with PLC inhibitor, IP(3) receptor antagonist, Ca(2+) chelator, and protein kinase C (PKC) inhibitors prevented the actions of corticosterone. Blocking adenylate cyclase (AC) and protein kinase A (PKA) caused a decrease in NMDA-evoked currents. Application of corticosterone partly reversed the inhibition of NMDA currents caused by blockage of AC and PKA. Intracerebroventricular administration of corticosterone significantly suppressed long-term potentiation (LTP) in the CA1 region of the hippocampus within 30 min in vivo, implicating the possibly physiological significance of rapid effects of GC on NMDA receptors. Taken together, our results indicate that GCs act on a putative G protein-coupled receptor to activate multiple signaling pathways in hippocampal neurons, and the rapid suppression of NMDA activity by GCs is dependent on PLC and downstream signaling.

N-Methyl-d-aspartate Modulation of Nucleus Accumbens Dopamine Release by Metabotropic Glutamate Receptors: Fast Cyclic Voltammetry Studies in Rat Brain Slices in Vitro.

PubMed

Yavas, Ersin; Young, Andrew M J

2017-02-15

The N-methyl-d-aspartate (NMDA) receptor antagonist, phencyclidine, induces behavioral changes in rodents mimicking symptoms of schizophrenia, possibly mediated through dysregulation of glutamatergic control of mesolimbic dopamine release. We tested the hypothesis that NMDA receptor activation modulates accumbens dopamine release, and that phencyclidine pretreatment altered this modulation. NMDA caused a receptor-specific, dose-dependent decrease in electrically stimulated dopamine release in nucleus accumbens brain slices. This decrease was unaffected by picrotoxin, making it unlikely to be mediated through GABAergic neurones, but was decreased by the metabotropic glutamate receptor antagonist, (RS)-α-methyl-4-sulfonophenylglycine, indicating that NMDA activates mechanisms controlled by these receptors to decrease stimulated dopamine release. The effect of NMDA was unchanged by in vivo pretreatment with phencyclidine (twice daily for 5 days), with a washout period of at least 7 days before experimentation, which supports the hypothesis that there is no enduring direct effect of PCP at NMDA receptors after this pretreatment procedure. We propose that NMDA depression of accumbal dopamine release is mediated by metabotropic glutamate receptors located pre- or perisynaptically, and suggest that NMDA evoked increased extrasynaptic spillover of glutamate is sufficient to activate these receptors that, in turn, inhibit dopamine release. Furthermore, we suggest that enduring functional changes brought about by subchronic phencyclidine pretreatment, modeling deficits in schizophrenia, are downstream effects consequent on chronic blockade of NMDA receptors, rather than direct effects on NMDA receptors themselves.

(+)-Pentazocine Reduces NMDA-Induced Murine Retinal Ganglion Cell Death Through a σR1-Dependent Mechanism

PubMed Central

Zhao, Jing; Mysona, Barbara A.; Qureshi, Azam; Kim, Lily; Fields, Taylor; Gonsalvez, Graydon B.; Smith, Sylvia B.; Bollinger, Kathryn E.

2016-01-01

Purpose To evaluate, in vivo, the effects of the sigma-1 receptor (σR1) agonist, (+)-pentazocine, on N-methyl-D-aspartate (NMDA)-mediated retinal excitotoxicity. Methods Intravitreal NMDA injections were performed in C57BL/6J mice (wild type [WT]) and σR1−/− (σR1 knockout [KO]) mice. Fellow eyes were injected with phosphate-buffered saline (PBS). An experimental cohort of WT and σR1 KO mice was administered (+)-pentazocine by intraperitoneal injection, and untreated animals served as controls. Retinas derived from mice were flat-mounted and labeled for retinal ganglion cells (RGCs). The number of RGCs was compared between NMDA and PBS-injected eyes for all groups. Apoptosis was assessed using TUNEL assay. Levels of extracellular-signal–regulated kinases (ERK1/2) were analyzed by Western blot. Results N-methyl-D-aspartate induced a significant increase in TUNEL-positive nuclei and a dose-dependent loss of RGCs. Mice deficient in σR1 showed greater RGC loss (≈80%) than WT animals (≈50%). (+)-Pentazocine treatment promoted neuronal survival, and this effect was prevented by deletion of σR1. (+)-Pentazocine treatment resulted in enhanced activation of ERK at the 6-hour time point following NMDA injection. The (+)-pentazocine–induced ERK activation was diminished in σR1 KO mice. Conclusions Targeting σR1 activation prevented RGC death while enhancing activation of the mitogen-activated protein kinase (MAPK), ERK1/2. Sigma-1 receptor is a promising therapeutic target for retinal neurodegenerative diseases. PMID:26868747

Postsynaptic density levels of the NMDA receptor NR1 subunit and PSD-95 protein in prefrontal cortex from people with schizophrenia

PubMed Central

Catts, Vibeke Sørensen; Derminio, Dominique Suzanne; Hahn, Chang-Gyu; Weickert, Cynthia Shannon

2015-01-01

Background: There is converging evidence of involvement of N-methyl-d-aspartate (NMDA) receptor hypofunction in the pathophysiology of schizophrenia. Our group recently identified a decrease in total NR1 mRNA and protein expression in the dorsolateral prefrontal cortex in a case-control study of individuals with schizophrenia (n=37/group). The NR1 subunit is critical to NMDA receptor function at the postsynaptic density, a cellular structure rich in the scaffolding protein, PSD-95. The extent to which the NMDA receptor NR1 subunit is altered at the site of action, in the postsynaptic density, is not clear. Aims: To extend our previous results by measuring levels of NR1 and PSD-95 protein in postsynaptic density-enriched fractions of prefrontal cortex from the same individuals in the case-control study noted above. Methods: Postsynaptic density-enriched fractions were isolated from fresh-frozen prefrontal cortex (BA10) and subjected to western blot analysis for NR1 and PSD-95. Results: We found a 20% decrease in NR1 protein (t(66)=−2.874, P=0.006) and a 30% decrease in PSD-95 protein (t(63)=−2.668, P=0.010) in postsynaptic density-enriched fractions from individuals with schizophrenia relative to unaffected controls. Conclusions: Individuals with schizophrenia have less NR1 protein, and therefore potentially fewer functional NMDA receptors, at the postsynaptic density. The associated decrease in PSD-95 protein at the postsynaptic density suggests that not only are glutamate receptors compromised in individuals with schizophrenia, but the overall spine architecture and downstream signaling supported by PSD-95 may also be deficient. PMID:27336043

NMDA receptor antagonist ketamine impairs feature integration in visual perception.

PubMed

Meuwese, Julia D I; van Loon, Anouk M; Scholte, H Steven; Lirk, Philipp B; Vulink, Nienke C C; Hollmann, Markus W; Lamme, Victor A F

2013-01-01

Recurrent interactions between neurons in the visual cortex are crucial for the integration of image elements into coherent objects, such as in figure-ground segregation of textured images. Blocking N-methyl-D-aspartate (NMDA) receptors in monkeys can abolish neural signals related to figure-ground segregation and feature integration. However, it is unknown whether this also affects perceptual integration itself. Therefore, we tested whether ketamine, a non-competitive NMDA receptor antagonist, reduces feature integration in humans. We administered a subanesthetic dose of ketamine to healthy subjects who performed a texture discrimination task in a placebo-controlled double blind within-subject design. We found that ketamine significantly impaired performance on the texture discrimination task compared to the placebo condition, while performance on a control fixation task was much less impaired. This effect is not merely due to task difficulty or a difference in sedation levels. We are the first to show a behavioral effect on feature integration by manipulating the NMDA receptor in humans.

A Metabotropic-Like Flux-Independent NMDA Receptor Regulates Ca2+ Exit from Endoplasmic Reticulum and Mitochondrial Membrane Potential in Cultured Astrocytes.

PubMed

Montes de Oca Balderas, Pavel; Aguilera, Penélope

2015-01-01

Astrocytes were long thought to be only structural cells in the CNS; however, their functional properties support their role in information processing and cognition. The ionotropic glutamate N-methyl D-aspartate (NMDA) receptor (NMDAR) is critical for CNS functions, but its expression and function in astrocytes is still a matter of research and debate. Here, we report immunofluorescence (IF) labeling in rat cultured cortical astrocytes (rCCA) of all NMDAR subunits, with phenotypes suggesting their intracellular transport, and their mRNA were detected by qRT-PCR. IF and Western Blot revealed GluN1 full-length synthesis, subunit critical for NMDAR assembly and transport, and its plasma membrane localization. Functionally, we found an iCa2+ rise after NMDA treatment in Fluo-4-AM labeled rCCA, an effect blocked by the NMDAR competitive inhibitors D(-)-2-amino-5-phosphonopentanoic acid (APV) and Kynurenic acid (KYNA) and dependent upon GluN1 expression as evidenced by siRNA knock down. Surprisingly, the iCa2+ rise was not blocked by MK-801, an NMDAR channel blocker, or by extracellular Ca2+ depletion, indicating flux-independent NMDAR function. In contrast, the IP3 receptor (IP3R) inhibitor XestosponginC did block this response, whereas a Ryanodine Receptor inhibitor did so only partially. Furthermore, tyrosine kinase inhibition with genistein enhanced the NMDA elicited iCa2+ rise to levels comparable to those reached by the gliotransmitter ATP, but with different population dynamics. Finally, NMDA depleted the rCCA mitochondrial membrane potential (mΔψ) measured with JC-1. Our results demonstrate that rCCA express NMDAR subunits which assemble into functional receptors that mediate a metabotropic-like, non-canonical, flux-independent iCa2+ increase.

Mechanistic Insights into Xenon Inhibition of NMDA Receptors from MD Simulations

PubMed Central

Liu, Lu Tian; Xu, Yan; Tang, Pei

2010-01-01

Inhibition of N-methyl-D-aspartate (NMDA) receptors has been viewed as a primary cause of xenon anesthesia, yet the mechanism is unclear. Here, we investigated interactions between xenon and the ligand-binding domain (LBD) of a NMDA receptor and examined xenon-induced structural and dynamical changes that are relevant to functional changes of the NMDA receptor. Several comparative molecular dynamics simulations were performed on two X-ray structures representing the open- and closed-cleft LBD of the NMDA receptor. We identified plausible xenon action sites in the LBD, including those nearby agonist sites, in the hinge region, and at the interface between two subunits. The xenon binding energy varies from −5.3 to −0.7 kcal/mol. Xenon's effect on the NMDA receptor is conformation-dependent and is produced through both competitive and non-competitive mechanisms. Xenon can promote cleft opening in the absence of agonists and consequently stabilizes the closed channel. Xenon can also bind at the interface of two subunits, alter the inter-subunit interaction, and lead to a reduction of the distance between GT-links. This reduction corresponds to a rearrangement of the channel toward a direction of pore size decreasing, implying a closed or desensitized channel. In addition to these non-competitive actions, xenon was found to weaken the glutamate binding, which could lead to low agonist efficacy and appear as competitive inhibition. PMID:20560662

NMDA receptor as a newly identified member of the metabotropic glutamate receptor family: clinical implications for neurodegenerative diseases.

PubMed

Chung, ChiHye

2013-08-01

Recent reports have proposed a novel function for the N-methyl-D-aspartate (NMDA) receptor (NMDAR), a well-known excitatory, ionotropic receptor. A series of observations employing pharmacological techniques has proposed that upon ligand binding, this ionotropic receptor can actually function via signaling cascades independent of traditional ionotropic action. Moreover, the "metabotropic" action of NMDARs is suggested to mediate a form of synaptic plasticity, namely long-term synaptic depression (LTD), which shares cellular mechanisms with the synaptic deficits observed in Alzheimer's disease. Given that a growing body of clinical and preclinical evidence strongly recommends NMDAR antagonists for their therapeutic potentials and advantages in a variety of diseases, further investigation into their molecular and cellular mechanisms is required to better understand the "metabotropic" action of NMDARs.

TRPA1, NMDA receptors and nitric oxide mediate mechanical hyperalgesia induced by local injection of magnesium sulfate into the rat hind paw.

PubMed

Srebro, Dragana P; Vučković, Sonja M; Savić Vujović, Katarina R; Prostran, Milica Š

2015-02-01

Previous studies have shown that while magnesium, an antagonist of the glutamate subtype of N-methyl-D-aspartate receptors, possesses analgesic properties, it can induce writhing in rodents. The aim of this study was to determine the effect and mechanism of action of local (intraplantar) administration of magnesium sulfate (MS) on the paw withdrawal threshold (PWT) to mechanical stimuli. The PWT was evaluated by the electronic von Frey test in male Wistar rats. Tested drugs were either co-administered intraplantarly (i.pl.) with MS or given into the contralateral paw to exclude systemic effects. MS at doses of 0.5, 1.5, 3 and 6.2 mg/paw (i.pl.) induced a statistically significant (as compared to 0.9% NaCl) and dose-dependent mechanical hyperalgesia. Only isotonic MS (250 mmol/l or 6.2% or 6.2 mg/paw) induced mechanical hyperalgesia that lasted at least six hours. Isotonic MS-induced mechanical hyperalgesia was reduced in a dose-dependent manner by co-injection of camphor, a non-selective TRPA1 antagonist (0.3, 1 and 2.5 μg/paw), MK-801, a NMDA receptor antagonist (0.001, 0.025 and 0.1 μg/paw), L-NAME, a non-selective nitric oxide (NO) synthase inhibitor (20, 50 and 100 μg/paw), ARL 17477, a selective neuronal NOS inhibitor (5.7 and 17 μg/paw), SMT, a selective inducible NOS inhibitor (1 and 2.78 μg/paw), and methylene blue, a guanylate cyclase inhibitor (5, 20 and 125 μg/paw). Drugs injected into the contralateral hind paw did not produce significant effects. These results suggest that an i.pl. injection of MS produces local peripheral mechanical hyperalgesia via activation of peripheral TRPA1 and NMDA receptors and peripheral production of NO. Copyright © 2014 Elsevier Inc. All rights reserved.

Excitotoxicity through NMDA receptors mediates cerebellar granule neuron apoptosis induced by prion protein 90-231 fragment.

PubMed

Thellung, Stefano; Gatta, Elena; Pellistri, Francesca; Corsaro, Alessandro; Villa, Valentina; Vassalli, Massimo; Robello, Mauro; Florio, Tullio

2013-05-01

Prion diseases recognize, as a unique molecular trait, the misfolding of CNS-enriched prion protein (PrP(C)) into an aberrant isoform (PrP(Sc)). In this work, we characterize the in vitro toxicity of amino-terminally truncated recombinant PrP fragment (amino acids 90-231, PrP90-231), on rat cerebellar granule neurons (CGN), focusing on glutamatergic receptor activation and Ca(2+) homeostasis impairment. This recombinant fragment assumes a toxic conformation (PrP90-231(TOX)) after controlled thermal denaturation (1 h at 53 °C) acquiring structural characteristics identified in PrP(Sc) (enrichment in β-structures, increased hydrophobicity, partial resistance to proteinase K, and aggregation in amyloid fibrils). By annexin-V binding assay, and evaluation of the percentage of fragmented and condensed nuclei, we show that treatment with PrP90-231(TOX), used in pre-fibrillar aggregation state, induces CGN apoptosis. This effect was associated with a delayed, but sustained elevation of [Ca(2+)]i. Both CGN apoptosis and [Ca(2+)]i increase were not observed using PrP90-231 in PrP(C)-like conformation. PrP90-231(TOX) effects were significantly reduced in the presence of ionotropic glutamate receptor antagonists. In particular, CGN apoptosis and [Ca(2+)]i increase were largely reduced, although not fully abolished, by pre-treatment with the NMDA antagonists APV and memantine, while the AMPA antagonist CNQX produced a lower, although still significant, effect. In conclusion, we report that CGN apoptosis induced by PrP90-231(TOX) correlates with a sustained elevation of [Ca(2+)]i mediated by the activation of NMDA and AMPA receptors.

Chronic administration of the anabolic androgenic steroid nandrolone alters neurosteroid action at the sigma-1 receptor but not at the sigma-2 or NMDA receptors.

PubMed

Elfverson, Martin; Johansson, Tobias; Zhou, Qin; Le Grevès, Pierre; Nyberg, Fred

2011-12-01

Studies have shown that anabolic androgenic steroids (AASs) can induce profound changes to mental health. Commonly reported psychiatric side effects among AAS users include aggression, anxiety, depression, drug abuse and cognitive disabilities. In experimental animals, many of these effects have been associated with alterations in a number of neurotransmitter systems. We have observed that chronic administration of the AAS nandrolone (nandrolone decanoate) can affect excitatory amino acids as well as monoaminergic and peptidergic pathways in a way that is compatible with nandrolone-induced behavioural changes. The aim of the present work was to further explore the mechanisms underlying nandrolone-induced effects, with a particular focus on components known to be involved in aggression and cognitive function. Male rats were given daily injections of nandrolone decanoate for 14 days and the effects on neurosteroid interactions with sites on the N-methyl-D-aspartyl (NMDA) and sigma receptors were examined. These receptors were chosen because of their involvement in aggressive and cognitive behaviors and the hypothesis that nandrolone might affect the brain via interaction with neurosteroids. Radiolabelled [³H]ifenprodil was used in the binding studies because of its significant affinity for the NMDA and sigma receptors. The results indicated that [³H]ifenprodil binds to both sigma-1 and sigma-2 sites and can be displaced to a certain extent from both sites by the neurosteroids pregnenolone sulphate (PS), pregnanolone sulphate (3α5βS) and dehydroepiandrosterone sulphate (DHEAS). The remainder of the [³H]ifenprodil was displaced from the sigma-1 site by the sigma-1 receptor-selective ligand (+)-SKF 10,047. Chronic nandrolone treatment changed the sigma-1 receptor target for the neurosteroids but not for ifenprodil. The sigma-2 receptor site was unaltered by treatment with nandrolone decanoate. The results also indicated that the neurosteroid-induced allosteric

Temporal and regional alterations in NMDA receptor expression in Mecp2-null mice

PubMed Central

Blue, Mary E.; Kaufmann, Walter E.; Bressler, Joseph; Eyring, Charlotte; O’Driscoll, Cliona; Naidu, SakkuBai; Johnston, Michael V.

2014-01-01

Our previous postmortem study of girls with Rett Syndrome (RTT), a development disorder caused by MECP2 mutations, found increases in the density of NMDA receptors in the prefrontal cortex of 2–8 year-old girls, while girls older than 10 years had reductions in NMDA receptors compared to age matched controls (Blue et al., 1999b). Using [3H]-CGP to label NMDA type glutamate receptors in 2 and 7 week old wildtype (WT), Mecp2-null and Mecp2-heterozygous (HET) mice (Bird model), we found that frontal areas of the brain also exhibited a bimodal pattern in NMDA expression, with increased densities of NMDA receptors in Mecp2-null mice at 2 weeks of age, but decreased densities at 7 weeks of age. Visual cortex showed a similar pattern, while other cortical regions only exhibited changes in NMDA receptor densities at 2 weeks (retrosplenial granular) or 7 weeks (somatosensory). In thalamus of null mice, NMDA receptors were increased at 2 and 7 weeks. No significant differences in density were found between HET and WT mice at both ages. Western blots for NMDAR1 expression in frontal brain showed higher levels of expression in Mecp2-null mice at two weeks of age, but not at 1 or 7 weeks of age. Our mouse data support the notion that deficient MeCP2 function is the primary cause of the NMDA receptor changes we observed in RTT. Furthermore, the findings of regional and temporal differences in NMDA expression illustrate the importance of age and brain region in evaluating different genotypes of mice. PMID:21901842

NMDA receptor gating of information flow through the striatum in vivo.

PubMed

Pomata, Pablo E; Belluscio, Mariano A; Riquelme, Luis A; Murer, M Gustavo

2008-12-10

A role of NMDA receptors in corticostriatal synaptic plasticity is widely acknowledged. However, the conditions that allow NMDA receptor activation in the striatum in vivo remain obscure. Here we show that NMDA receptors contribute to sustain the membrane potential of striatal medium spiny projection neurons close to threshold during spontaneous UP states in vivo. Moreover, we found that the blockade of striatal NMDA receptors reduces markedly the spontaneous firing of ensembles of medium spiny neurons during slow waves in urethane-anesthetized rats. We speculate that recurrent activation of NMDA receptors during UP states allows off-line information flow through the striatum and system level consolidation during habit formation.

G protein‐coupled receptor 37‐like 1 modulates astrocyte glutamate transporters and neuronal NMDA receptors and is neuroprotective in ischemia

PubMed Central

Jolly, Sarah; Bazargani, Narges; Quiroga, Alejandra C.; Pringle, Nigel P.

2017-01-01

Abstract We show that the G protein‐coupled receptor GPR37‐like 1 (GPR37L1) is expressed in most astrocytes and some oligodendrocyte precursors in the mouse central nervous system. This contrasts with GPR37, which is mainly in mature oligodendrocytes. Comparison of wild type and Gpr37l1–/– mice showed that loss of GPR37L1 did not affect the input resistance or resting potential of astrocytes or neurons in the hippocampus. However, GPR37L1‐mediated signalling inhibited astrocyte glutamate transporters and – surprisingly, given its lack of expression in neurons – reduced neuronal NMDA receptor (NMDAR) activity during prolonged activation of the receptors as occurs in ischemia. This effect on NMDAR signalling was not mediated by a change in the release of D‐serine or TNF‐α, two astrocyte‐derived agents known to modulate NMDAR function. After middle cerebral artery occlusion, Gpr37l1 expression was increased around the lesion. Neuronal death was increased by ∼40% in Gpr37l1–/– brain compared to wild type in an in vitro model of ischemia. Thus, GPR37L1 protects neurons during ischemia, presumably by modulating extracellular glutamate concentration and NMDAR activation. PMID:28795439

Cross-talk between an activator of nuclear receptors-mediated transcription and the D1 dopamine receptor signaling pathway.

PubMed

Schmidt, Azriel; Vogel, Robert; Rutledge, Su Jane; Opas, Evan E; Rodan, Gideon A; Friedman, Eitan

2005-03-01

Nuclear receptors are transcription factors that usually interact, in a ligand-dependent manner, with specific DNA sequences located within promoters of target genes. The nuclear receptors can also be controlled in a ligand-independent manner via the action of membrane receptors and cellular signaling pathways. 5-Tetradecyloxy-2-furancarboxylic acid (TOFA) was shown to stimulate transcription from the MMTV promoter via chimeric receptors that consist of the DNA binding domain of GR and the ligand binding regions of the PPARbeta or LXRbeta nuclear receptors (GR/PPARbeta and GR/LXRbeta). TOFA and hydroxycholesterols also modulate transcription from NF-kappaB- and AP-1-controlled reporter genes and induce neurite differentiation in PC12 cells. In CV-1 cells that express D(1) dopamine receptors, D(1) dopamine receptor stimulation was found to inhibit TOFA-stimulated transcription from the MMTV promoter that is under the control of chimeric GR/PPARbeta and GR/LXRbeta receptors. Treatment with the D(1) dopamine receptor antagonist, SCH23390, prevented dopamine-mediated suppression of transcription, and by itself increased transcription controlled by GR/LXRbeta. Furthermore, combined treatment of CV-1 cells with TOFA and SCH23390 increased transcription controlled by the GR/LXRbeta chimeric receptor synergistically. The significance of this in vitro synergy was demonstrated in vivo, by the observation that SCH23390 (but not haloperidol)-mediated catalepsy in rats was potentiated by TOFA, thus showing that an agent that mimics the in vitro activities of compounds that activate members of the LXR and PPAR receptor families can influence D1 dopamine receptor elicited responses.

Relationship between ketamine-induced developmental neurotoxicity and NMDA receptor-mediated calcium influx in neural stem cell-derived neurons.

PubMed

Wang, Cheng; Liu, Fang; Patterson, Tucker A; Paule, Merle G; Slikker, William

2017-05-01

Ketamine, a noncompetitive NMDA receptor antagonist, is used as a general anesthetic and recent data suggest that general anesthetics can cause neuronal damage when exposure occurs during early brain development. To elucidate the underlying mechanisms associated with ketamine-induced neurotoxicity, stem cell-derived models, such as rodent neural stem cells harvested from rat fetuses and/or neural stem cells derived from human induced pluripotent stem cells (iPSC) can be utilized. Prolonged exposure of rodent neural stem cells to clinically-relevant concentrations of ketamine resulted in elevated NMDA receptor levels as indicated by NR1subunit over-expression in neurons. This was associated with enhanced damage in neurons. In contrast, the viability and proliferation rate of undifferentiated neural stem cells were not significantly affected after ketamine exposure. Calcium imaging data indicated that 50μM NMDA did not cause a significant influx of calcium in typical undifferentiated neural stem cells; however, it did produce an immediate elevation of intracellular free Ca 2+ [Ca 2+ ] i in differentiated neurons derived from the same neural stem cells. This paper reviews the literature on this subject and previous findings suggest that prolonged exposure of developing neurons to ketamine produces an increase in NMDA receptor expression (compensatory up-regulation) which allows for a higher/toxic influx of calcium into neurons once ketamine is removed from the system, leading to neuronal cell death likely due to elevated reactive oxygen species generation. The absence of functional NMDA receptors in cultured neural stem cells likely explains why clinically-relevant concentrations of ketamine did not affect undifferentiated neural stem cell viability. Published by Elsevier B.V.

The NMDA receptor NR2A subunit regulates proliferation of MKN45 human gastric cancer cells

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

Watanabe, Kanako; Department of Anesthesiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501; Kanno, Takeshi

2008-03-07

The present study investigated proliferation of MKN28 and MKN45 human gastric cancer cells regulated by the N-methyl-D-aspartate (NMDA) receptor subunit. The NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (AP5) inhibited proliferation of MKN45 cells, but not MKN28 cells. Of the NMDA subunits such as NR1, NR2 (2A, 2B, 2C, and 2D), and NR3 (3A and 3B), all the NMDA subunit mRNAs except for the NR2B subunit mRNA were expressed in both MKN28 and MKN45 cells. MKN45 cells were characterized by higher expression of the NR2A subunit mRNA and lower expression of the NR1 subunit mRNA, but MKN28 otherwise by higher expression ofmore » the NR1 subunit mRNA and lower expression of the NR2A subunit mRNA. MKN45 cell proliferation was also inhibited by silencing the NR2A subunit-targeted gene. For MKN45 cells, AP5 or knocking-down the NR2A subunit increased the proportion of cells in the G{sub 1} phase of cell cycling and decreased the proportion in the S/G{sub 2} phase. The results of the present study, thus, suggest that blockage of NMDA receptors including the NR2A subunit suppresses MKN45 cell proliferation due to cell cycle arrest at the G{sub 1} phase; in other words, the NR2A subunit promotes MKN45 cell proliferation by accelerating cell cycling.« less

NMDA Receptor Antagonism Impairs Reversal Learning in Developing Rats

PubMed Central

Chadman, Kathryn K.; Watson, Deborah J.; Stanton, Mark E.

2014-01-01

Four experiments examined the effect of dizocilpine maleate (MK-801), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, on reversal learning during development. On postnatal days (PND) 21, 26, or 30, rats were trained on spatial discrimination and reversal in a T-maze. When MK-801 was administered (intraperitoneally) before both acquisition and reversal, 0.18 mg/kg generally impaired performance, whereas doses of 0.06 mg/kg and 0.10 mg/kg, but not 0.03 mg/kg, selectively impaired reversal learning (Experiments 1 and 3). The selective effect on reversal was not a result of sensitization to the second dose of MK-801 (Experiment 2) and was observed when the drug was administered only during reversal in an experiment addressing state-dependent learning (Experiment 4). Spatial reversal learning is more sensitive to NMDA-receptor antagonism than is acquisition. No age differences in sensitivity to MK-801 were found between PND 21 and 30. PMID:17014258

NMDA receptor antagonists attenuate the proconvulsant effect of juvenile social isolation in male mice.

PubMed

Amiri, Shayan; Haj-Mirzaian, Arya; Amini-khoei, Hossein; Momeny, Majid; Shirzadian, Armin; Rahimi-Balaei, Maryam; Zarrinrad, Ghazaleh; Ghazi-Khansari, Mahmoud; Azizi, Romina; Dehpour, Ahmad Reza; Mehr, Shahram Ejtemaei

2016-03-01

Experiencing psychosocial stress in early life, such as social isolation stress (SIS), is known to have negative enduring effects on the development of the brain and behavior. In addition to anxiety and depressive-like behaviors, we previously showed that juvenile SIS increases susceptibility to pentylenetetrazole (PTZ)-induced seizures in mice through enhancing the nitrergic system activity in the hippocampus. In this study, we investigated the possible involvement of N-methyl-D-aspartate (NMDA) receptors in proconvulsant effects of juvenile SIS. Applying 4 weeks of SIS to juvenile male mice at postnatal day 21-23, we observed an increased susceptibility to PTZ as well as anxiety and depressive-like behaviors in adult mice. Intraperitoneal (i.p.) administration of NMDA receptor antagonists, MK-801 (0.05 mg/kg) and ketamine (0.5mg/kg), reversed the proconvulsant effects of SIS in Isolated (and not social) housed animals. Co-administration of non-effective doses of nitric oxide synthase (NOS) inhibitors, 7NI (25mg/kg) and L-NAME (10mg/kg), with NMDA receptor antagonists, MK-801 (0.01 mg/kg) and ketamine (0.1mg/kg) attenuated the proconvulsant effects of juvenile SIS only in isolated housed mice. Also, using real time RT-PCR, we showed that hippocampal upregulation of NR2B subunit of NMDA receptor may play a critical role in proconvulsant effects of juvenile SIS by dysregulation of NMDA/NO pathway. In conclusion, results of present study revealed that experiencing SIS during adolescence predisposes the co-occurrence of seizure disorders with psychiatric comorbidities and also, alteration of NMDA receptor structure and function in hippocampus plays a role in proconvulsant effects of juvenile SIS through enhancing the NMDA/NO pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

Potentiation of GluN2C/D NMDA receptor subtypes in the amygdala facilitates the retention of fear and extinction learning in mice.

PubMed

Ogden, Kevin K; Khatri, Alpa; Traynelis, Stephen F; Heldt, Scott A

2014-02-01

NMDA receptors are glutamate receptor ion channels that contribute to synaptic plasticity and are important for many forms of learning and memory. In the amygdala, NMDA receptors are critical for the acquisition, retention, and extinction of classically conditioned fear responses. Although the GluN2B subunit has been implicated in both the acquisition and extinction of conditioned fear, GluN2C-knockout mice show reduced conditioned fear responses. Moreover, D-cycloserine (DCS), which facilitates fear extinction, selectively enhances the activity of GluN2C-containing NMDA receptors. To further define the contribution of GluN2C receptors to fear learning, we infused the GluN2C/GluN2D-selective potentiator CIQ bilaterally into the basolateral amygdala (3, 10, or 30 μg/side) following either fear conditioning or fear extinction training. CIQ both increased the expression of conditioned fear 24 h later and enhanced the extinction of the previously conditioned fear response. These results support a critical role for GluN2C receptors in the amygdala in the consolidation of learned fear responses and suggest that increased activity of GluN2C receptors may underlie the therapeutic actions of DCS.

Acute Ethanol Exposure Prevents PMA-mediated Augmentation of N-methyl-d-aspartate Receptor Function in Primary Cultured Cerebellar Granule Cells

PubMed Central

Reneau, Jason; Reyland, Mary E.; Popp, R. Lisa

2011-01-01

Many intracellular proteins and signaling cascades contribute to the ethanol sensitivity of native N-methyl-d-aspartate receptors (NMDARs). One putative protein is the serine / threonine kinase, Protein kinase C (PKC). The purpose of this study was to assess if PKC modulates the ethanol sensitivity of native NMDARs expressed in primary cultured cerebellar granule cells (CGCs). With the whole-cell patch-clamp technique, we assessed if ethanol inhibition of NMDA-induced currents (INMDA) (100 μM NMDA plus 10 μM glycine) were altered in CGCs in which the novel and classical PKC isoforms were activated by phorbol-12-myristate-13-acetate (PMA). Percent inhibition by 10, 50 or 100 mM ethanol of NMDA-induced steady-state (ISS) or peak current amplitudes (IPk) of NMDARs expressed in CGCs in which PKC was activated by a 12.5 min, 100 nM PMA exposure at 37° C did not differ from currents obtained from receptors contained in control cells. However, PMA-mediated augmentation of IPk in the absence of ethanol was abolished after brief applications of 10 or 1 mM ethanol co-applied with agonists, and this suppression of enhanced receptor function was observed for up to eight minutes post-ethanol exposure. Because we had previously shown that PMA-mediated augmentation of INMDA of NMDARs expressed in these cells is by activation of PKCα, we assessed the effect of ethanol (1, 10, 50 and 100 mM) on PKCα activity. Ethanol decreased PKCα activity by 18% for 1 mM ethanol and activity decreased with increasing ethanol concentrations with a 50% inhibition observed with 100 mM ethanol. The data suggest that ethanol disruption of PMA-mediated augmentation of INMDA may be due to a decrease in PKCα activity by ethanol. However, given the incomplete blockade of PKCα activity and the low concentration of ethanol at which this phenomenon is observed, other ethanol-sensitive signaling cascades must also be involved. PMID:21624785

Cocaine Disrupts Histamine H3 Receptor Modulation of Dopamine D1 Receptor Signaling: σ1-D1-H3 Receptor Complexes as Key Targets for Reducing Cocaine's Effects

PubMed Central

Moreno, Estefanía; Moreno-Delgado, David; Navarro, Gemma; Hoffmann, Hanne M.; Fuentes, Silvia; Rosell-Vilar, Santi; Gasperini, Paola; Rodríguez-Ruiz, Mar; Medrano, Mireia; Mallol, Josefa; Cortés, Antoni; Casadó, Vicent; Lluís, Carme; Ferré, Sergi; Ortiz, Jordi; Canela, Enric

2014-01-01

The general effects of cocaine are not well understood at the molecular level. What is known is that the dopamine D1 receptor plays an important role. Here we show that a key mechanism may be cocaine's blockade of the histamine H3 receptor-mediated inhibition of D1 receptor function. This blockade requires the σ1 receptor and occurs upon cocaine binding to σ1-D1-H3 receptor complexes. The cocaine-mediated disruption leaves an uninhibited D1 receptor that activates Gs, freely recruits β-arrestin, increases p-ERK 1/2 levels, and induces cell death when over activated. Using in vitro assays with transfected cells and in ex vivo experiments using both rats acutely treated or self-administered with cocaine along with mice depleted of σ1 receptor, we show that blockade of σ1 receptor by an antagonist restores the protective H3 receptor-mediated brake on D1 receptor signaling and prevents the cell death from elevated D1 receptor signaling. These findings suggest that a combination therapy of σ1R antagonists with H3 receptor agonists could serve to reduce some effects of cocaine. PMID:24599455

Schizophrenia, dissociative anaesthesia and near-death experience; three events meeting at the NMDA receptor.

PubMed

Bonta, Iván L

2004-01-01

The three events, viz. schizophrenia, dissociative anaesthesia and Near-Death Experience, despite their seemingly unrelated manifestation to each other, have nevertheless similar functional basis. All three events are linked to the glutamate sensitive N-methyl-D-aspartate (NMDA) receptor complex, which serves as their common functional denominator. Arguments and speculations are presented in favor of the view that, the three events might be considered as functional models of each other. Antagonism to the recognition NMDA-site of the receptor induces dissociative anaesthesia and precipitates Near-Death Experience. Agonist reinforcement at the modulatory glycine-site of the receptor counteracts negative symptoms of schizophrenia. Both types of challenges towards the receptor are compatible with a glutamate deficiency concept which underlies the meeting of the three events at the NMDA receptor.

Timosaponin derivative YY-23 acts as a non-competitive NMDA receptor antagonist and exerts a rapid antidepressant-like effect in mice.

PubMed

Zhang, Qi; Guo, Fei; Fu, Zhi-wen; Zhang, Bing; Huang, Cheng-gang; Li, Yang

2016-02-01

N-methyl-D-aspartic acid (NMDA) receptor modulators have shown promising results as potential antidepressant agents, whereas timosaponins extracted from the Chinese herb Rhizoma Anemarrhenae exhibit antidepressant activities. In the present study we examined whether YY-23, a modified metabolite of timosaponin B-III, could affect NMDA receptors in rat hippocampal neurons in vitro, and evaluated its antidepressant-like effects in stressed mice. NMDA-induced currents were recorded in acutely dissociated rat hippocampal CA1 neurons using a whole-cell recording technique. C57BL/6 mice were exposed to a 6-week chronic mild stress (CMS) or a 10-d chronic social defeat stress (CSDS). The stressed mice were treated with YY-23 (20 mg·kg(-1)·d(-1)) or a positive-control drug, fluoxetine (10 mg·kg(-1)·d(-1)) for 3 weeks. Behavioral assessments were carried out every week. In acutely dissociated rat hippocampal CA1 neurons, YY-23 selectively and reversibly inhibited NMDA-induced currents with an EC50 value of 2.8 μmol/L. This inhibition of NMDA-induced currents by YY-23 was non-competitive, and had no features of voltage-dependency or use-dependency. Treatment of the stressed mice with YY-23 not only reversed CMS-induced deficiency of sucrose preference and immobility time, and CSDS-induced reduction of social interaction, but also had faster onset as compared to fluoxetine. YY-23 is a novel non-competitive antagonist of NMDA receptors with promising rapid antidepressant-like effects in mouse models of CMS and CSDS depression.

Anti-NMDA Receptor Encephalitis in the Polar Bear (Ursus maritimus) Knut.

PubMed

Prüss, H; Leubner, J; Wenke, N K; Czirják, G Á; Szentiks, C A; Greenwood, A D

2015-08-27

Knut the polar bear of the Berlin Zoological Garden drowned in 2011 following seizures and was diagnosed as having suffered encephalitis of unknown etiology after exhaustive pathogen screening. Using the diagnostic criteria applied to human patients, we demonstrate that Knut's encephalitis is almost identical to anti-NMDA receptor encephalitis which is a severe autoimmune disease representing the most common non-infectious encephalitis in humans. High concentrations of antibodies specific against the NR1 subunit of the NMDA receptor were detected in Knut's cerebrospinal fluid. Histological examination demonstrated very similar patterns of plasma cell infiltration and minimal neuronal loss in affected brain areas. We conclude that Knut suffered anti-NMDA receptor encephalitis making his the first reported non-human case of this treatable disease. The results suggest that anti-NMDA receptor encephalitis may be a disease of broad relevance to mammals that until now has remained undiagnosed.

MDMA-induced loss of parvalbumin interneurons within the dentate gyrus is mediated by 5HT2A and NMDA receptors

PubMed Central

Collins, Stuart A.; Gudelsky, Gary A.; Yamamoto, Bryan K.

2015-01-01

MDMA is a widely abused psychostimulant which causes a rapid and robust release of the monoaminergic neurotransmitters dopamine and serotonin. Recently, it was shown that MDMA increases extracellular glutamate concentrations in the dorsal hippocampus, which is dependent on serotonin release and 5HT2A/2C receptor activation. The increased extracellular glutamate concentration coincides with a loss of parvalbumin-immunoreactive (PV-IR) interneurons of the dentate gyrus region. Given the known susceptibility of PV interneurons to excitotoxicity, we examined whether MDMA-induced increases in extracellular glutamate in the dentate gyrus are necessary for the loss of PV cells in rats. Extracellular glutamate concentrations increased in the dentate gyrus during systemic and local administration of MDMA. Administration of the NMDA receptor antagonist, MK-801, during systemic injections of MDMA, prevented the loss of PV-IR interneurons seen 10 days after MDMA exposure. Local administration of MDL100907, a selective 5HT2A receptor antagonist, prevented the increases in glutamate caused by reverse dialysis of MDMA directly into the dentate gyrus and prevented the reduction of PV-IR. These findings provide evidence that MDMA causes decreases in PV within the dentate gyrus through a 5HT2A receptor-mediated increase in glutamate and subsequent NMDA receptor activation. PMID:25936514

NMDA Receptor as a Newly Identified Member of the Metabotropic Glutamate Receptor Family: Clinical Implications for Neurodegenerative Diseases

PubMed Central

Chung, ChiHye

2013-01-01

Recent reports have proposed a novel function for the N-methyl-d-aspartate (NMDA) receptor (NMDAR), a well-known excitatory, ionotropic receptor. A series of observations employing pharmacological techniques has proposed that upon ligand binding, this ionotropic receptor can actually function via signaling cascades independent of traditional ionotropic action. Moreover, the “metabotropic” action of NMDARs is suggested to mediate a form of synaptic plasticity, namely long-term synaptic depression (LTD), which shares cellular mechanisms with the synaptic deficits observed in Alzheimer’s disease. Given that a growing body of clinical and preclinical evidence strongly recommends NMDAR antagonists for their therapeutic potentials and advantages in a variety of diseases, further investigation into their molecular and cellular mechanisms is required to better understand the “metabotropic” action of NMDARs. PMID:23740429

Fluoxetine reverses the behavioral despair induced by neurogenic stress in mice: role of N-methyl-d-aspartate and opioid receptors.

PubMed

Haj-Mirzaian, Arya; Kordjazy, Nastaran; Ostadhadi, Sattar; Amiri, Shayan; Haj-Mirzaian, Arvin; Dehpour, AhmadReza

2016-06-01

Opioid and N-methyl-d-aspartate (NMDA) receptors mediate different effects of fluoxetine. We investigated whether opioid and NMDA receptors are involved in the protective effect of fluoxetine against the behavioral despair induced by acute physical stress in male mice. We used the forced swimming test (FST), tail suspension test (TST), and open-field test (OFT) for behavioral evaluation. We used fluoxetine, naltrexone (opioid receptor antagonist), MK-801 (NMDA receptor antagonist), morphine (opioid receptor agonist), and NMDA (NMDA receptor agonist). Acute foot-shock stress (FSS) significantly induced behavioral despair (depressive-like) and anxiety-like behaviors in tests. Fluoxetine (5 mg/kg) reversed the depressant-like effect of FSS, but it did not alter the locomotion and anxiety-like behavior in animals. Acute administration of subeffective doses of naltrexone (0.3 mg/kg) or MK-801 (0.01 mg/kg) potentiated the antidepressant-like effect of fluoxetine, while subeffective doses of morphine (1 mg/kg) and NMDA (75 mg/kg) abolished this effect of fluoxetine. Also, co-administration of subeffective doses of naltrexone (0.05 mg/kg) and MK-801 (0.003 mg/kg) with fluoxetine (1 mg/kg) induced a significant decrease in the immobility time in FST and TST. Our results showed that opioid and NMDA receptors (alone or in combination) are involved in the antidepressant-like effect of fluoxetine against physical stress.

GluN2C/GluN2D subunit-selective NMDA receptor potentiator CIQ reverses MK-801-induced impairment in prepulse inhibition and working memory in Y-maze test in mice

PubMed Central

Suryavanshi, P S; Ugale, R R; Yilmazer-Hanke, D; Stairs, D J; Dravid, S M

2014-01-01

Background and Purpose Despite ample evidence supporting the N-methyl-d-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia, progress in the development of effective therapeutics based on this hypothesis has been limited. Facilitation of NMDA receptor function by co-agonists (d-serine or glycine) only partially alleviates the symptoms in schizophrenia; other means to facilitate NMDA receptors are required. NMDA receptor sub-types differ in their subunit composition, with varied GluN2 subunits (GluN2A-GluN2D) imparting different physiological, biochemical and pharmacological properties. CIQ is a positive allosteric modulator that is selective for GluN2C/GluN2D-containing NMDA receptors (Mullasseril et al.). Experimental Approach The effect of systemic administration of CIQ was tested on impairment in prepulse inhibition (PPI), hyperlocomotion and stereotypy induced by i.p. administration of MK-801 and methamphetamine. The effect of CIQ was also tested on MK-801-induced impairment in working memory in Y-maze spontaneous alternation test. Key Results We found that systemic administration of CIQ (20 mg·kg−1, i.p.) in mice reversed MK-801 (0.15 mg·kg−1, i.p.)-induced, but not methamphetamine (3 mg·kg−1, i.p.)-induced, deficit in PPI. MK-801 increased the startle amplitude to pulse alone, which was not reversed by CIQ. In contrast, methamphetamine reduced the startle amplitude to pulse alone, which was reversed by CIQ. CIQ also partially attenuated MK-801- and methamphetamine-induced hyperlocomotion and stereotyped behaviours. Additionally, CIQ reversed the MK-801-induced working memory deficit in spontaneous alternation in a Y-maze. Conclusion and Implications Together, these results suggest that facilitation of GluN2C/GluN2D-containing receptors may serve as an important therapeutic strategy for treating positive and cognitive symptoms in schizophrenia. PMID:24236947

Involvement of NMDA receptors in the antidepressant-like effect of tramadol in the mouse forced swimming test.

PubMed

Ostadhadi, Sattar; Norouzi-Javidan, Abbas; Chamanara, Mohsen; Akbarian, Reyhaneh; Imran-Khan, Muhammad; Ghasemi, Mehdi; Dehpour, Ahmad-Reza

2017-09-01

Tramadol is an analgesic agent that is mainly used to treat moderate to severe pain. There is evidence that tramadol may have antidepressant property. However, the mechanisms underlying the antidepressant effects of tramadol have not been elucidated yet. Considering that fact that N-methyl-d-aspartate (NMDA) receptor signaling may play an important role in the pathophysiology of depression, the aim of the present study was to investigate the role of NMDA receptor signaling in the possible antidepressant-like effects of tramadol in the mouse forced swimming test (mFST). We found that tramadol exerted antidepressant-like effects at high dose (40mg/kg, intraperitoneally [i.p.]) in the mFST. Co-administration of non-effective doses of NMDA receptor antagonists (ketamine [1mg/kg, i.p.], MK-801 [0.05mg/kg, i.p.], or magnesium sulfate [10mg/kg, i.p.]) with sub-effective dose of tramadol (20mg/kg, i.p.) exerted significant antidepressant-like effects in the mFST. The antidepressant-like effects of tramadol (40mg/kg) was also inhibited by pre-treatment with non-effective dose of the NMDA receptor agonist NMDA (75mg/kg, i.p.). Our data suggest a role for NMDA receptor signaling in the antidepressant-like effects of tramadol in the mFST. Copyright © 2017 Elsevier Inc. All rights reserved.

Involvement of ERK in NMDA receptor-independent cortical neurotoxicity of hydrogen sulfide

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

Kurokawa, Yuko; Sekiguchi, Fumiko; Kubo, Satoko

2011-11-04

Highlights: Black-Right-Pointing-Pointer Hydrogen sulfide causes NMDA receptor-independent neurotoxicity in mouse fetal cortical neurons. Black-Right-Pointing-Pointer Activation of ERK mediates the toxicity of hydrogen sulfide. Black-Right-Pointing-Pointer Apoptotic mechanisms are involved in the hydrogen-induced cell death. -- Abstract: Hydrogen sulfide (H{sub 2}S), a gasotransmitter, exerts both neurotoxicity and neuroprotection, and targets multiple molecules including NMDA receptors, T-type calcium channels and NO synthase (NOS) that might affect neuronal viability. Here, we determined and characterized effects of NaHS, an H{sub 2}S donor, on cell viability in the primary cultures of mouse fetal cortical neurons. NaHS caused neuronal death, as assessed by LDH release and trypanmore » blue staining, but did not significantly reduce the glutamate toxicity. The neurotoxicity of NaHS was resistant to inhibitors of NMDA receptors, T-type calcium channels and NOS, and was blocked by inhibitors of MEK, but not JNK, p38 MAP kinase, PKC and Src. NaHS caused prompt phosphorylation of ERK and upregulation of Bad, followed by translocation of Bax to mitochondria and release of mitochondrial cytochrome c, leading to the nuclear condensation/fragmentation. These effects of NaHS were suppressed by the MEK inhibitor. Our data suggest that the NMDA receptor-independent neurotoxicity of H{sub 2}S involves activation of the MEK/ERK pathway and some apoptotic mechanisms.« less

NMDA receptor content of synapses in stratum radiatum of the hippocampal CA1 area.

PubMed

Racca, C; Stephenson, F A; Streit, P; Roberts, J D; Somogyi, P

2000-04-01

Glutamate receptors activated by NMDA (NMDARs) or AMPA (AMPARs) are clustered on dendritic spines of pyramidal cells. Both the AMPAR-mediated postsynaptic responses and the synaptic AMPAR immunoreactivity show a large intersynapse variability. Postsynaptic responses mediated by NMDARs show less variability. To assess the variability in NMDAR content and the extent of their coexistence with AMPARs in Schaffer collateral-commissural synapses of adult rat CA1 pyramidal cells, electron microscopic immunogold localization of receptors has been used. Immunoreactivity of NMDARs was detected in virtually all synapses on spines, but AMPARs were undetectable, on average, in 12% of synapses. A proportion of synapses had a very high AMPAR content relative to the mean content, resulting in a distribution more skewed toward larger values than that of NMDARs. The variability of synaptic NMDAR content [coefficient of variation (CV), 0.64-0.70] was much lower than that of the AMPAR content (CV, 1.17-1.45). Unlike the AMPAR content, the NMDAR content showed only a weak correlation with synapse size. As reported previously for AMPARs, the immunoreactivity of NMDARs was also associated with the spine apparatus within spines. The results demonstrate that the majority of the synapses made by CA3 pyramidal cells onto spines of CA1 pyramids express both NMDARs and AMPARs, but with variable ratios. A less-variable NMDAR content is accompanied by a wide variability of AMPAR content, indicating that the regulation of expression of the two receptors is not closely linked. These findings support reports that fast excitatory transmission at some of these synapses is mediated by activation mainly of NMDARs.

Metabotropic glutamate receptor 5 upregulates surface NMDA receptor expression in striatal neurons via CaMKII.

PubMed

Jin, Dao-Zhong; Xue, Bing; Mao, Li-Min; Wang, John Q

2015-10-22

Metabotropic and ionotropic glutamate receptors are closely clustered in postsynaptic membranes and are believed to interact actively with each other to control excitatory synaptic transmission. Metabotropic glutamate receptor 5 (mGluR5), for example, has been well documented to potentiate ionotropic NMDA receptor activity, although underlying mechanisms are poorly understood. In this study, we investigated the role of mGluR5 in regulating trafficking and subcellular distribution of NMDA receptors in adult rat striatal neurons. We found that the mGluR1/5 agonist DHPG concentration-dependently increased NMDA receptor GluN1 and GluN2B subunit expression in the surface membrane. Meanwhile, DHPG reduced GluN1 and GluN2B levels in the intracellular compartment. The effect of DHPG was blocked by an mGluR5 selective antagonist MTEP but not by an mGluR1 selective antagonist 3-MATIDA. Pretreatment with an inhibitor or a specific inhibitory peptide for synapse-enriched Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) also blocked the DHPG-stimulated redistribution of GluN1 and GluN2B. In addition, DHPG enhanced CaMKIIα activity and elevated GluN2B phosphorylation at a CaMKII-sensitive site (serine 1303). These results demonstrate that mGluR5 regulates trafficking of NMDA receptors in striatal neurons. Activation of mGluR5 appears to induce rapid trafficking of GluN1 and GluN2B to surface membranes through a signaling pathway involving CaMKII. Copyright © 2015 Elsevier B.V. All rights reserved.

Adenosine A2A receptors are required for glutamate mGluR5- and dopamine D1 receptor-evoked ERK1/2 phosphorylation in rat hippocampus: involvement of NMDA receptor.

PubMed

Krania, Paraskevi; Dimou, Eleni; Bantouna, Maria; Kouvaros, Stylianos; Tsiamaki, Eirini; Papatheodoropoulos, Costas; Sarantis, Konstantinos; Angelatou, Fevronia

2018-05-01

Interaction between mGluR5 and NMDA receptors (NMDAR) is vital for synaptic plasticity and cognition. We recently demonstrated that stimulation of mGluR5 enhances NMDAR responses in hippocampus by phosphorylating NR2B(Tyr1472) subunit, and this reaction was enabled by adenosine A 2A receptors (A 2A R) (J Neurochem, 135, 2015, 714). In this study, by using in vitro phosphorylation and western blot analysis in hippocampal slices of male Wistar rats, we show that mGluR5 stimulation or mGluR5/NMDARs co-stimulation synergistically activate ERK1/2 signaling leading to c-Fos expression. Interestingly, both reactions are under the permissive control of endogenous adenosine acting through A 2A Rs. Moreover, mGluR5-mediated ERK1/2 phosphorylation depends on NMDAR, which however exhibits a metabotropic way of function, since no ion influx through its ion channel is required. Furthermore, our results demonstrate that mGluR5 and mGluR5/NMDAR-evoked ERK1/2 activation correlates well with the mGluR5/NMDAR-evoked NR2B(Tyr1472) phosphorylation, since both phenomena coincide temporally, are Src dependent, and are both enabled by A 2A Rs. This indicates a functional involvement of NR2B(Tyr1472) phosphorylation in the ERK1/2 activation. Our biochemical results are supported by electrophysiological data showing that in CA1 region of hippocampus, the theta burst stimulation (TBS)-induced long-term potentiation coincides temporally with an increase in ERK1/2 activation and both phenomena are dependent on the tripartite A 2A , mGlu5, and NMDARs. Furthermore, we show that the dopamine D1 receptors evoked ERK1/2 activation as well as the NR2B(Tyr1472) phosphorylation are also regulated by endogenous adenosine and A 2A Rs. In conclusion, our results highlight the A 2A Rs as a crucial regulator not only for NMDAR responses, but also for regulating ERK1/2 signaling and its downstream pathways, leading to gene expression, synaptic plasticity, and memory consolidation. © 2017 International

Opiate physical dependence and N-methyl-D-aspartate receptors.

PubMed

Noda, Yukihiro; Nabeshima, Toshitaka

2004-10-01

The present review focused the involvement of N-methyl-D-aspartate (NMDA) receptors in morphine physical dependence. The increased levels of extracellular glutamate, NMDA receptor zeta subunit (NR1) mRNA, NMDA receptor epsilon 1 subunit (NR2A) protein, phosphorylated Ca(2+)/calmodulin kinase II (p-CaMKII) protein, c-fos mRNA, c-Fos protein, are observed in the specific brain areas of mice and/or rats showing signs of naloxone-precipitated withdrawal. In preclinical and clinical studies, a variety of NMDA receptor antagonists and pretreatment with an antisense oligonucleotide of the NR1 have been reported to inhibit the development, expression and/or maintenance of opiate physical dependence. In contrast to data obtained in adult animals, NMDA receptor antagonists are neither effective in blocking the development of opiate dependence nor the expression of opiate withdrawal in neonatal rats. In the NMDA receptor-deficient mice, the NR2A knockout mice show the marked loss of typical withdrawal abstinence behaviors precipitated by naloxone. The rescue of NR2A protein by electroporation into the nucleus accumbens of NR2A knockout mice reverses the loss of abstinence behaviors. The activation of CaMKII and increased expression of c-Fos protein in the brain of animals with naloxone-precipitated withdrawal syndrome are prevented by NMDA receptor antagonists, whereas the increased levels of extracellular glutamate are not prevented by them. These findings indicate that glutamatergic neurotransmission at the NMDA receptor site contributes to the development, expression and maintenance of opiate dependence, and suggest that NMDA receptor antagonists may be a useful adjunct in the treatment of opiate dependence.

Synthesis and characterization of a series of diarylguanidines that are noncompetitive N-methyl-D-aspartate receptor antagonists with neuroprotective properties

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

Keana, J.F.W.; McBurney, R.N.; Scherz, M.W.

1989-07-01

Four diarylguanidine derivatives were synthesized. These compounds were found to displace, at submicromolar concentrations, {sup 3}H-labeled 1-(1-(2-thienyl)cyclohexyl)piperidine and (+)-({sup 3}H)MK-801 from phencyclidine receptors in brain membrane preparations. In electrophysiological experiments the diarylguanidines blocked N-methyl-D-aspartate (NMDA)-activated ion channels. These dairylguanidines also protected rat hippocampal neurons in vitro from glutamate-induced cell death. The results show that some diarylguanidines are noncompetitive antagonists of NMDA receptor-mediated responses and have the neuroprotective property that is commonly associated with blockers of the NMDA receptor-gated cation channel. Diarylguanidines are structurally unrelated to known blockers of NMDA channels and, therefore, represent a new compound series for the developmentmore » of neuroprotective agents with therapeutic value in patients suffering from stroke, from brain or spinal cord trauma, from hypoglycemia, and possibly from brain ischemia due to heart attack.« less

Schizophrenia susceptibility and NMDA-receptor mediated signalling: an association study involving 32 tagSNPs of DAO, DAOA, PPP3CC, and DTNBP1 genes

PubMed Central

2013-01-01

Background Recent studies supported associations between four NMDA-receptor-mediated signalling genes (D-amino acid oxidase, DAO; D-amino acid oxidase activator, DAOA; protein phosphatase 3 catalytic subunit gamma isoform, PPP3CC; dystrobrevin-binding protein 1, DTNBP1) and schizophrenia susceptibility, even though with contrasting results. Methods In an attempt to replicate these findings for the first time in an Italian population, a panel of 32 tagSNPs was analysed in a representative case-control sample involving 879 subjects. Results An association in the allele frequency was observed for the estimated PPP3CC CAG triplotype in the SNP window rs4872499 T/C-rs11780915 A/G-rs13271367 G/A (pcorrect = 0.001). Similarly, the clustered genotype frequencies of the estimated/phased CAG triplotype differed between cases and controls (p = 0.004), with the carriers having a higher frequency in the control population (p = 0.002, odd ratio OR = 0.59, 95% confident interval CI: 0.43-0.82). Following the phenotypic dissection strategy, the analysis of single SNPs evidenced a protective effect in males of rs11780915 and rs13271367 in PPP3CC gene (pcorrect = 0.02, pcorrect = 0.04 respectively). Moreover the estimated/phased GT diplotype (rs2070586A/G-rs3741775G/T) carriers of the DAO gene were more highly represented in female controls (p = 0.017, OR = 0.58, 95% CI: 0.37-0.90), as were the estimated/phased CAG triplotype carriers of the PPP3CC gene in females (p = 0.01, OR = 0.53, 95% CI: 0.32-0.87). In addition, we performed an interaction analysis, and a 66% (p = 0.003, OR = 0.34, 95% CI: 0.17-0.70) lower risk of developing schizophrenia for female (CAG + GT) carriers versus non-CAG or -GT carriers was observed. For DTNBP1, we found a protective effect in males for the rs6459409 (pcorrect = 0.02) and the estimated/phased CT diplotype (rs6459409-rs9476886) carriers (p = 3x10-4, OR = 0.46, 95% CI: 0.30-0.70). In

Targeting of glycine site on NMDA receptor as a possible new strategy for autism treatment.

PubMed

Ghanizadeh, Ahmad

2011-05-01

The exact pathophysiology of the neurodevelopment disorder of autism is not clear and there is not any curative approach for it. There is only one FDA-approved medication for its management. Therefore, providing of novel treatments is highly required. The hypofunction of GABAergic system and glutamate toxicity are generally believed to have a causal role for autism. The antagonist of the N-methyl-D-aspartic acid (NMDA) glutamate receptor improves autism. Glycine is required for the activation of NMDA receptor. The antagonist of glycine site decreases NMDA receptor conductance. It is hypothesis that glycine site antagonists can be tested as a new strategy for the management of autism.

Dopamine receptor D5 deficiency results in a selective reduction of hippocampal NMDA receptor subunit NR2B expression and impaired memory.

PubMed

Moraga-Amaro, Rodrigo; González, Hugo; Ugalde, Valentina; Donoso-Ramos, Juan Pablo; Quintana-Donoso, Daisy; Lara, Marcelo; Morales, Bernardo; Rojas, Patricio; Pacheco, Rodrigo; Stehberg, Jimmy

2016-04-01

Pharmacological evidence associates type I dopamine receptors, including subtypes D1 and D5, with learning and memory. Analyses using genetic approaches have determined the relative contribution of dopamine receptor D1 (D1R) in cognitive tasks. However, the lack of drugs that can discriminate between D1R and D5R has made the pharmacological distinction between the two receptors difficult. Here, we aimed to determine the role of D5R in learning and memory. In this study we tested D5R knockout mice and wild-type littermates in a battery of behavioral tests, including memory, attention, locomotion, anxiety and motivational evaluations. Our results show that genetic deficiency of D5R significantly impairs performance in the Morris water maze paradigm, object location and object recognition memory, indicating a relevant role for D5R in spatial memory and recognition memory. Moreover, the lack of D5R resulted in decreased exploration and locomotion. In contrast, D5R deficiency had no impact on working memory, anxiety and depressive-like behavior, measured using the spontaneous alternation, open-field, tail suspension test, and forced swimming test. Electrophysiological analyses performed on hippocampal slices showed impairment in long-term-potentiation in mice lacking D5R. Further analyses at the molecular level showed that genetic deficiency of D5R results in a strong and selective reduction in the expression of the NMDA receptor subunit NR2B in the hippocampus. These findings demonstrate the relevant contribution of D5R in memory and suggest a functional interaction of D5R with hippocampal glutamatergic pathways. Copyright © 2015 Elsevier Ltd. All rights reserved.

Antidepressant effect of pramipexole in mice forced swimming test: A cross talk between dopamine receptor and NMDA/nitric oxide/cGMP pathway.

PubMed

Ostadhadi, Sattar; Imran Khan, Muhammad; Norouzi-Javidan, Abbas; Dehpour, Ahmad-Reza

2016-07-01

Pramipexole is a dopamine D2 receptor agonist indicated for treating Parkinson disorder. This study was aimed to investigate the effect of pramipexole in forced swimming test (FST) in mice and the possible involvement of activation of D2 receptors and inhibition of N-methyl-d-aspartate (NMDA) receptors and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) on this effect. Intraperitoneal administration of pramipexole (1-3mg/kg) reduced the immobility time in the FST similar to fluoxetine (20mg/kg, i.p.). This effect of pramipexole (1mg/kg, i.p.) was ceased when mice were pretreated with haloperidol (0.15mg/kg, i.p,) and sulpiride (5mg/kg, i.p) as D2 receptor antagonists, NMDA (75mg/kg,i.p.), l-arginine (750mg/kg, i.p., a substrate for nitric oxide synthase) or sildenafil (5mg/kg, i.p., a phosphodiesterase 5 inhibitor). The administration of MK-801 (0.05mg/kg, i.p., a NMDA receptor antagonist) l-NG-Nitro arginine methyl ester (l-NAME, 10mg/kg, i.p., a non-specific nitric oxide synthase (NOS) inhibitor), 7-nitroindazole (30mg/kg, i.p., a neuronal NOS inhibitor) and methylene blue (10mg/kg, i.p.), an inhibitor of both NOS and soluble guanylyl cyclase (sGC) in combination with the sub-effective dose of pramipexole (0.3mg/kg, i.p.) reduced the immobility. Altogether, our data suggest that the antidepressant-like effect of pramipexole is dependent on the activation of D2 receptor and inhibition of either NMDA receptors and/or NO-cGMP synthesis. These results contribute to the understanding of the mechanisms underlying the antidepressant-like effect of pramipexole and reinforce the role of D2 receptors, NMDA receptors and l-arginine-NO-GMP pathway in the antidepressant mechanism of this agent. Copyright © 2016. Published by Elsevier Masson SAS.

Spinal N-methyl-D-aspartate receptors and nociception-evoked release of primary afferent substance P.

PubMed

Nazarian, A; Gu, G; Gracias, N G; Wilkinson, K; Hua, X Y; Vasko, M R; Yaksh, T L

2008-03-03

Dorsal horn N-methyl-D-aspartate (NMDA) receptors contribute significantly to spinal nociceptive processing through an effect postsynaptic to non-primary glutamatergic axons, and perhaps presynaptic to the primary afferent terminals. The present study sought to examine the regulatory effects of NMDA receptors on primary afferent release of substance P (SP), as measured by neurokinin 1 receptor (NK1r) internalization in the spinal dorsal horn of rats. The effects of intrathecal NMDA alone or in combination with D-serine (a glycine site agonist) were initially examined on basal levels of NK1r internalization. NMDA alone or when co-administered with D-serine failed to induce NK1r internalization, whereas activation of spinal TRPV1 receptors by capsaicin resulted in a notable NK1r internalization. To determine whether NMDA receptor activation could potentiate NK1r internalization or pain behavior induced by a peripheral noxious stimulus, intrathecal NMDA was given prior to an intraplantar injection of formalin. NMDA did not alter the formalin-induced NK1r internalization nor did it enhance the formalin paw flinching behavior. To further characterize the effects of presynaptic NMDA receptors, the NMDA antagonists DL-2-amino-5-phosphonopentanoic acid (AP-5) and MK-801 were intrathecally administered to assess their regulatory effects on formalin-induced NK1r internalization and pain behavior. AP-5 had no effect on formalin-induced NK1r internalization, whereas MK-801 produced only a modest reduction. Both antagonists, however, reduced the formalin paw flinching behavior. In subsequent in vitro experiments, perfusion of NMDA in spinal cord slice preparations did not evoke basal release of SP or calcitonin gene-related peptide (CGRP). Likewise, perfusion of NMDA did not enhance capsaicin-evoked release of the two peptides. These results suggest that presynaptic NMDA receptors in the spinal cord play little if any role on the primary afferent release of SP.

Ethanol Inhibition of Recombinant NMDA Receptors Is Not Altered by Co-Expression of CaMKII-α or CaMKII-β

PubMed Central

Xu, Minfu; Chandler, L. Judson; Woodward, John J.

2008-01-01

Previous studies have shown that the N-methyl-D-aspartate (NMDA) receptor is an important target for the actions of ethanol in the brain. NMDA receptors are glutamate-activated ion channels that are highly expressed in neurons. They are activated during periods of significant glutamatergic synaptic activity and are an important source of the signaling molecule calcium in the post-synaptic spine. Alterations in the function of NMDA receptors by drugs or disease are associated with deficits in motor, sensory and cognitive processes of the brain. Acutely, ethanol inhibits ion flow through NMDA receptors while sustained exposure to ethanol can induce compensatory changes in the density and localization of the receptor. Defining factors that govern the acute ethanol sensitivity of NMDA receptors is an important step in how an individual responds to ethanol. In the present study, we investigated the effect of calcium-calmodulin dependent protein kinase II (CaMKII) on the ethanol sensitivity of recombinant NMDA receptors. CaMKII is a major constituent of the post-synaptic density and is critically involved in various forms of learning and memory. NMDA receptor subunits were transiently expressed in human embryonic kidney 293 cells (HEK 293) along with CaMKII-α or CaMKII-β tagged with the green fluorescent protein (GFP). Whole cell currents were elicited by brief exposures to glutamate and were measured using patchclamp electrophysiology. Neither CaMKII-α or CaMKII-β had any significant effect on the ethanol inhibition of NR1/2A or NR1/2B receptors. Ethanol inhibition was also unaltered by deletion of CaMKII binding domains in NR1 or NR2 subunits or by phospho-site mutants that mimic or occlude CaMKII phosphorylation. Chronic treatment of cortical neurons with ethanol had no significant effect on the expression of CaMKII-α or CaMKII-β. The results of this study suggest that CaMKII is not involved in regulating the acute ethanol sensitivity of NMDA receptors. PMID

MDMA-induced loss of parvalbumin interneurons within the dentate gyrus is mediated by 5HT2A and NMDA receptors.

PubMed

Collins, Stuart A; Gudelsky, Gary A; Yamamoto, Bryan K

2015-08-15

MDMA is a widely abused psychostimulant which causes a rapid and robust release of the monoaminergic neurotransmitters dopamine and serotonin. Recently, it was shown that MDMA increases extracellular glutamate concentrations in the dorsal hippocampus, which is dependent on serotonin release and 5HT2A/2C receptor activation. The increased extracellular glutamate concentration coincides with a loss of parvalbumin-immunoreactive (PV-IR) interneurons of the dentate gyrus region. Given the known susceptibility of PV interneurons to excitotoxicity, we examined whether MDMA-induced increases in extracellular glutamate in the dentate gyrus are necessary for the loss of PV cells in rats. Extracellular glutamate concentrations increased in the dentate gyrus during systemic and local administration of MDMA. Administration of the NMDA receptor antagonist, MK-801, during systemic injections of MDMA, prevented the loss of PV-IR interneurons seen 10 days after MDMA exposure. Local administration of MDL100907, a selective 5HT2A receptor antagonist, prevented the increases in glutamate caused by reverse dialysis of MDMA directly into the dentate gyrus and prevented the reduction of PV-IR. These findings provide evidence that MDMA causes decreases in PV within the dentate gyrus through a 5HT2A receptor-mediated increase in glutamate and subsequent NMDA receptor activation. Copyright © 2015 Elsevier B.V. All rights reserved.

Neuropsychiatric disturbances in SLE are associated with antibodies against NMDA receptors.

PubMed

Omdal, R; Brokstad, K; Waterloo, K; Koldingsnes, W; Jonsson, R; Mellgren, S I

2005-05-01

To determine whether neuropsychiatric manifestations in patients with systemic lupus erythematosus (SLE) are influenced by antibodies against the human N-methyl-D-aspartate (NMDA) receptor types NR2a or NR2b. A decapeptide was synthesized containing a sequence motif present in the extracellular ligand-binding domain of NMDA receptors NR2a and NR2b, bound by the monoclonal murine anti-DNA antibody R4A. In an ELISA with the murine monoclonal R4v as positive control, plasma samples of 57 patients with SLE were examined for the anti-peptide (anti-NR2) antibody after the patients had been subjected to comprehensive psychological and cognitive testing. Poor performance on the Visual Paired Associates test (immediate), the Grooved Pegboard test, as well as high scores on the Beck Depression Inventory, and scales D-2 (depression), Pd-4 (psychopathic deviate), Sc-8 (schizophrenia), and Ma-9 (hypomania) of the MMPI-2 were significantly associated with elevated levels of anti-NR2 antibodies. The findings in several domains indicate an association between anti-NR2 antibodies and depressed mood in addition to decreased short-time memory and learning. Antibodies to NMDA receptors thus may represent one of several mechanisms for cerebral dysfunction in patients with SLE.

NMDA and AMPA receptors in the anterior cingulate cortex mediates visceral pain in visceral hypersensitivity rats.

PubMed

Zhou, Lin; Huang, Junjing; Gao, Jun; Zhang, Guanpo; Jiang, Jinjin

2014-02-01

Several studies have shown that N-methyl-D-aspartate (NMDA)-receptor activation in anterior cingulate cortex (ACC) neurons plays critical roles in modulating visceral pain responses in visceral hypersensitivity (VH) rats. However, there are few reports about the expressions of NMDA and α-amino-3-hydroxy-5-methyl-4-isox-azolepropionic-acid (AMPA) receptor subtypes in ACC of VH model rats at different time points. The current study was undertaken to investigate NR2A, NR2B and GluR2 expressions in ACC of VH rats that were induced by administration with 5% mustard oil. Our results indicated that NR2B, but not NR2A, was highly expressed in VH model group on day 15, 22, and 36 compared with normal group (p < 0.05). GluR2 expression was also higher in VH model group on day 15, 22, and 36 than that of normal group (p < 0.05). These findings suggested increased expression of NR2B and GluR2 might be key mechanisms for long-term synaptic plastic changes in VH rats. Copyright © 2014. Published by Elsevier Inc.

H-Ras Modulates N-Methyl-d-aspartate Receptor Function via Inhibition of Src Tyrosine Kinase Activity*

PubMed Central

Thornton, Claire; Yaka, Rami; Dinh, Son; Ron, Dorit

2005-01-01

Tyrosine phosphorylation of the NR2A and NR2B subunits of the N-methyl-d-aspartate (NMDA) receptor by Src protein-tyrosine kinases modulates receptor channel activity and is necessary for the induction of long term potentiation (LTP). Deletion of H-Ras increases both NR2 tyrosine phosphorylation and NMDA receptor-mediated hippocampal LTP. Here we investigated whether H-Ras regulates phosphorylation and function of the NMDA receptor via Src family protein-tyrosine kinases. We identified Src as a novel H-Ras binding partner. H-Ras bound to Src but not Fyn both in vitro and in brain via the Src kinase domain. Cotransfection of H-Ras and Src inhibited Src activity and decreased NR2A tyrosine phosphorylation. Treatment of rat brain slices with Tat-H-Ras depleted NR2A from the synaptic membrane, decreased endogenous Src activity and NR2A phosphorylation, and decreased the magnitude of hip-pocampal LTP. No change was observed for NR2B. We suggest that H-Ras negatively regulates Src phosphorylation of NR2A and retention of NR2A into the synaptic membrane leading to inhibition of NMDA receptor function. This mechanism is specific for Src and NR2A and has implications for studies in which regulation of NMDA receptor-mediated LTP is important, such as synaptic plasticity, learning, and memory and addiction. PMID:12695509

The Sleep-Promoting and Hypothermic Effects of Glycine are Mediated by NMDA Receptors in the Suprachiasmatic Nucleus

PubMed Central

Kawai, Nobuhiro; Sakai, Noriaki; Okuro, Masashi; Karakawa, Sachie; Tsuneyoshi, Yosuke; Kawasaki, Noriko; Takeda, Tomoko; Bannai, Makoto; Nishino, Seiji

2015-01-01

The use of glycine as a therapeutic option for improving sleep quality is a novel and safe approach. However, despite clinical evidence of its efficacy, the details of its mechanism remain poorly understood. In this study, we investigated the site of action and sleep-promoting mechanisms of glycine in rats. In acute sleep disturbance, oral administration of glycine-induced non-rapid eye movement (REM) sleep and shortened NREM sleep latency with a simultaneous decrease in core temperature. Oral and intracerebroventricular injection of glycine elevated cutaneous blood flow (CBF) at the plantar surface in a dose-dependent manner, resulting in heat loss. Pretreatment with N-methyl-D-aspartate (NMDA) receptor antagonists AP5 and CGP78608 but not the glycine receptor antagonist strychnine inhibited the CBF increase caused by glycine injection into the brain. Induction of c-Fos expression was observed in the hypothalamic nuclei, including the medial preoptic area (MPO) and the suprachiasmatic nucleus (SCN) shell after glycine administration. Bilateral microinjection of glycine into the SCN elevated CBF in a dose-dependent manner, whereas no effect was observed when glycine was injected into the MPO and dorsal subparaventricular zone. In addition, microinjection of D-serine into the SCN also increased CBF, whereas these effects were blocked in the presence of L-701324. SCN ablation completely abolished the sleep-promoting and hypothermic effects of glycine. These data suggest that exogenous glycine promotes sleep via peripheral vasodilatation through the activation of NMDA receptors in the SCN shell. PMID:25533534

The sleep-promoting and hypothermic effects of glycine are mediated by NMDA receptors in the suprachiasmatic nucleus.

PubMed

Kawai, Nobuhiro; Sakai, Noriaki; Okuro, Masashi; Karakawa, Sachie; Tsuneyoshi, Yosuke; Kawasaki, Noriko; Takeda, Tomoko; Bannai, Makoto; Nishino, Seiji

2015-05-01

The use of glycine as a therapeutic option for improving sleep quality is a novel and safe approach. However, despite clinical evidence of its efficacy, the details of its mechanism remain poorly understood. In this study, we investigated the site of action and sleep-promoting mechanisms of glycine in rats. In acute sleep disturbance, oral administration of glycine-induced non-rapid eye movement (REM) sleep and shortened NREM sleep latency with a simultaneous decrease in core temperature. Oral and intracerebroventricular injection of glycine elevated cutaneous blood flow (CBF) at the plantar surface in a dose-dependent manner, resulting in heat loss. Pretreatment with N-methyl-D-aspartate (NMDA) receptor antagonists AP5 and CGP78608 but not the glycine receptor antagonist strychnine inhibited the CBF increase caused by glycine injection into the brain. Induction of c-Fos expression was observed in the hypothalamic nuclei, including the medial preoptic area (MPO) and the suprachiasmatic nucleus (SCN) shell after glycine administration. Bilateral microinjection of glycine into the SCN elevated CBF in a dose-dependent manner, whereas no effect was observed when glycine was injected into the MPO and dorsal subparaventricular zone. In addition, microinjection of D-serine into the SCN also increased CBF, whereas these effects were blocked in the presence of L-701324. SCN ablation completely abolished the sleep-promoting and hypothermic effects of glycine. These data suggest that exogenous glycine promotes sleep via peripheral vasodilatation through the activation of NMDA receptors in the SCN shell.

Exploring the Interaction between TSC2, PTEN, and the NMDA Receptor in Animal Models of Tuberous Sclerosis

DTIC Science & Technology

2014-09-01

Sunnen CN, Crowell B, Lee GH, Anderson AE, and D’Arcangelo G. Examination of the Role of Pten in Ionotropic Glutamate Receptor Expression. National...PTEN, and the NMDA Receptor in Animal Models of Tuberous Sclerosis PRINCIPAL INVESTIGATOR: D’Arcangelo, Gabriella CONTRACTING...June 2014 4. TITLE AND SUBTITLE Exploring the Interaction between TSC2, PTEN, and the NMDA Receptor in Animal Models of Tuberous Sclerosis 5a

Anti-N-Methyl-D-Aspartate Receptor Encephalitis and Rasmussen-like Syndrome: An Association?

PubMed

Gurcharran, Kevin; Karkare, Shefali

2017-01-01

N-methyl-D-aspartate (NMDA) receptor encephalitis is an immune-mediated condition that has a broad spectrum of manifestations, including seizures, coma, psychosis, and focal neurological deficits. Although usually a diffuse process, unihemispheric involvement mimicking early stages of Rasmussen encephalitis can occur. Rasmussen's encephalitis is a unique syndrome characterized by progressive hemiplegia, drug-resistant focal epilepsy, cognitive decline, and hemispheric brain atrophy contralateral to the hemiplegia. We describe a two-year-old girl with progressive right weakness and epilepsia partialis continua, concerning for early Rasmussen's encephalitis, who tested positive for anti-NMDA receptor antibodies. She experienced complete clinical recovery after immunotherapy. Anti-NMDA receptor antibodies were absent at three weeks and again at one year after the first treatment of intravenous immunoglobulin. There are few reports of Rasmussen-like encephalitis in individuals with anti-NMDA receptor antibody positivity. Thus the clinical significance of this association is yet to be determined. In addition, several other antibodies have been documented in individuals with Rasmussen encephalitis. The lack of a consistently reported antibody in Rasmussen encephalitis patients and the temporary nature of the anti-NMDA receptor antibody in our patient raise the following question: Is the presence of anti-NMDA receptor antibodies the cause of the symptoms or secondary to the pathogenic process? Copyright © 2016 Elsevier Inc. All rights reserved.

Depression of NMDA receptor-mediated synaptic transmission by four α2 adrenoceptor agonists on the in vitro rat spinal cord preparation

PubMed Central

Faber, E S L; Chambers, J P; Evans, R H

1998-01-01

α2-Adrenoceptor agonists have a spinal site of analgesic action. In the current study the synaptic depressant actions of xylazine, detomidine, romifidine and dexmedetomidine have been compared on segmental reflexes containing NMDA receptor-mediated components in the neonatal rat hemisected spinal cord preparation in vitro.Reflexes were evoked in the ventral root following either supramaximal electrical stimulation of the corresponding ipsilateral lumbar dorsal root to evoke the high intensity excitatory postsynaptic potential (e.p.s.p.) involving all primary afferent fibres, or low intensity stimulation to evoke the solely A fibre-mediated low intensity e.p.s.p. The high intensity e.p.s.p. contains a greater NMDA receptor-mediated component.Xylazine, romifidine, detomidine and dexmedetomidine all depressed both the high intensity e.p.s.p. and the low intensity e.p.s.p. giving respective EC50 values of 0.91±0.2 μM (n=12), 23.4±3 nM (n=12), 37.7±7 nM (n=8) and 0.84±0.1 nM (n=4) for depression of the high intensity e.p.s.p. and 0.76±0.1 μM (n=12), 22.0±3 nM (n=12), 24.9±6 nM (n=4) and 2.7±0.6 nM (n=4) for depression of the low intensity e.p.s.p., respectively. Unlike the other three drugs, the two values for dexmedetomidine, showing a greater selectivity for the high intensity e.p.s.p., are significantly different.Each of these depressant actions was reversed by the selective α2-adrenoceptor antagonist atipamezole (1 μM).In contrast to previous reports of the actions of α2-adrenoceptor agonists on the in vitro spinal cord preparation, at concentrations ten fold higher than the above EC50 values xylazine, romifidine, detomidine and dexmedetomidine depressed the initial population spike of motoneurons (MSR). This depression was not reversed by atipamezole.Comparison of the rank order of the present EC50 values for depression of the high intensity e.p.s.p. with potency ratios from in vivo analgesic tests in previous studies show a close

Vitamin C modulates glutamate transport and NMDA receptor function in the retina.

PubMed

Domith, Ivan; Socodato, Renato; Portugal, Camila C; Munis, Andressa F; Duarte-Silva, Aline T; Paes-de-Carvalho, Roberto

2018-02-01

Vitamin C (in the reduced form ascorbate or in the oxidized form dehydroascorbate) is implicated in signaling events throughout the central nervous system (CNS). In the retina, a high-affinity transport system for ascorbate has been described and glutamatergic signaling has been reported to control ascorbate release. Here, we investigated the modulatory role played by vitamin C upon glutamate uptake and N-methyl-d-aspartate (NMDA) receptor activation in cultured retinal cells or in intact retinal tissue using biochemical and imaging techniques. We show that both forms of vitamin C, ascorbate or dehydroascorbate, promote an accumulation of extracellular glutamate by a mechanism involving the inhibition of glutamate uptake. This inhibition correlates with the finding that ascorbate promotes a decrease in cell surface levels of the neuronal glutamate transporter excitatory amino acid transporter 3 in retinal neuronal cultures. Interestingly, vitamin C is prone to increase the activity of NMDA receptors but also promotes a decrease in glutamate-stimulated [ 3 H] MK801 binding and decreases cell membrane content of NMDA receptor glutamate ionotropic receptor subunit 1 (GluN1) subunits. Both compounds were also able to increase cAMP response element-binding protein phosphorylation in neuronal nuclei in a glutamate receptor and calcium/calmodulin kinase-dependent manner. Moreover, the effect of ascorbate is not blocked by sulfinpyrazone and then does not depend on its uptake by retinal cells. Overall, these data indicate a novel molecular and functional target for vitamin C impacting on glutamate signaling in retinal neurons. © 2017 International Society for Neurochemistry.

Trace and contextual fear conditioning require neural activity and NMDA receptor-dependent transmission in the medial prefrontal cortex

PubMed Central

Gilmartin, Marieke R.; Helmstetter, Fred J.

2010-01-01

The contribution of the medial prefrontal cortex (mPFC) to the formation of memory is a subject of considerable recent interest. Notably, the mechanisms supporting memory acquisition in this structure are poorly understood. The mPFC has been implicated in the acquisition of trace fear conditioning, a task that requires the association of a conditional stimulus (CS) and an aversive unconditional stimulus (UCS) across a temporal gap. In both rat and human subjects, frontal regions show increased activity during the trace interval separating the CS and UCS. We investigated the contribution of prefrontal neural activity in the rat to the acquisition of trace fear conditioning using microinfusions of the γ-aminobutyric acid type A (GABAA) receptor agonist muscimol. We also investigated the role of prefrontal N-methyl-d-aspartate (NMDA) receptor-mediated signaling in trace fear conditioning using the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (APV). Temporary inactivation of prefrontal activity with muscimol or blockade of NMDA receptor-dependent transmission in mPFC impaired the acquisition of trace, but not delay, conditional fear responses. Simultaneously acquired contextual fear responses were also impaired in drug-treated rats exposed to trace or delay, but not unpaired, training protocols. Our results support the idea that synaptic plasticity within the mPFC is critical for the long-term storage of memory in trace fear conditioning. PMID:20504949

Alteration in 5-HT₂C, NMDA receptor and IP3 in cerebral cortex of epileptic rats: restorative role of Bacopa monnieri.

PubMed

Krishnakumar, Amee; Anju, T R; Abraham, Pretty Mary; Paulose, C S

2015-01-01

Bacopa monnieri is effective in stress management, brain function and a balanced mood. 5-HT2C receptors have been implicated in stress whereas NMDA receptors and mGlu5 play crucial role in memory and cognition. In the present study, we investigated the role of B. monnieri extract in ameliorating pilocarpine induced temporal lobe epilepsy through regulation of 5-HT2C and NMDA receptors in cerebral cortex. Our studies confirmed an increased 5-HT2C receptor function during epilepsy thereby facilitating IP3 release. We also observed an decreased NMDA receptor function with an elevated mGlu5 and GLAST gene expression in epileptic condition indicating the possibility for glutamate mediated excitotoxicity. These alterations lead to impaired behavioural functions as indicated by the Elevated Plus maze test. Carbamazepine and B. monnieri treatments to epileptic rats reversed the alterations in 5-HT2C, NMDA receptor functions and IP3 content thereby effectively managing the neurotransmitter balance in the cerebral cortex.

Evidence that NMDA-dependent limbic neural plasticity in the right hemisphere mediates pharmacological stressor (FG-7142)-induced lasting increases in anxiety-like behavior. Study 1--Role of NMDA receptors in efferent transmission from the cat amygdala.

PubMed

Adamec, R E

1998-01-01

The anxiogenic beta-carboline, FG-7142, produces intense anxiety in humans and anxiety-like behavior in animals. FG-7142 also mimics the effects of exogenous stressors. In cats, FG-7142 lastingly changes defensive and aggressive behavior. Long-term potentiation (LTP) of neural transmission between limbic structures known to modulate feline defensive response to threat accompany behavioral changes. A series of three reports describes experiments designed to test the hypothesis that behavioral changes depend upon an N-methyl-D-aspartate (NMDA) receptor-based LTP of efferent transmission from the amygdala. This first study characterizes the dose and time effects of injection of the NMDA receptor blocker 7-amino-phosphono-heptanoic acid (AP7) on efferent transmission from the cat amygdala to the ventromedial hypothalamus (VMH). Effects of doses of 0.5-10mg/kg (i.v.) of AP7 on potentials evoked in the VMH by single pulse stimulation of the basal amygdala were examined. In order to localize the action of the drug, concurrent measurements were taken of potentials evoked in the VMH by stimulation of the efferent fibers from the amygdala to the VMH (ventral amygdalofugal pathway, VAF). There was a dose-dependent reduction in the amygdalo-VMH evoked potential. The greatest reduction occurred at 5 mg/kg. Effects peaked at 10 min, and persisted for at least 1 h after injection. In contrast, AP7 increased the VAF-VMH-evoked potential at 10 min after injection, with a maximal increase at 5mg/kg. The data suggest that NMDA receptors intrinsic to the amygdala modulate excitatory efferent transmission from amygdala to VMH in the cat. It is speculated that a glutamatergic projection to gamma-aminobutyric acid tonic inhibitory systems in the VMH accounts for the VAF-VMH results.

Anti-NMDA receptor encephalitis presenting as atypical anorexia nervosa: an adolescent case report.

PubMed

Mechelhoff, David; van Noort, Betteke Maria; Weschke, Bernhard; Bachmann, Christian J; Wagner, Christiane; Pfeiffer, Ernst; Winter, Sibylle

2015-11-01

Since 2007, more than 600 patients have been diagnosed with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, with almost 40 % of those affected being children or adolescents. In early phases of the illness, this life-threatening disease is characterized by psychiatric symptoms, such as depression, anxiety, obsessions, hallucinations or delusions. Consequently, a high percentage of patients receive psychiatric diagnoses at first, hindering the crucial early diagnosis and treatment of the anti-NMDA receptor encephalitis. We report on a 15-year-old girl initially presenting with pathological eating behaviour and significant weight loss resulting in an (atypical) anorexia nervosa (AN) diagnosis. Her early course of illness, diagnostic process, treatment and short-term outcome are described. This case report aims to raise awareness about the association between anorectic behaviour and anti-NMDA receptor encephalitis and highlight the importance of multidisciplinary teams in child and adolescent services.

In Adult Female Hamsters Hypothyroidism Stimulates D1 Receptor-mediated Breathing without altering D1 Receptor Expression

PubMed Central

Schlenker, Evelyn H.; Rio, Rodrigo Del; Schultz, Harold D.

2015-01-01

Hypothyroidism affects cardiopulmonary regulation and function of dopaminergic receptors. Here we evaluated effects of 5 months of hypothyroidism on dopamine D1 receptor modulation of breathing in female hamsters using a D1 receptor antagonist SCH23390. Euthyroid hamsters (EH) served as controls. Results indicated that hypothyroid female hamsters (HH) exhibited decreased body weights and minute ventilation (VE) following hypoxia due to decreased frequency of breathing (F). Moreover, SCH 23390 administration in HH increased VE by increasing tidal volume during exposure to air, hypoxia and following hypoxia. Relative to vehicle, SCH 23390 treatment decreased body temperature and hypoxic VE responsiveness in both groups. In EH, SCH 23390 decreased F in air, hypoxia and post hypoxia, and VE during hypoxia trended to decrease (P=0.053). Finally, expression of D1 receptor protein was not different between the two groups in any region evaluated. Thus, hypothyroidism in older female hamsters affected D1 receptor modulation of ventilation differently relative to euthyroid animals, but not expression of D1 receptors. PMID:26232642

In adult female hamsters hypothyroidism stimulates D1 receptor-mediated breathing without altering D1 receptor expression.

PubMed

Schlenker, Evelyn H; Del Rio, Rodrigo; Schultz, Harold D

2015-11-01

Hypothyroidism affects cardiopulmonary regulation and function of dopaminergic receptors. Here we evaluated effects of 5 months of hypothyroidism on dopamine D1 receptor modulation of breathing in female hamsters using a D1 receptor antagonist SCH 23390. Euthyroid hamsters (EH) served as controls. Results indicated that hypothyroid female hamsters (HH) exhibited decreased body weights and minute ventilation (VE) following hypoxia due to decreased frequency of breathing (F). Moreover, SCH 23390 administration in HH increased VE by increasing tidal volume during exposure to air, hypoxia and following hypoxia. Relative to vehicle, SCH 23390 treatment decreased body temperature and hypoxic VE responsiveness in both groups. In EH, SCH 23390 decreased F in air, hypoxia and post hypoxia, and VE during hypoxia trended to decrease (P=0.053). Finally, expression of D1 receptor protein was not different between the two groups in any region evaluated. Thus, hypothyroidism in older female hamsters affected D1 receptor modulation of ventilation differently relative to euthyroid animals, but not expression of D1 receptors. Copyright © 2015 Elsevier B.V. All rights reserved.

Convulsions induced by centrally administered NMDA in mice: effects of NMDA antagonists, benzodiazepines, minor tranquilizers and anticonvulsants.

PubMed Central

Moreau, J. L.; Pieri, L.; Prud'hon, B.

1989-01-01

1. Convulsions were induced reproducibly by intracerebroventricular injection of N-methyl-D-aspartic acid (NMDA) to conscious mice. 2. Competitive (carboxypiperazine-propylphosphonic acid, CPP; 2-amino-7-phosphonoheptanoic acid, AP7) and non-competitive (MK801; phencyclidine, PCP; thienylcyclohexylpiperidine, TCP; dextrorphan; dextromethorphan) NMDA antagonists prevented NMDA-induced convulsions. 3. Benzodiazepine receptor agonists and partial agonists (triazolam, diazepam, clonazepam, Ro 16-6028), classical anticonvulsants (diphenylhydantoin, phenobarbitone, sodium valproate) and meprobamate were also found to prevent NMDA-induced convulsions. 4. Flumazenil (a benzodiazepine receptor antagonist) and the GABA agonists THIP and muscimol (up to subtoxic doses) were without effect. 5. Flumazenil reversed the anticonvulsant action of diazepam, but not that of MK801. 6. Results obtained in this model differ somewhat from those described in a seizure model with systemic administration of NMDA. An explanation for this discrepancy is offered. 7. This model is a simple test for assessing the in vivo activity of NMDA antagonists and also expands the battery of chemically-induced seizure models for characterizing anticonvulsants not acting at NMDA receptors. PMID:2574061

Activation of the sigma receptor 1 modulates AMPA receptor-mediated light-evoked excitatory postsynaptic currents in rat retinal ganglion cells.

PubMed

Liu, Lei-Lei; Deng, Qin-Qin; Weng, Shi-Jun; Yang, Xiong-Li; Zhong, Yong-Mei

2016-09-22

Sigma receptor (σR), a unique receptor family, is classified into three subtypes: σR1, σR2 and σR3. It was previously shown that σR1 activation induced by 1μM SKF10047 (SKF) suppressed N-methyl-d-aspartate (NMDA) receptor-mediated responses of rat retinal ganglion cells (GCs) and the suppression was mediated by a distinct Ca(2+)-dependent phospholipase C (PLC)-protein kinase C (PKC) pathway. In the present work, using whole-cell patch-clamp techniques in rat retinal slice preparations, we further demonstrate that SKF of higher dosage (50μM) significantly suppressed AMPA receptor (AMPAR)-mediated light-evoked excitatory postsynaptic currents (L-EPSCs) of retinal ON-type GCs (ON GCs), and the effect was reversed by the σR1 antagonist BD1047, suggesting the involvement of σR1. The SKF (50μM) effect was unlikely due to a change in glutamate release from bipolar cells, as suggested by the unaltered paired-pulse ratio (PPR) of AMPAR-mediated EPSCs of ON GCs. SKF (50μM) did not change L-EPSCs of ON GCs when the G protein inhibitor GDP-β-S or the protein kinase G (PKG) inhibitor KT5823 was intracellularly infused. Calcium imaging further revealed that SKF (50μM) did not change intracellular calcium concentration in GCs and persisted to suppress L-EPSCs when intracellular calcium was chelated by BAPTA. The SKF (50μM) effect was intact when protein kinase A (PKA) and phosphatidylinostiol (PI)-PLC signaling pathways were both blocked. We conclude that the SKF (50μM) effect is Ca(2+)-independent, PKG-dependent, but not involving PKA, PI-PLC pathways. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Alpha7 Nicotinic Acetylcholine Receptors Play a Predominant Role in the Cholinergic Potentiation of N-Methyl-D-Aspartate Evoked Firing Responses of Hippocampal CA1 Pyramidal Cells

PubMed Central

Bali, Zsolt K.; Nagy, Lili V.; Hernádi, István

2017-01-01

The aim of the present study was to identify in vivo electrophysiological correlates of the interaction between cholinergic and glutamatergic neurotransmission underlying memory. Extracellular spike recordings were performed in the hippocampal CA1 region of anesthetized rats in combination with local microiontophoretic administration of N-methyl-D-aspartate (NMDA) and acetylcholine (ACh). Both NMDA and ACh increased the firing rate of the neurons. Furthermore, the simultaneous delivery of NMDA and ACh resulted in a more pronounced excitatory effect that was superadditive over the sum of the two mono-treatment effects and that was explained by cholinergic potentiation of glutamatergic neurotransmission. Next, animals were systemically treated with scopolamine or methyllycaconitine (MLA) to assess the contribution of muscarinic ACh receptor (mAChR) or α7 nicotinic ACh receptor (nAChR) receptor-mediated mechanisms to the observed effects. Scopolamine totally inhibited ACh-evoked firing, and attenuated the firing rate increase evoked by simultaneous application of NMDA and ACh. However, the superadditive nature of the combined effect was preserved. The α7 nAChR antagonist MLA robustly decreased the firing response to simultaneous application of NMDA and ACh, suspending their superadditive effect, without modifying the tonic firing rate increasing effect of ACh. These results provide the first in vivo electrophysiological evidence that, in the hippocampal CA1 region, α7 nAChRs contribute to pyramidal cell activity mainly through potentiation of glutamatergic signaling, while the direct cholinergic modulation of tonic firing is notably mediated by mAChRs. Furthermore, the present findings also reveal cellular physiological correlates of the interplay between cholinergic and glutamatergic agents in behavioral pharmacological models of cognitive decline. PMID:28928637

Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits

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

Lind, Genevieve E.; Mou, Tung-Chung; Tamborini, Lucia

NMDA-type glutamate receptors are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system (CNS). Most NMDA receptors comprise two glycine-binding GluN1 and two glutamate-binding GluN2 subunits (GluN2A–D). We describe highly potent (S)-5-[(R)-2-amino-2-carboxyethyl]-4,5-dihydro-1H-pyrazole-3-carboxylic acid (ACEPC) competitive GluN2 antagonists, of which ST3 has a binding affinity of 52 nM at GluN1/2A and 782 nM at GluN1/2B receptors. This 15-fold preference of ST3 for GluN1/2A over GluN1/2B is improved compared with NVP-AAM077, a widely used GluN2A-selective antagonist, which we show has 11-fold preference for GluN1/2A over GluN1/2B. Crystal structures of the GluN1/2A agonist binding domain (ABD) heterodimer with boundmore » ACEPC antagonists reveal a binding mode in which the ligands occupy a cavity that extends toward the subunit interface between GluN1 and GluN2A ABDs. Mutational analyses show that the GluN2A preference of ST3 is primarily mediated by four nonconserved residues that are not directly contacting the ligand, but positioned within 12 Å of the glutamate binding site. Two of these residues influence the cavity occupied by ST3 in a manner that results in favorable binding to GluN2A, but occludes binding to GluN2B. Thus, we reveal opportunities for the design of subunit-selective competitive NMDA receptor antagonists by identifying a cavity for ligand binding in which variations exist between GluN2A and GluN2B subunits. This structural insight suggests that subunit selectivity of glutamate-site antagonists can be mediated by mechanisms in addition to direct contributions of contact residues to binding affinity.« less

Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits

PubMed Central

Lind, Genevieve E.; Mou, Tung-Chung; Tamborini, Lucia; Pomper, Martin G.; De Micheli, Carlo; Conti, Paola; Pinto, Andrea

2017-01-01

NMDA-type glutamate receptors are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system (CNS). Most NMDA receptors comprise two glycine-binding GluN1 and two glutamate-binding GluN2 subunits (GluN2A–D). We describe highly potent (S)-5-[(R)-2-amino-2-carboxyethyl]-4,5-dihydro-1H-pyrazole-3-carboxylic acid (ACEPC) competitive GluN2 antagonists, of which ST3 has a binding affinity of 52 nM at GluN1/2A and 782 nM at GluN1/2B receptors. This 15-fold preference of ST3 for GluN1/2A over GluN1/2B is improved compared with NVP-AAM077, a widely used GluN2A-selective antagonist, which we show has 11-fold preference for GluN1/2A over GluN1/2B. Crystal structures of the GluN1/2A agonist binding domain (ABD) heterodimer with bound ACEPC antagonists reveal a binding mode in which the ligands occupy a cavity that extends toward the subunit interface between GluN1 and GluN2A ABDs. Mutational analyses show that the GluN2A preference of ST3 is primarily mediated by four nonconserved residues that are not directly contacting the ligand, but positioned within 12 Å of the glutamate binding site. Two of these residues influence the cavity occupied by ST3 in a manner that results in favorable binding to GluN2A, but occludes binding to GluN2B. Thus, we reveal opportunities for the design of subunit-selective competitive NMDA receptor antagonists by identifying a cavity for ligand binding in which variations exist between GluN2A and GluN2B subunits. This structural insight suggests that subunit selectivity of glutamate-site antagonists can be mediated by mechanisms in addition to direct contributions of contact residues to binding affinity. PMID:28760974

Common influences of non-competitive NMDA receptor antagonists on the consolidation and reconsolidation of cocaine-cue memory.

PubMed

Alaghband, Yasaman; Marshall, John F

2013-04-01

Environmental stimuli or contexts previously associated with rewarding drugs contribute importantly to relapse among addicts, and research has focused on neurobiological processes maintaining those memories. Much research shows contributions of cell surface receptors and intracellular signaling pathways in maintaining associations between rewarding drugs (e.g., cocaine) and concurrent cues/contexts; these memories can be degraded at the time of their retrieval through reconsolidation interference. Much less studied is the consolidation of drug-cue memories during their acquisition. The present experiments use the cocaine-conditioned place preference (CPP) paradigm in rats to directly compare, in a consistent setting, the effects of N-methyl-D-aspartate (NMDA) glutamate receptor antagonists MK-801 and memantine on the consolidation and reconsolidation of cocaine-cue memories. For the consolidation studies, animals were systemically administered MK-801 or memantine immediately following training sessions. To investigate the effects of these NMDA receptor antagonists on the retention of previously established cocaine-cue memories, animals were systemically administered MK-801 or memantine immediately after memory retrieval. Animals given either NMDA receptor antagonist immediately following training sessions did not establish a preference for the cocaine-paired compartment. Post-retrieval administration of either NMDA receptor antagonist attenuated the animals' preference for the cocaine-paired compartment. Furthermore, animals given NMDA receptor antagonists post-retrieval showed a blunted response to cocaine-primed reinstatement. Using two distinct NMDA receptor antagonists in a common setting, these findings demonstrate that NMDA receptor-dependent processes contribute both to the consolidation and reconsolidation of cocaine-cue memories, and they point to the potential utility of treatments that interfere with drug-cue memory reconsolidation.

Immunocytochemical localization of the NMDA-R2A receptor subunit in the cat retina.

PubMed

Goebel, D J; Aurelia, J L; Tai, Q; Jojich, L; Poosch, M S

1998-10-19

+, Brain Res. 664 (1994) 252-256; G.D. Zeevalk, W.J. Nicklas, Action of the anti-ischemic agent ifenprodil on N-methyl-d-aspartate and kainate-mediated excitotoxicity, Brain Res. 522 (1990) 135-139; R. Huba, H.D. Hofmann, Transmitter-gated currents of GABAergic amacrine-like cells in chick retinal cultures, Vis. Neurosci. 6 (1991) 303-314; M. Yamashita, R. Huba, H.D. Hofmann, Early in vitro development of voltage- and transmitter-gated currents in GABAergic amacrine cells, Dev. Brain Res. 82 (1994) 95-102; R. Ientile, S. Pedale, V. Picciurro, V. Macaione, C. Fabiano, S. Macaione, Nitric oxide mediates NMDA-evoked [3H]GABA release from chick retina cells, FEBS Lett. 417 (1997) 345-348; R.C. Kubrusly, M.C. deMello, F.G. deMello, Aspartate as a selective NMDA agonist in cultured cells from the avian retina, Neurochem. Intl. 32 (1998) 47-52] or reduction of GABA in vivo [N.N. Osborn, A.J. Herrera, The effect of experimental ischaemia and excitatory amino acid agonist on the GABA and serotonin immunoreactivities in the rabbit retina, Neurosci. 59 (1994) 1071-1081]. Since the majority of GABAergic synapses in the inner retina are onto both rod and cone bipolar axon terminals [R.G. Pourcho, M.T. Owzcarzak, Distribution of GABA immunoreactivity in the cat retina: A light and electron-microscopic study, Vis. Neurosci. 2 (1989) 425-435], we hypothesize that the NMDA-receptor plays a crucial role in providing feedback inhibition onto rod and cone bipolar cells. Copyright 1998 Elsevier Science B.V.

EVALUATING THE NMDA-GLUTAMATE RECEPTOR AS A SITE OF ACTION FOR TOLUENE, IN VIVO

EPA Science Inventory

In vitro, toluene disrupts the function of NMDA-glutamate receptors, indicating that effects on NMDA receptor function may contribute to toluene neurotoxicity. NMDA-glutamate receptors are widely present in the visual system and contribute to pattern-elicited visual evoked potent...

Implication of NMDA type glutamate receptors in neural regeneration and neoformation of synapses after excitotoxic injury in the guinea pig cochlea.

PubMed

d'Aldin, C G; Ruel, J; Assié, R; Pujol, R; Puel, J L

1997-07-01

In the adult mammalian cochlea, the ability of nerve fibres to regenerate has been observed following disruption of the organ of Corti by various means, or transsection of the cochlear nerve in the internal auditory meatus. Based upon the implication of glutamate as a neurotransmitter at synapses between sensory hair cells and terminal dendrites of the auditory nerve in the mammalian cochlea, we have developed, in a previous study, an in vivo model of neural regeneration and formation of synapses after the destruction of the afferent nerve endings by local application of the glutamate agonist alpha-amino-3-hydroxy-5-methyl-isoxazol-propionic acid (AMPA). In situ hybridization experiments performed during the re-innervation process revealed an overexpression of mRNA coding for NR1 subunit of N-methyl-D-aspartate (NMDA) receptors in the spiral ganglion neurons, suggesting that these receptors are implicated in neural regenerative processes. The present study has been designed to study the functional implication of NMDA receptors in the regrowth and synaptic repair of auditory dendrites in the guinea pig cochlea, by blocking the NMDA receptors during the period of normal functional recovery. In a first set of experiments, we recorded compound action potential after acute perilymphatic perfusion of cumulative doses (0.03-10mM) of DL 2-amino-5-phosphonovalerate (D-AP5), a NMDA antagonist, to determine the efficiency of the drug. In a second set of experiments, the auditory dendrites were destroyed by local application of the glutamate agonist AMPA. The blockage of NMDA by the antagonist D-AP5 applied with an osmotic micropump delayed the functional recovery and the regrowth of auditory dendrites. The findings of our study support the hypothesis that, in addition to acting as a fast transmitter, glutamate has a neurotrophic role via the activation of NMDA receptors.

Toxicological Differences Between NMDA Receptor Antagonists and Cholinesterase Inhibitors.

PubMed

Shi, Xiaodong; Lin, Xiaotian; Hu, Rui; Sun, Nan; Hao, Jingru; Gao, Can

2016-08-01

Cholinesterase inhibitors (ChEIs), represented by donepezil, rivastigmine, and galantamine, used to be the only approved class of drugs for the treatment of Alzheimer's disease. After the approval of memantine by the Food and Drug Administration (FDA), N-methyl-d-aspartic acid (NMDA) receptor antagonists have been recognized by authorities and broadly used in the treatment of Alzheimer's disease. Along with complementary mechanisms of action, NMDA antagonists and ChEIs differ not only in therapeutic effects but also in adverse reactions, which is an important consideration in clinical drug use. And the number of patients using NMDA antagonists and ChEIs concomitantly has increased, making the matter more complicated. Here we used the FDA Adverse Event Reporting System for statistical analysis , in order to compare the adverse events of memantine and ChEIs. In general, the clinical evidence confirmed the safety advantages of memantine over ChEIs, reiterating the precautions of clinical drug use and the future direction of antidementia drug development. © The Author(s) 2016.

The endocannabinoid 2-arachidonoylglycerol mediates D1 and D2 receptor cooperative enhancement of rat nucleus accumbens core neuron firing.

PubMed

Seif, T; Makriyannis, A; Kunos, G; Bonci, A; Hopf, F W

2011-10-13

Many motivated and addiction-related behaviors are sustained by activity of both dopamine D1- and D2-type receptors (D1Rs and D2Rs) as well as CB1 receptors (CB1Rs) in the nucleus accumbens (NAc). Here, we use in vitro whole-cell patch-clamp electrophysiology to describe an endocannabinoid (eCB)-dopamine receptor interaction in adult rat NAc core neurons. D1R and D2R agonists in combination enhanced firing, with no effect of a D1R or D2R agonist alone. This D1R+D2R-mediated firing increase required CB1Rs, since it was prevented by the CB1R antagonists AM251 and Rimonabant. The D1R+D2R firing increase also required phospholipase C (PLC), the major synthesis pathway for the eCB 2-arachidonoylglycerol (2-AG) and one of several pathways for anandamide. Further, inhibition of 2-AG hydrolysis with the monoglyceride lipase (MGL) inhibitor JZL184 allowed subthreshold levels of D1R+D2R receptor agonists to enhance firing, while inhibition of anandamide hydrolysis with the fatty acid amide hydrolase (FAAH) inhibitors URB597 or AM3506 did not. Filling the postsynaptic neuron with 2-AG enabled subthreshold D1R+D2R agonists to increase firing, and the 2AG+D1R+D2R increase in firing was prevented by a CB1R antagonist. Also, the metabotropic glutamate receptor 5 (mGluR5) blocker MPEP prevented the ability of JZL184 to promote subthreshold D1R+D2R enhancement of firing, while the 2-AG+D1R+D2R increase in firing was not prevented by the mGluR5 blocker, suggesting that mGluR5s acted upstream of 2-AG production. Thus, our results taken together are consistent with the hypothesis that NAc core eCBs mediate dopamine receptor (DAR) enhancement of firing, perhaps providing a cellular mechanism underlying the central role of NAc core D1Rs, D2Rs, CB1Rs, and mGluR5s during many drug-seeking behaviors. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

THE ENDOCANNABINOID 2-ARACHIDONOYLGLYCEROL MEDIATES D1 AND D2 RECEPTOR COOPERATIVE ENHANCEMENT OF RAT NUCLEUS ACCUMBENS CORE NEURON FIRING

PubMed Central

Seif, T.; Makriyannis, A.; Kunos, G.; Bonci, A.; Hopf, F. W.

2011-01-01

Many motivated and addiction-related behaviors are sustained by activity of both dopamine D1- and D2-type receptors (D1Rs and D2Rs) as well as CB1 receptors (CB1Rs) in the nucleus accumbens (NAc). Here, we use in vitro whole-cell patch-clamp electrophysiology to describe an endocannabinoid (eCB)–dopamine receptor interaction in adult rat NAc core neurons. D1R and D2R agonists in combination enhanced firing, with no effect of a D1R or D2R agonist alone. This D1R+D2R-mediated firing increase required CB1Rs, since it was prevented by the CB1R antagonists AM251 and Rimonabant. The D1R+D2R firing increase also required phospholipase C (PLC), the major synthesis pathway for the eCB 2-arachidonoylglycerol (2-AG) and one of several pathways for anandamide. Further, inhibition of 2-AG hydrolysis with the monoglyceride lipase (MGL) inhibitor JZL184 allowed subthreshold levels of D1R+D2R receptor agonists to enhance firing, while inhibition of anandamide hydrolysis with the fatty acid amide hydrolase (FAAH) inhibitors URB597 or AM3506 did not. Filling the postsynaptic neuron with 2-AG enabled subthreshold D1R+D2R agonists to increase firing, and the 2AG+D1R+D2R increase in firing was prevented by a CB1R antagonist. Also, the metabotropic glutamate receptor 5 (mGluR5) blocker MPEP prevented the ability of JZL184 to promote subthreshold D1R+D2R enhancement of firing, while the 2-AG+D1R+D2R increase in firing was not prevented by the mGluR5 blocker, suggesting that mGluR5s acted upstream of 2-AG production. Thus, our results taken together are consistent with the hypothesis that NAc core eCBs mediate dopamine receptor (DAR) enhancement of firing, perhaps providing a cellular mechanism underlying the central role of NAc core D1Rs, D2Rs, CB1Rs, and mGluR5s during many drug-seeking behaviors. PMID:21821098

NMDA receptors mediate lasting increases in anxiety-like behavior produced by the stress of predator exposure--implications for anxiety associated with posttraumatic stress disorder.

PubMed

Adamec, R E; Burton, P; Shallow, T; Budgell, J

It has been proposed that NMDA-dependent long-term potentiation (LTP) of limbic system circuits controlling defensive behavior underlies stressor-induced lasting increases in anxiety-like behavior (ALB). Findings in cats given the stress-inducing beta-carboline, FG-7142, support this hypothesis. An animal model of lasting affective change following traumatic stress has recently been developed. In this model, lasting increases in anxiety-like behavior (ALB) assessed in the elevated plus maze are produced by a single 5-min exposure of a rat to a cat. Rats become more anxious in the plus maze for up to 3 weeks after the exposure. The present study demonstrates that blockade of NMDA receptors in rats with MK-801, AP7, or CPP, given 30 min prior to exposure to a cat, prevents the increase in ALB assessed 1 week later. MK-801 or AP7, given 30 min after exposure to a cat, do not prevent the increase in ALB seen 1 week later, however. MK-801, but not CPP or AP7, promotes approaches to cats during exposure. This "fearlessness" may reflect some anxiolytic action of MK-801. Approach to cats following injection of MK-801 was eliminated by prior injection of Prazosin. Prazosin did not interfere with the block of increases in ALB following cat exposure, however. These findings are consistent with the view that NMDA receptors are involved in initiation, but not maintenance of neural changes mediating lasting increases in anxiety following severe stress. The significance of these findings for PTSD are discussed.

Activity-dependent ubiquitination of GluA1 mediates a distinct AMPA receptor endocytosis and sorting pathway.

PubMed

Schwarz, Lindsay A; Hall, Benjamin J; Patrick, Gentry N

2010-12-08

The accurate trafficking of AMPA receptors (AMPARs) to and from the synapse is a critical component of learning and memory in the brain, whereas dysfunction of AMPAR trafficking is hypothesized to be an underlying mechanism of Alzheimer's disease. Previous work has shown that ubiquitination of integral membrane proteins is a common posttranslational modification used to mediate endocytosis and endocytic sorting of surface proteins in eukaryotic cells. Here we report that mammalian AMPARs become ubiquitinated in response to their activation. Using a mutant of GluA1 that is unable to be ubiquitinated at lysines on its C-terminus, we demonstrate that ubiquitination is required for internalization of surface AMPARs and their trafficking to the lysosome in response to the AMPAR agonist AMPA but not for internalization of AMPARs in response to the NMDA receptor agonist NMDA. Through overexpression or RNA interference-mediated knockdown, we identify that a specific E3 ligase, Nedd4-1 (neural-precursor cell-expressed developmentally downregulated gene 4-1), is necessary for this process. Finally, we show that ubiquitination of GluA1 by Nedd4-1 becomes more prevalent as neurons mature. Together, these data show that ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome. Furthermore, these results provide insight into how hippocampal neurons regulate AMPAR trafficking and degradation with high specificity in response to differing neuronal signaling cues and suggest that changes to this pathway may occur as neurons mature.

Regulation of tyrosine hydroxylase activity and phosphorylation at Ser(19) and Ser(40) via activation of glutamate NMDA receptors in rat striatum.

PubMed

Lindgren, N; Xu, Z Q; Lindskog, M; Herrera-Marschitz, M; Goiny, M; Haycock, J; Goldstein, M; Hökfelt, T; Fisone, G

2000-06-01

The activity of tyrosine hydroxylase, the rate-limiting enzyme in the biosynthesis of dopamine, is stimulated by phosphorylation. In this study, we examined the effects of activation of NMDA receptors on the state of phosphorylation and activity of tyrosine hydroxylase in rat striatal slices. NMDA produced a time-and concentration-dependent increase in the levels of phospho-Ser(19)-tyrosine hydroxylase in nigrostriatal nerve terminals. This increase was not associated with any changes in the basal activity of tyrosine hydroxylase, measured as DOPA accumulation. Forskolin, an activator of adenylyl cyclase, stimulated tyrosine hydroxylase phosphorylation at Ser(40) and caused a significant increase in DOPA accumulation. NMDA reduced forskolin-mediated increases in both Ser(40) phosphorylation and DOPA accumulation. In addition, NMDA reduced the increase in phospho-Ser(40)-tyrosine hydroxylase produced by okadaic acid, an inhibitor of protein phosphatase 1 and 2A, but not by a cyclic AMP analogue, 8-bromo-cyclic AMP. These results indicate that, in the striatum, glutamate decreases tyrosine hydroxylase phosphorylation at Ser(40) via activation of NMDA receptors by reducing cyclic AMP production. They also provide a mechanism for the demonstrated ability of NMDA to decrease tyrosine hydroxylase activity and dopamine synthesis.

NMDA or non-NMDA receptor antagonism within the amygdaloid central nucleus suppresses the affective dimension of pain in rats: evidence for hemispheric synergy.

PubMed

Spuz, Catherine A; Borszcz, George S

2012-04-01

The amygdala contributes to generation of affective behaviors to threats. The prototypical threat to an individual is exposure to a noxious stimulus and the amygdaloid central nucleus (CeA) receives nociceptive input that is mediated by glutamatergic neurotransmission. The present study evaluated the contribution of glutamate receptors in CeA to generation of the affective response to acute pain in rats. Vocalizations that occur following a brief noxious tail shock (vocalization afterdischarges) are a validated rodent model of pain affect, and were preferentially suppressed by bilateral injection into CeA of the NMDA receptor antagonist D-2-amino-5-phosphonovalerate (AP5, 1 μg, 2 μg, or 4 μg) or the non-NMDA receptor antagonist 6-Cyano-7-nitroquinoxaline-2,3-dione disodium (CNQX, .25 μg, .5 μg, 1 μg, or 2 μg). Vocalizations that occur during tail shock were suppressed to a lesser degree, whereas spinal motor reflexes (tail flick and hind limb movements) were unaffected by injection of AP5 or CNQX into CeA. Unilateral administration of AP5 or CNQX into CeA of either hemisphere also selectively elevated vocalization thresholds. Bilateral administration of AP5 or CNQX produced greater increases in vocalization thresholds than the same doses of antagonists administered unilaterality into either hemisphere indicating synergistic hemispheric interactions. The amygdala contributes to production of emotional responses to environmental threats. Blocking glutamate neurotransmission within the central nucleus of the amygdala suppressed rats' emotional response to acute painful stimulation. Understanding the neurobiology underlying emotional responses to pain will provide insights into new treatments for pain and its associated affective disorders. Copyright © 2012 American Pain Society. Published by Elsevier Inc. All rights reserved.

Monosodium glutamate alters the response properties of rat trigeminovascular neurons through activation of peripheral NMDA receptors.

PubMed

O'Brien, Melissa; Cairns, Brian E

2016-10-15

Ingestion of monosodium glutamate (MSG) has been shown to cause headaches in healthy individuals and trigger migraine-like headaches in migraine sufferers. We combined immunohistochemistry, in vivo electrophysiology, and laser Doppler recordings of dural vasculature to investigate the effect of systemic administration of MSG on the trigeminovascular pathway. Immunohistochemical analysis confirmed the expression of NMDA receptors on nerve fibers innervating dural blood vessels and excitatory amino acid transporter 2 on dural blood vessels. Systemic administration of MSG (50mg/kg) evoked an increase in ongoing discharge in 5/6 spinal trigeminal subnucleus caudalis (SpVc) neurons with dural input recorded from male and female rats, respectively, as well as lowering their mechanical activation threshold. There were no sex-related differences in these effects of MSG. Neuronal discharge and mechanical sensitization were significantly attenuated by co-injection with the peripherally restricted NMDA receptor antagonist (2R)-amino-5-phosphonovaleric acid (APV) in both sexes. Systemic administration of MSG induced a 24.5% and 20.6% increase in dural flux in male and female rats, respectively. These results suggest that MSG-induced headache is mediated by the activation of peripheral NMDA receptors and subsequent dural vasodilation. Peripheral NMDA receptors are a potential target for the development of new drugs to treat headaches. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Interaction of blockers of ionotropic NMDA receptors and metabotropic glutamate receptors in a working memory test in rats.

PubMed

Novitskaya, Y A; Dravolina, O A; Zvartau, E E; Danysz, W; Bespalov, A Y

2010-09-01

Glutamate, the main excitatory neurotransmitter in the mammalian CNS, acts via ionotropic and metabotropic receptors. Results from in vitro studies demonstrating tight interactions between ionotropic NMDA receptors and subtype 5 metabotropic glutamate receptors (mGlu5) have shown that blockade of mGlu5 receptors increases the behavioral effects of NMDA receptor antagonists. The aim of the present work was to study the actions of the highly selective mGlu5 receptor antagonist MTEP alone and in combination with MK-801, a blocker of the NMDA receptor-associated ion channel, on performance of a delayed selection task (a test of working memory) in rats. MK-801 (0.1 mg/kg) induced a specific impairment to working memory, with proactive interference (degradation of the ability to remember current information because of the effects of previously learned material). Administration of MTEP (5.0 mg/kg) combined with both solvent and with MK-801 had no significant effects, demonstrating the small or nonexistent involvement of mGlu5 receptors in the mechanisms of working memory.

IRSp53/BAIAP2 in dendritic spine development, NMDA receptor regulation, and psychiatric disorders.

PubMed

Kang, Jaeseung; Park, Haram; Kim, Eunjoon

2016-01-01

IRSp53 (also known as BAIAP2) is a multi-domain scaffolding and adaptor protein that has been implicated in the regulation of membrane and actin dynamics at subcellular structures, including filopodia and lamellipodia. Accumulating evidence indicates that IRSp53 is an abundant component of the postsynaptic density at excitatory synapses and an important regulator of actin-rich dendritic spines. In addition, IRSp53 has been implicated in diverse psychiatric disorders, including autism spectrum disorders, schizophrenia, and attention deficit/hyperactivity disorder. Mice lacking IRSp53 display enhanced NMDA (N-methyl-d-aspartate) receptor function accompanied by social and cognitive deficits, which are reversed by pharmacological suppression of NMDA receptor function. These results suggest the hypothesis that defective actin/membrane modulation in IRSp53-deficient dendritic spines may lead to social and cognitive deficits through NMDA receptor dysfunction. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Unilateral block of NMDA receptors in the amygdala prevents predator stress-induced lasting increases in anxiety-like behavior and unconditioned startle--effective hemisphere depends on the behavior.

PubMed

Adamec, R E; Burton, P; Shallow, T; Budgell, J

Lasting increases in anxiety-like behavior (ALB) in the elevated plus-maze are produced by a single 5-min exposure of a rat to a cat. Rats become more anxious in the plus-maze for up to 3 weeks after the exposure. The first study in this series demonstrated that blockade of NMDA receptors in rats with MK-801, AP7, or CPP, given systemically 30 min prior to exposure to a cat prevents the increase in ALB assessed 1 week later in the elevated plus-maze. To localize the site of action of systemic MK-801, MK-801 was injected in the amygdala 30 min prior to predator stress. Injections were given either unilaterally in either hemisphere, or bilaterally in both hemispheres. The target of the injection was the basolateral amygdala. The effects of injection depended on both the type of behavior and the hemisphere of injection. Injections of MK-801 in a variety of sites in the basolateral amygdala had no effect on the suppression of open-arm exploration produced by predator stress. Other amygdala nuclei or other limbic sites likely mediate the effects of systemically administered MK-801 on this behavior. In contrast, NMDA receptors in the left lateral amygdala mediate lasting suppression of risk assessment. MK-801, in a variety of sites in the left but not right lateral amygdala, blocked the effects of predator stress on risk assessment. This is clear evidence of separability of neural mechanisms controlling open-arm exploration and risk assessment. Different NMDA-dependent amygdala circuitry mediated effects of predator stress on unconditioned acoustic startle 1 week after cat exposure. The data indicate that integrity of the left lateral amygdala is necessary for potentiation of startle amplitude by predator stress, though NMDA receptors are not involved in this function. Nevertheless, NMDA receptors in the right, but not the left lateral amygdala, mediate initiation of changes in startle. The data also suggest that the right amygdala action is "downstream" from the left

Decrement of GABAA receptor-mediated inhibitory postsynaptic currents in dentate granule cells in epileptic hippocampus.

PubMed

Isokawa, M

1996-05-01

1. Inhibitory postsynaptic currents (IPSCs) were studied in hippocampal dentate granule cells (DGCs) in the pilocarpine model and human temporal lobe epilepsy, with the use of the whole cell patch-clamp recording technique in slice preparations. 2. In the pilocarpine model, hippocampal slices were prepared from rats that were allowed to experience spontaneous seizures for 2 mo. Human hippocampal specimens were obtained from epileptic patients who underwent surgical treatment for medically intractable seizures. 3. IPSCs were generated by single perforant path stimulation and recorded at a membrane potential (Vm) of 0 mV near the reversal potential of glutamate excitatory postsynaptic currents in the voltage-clamp recording. IPSCs were pharmacologically identified as gamma-aminobutyric acid-A (GABAA) IPSCs by 10 microM bicuculline methiodide. 4. During low-frequency stimulation, IPSCs were not different in amplitude among non-seizure-experienced rat hippocampi, human nonsclerotic hippocampi, seizure-experienced rat hippocampi, and human sclerotic hippocampi. In the last two groups of DGCs, current-clamp recordings indicated the presence of prolonged excitatory postsynaptic potentials (EPSPs) mediated by the N-methyl-D-aspartate (NMDA) receptor. 5. High-frequency stimulation, administered at Vm = -30 mV to activate NMDA currents, reduced GABAA IPSC amplitude specifically in seizure-experienced rat hippocampi (t = 2.5, P < 0.03) and human sclerotic hippocampi (t = 7.7, P < 0.01). This reduction was blocked by an NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid (APV) (50 microM). The time for GABAA IPSCs to recover to their original amplitude was also shortened by the application of APV. 6. I conclude that, when intensively activated, NMDA receptor-mediated excitatory transmission may interact with GABAergic synaptic inhibition in DGCs in seizure-experienced hippocampus to transiently reduce GABA(A) receptor-channel function. Such interactions may contribute to

Memory in aged mice is rescued by enhanced expression of the GluN2B subunit of the NMDA receptor

PubMed Central

Brim, B. L.; Haskell, R.; Awedikian, R.; Ellinwood, N.M.; Jin, L.; Kumar, A.; Foster, T.C.; Magnusson, K.

2012-01-01

The GluN2B subunit of the N-methyl-D-aspartate (NMDA) receptor shows age-related declines in expression across the frontal cortex and hippocampus. This decline is strongly correlated to age-related memory declines. This study was designed to determine if increasing GluN2B subunit expression in the frontal lobe or hippocampus would improve memory in aged mice. Mice were injected bilaterally with either the GluN2B vector, containing cDNA specific for the GluN2B subunit and enhanced Green Fluorescent Protein (eGFP); a control vector or vehicle. Spatial memory, cognitive flexibility, and associative memory were assessed using the Morris water maze. Aged mice, with increased GluN2B subunit expression, exhibited improved long-term spatial memory, comparable to young mice. However, memory was rescued on different days in the Morris water maze; early for hippocampal GluN2B subunit enrichment and later for the frontal lobe. A higher concentration of the GluN2B antagonist, Ro 25-6981, was required to impair long-term spatial memory in aged mice with enhanced GluN2B expression, as compared to aged controls, suggesting there was an increase in the number of GluN2B-containing NMDA receptors. In addition, hippocampal slices from aged mice with increased GluN2B subunit expression exhibited enhanced NMDA receptor-mediated excitatory post-synaptic potentials (EPSP). Treatment with Ro 25-6981 showed that a greater proportion of the NMDA receptor-mediated EPSP was due to the GluN2B subunit in these animals, as compared to aged controls. These results suggest that increasing the production of the GluN2B subunit in aged animals enhances memory and synaptic transmission. Therapies that enhance GluN2B subunit expression within the aged brain may be useful for ameliorating age-related memory declines. PMID:23103326

Agmatine protects against cell damage induced by NMDA and glutamate in cultured hippocampal neurons

PubMed Central

Wang, Wei-Ping; Iyo, Abiye H.; Miguel-Hidalgo, Javier; Regunathan, Soundar; Zhu, Meng-Yang

2010-01-01

Agmatine is a polyamine and has been considered as a novel neurotransmitter or neuromodulator in the central nervous system. In the present study, the neuroprotective effect of agmatine against cell damage caused by N-methyl-d-aspartate (NMDA) and glutamate was investigated in cultured rat hippocampal neurons. Lactate dehydrogenase (LDH) activity assay, β-tubulin III immunocytochemical staining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end-labeling (TUNEL) assay were conducted to detect cell damage. Exposure of 12-day neuronal cultures of rat hippocampus to NMDA or glutamate for 1 h caused a concentration-dependent neurotoxicity, as indicated by the significant increase in released LDH activities. Addition of 100 µM agmatine into media ablated the neurotoxicity induced by NMDA or glutamate, an effect also produced by the specific NMDA receptor antagonist dizocilpine hydrogen maleate (MK801). Arcaine, an analog of agmatine with similar structure as agmatine, fully prevented the NMDA- or glutamate-induced neuronal damage. Spermine and putrescine, the endogenous polyamine and metabolic products of agmatine without the guanidine moiety of agmatine, failed to show this effect, indicating a structural relevance for this neuroprotection. Immunocytochemical staining and TUNEL assay confirmed the findings in the LDH measurement. That is, agmatine and MK801 markedly attenuated NMDA-induced neuronal death and significantly reduced TUNEL-positive cell numbers induced by exposure of cultured hippocampal neurons to NMDA. Taken together, these results demonstrate that agmatine can protect cultured hippocampal neurons from NMDA- or glutamate-induced excitotoxicity, through a possible blockade of the NMDA receptor channels or a potential anti-apoptotic property. PMID:16546145

Effects of N-methyl-D-aspartate receptor ligands on sensitivity to reinforcer magnitude and delayed reinforcement in a delay-discounting procedure

PubMed Central

Yates, Justin R; Gunkel, Benjamin T; Rogers, Katherine K; Hughes, Mallory N; Prior, Nicholas A

2016-01-01

Rationale The N-methyl-D-aspartate (NMDA) receptor has been recently identified as an important mediator of impulsive choice, as assessed in delay discounting. Although discounting is independently influenced by sensitivity to reinforcer magnitude and delayed reinforcement, few studies have examined how NMDA receptor ligands differentially affect these parameters. Objectives The current study examined the effects of various NMDA receptor ligands on sensitivity to reinforcer magnitude and delayed reinforcement in a delay-discounting procedure. Methods Following behavioral training, rats received treatments of the following NMDA receptor ligands: the uncompetitive antagonists ketamine (0, 1.0, 5.0, or 10.0 mg/kg; i.p.), MK-801 (0, 0.003, 0.01, or 0.03 mg/kg; s.c.), and memantine (0, 2.5, 5.0, or 10.0 mg/kg; i.p.), the competitive antagonist CGS 19755 (0, 5.0, 10.0, or 20.0 mg/kg; s.c.), the non-competitive NR2B subunit-selective antagonist ifenprodil (0, 1.0, 3.0, or 10.0 mg/kg; i.p), and the partial agonist D-cycloserine (0, 3.25, 15.0, or 30.0 mg/kg; s.c.). Results When an exponential model was used to describe discounting, CGS 19755 (5.0 mg/kg) increased impulsive choice without altering sensitivity to reinforcer magnitude. Conversely, ketamine (10.0 mg/kg), memantine (5.0 mg/kg), and ifenprodil (10.0 mg/kg) decreased sensitivity to reinforcer magnitude without altering impulsive choice. MK-801 and D-cycloserine did not alter delay-discounting performance, although two-way ANOVA analyses indicated D-cycloserine (15.0 mg/kg) decreased impulsive choice. Conclusions The behavioral changes observed in delay discounting following administration of NMDA receptor antagonists do not always reflect an alteration in impulsive choice. These results emphasize the utility in employing quantitative methods to assess drug effects in delay discounting. PMID:27837332

Non-conventional apoptotic response to ionising radiation mediated by N-methyl D-aspartate receptors in immature neuronal cells

PubMed Central

SAMARI, NADA; DE SAINT-GEORGES, LOUIS; PANI, GIUSEPPE; BAATOUT, SARAH; LEYNS, LUC; BENOTMANE, MOHAMMED ABDERRAFI

2013-01-01

During cortical development, N-methyl D-aspartate (NMDA) receptors are highly involved in neuronal maturation and synapse establishment. Their implication in the phenomenon of excitotoxicity has been extensively described in several neurodegenerative diseases due to the permissive entry of Ca2+ ions and massive accumulation in the intracellular compartment, which is highly toxic to cells. Ionising radiation is also a source of stress to the cells, particularly immature neurons. Their capacity to induce cell death has been described for various cell types either by directly damaging the DNA or indirectly through the generation of reactive oxygen species responsible for the activation of a battery of stress response effectors leading in certain cases, to cell death. In this study, in order to determine whether a link exists between NMDA receptors-mediated excitotoxicity and radiation-induced cell death, we evaluated radiation-induced cell death in vitro and in vivo in maturing neurons during the fetal period. Cell death induction was assessed by TUNEL, caspase-3 activity and DNA ladder assays, with or without the administration of dizocilpine (MK-801), a non-competitive NMDA receptor antagonist which blocks neuronal Ca2+ influx. To further investigate the possible involvement of Ca2+-dependent enzyme activation, known to occur at high Ca2+ concentrations, we examined the protective effect of a calpain inhibitor on cell death induced by radiation. Doses ranging from 0.2 to 0.6 Gy of X-rays elicited a clear apoptotic response that was prevented by the injection of dizocilpine (MK-801) or calpain inhibitor. These data demonstrate the involvement of NMDA receptors in radiation-induced neuronal death by the activation of downstream effectors, including calpain-related pathways. An increased apoptotic process elicited by radiation, occurring independently of the normal developmental scheme, may eliminate post-mitotic but immature neuronal cells and deeply impair the

Modulation of AMPA receptor mediated current by nicotinic acetylcholine receptor in layer I neurons of rat prefrontal cortex

PubMed Central

Tang, Bo; Luo, Dong; Yang, Jie; Xu, Xiao-Yan; Zhu, Bing-Lin; Wang, Xue-Feng; Yan, Zhen; Chen, Guo-Jun

2015-01-01

Layer I neurons in the prefrontal cortex (PFC) exhibit extensive synaptic connections with deep layer neurons, implying their important role in the neural circuit. Study demonstrates that activation of nicotinic acetylcholine receptors (nAChRs) increases excitatory neurotransmission in this layer. Here we found that nicotine selectively increased the amplitude of AMPA receptor (AMPAR)-mediated current and AMPA/NMDA ratio, while without effect on NMDA receptor-mediated current. The augmentation of AMPAR current by nicotine was inhibited by a selective α7-nAChR antagonist methyllycaconitine (MLA) and intracellular calcium chelator BAPTA. In addition, nicotinic effect on mEPSC or paired-pulse ratio was also prevented by MLA. Moreover, an enhanced inward rectification of AMPAR current by nicotine suggested a functional role of calcium permeable and GluA1 containing AMPAR. Consistently, nicotine enhancement of AMPAR current was inhibited by a selective calcium-permeable AMPAR inhibitor IEM-1460. Finally, the intracellular inclusion of synthetic peptide designed to block GluA1 subunit of AMPAR at CAMKII, PKC or PKA phosphorylation site, as well as corresponding kinase inhibitor, blocked nicotinic augmentation of AMPA/NMDA ratio. These results have revealed that nicotine increases AMPAR current by modulating the phosphorylation state of GluA1 which is dependent on α7-nAChR and intracellular calcium. PMID:26370265

Computationally Discovered Potentiating Role of Glycans on NMDA Receptors

NASA Astrophysics Data System (ADS)

Sinitskiy, Anton V.; Stanley, Nathaniel H.; Hackos, David H.; Hanson, Jesse E.; Sellers, Benjamin D.; Pande, Vijay S.

2017-04-01

N-methyl-D-aspartate receptors (NMDARs) are glycoproteins in the brain central to learning and memory. The effects of glycosylation on the structure and dynamics of NMDARs are largely unknown. In this work, we use extensive molecular dynamics simulations of GluN1 and GluN2B ligand binding domains (LBDs) of NMDARs to investigate these effects. Our simulations predict that intra-domain interactions involving the glycan attached to residue GluN1-N440 stabilize closed-clamshell conformations of the GluN1 LBD. The glycan on GluN2B-N688 shows a similar, though weaker, effect. Based on these results, and assuming the transferability of the results of LBD simulations to the full receptor, we predict that glycans at GluN1-N440 might play a potentiator role in NMDARs. To validate this prediction, we perform electrophysiological analysis of full-length NMDARs with a glycosylation-preventing GluN1-N440Q mutation, and demonstrate an increase in the glycine EC50 value. Overall, our results suggest an intramolecular potentiating role of glycans on NMDA receptors.

NMDA inhibits oxotremorine-induced acid secretion via the NO-dependent cyclic GMP system in rat stomach.

PubMed

Tsai, L H; Lee, Y J

2001-12-31

The mechanism of N-methyl-D-aspartate (NMDA) inhibits oxotremorine-induced acid secretion was examined in rat stomach, in relation to the cyclic GMP system. NMDA (10(-7) M) did not affect the spontaneous acid secretion from the everted preparations of isolated rat stomach, but inhibited the acid secretion stimulated by oxotremorine, and this effect of NMDA was antagonized by 2-amino-5-phosphonovaleric acid (AP-5), (+/-)3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) or N(G)-nitro-L-arginine (L-NNA). NMDA also elevated the cyclic GMP content of mucosal slices from rat stomach, and this effect of NMDA was antagonized by L-NNA. These results indicate that NMDA receptors are present in the rat stomach and regulate the gastric acid secretion. The mechanism underlying the effect of NMDA inhibits oxotremorine-induced acid secretion may be mediated by the NO-dependent cyclic GMP system.

Effects of ibuprofen on cognition and NMDA receptor subunit expression across aging.

PubMed

Márquez Loza, Alejandra; Elias, Valerie; Wong, Carmen P; Ho, Emily; Bermudez, Michelle; Magnusson, Kathy R

2017-03-06

Age-related declines in long- and short-term memory show relationships to decreases in N-methyl-d-aspartate (NMDA) receptor expression, which may involve inflammation. This study was designed to determine effects of an anti-inflammatory drug, ibuprofen, on cognitive function and NMDA receptor expression across aging. Male C57BL/6 mice (ages 5, 14, 20, and 26months) were fed ibuprofen (375ppm) in NIH31 diet or diet alone for 6weeks prior to testing. Behavioral testing using the Morris water maze showed that older mice performed significantly worse than younger in spatial long-term memory, reversal, and short-term memory tasks. Ibuprofen enhanced overall performance in the short-term memory task, but this appeared to be more related to improved executive function than memory. Ibuprofen induced significant decreases over all ages in the mRNA densities for GluN2B subunit, all GluN1 splice variants, and GluN1-1 splice forms in the frontal cortex and in protein expression of GluN2A, GluN2B and GluN1 C2' cassettes in the hippocampus. GluN1-3 splice form mRNA and C2' cassette protein were significantly increased across ages in frontal lobes of ibuprofen-treated mice. Ibuprofen did not alter expression of pro-inflammatory cytokines IL-1β and TNFα, but did reduce the area of reactive astrocyte immunostaining in frontal cortex of aged mice. Enhancement in executive function showed a relationship to increased GluN1-3 mRNA and decreased gliosis. These findings suggest that inflammation may play a role in executive function declines in aged animals, but other effects of ibuprofen on NMDA receptors appeared to be unrelated to aging or inflammation. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Effects of Ibuprofen on Cognition and NMDA Receptor Subunit Expression Across Aging

PubMed Central

Loza, Alejandra Márquez; Elias, Valerie; Wong, Carmen P.; Ho, Emily; Bermudez, Michelle; Magnusson, Kathy R.

2017-01-01

Age-related declines in long- and short-term memory show relationships to decreases in N-methyl-D-aspartate (NMDA) receptor expression, which may involve inflammation. This study was designed to determine effects of an anti-inflammatory drug, ibuprofen, on cognitive function and NMDA receptor expression across aging. Male C57BL/6 mice (ages 5, 14, 20, and 26 months) were fed ibuprofen (375 ppm) in NIH31 diet or diet alone for 6 weeks prior to testing. Behavioral testing using the Morris water maze showed that older mice performed significantly worse than younger in spatial long-term memory, reversal, and short-term memory tasks. Ibuprofen enhanced overall performance in the short-term memory task, but this appeared to be more related to improved executive function than memory. Ibuprofen induced significant decreases over all ages in the mRNA densities for GluN2B subunit, all GluN1 splice variants, and GluN1-1 splice forms in the frontal cortex and in protein expression of GluN2A, GluN2B and GluN1 C2′ cassettes in the hippocampus. GluN1-3 splice form mRNA and C2′ cassette protein were significantly increased across ages in frontal lobes of ibuprofen-treated mice. Ibuprofen did not alter expression of pro-inflammatory cytokines IL-1β and TNFα, but did reduce the area of reactive astrocyte immunostaining in frontal cortex of aged mice. Enhancement in executive function showed a relationship to increased GluN1-3 mRNA and decreased gliosis. These findings suggest that inflammation may play a role in executive function declines in aged animals, but other effects of ibuprofen on NMDA receptors appeared to be unrelated to aging or inflammation. PMID:28057539

Synaptic GluN2A and GluN2B Containing NMDA Receptors within the Superficial Dorsal Horn Activated following Primary Afferent Stimulation

PubMed Central

MacDermott, Amy B.

2014-01-01

NMDA receptors are important elements in pain signaling in the spinal cord dorsal horn. They are heterotetramers, typically composed of two GluN1 and two of four GluN2 subunits: GluN2A-2D. Mice lacking some of the GluN2 subunits show deficits in pain transmission yet functional synaptic localization of these receptor subtypes in the dorsal horn has not been fully resolved. In this study, we have investigated the composition of synaptic NMDA receptors expressed in monosynaptic and polysynaptic pathways from peripheral sensory fibers to lamina I neurons in rats. We focused on substance P receptor-expressing (NK1R+) projection neurons, critical for expression of hyperalgesia and allodynia. EAB-318 and (R)-CPP, GluN2A/B antagonists, blocked both monosynaptic and polysynaptic NMDA EPSCs initiated by primary afferent activation by ∼90%. Physiological measurements exploiting the voltage dependence of monosynaptic EPSCs similarly indicated dominant expression of GluN2A/B types of synaptic NMDA receptors. In addition, at synapses between C fibers and NK1R+ neurons, NMDA receptor activation initiated a secondary, depolarizing current. Ifenprodil, a GluN2B antagonist, caused modest suppression of monosynaptic NMDA EPSC amplitudes, but had a widely variable, sometimes powerful, effect on polysynaptic responses following primary afferent stimulation when inhibitory inputs were blocked to mimic neuropathic pain. We conclude that GluN2B subunits are moderately expressed at primary afferent synapses on lamina I NK1R+ neurons, but play more important roles for polysynaptic NMDA EPSCs driven by primary afferents following disinhibition, supporting the view that the analgesic effect of the GluN2B antagonist on neuropathic pain is at least in part, within the spinal cord. PMID:25122884

Functional interaction of mGlu5 and NMDA receptors in aversive learning in rats

PubMed Central

Fowler, S.W.; Ramsey, A.K.; Walker, J.M.; Serfozo, P.; Olive, M.F.; Schachtman, T.R.; Simonyi, A.

2010-01-01

Metabotropic glutamate receptor 5 (mGlu5) has been implicated in a variety of learning processes and is important for inhibitory avoidance and conditioned taste aversion learning. MGlu5 receptors are physically connected with NMDA receptors and they interact with, and modulate, the function of one another in several brain regions. The present studies used systemic co-administration of an mGlu5 receptor positive allosteric modulator, 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and an NMDA receptor antagonist dizocilpine maleate (MK-801) to characterize the interactions of these receptors in two aversive learning tasks. Male Sprague-Dawley rats were trained in a single-trial step-down inhibitory avoidance or conditioned taste aversion task. CDPPB (3 or 10 mg/kg, s.c.), delivered by itself prior to the conditioning trial, did not have any effect on performance in either task 48 hours after training. However, CDPPB (at 3 mg/kg) attenuated the MK-801 (0.2 mg/kg, i.p.) induced learning deficit in both tasks. CDPPB also reduced MK-801-induced hyperactivity. These results underlie the importance of mGlu5 and NMDA receptor interactions in modulating memory processing, and are consistent with findings showing the efficacy of positive allosteric modulators of mGlu5 receptors in reversing the negative effects of NMDA receptor antagonists on other behaviors such as stereotypy, sensorimotor gating, or working, spatial and recognition memory. PMID:21093598

Protection by imidazol(ine) drugs and agmatine of glutamate-induced neurotoxicity in cultured cerebellar granule cells through blockade of NMDA receptor

PubMed Central

Olmos, Gabriel; DeGregorio-Rocasolano, Nuria; Regalado, M Paz; Gasull, Teresa; Boronat, M Assumpció; Trullas, Ramón; Villarroel, Alvaro; Lerma, Juan; García-Sevilla, Jesús A

1999-01-01

This study was designed to assess the potential neuroprotective effect of several imidazol(ine) drugs and agmatine on glutamate-induced necrosis and on apoptosis induced by low extracellular K+ in cultured cerebellar granule cells.Exposure (30 min) of energy deprived cells to L-glutamate (1–100 μM) caused a concentration-dependent neurotoxicity, as determined 24 h later by a decrease in the ability of the cells to metabolize 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) into a reduced formazan product. L-glutamate-induced neurotoxicity (EC50=5 μM) was blocked by the specific NMDA receptor antagonist MK-801 (dizocilpine).Imidazol(ine) drugs and agmatine fully prevented neurotoxicity induced by 20 μM (EC100) L-glutamate with the rank order (EC50 in μM): antazoline (13)>cirazoline (44)>LSL 61122 [2-styryl-2-imidazoline] (54)>LSL 60101 [2-(2-benzofuranyl) imidazole] (75)>idazoxan (90)>LSL 60129 [2-(1,4-benzodioxan-6-yl)-4,5-dihydroimidazole] (101)>RX821002 (2-methoxy idazoxan) (106)>agmatine (196). No neuroprotective effect of these drugs was observed in a model of apoptotic neuronal cell death (reduction of extracellular K+) which does not involve stimulation of NMDA receptors.Imidazol(ine) drugs and agmatine fully inhibited [3H]-(+)-MK-801 binding to the phencyclidine site of NMDA receptors in rat brain. The profile of drug potency protecting against L-glutamate neurotoxicity correlated well (r=0.90) with the potency of the same compounds competing against [3H]-(+)-MK-801 binding.In HEK-293 cells transfected to express the NR1-1a and NR2C subunits of the NMDA receptor, antazoline and agmatine produced a voltage- and concentration-dependent block of glutamate-induced currents. Analysis of the voltage dependence of the block was consistent with the presence of a binding site for antazoline located within the NMDA channel pore with an IC50 of 10–12 μM at 0 mV.It is concluded that imidazol(ine) drugs and agmatine are

The effect of 1800MHz radio-frequency radiation on NMDA receptor subunit NR1 expression and peroxidation in the rat brain in healthy and inflammatory states.

PubMed

Bodera, Paweł; Makarova, Katerina; Zawada, Katarzyna; Antkowiak, Bożena; Paluch, Małgorzata; Sobiczewska, Elżbieta; Sirav, Bahriye; Siwicki, Andrzej K; Stankiewicz, Wanda

2017-08-01

The aim of this study was to evaluate the effect of repeated exposure (5 times for 15min) of 1800MHz radio-frequency radiation (RFR) on N-methyl-d-aspartate receptor subunit NR1 (NMDA-NR1) expression in the brains of rats in a persistent inflammatory state. We also measured the effect of RFR combined with tramadol (TRAM) to determine the potential antioxidant capacity of this agent. The effects of the Global System for Mobile Communication (GSM) modulated 1800MHz RFR exposure on the expression and activity of glutamate receptor channels with antioxidative activity in brain tissue was measured using oxygen radical absorbance capacity (ORAC) and electron spin resonance (ESR) detection of the hydroxyl radical generated by the Fenton reaction. NMDA-NR1 was measured in the cerebral tissue of rats with inflammation (complete Freund's adjuvent) and those injected with tramadol after RFR exposure (RFR, RFR/TRAM) and in non-exposed (baseline, TRAM) rats. No differences between the baseline group and the exposed group (RFR) were observed. NMDA-NR1 expression decreased after CFA injection and RFR exposure, and an elevated expression of NMDA-NR1 was observed in healthy control rats of both groups: TRAM/RFR and RFR. ORAC assessment revealed a robust effect of RFR, however the other experiments revealed equivocal effects. Further studies examining the combination of ORAC with NMDA are warranted to elucidate more clearly the effect of RFR on the brain. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Synthesis of water-soluble polyamine derivatives effective as N-methyl-D-aspartate receptor antagonists.

PubMed

Masuko, Takashi; Yoshida, Shuhei; Metori, Koichi; Kizawa, Yasuo; Kusama, Tadashi; Miyake, Muneharu

2010-06-01

The novel water-soluble N-methyl-D-aspartate (NMDA) receptor antagonists, N-{4-[4-(4-Guanidinobutylamino)butylamino]butyl}-p-toluenesulfonamide trihydrochloride (1a, TsHSPMG), N-{4-[4-(4-Guanidinobutylamino)butylamino]butyl}butane-1-sulfonamide trihydrochloride (1b, BsHSPMG), N-{3-[4-(3-Guanidinopropylamino)butylamino]propyl}-p-toluenesulfonamide trihydrochroride (2a, TsSPMG) and N-{3-[4-(3-Guanidinopropylamino)butylamino]propyl}butane-1-sulfonamide trihydrochroride (2b, BsSPMG), were synthesized, and the effects of these polyamine derivatives on NMDA receptors were studied using voltage-clamp recordings of recombinant NMDA receptors expressed in Xenopus oocytes. Although spermine potentiates 153% and 310% of NMDA (NR1A/NR2B) receptors in the presence of saturated and unsaturated glycine, respectively, all the novel polyamine derivatives, TsHSPMG (1a), BsHSPMG (1b), TsSPMG (2a) and BsSPMG (2b), significantly inhibited NR1A/NR2B receptors in both conditions. The degree of NMDA receptor inhibition by TsHSPMG (1a) and BsHSPMG (1b) was stronger than that by TsSPMG (2a) and BsSPMG (2b).

Single-channel activations and concentration jumps: comparison of recombinant NR1a/NR2A and NR1a/NR2D NMDA receptors

PubMed Central

Wyllie, David J A; Béhé, Philippe; Colquhoun, David

1998-01-01

We have expressed recombinant NR1a/NR2A and NR1a/NR2D N-methyl-D-aspartate (NMDA) receptor channels in Xenopus oocytes and made recordings of single-channel and macroscopic currents in outside-out membrane patches. For each receptor type we measured (a) the individual single-channel activations evoked by low glutamate concentrations in steady-state recordings, and (b) the macroscopic responses elicited by brief concentration jumps with high agonist concentrations, and we explore the relationship between these two sorts of observation. Low concentration (5–100 nM) steady-state recordings of NR1a/NR2A and NR1a/NR2D single-channel activity generated shut-time distributions that were best fitted with a mixture of five and six exponential components, respectively. Individual activations of either receptor type were resolved as bursts of openings, which we refer to as ‘super-clusters’. During a single activation, NR1a/NR2A receptors were open for 36 % of the time, but NR1a/NR2D receptors were open for only 4 % of the time. For both, distributions of super-cluster durations were best fitted with a mixture of six exponential components. Their overall mean durations were 35.8 and 1602 ms, respectively. Steady-state super-clusters were aligned on their first openings and averaged. The average was well fitted by a sum of exponentials with time constants taken from fits to super-cluster length distributions. It is shown that this is what would be expected for a channel that shows simple Markovian behaviour. The current through NR1a/NR2A channels following a concentration jump from zero to 1 mM glutamate for 1 ms was well fitted by three exponential components with time constants of 13 ms (rising phase), 70 ms and 350 ms (decaying phase). Similar concentration jumps on NR1a/NR2D channels were well fitted by two exponentials with means of 45 ms (rising phase) and 4408 ms (decaying phase) components. During prolonged exposure to glutamate, NR1a/NR2A channels desensitized

The role of NMDA receptors in human eating behavior: evidence from a case of anti-NMDA receptor encephalitis.

PubMed

Perogamvros, Lampros; Schnider, Armin; Leemann, Beatrice

2012-06-01

Research in animal models has implicated N-methyl-D-aspartate (NMDA) receptors (NMDARs) in the control of food intake. Until now, these findings have been not replicated in humans. Here we describe a 22-year-old woman with anti-NMDAR encephalitis and no prior neurological or psychiatric history. Her clinical course was marked by successive eating disorders: anorexia followed by hyperphagia. We propose that, much as they do in other animals, NMDARs in humans interact with the neuroendocrine, homeostatic, and reward systems controlling food intake in the central and peripheral nervous system structures related to feeding and satiety.

The NMDA receptor/ion channel complex: a drug target for modulating synaptic plasticity and excitotoxicity.

PubMed

Albensi, Benedict C

2007-01-01

A recent search on PubMed for the phrase NMDA receptor results in 2,190 hits on this topic for review articles and 20,100 hits for experimental papers. This is a direct reflection of the intensiveness, significance, and complexity associated with the research on this key receptor protein over the last several decades. In this review, we briefly describe the NMDA receptor structure, discuss the role of NMDA receptors in modulating synaptic plasticity and excitotoxicity, explore age-dependent changes in NMDA receptor functioning, and survey interesting NMDA receptor blockers. Given the huge existing literature on the subject, an exhaustive review has not been endeavored. Instead, an attempt was made to point out those studies that have been instrumental in the field or that are of special interest.

Spinal NMDA-receptor dependent amplification of nociceptive transmission to rat primary somatosensory cortex (SI).

PubMed

Kalliomäki, Jarkko; Granmo, Marcus; Schouenborg, Jens

2003-07-01

The role of NMDA mechanisms in spinal pathways mediating acute nociceptive input to the somatosensory cortex is not clear. In this study, the effect of NMDA-antagonists on nociceptive C fibre transmission to the primary somatosensory cortex (SI) was investigated. Cortical field potentials evoked by CO(2)-laser stimulation of the skin were recorded in the halothane/nitrous oxide anaesthetized rat. The SI nociceptive evoked potential (EP) amplitudes were dependent on the frequency of noxious heat stimulation. The amplitudes of SI potentials evoked by CO(2)-laser pulses (duration 15-20 ms, stimulation energy 21-28 mJ/mm(2)) delivered at a frequency of 0.1 Hz were approximately 40% of the amplitudes of potentials evoked by 1.0 Hz stimulation. After intrathecal lumbar application of either of the NMDA-antagonists CPP or MK-801, the amplitudes of nociceptive SI potentials, evoked by 1.0 Hz stimulation of the contralateral hindpaw, were reduced to approximately 40% of controls. By contrast, field potentials evoked by 0.1 Hz stimulation of the hindpaw were unaffected by MK-801. SI potentials evoked by 1.0 Hz stimulation of the contralateral forepaw did not change after lumbar application of CPP or MK-801, indicating that the depression of hindpaw EPs was due to a segmental effect in the spinal cord. It is concluded that spinal NMDA-receptor mechanisms amplify the acute transmission of nociceptive C fiber input to SI in a frequency-dependent way.

Dopamine D2/D3 but not dopamine D1 receptors are involved in the rapid antidepressant-like effects of ketamine in the forced swim test.

PubMed

Li, Yan; Zhu, Zhuo R; Ou, Bao C; Wang, Ya Q; Tan, Zhou B; Deng, Chang M; Gao, Yi Y; Tang, Ming; So, Ji H; Mu, Yang L; Zhang, Lan Q

2015-02-15

Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses. The traditional antidepressants often take several weeks, even months, to obtain clinical effects. However, recent clinical studies have shown that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, exerts rapid antidepressant effects within 2h and are long-lasting. The aim of the present study was to investigate whether dopaminergic system was involved in the rapid antidepressant effects of ketamine. The acute administration of ketamine (20 mg/kg) significantly reduced the immobility time in the forced swim test. MK-801 (0.1 mg/kg), the more selective NMDA antagonist, also exerted rapid antidepressant-like effects. In contrast, fluoxetine (10 mg/kg) did not significantly reduced the immobility time in the forced swim test after 30 min administration. Notably, pretreatment with haloperidol (0.15 mg/kg, a nonselective dopamine D2/D3 antagonist), but not SCH23390 (0.04 and 0.1 mg/kg, a selective dopamine D1 receptor antagonist), significantly prevented the effects of ketamine or MK-801. Moreover, the administration of sub-effective dose of ketamine (10 mg/kg) in combination with pramipexole (0.3 mg/kg, a dopamine D2/D3 receptor agonist) exerted antidepressant-like effects compared with each drug alone. In conclusion, our results indicated that the dopamine D2/D3 receptors, but not D1 receptors, are involved in the rapid antidepressant-like effects of ketamine. Copyright © 2014 Elsevier B.V. All rights reserved.

Alterations in NMDA receptor expression during retinal degeneration in the RCS rat.

PubMed

Gründer, T; Kohler, K; Guenther, E

2001-01-01

To determine how a progressive loss of photoreceptor cells and the concomitant loss of glutamatergic input to second-order neurons can affect inner-retinal signaling, glutamate receptor expression was analyzed in the Royal College of Surgeons (RCS) rat, an animal model of retinitis pigmentosa. Immunohistochemistry was performed on retinal sections of RCS rats and congenic controls between postnatal (P) day 3 and the aged adult (up to P350) using specific antibodies against N-methyl-D-aspartate (NMDA) subunits. All NMDA subunits (NR1, NR2A-2D) were expressed in control and dystrophic retinas at all ages, and distinct patterns of labeling were found in horizontal cells, subpopulations of amacrine cells and ganglion cells, as well as in the outer and inner plexiform layer (IPL). NRI immunoreactivity in the inner plexiform layer of adult control retinas was concentrated in two distinct bands, indicating a synaptic localization of NMDA receptors in the OFF and ON signal pathways. In the RCS retina, these bands of NRI immunoreactivity in the IPL were much weaker in animals older than P40. In parallel, NR2B immunoreactivity in the outer plexiform layer (OPL) of RCS rats was always reduced compared to controls and vanished between P40 and P120. The most striking alteration observed in the degenerating retina, however, was a strong expression of NRI immunoreactivity in Müller cell processes in the inner retina which was not observed in control animals and which was present prior to any visible sign of photoreceptor degeneration. The results suggest functional changes in glutamatergic receptor signaling in the dystrophic retina and a possible involvement of Müller cells in early processes of this disease.

Enhancing and impairing extinction of habit memory through modulation of NMDA receptors in the dorsolateral striatum.

PubMed

Goodman, Jarid; Ressler, Reed L; Packard, Mark G

2017-06-03

The present experiments investigated the involvement of N-methyl-d-aspartate (NMDA) receptors of the dorsolateral striatum (DLS) in consolidation of extinction in a habit memory task. Adult male Long-Evans rats were initially trained in a food-reinforced response learning version of a plus-maze task and were subsequently given extinction training in which the food was removed from the maze. In experiment 1, immediately after the first day of extinction training, rats received bilateral intra-DLS injections of the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5; 2µg/side) or physiological saline. In experiment 2, immediately following the first day of extinction training, animals were given intra-DLS injections of NMDA receptor partial agonist d-cycloserine (DCS; 10 or 20µg/side) or saline. In both experiments, the number of perseverative trials (a trial in which a rat made the same previously reinforced body-turn response) and latency to reach the previously correct food well were used as measures of extinction behavior. Results indicated that post-training intra-DLS injections of AP5 impaired extinction. In contrast, post-training intra-DLS infusions of DCS (20µg) enhanced extinction. Intra-DLS administration of AP5 or DCS given two hours after extinction training did not influence extinction of response learning, indicating that immediate post-training administration of AP5 and DCS specifically influenced consolidation of the extinction memory. The present results indicate a critical role for DLS NMDA receptors in modulating extinction of habit memory and may be relevant to developing therapeutic approaches to combat the maladaptive habits observed in human psychopathologies in which DLS-dependent memory has been implicated (e.g. drug addiction and relapse and obsessive compulsive disorder). Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

NR2B-containing NMDA receptors promote neural progenitor cell proliferation through CaMKIV/CREB pathway

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

Li, Mei, E-mail: limeihit@163.com; Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing; Zhang, Dong-Qing

2011-08-12

Highlights: {yields} The NR2B component of the NMDARs is important for the NSPC proliferation. {yields} pCaMKIV and pCREB exist in NSPCs. {yields} The CaMKIV/CREB pathway mediates NSPC proliferation. -- Abstract: Accumulating evidence indicates the involvement of N-methyl-D-aspartate receptors (NMDARs) in regulating neural stem/progenitor cell (NSPC) proliferation. Functional properties of NMDARs can be markedly influenced by incorporating the regulatory subunit NR2B. Here, we aim to analyze the effect of NR2B-containing NMDARs on the proliferation of hippocampal NSPCs and to explore the mechanism responsible for this effect. NSPCs were shown to express NMDAR subunits NR1 and NR2B. The NR2B selective antagonist, Romore » 25-6981, prevented the NMDA-induced increase in cell proliferation. Moreover, we demonstrated that the phosphorylation levels of calcium/calmodulin-dependent protein kinase IV (CaMKIV) and cAMP response element binding protein (CREB) were increased by NMDA treatment, whereas Ro 25-6981 decreased them. The role that NR2B-containing NMDARs plays in NSPC proliferation was abolished when CREB phosphorylation was attenuated by CaMKIV silencing. These results suggest that NR2B-containing NMDARs have a positive role in regulating NSPC proliferation, which may be mediated through CaMKIV phosphorylation and subsequent induction of CREB activation.« less

Sensory transduction of weak electromagnetic fields: role of glutamate neurotransmission mediated by NMDA receptors.

PubMed

Frilot, C; Carrubba, S; Marino, A A

2014-01-31

Subliminal electromagnetic fields (EMFs) triggered nonlinear evoked potentials in awake but not anesthetized animals, and increased glucose metabolism in the hindbrain. Field detection occurred somewhere in the head and possibly was an unrecognized function of sensory neurons in facial skin, which synapse in the trigeminal nucleus and project to the thalamus via glutamate-dependent pathways. If so, anesthetic agents that antagonize glutamate neurotransmission would be expected to degrade EMF-evoked potentials (EEPs) to a greater extent than agents having different pharmacological effects. We tested the hypothesis using ketamine which blocks N-methyl-d-aspartate (NMDA) receptors (NMDARs), and xylazine which is an α₂-adrenoreceptor agonist. Electroencephalograms (EEGs) of rats were examined using recurrence analysis to observe EEPs in the presence and absence of ketamine and/or xylazine anesthesia. Auditory evoked potentials (AEPs) served as positive controls. The frequency of observation of evoked potentials in a given condition (wake or anesthesia) was compared with that due to chance using the Fisher's exact test. EEPs were observed in awake rats but not while they were under anesthesia produced using a cocktail of xylazine and ketamine. In another experiment each rat was measured while awake and while under anesthesia produced using either xylazine or ketamine. EEPs and AEPs were detected during wake and under xylazine (P<0.05 in each of the four measurements). In contrast, neither EEPs nor AEPs were observed when anesthesia was produced partly or wholly using ketamine. The duration and latency of the EEPs was unaltered by xylazine anesthesia. The afferent signal triggered by the transduction of weak EMFs was likely mediated by NMDAR-mediated glutamate neurotransmission. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Prenatal exposure to an NMDA receptor antagonist, MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to methamphetamine in postpubertal rats.

PubMed

Abekawa, Tomohiro; Ito, Koki; Nakagawa, Shin; Koyama, Tsukasa

2007-06-01

Neurodevelopmental deficits of parvalbumin-immunoreactive gamma-aminobutyric acid (GABA)ergic interneurons in prefrontal cortex have been reported in schizophrenia. Glutamate influences the proliferation of this type of interneuron by an N-methyl-D-aspartate (NMDA)-receptor-mediated mechanism. The present study hypothesized that prenatal blockade of NMDA receptors would disrupt GABAergic neurodevelopment, resulting in differences in effects on behavioral responses to a noncompetitive NMDA antagonist, phencyclidine (PCP), and a dopamine releaser, methamphetamine (METH). GABAergic neurons were immunohistochemically stained with parvalbumin antibody. Psychostimulant-induced hyperlocomotion was measured using an infrared sensor. Prenatal exposure (E15-E18) to the NMDA receptor antagonist MK-801 reduced the density of parvalbumin-immunoreactive neurons in rat medial prefrontal cortex on postnatal day 63 (P63) and enhanced PCP-induced hyperlocomotion but not the acute effects of METH on P63 or the development of behavioral sensitization. Prenatal exposure to MK-801 reduced the number of parvalbumin-immunoreactive neurons even on postnatal day 35 (P35) and did not enhance PCP-induced hyperlocomotion, the acute effects of METH on P35, or the development of behavioral sensitization to METH. These findings suggest that prenatal blockade of NMDA receptors disrupts GABAergic neurodevelopment in medial prefrontal cortex, and that this disruption of GABAergic development may be related to the enhancement of the locomotion-inducing effect of PCP in postpubertal but not juvenile offspring. GABAergic deficit is unrelated to the effects of METH. This GABAergic neurodevelopmental disruption and the enhanced PCP-induced hyperlocomotion in adult offspring prenatally exposed to MK-801 may prove useful as a new model of the neurodevelopmental process of pathogenesis of treatment-resistant schizophrenia via an NMDA-receptor-mediated hypoglutamatergic mechanism.

Temporal-difference prediction errors and Pavlovian fear conditioning: role of NMDA and opioid receptors.

PubMed

Cole, Sindy; McNally, Gavan P