Glycine Binding Site Research Articles

Exploring the Activation Process of the Glycine Receptor.

Glycine receptors (GlyR) conduct inhibitory glycinergic neurotransmission in the spinal cord and the brainstem. They play an important role in muscle tone, motor coordination, respiration, and pain perception. However, the mechanism underlying GlyR activation remains unclear. There are five potential glycine binding sites in α1 GlyR, and different binding patterns may cause distinct activation or desensitization behaviors. In this study, we investigated the coupling of protein conformational changes and glycine binding events to elucidate the influence of binding patterns on the activation and desensitization processes of α1 GlyRs. Subsequently, we explored the energetic distinctions between the apical and lateral pathways during α1 GlyR conduction to identify the pivotal factors in the ion conduction pathway preference. Moreover, we predicted the mutational effects of the key residues and verified our predictions using electrophysiological experiments. For the mutants that can be activated by glycine, the predictions of the mutational directions were all correct. The strength of the mutational effects was assessed using Pearson's correlation coefficient, yielding a value of -0.77 between the calculated highest energy barriers and experimental maximum current amplitudes. These findings contribute to our understanding of GlyR activation, identify the key residues of GlyRs, and provide guidance for mechanistic studies on other pLGICs.

Dual-step pharmacological intervention for traumatic-like memories: implications from D-cycloserine and cannabidiol or clonidine in male and female rats.

Therapeutic approaches to mitigating traumatic memories have often faced resistance. Exploring safe reconsolidation blockers, drugs capable of reducing the emotional valence of the memory upon brief retrieval and reactivation, emerges as a promising pharmacological strategy. Towards this objective, preclinical investigations should focus on aversive memories resulting in maladaptive outcomes and consider sex-related differences to enhance their translatability. After selecting a relatively high training magnitude leading to the formation of a more intense and generalized fear memory in adult female and male rats, we investigated whether two clinically approved drugs disrupting its reconsolidation remain effective. We found resistant reconsolidation impairment by the α2-adrenergic receptor agonist clonidine or cannabidiol, a major non-psychotomimetic Cannabis sativa component. However, pre-retrieval administration of D-cycloserine, a partial agonist at the glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor complex, facilitated their impairing effects on reconsolidation. A similar reconsolidation blockade by clonidine or cannabidiol was achieved following exposure to a non-conditioned but generalized context after D-cycloserine administration. This suggests that sufficient memory destabilization can accompany generalized fear expression. Combining clonidine with cannabidiol without potentiating memory destabilization by D-cycloserine was ineffective. These findings highlight the importance of NMDA receptor signaling in memory destabilization and underscore the efficacy of a dual-step pharmacological intervention in attenuating traumatic-like memories, even in a context different from the original learning environment.

Design, synthesis and evaluation of novel 1-phenyl-pyrrolo[1,2-b]isoquinolin-3-one derivatives as antagonists for the glycine binding site of the NMDA receptor

A new series of 1-phenyl-pyrrolo[1,2-b]isoquinolin-3-one derivatives were designed, synthesized and demonstrated to act as antagonists for the glycine binding site of the NMDA receptor. These new derivatives protected PC12 cells against NMDA-induced injury and cell apoptosis in vitro, among which compound 13b exhibited excellent cytoneuroprotective potency and shown a dose-dependent prevention. The increased intracellular Ca2+ influx caused by NMDA in PC12 cells was reversed when pretreated with compound 13b. Furthermore, the interaction between compound 13b and the glycine binding site of the NMDA receptor was validated via MST assay. It was observed that the stereochemistry of compound 13b did not influence the binding affinity, which was consistent with the neuroprotective result. Molecular docking study confirmed the observed activity of compound 13b by virtue of their Pi-stacking, cation-Pi, H-bonding and Pi-electron interactions with the key amino acids in the glycine binding pocket. These results confirm the potential of 1-phenyl-pyrrolo[1,2-b]isoquinolin-3-one derivatives as neuroprotective agents targeting the glycine binding site of the NMDA receptor.

NMDA Receptor Glycine Binding Site Modulators for Prevention and Treatment of Ketamine Use Disorder.

Ketamine offers a fast-acting approach to relieving treatment-resistant depression, but its abuse potential is an issue of concern. As ketamine is a noncompetitive N-methyl-D-aspartate receptor (NMDAR) ion channel blocker, modulation of NMDAR might be an effective strategy to counteract the abuse liability of ketamine and even to treat ketamine use disorder. This study evaluated whether NMDAR modulators that act on glycine binding sites can decrease motivation to obtain ketamine and reduce reinstatement to ketamine-seeking behavior. Two NMDAR modulators, D-serine and sarcosine were examined. Male Sprague-Dawley rats underwent training to acquire the ability to self-administer ketamine. The motivation to self-administer ketamine or sucrose pellets was examined under a progressive ratio (PR) schedule. The reinstatement of ketamine-seeking and sucrose pellet-seeking behaviors were assessed after extinction. The results showed that both D-serine and sarcosine significantly decreased the breakpoints for ketamine and prevented reinstatement of ketamine seeking. However, these modulators did not alter motivated behavior for sucrose pellets, the ability of the cue and sucrose pellets to reinstate sucrose-seeking behavior or spontaneous locomotor activity. These findings indicate that two NMDAR modulators can specifically reduce the measures of motivation and relapse for ketamine in rats, suggesting that targeting the glycine binding site of the NMDAR is a promising approach for preventing and treating ketamine use disorder.

Allosteric modulation of GluN1/GluN3 NMDA receptors by GluN1-selective competitive antagonists.

NMDA-type ionotropic glutamate receptors are critical for normal brain function and are implicated in central nervous system disorders. Structure and function of NMDA receptors composed of GluN1 and GluN3 subunits are less understood compared to those composed of GluN1 and GluN2 subunits. GluN1/3 receptors display unusual activation properties in which binding of glycine to GluN1 elicits strong desensitization, while glycine binding to GluN3 alone is sufficient for activation. Here, we explore mechanisms by which GluN1-selective competitive antagonists, CGP-78608 and L-689,560, potentiate GluN1/3A and GluN1/3B receptors by preventing glycine binding to GluN1. We show that both CGP-78608 and L-689,560 prevent desensitization of GluN1/3 receptors, but CGP-78608-bound receptors display higher glycine potency and efficacy at GluN3 subunits compared to L-689,560-bound receptors. Furthermore, we demonstrate that L-689,560 is a potent antagonist of GluN1FA+TL/3A receptors, which are mutated to abolish glycine binding to GluN1, and that this inhibition is mediated by a non-competitive mechanism involving binding to the mutated GluN1 agonist binding domain (ABD) to negatively modulate glycine potency at GluN3A. Molecular dynamics simulations reveal that CGP-78608 and L-689,560 binding or mutations in the GluN1 glycine binding site promote distinct conformations of the GluN1 ABD, suggesting that the GluN1 ABD conformation influences agonist potency and efficacy at GluN3 subunits. These results uncover the mechanism that enables activation of native GluN1/3A receptors by application of glycine in the presence of CGP-78608, but not L-689,560, and demonstrate strong intra-subunit allosteric interactions in GluN1/3 receptors that may be relevant to neuronal signaling in brain function and disease.

Common and Specific Effects of Selank, Noopept, and Semax to Glycine Site of the NMDA Receptor in BALB/c and C57Bl/6 Mice Brain

The effects of the nootropic peptides selank (300 mg/kg), noopept (1 mg/kg), and semax (0.6 mg/kg) after subchronic intraperitoneal (i.p.) and intranasal (i.n.) administration on the binding of [3H]-MDL105,51 to NMDA glycine site in BALB/c and C57Bl/6 mice brain were examined. It was found that in C57Bl/6 mice in comparison with BALB/c the number of glycine binding sites (Bmax) at baseline was 15% higher in the cortex and 47% lower in the hippocampus. In the cortex i.n. administration of selank, noopept, and semax resulted in 18, 19, and 66% decrease in the number of glycine binding sites in BALB/c mice, and in 53, 49, and 66% in C57Bl/6 mice, respectively. In the hippocampus i.n. administration of selank, noopept, and semax resulted in 15, 63, and 95% increase in the number of glycine binding sites in BALB/c mice, respectively, while in C57Bl/6 mice all three peptides were not effective. In the cortex i.p. administration of selank and semax decreased glycine binding sites by 24 and 40% in the cortex and by 11 and 19% in the hippocampus in BALB/c mice, while in C57Bl/6 mice the reduction was 15% and 47% in the cortex and 45 and 24% in the hippocampus, respectively. Noopept did not affect the binding. These patterns observed in the cortex after i.n. and i.p. administration appear to be common to the both mice strains suggesting an engagement of the cortical NMDA glycine site in action(s) that underlie some common pharmacological effects of the selected peptides. Whereas the specific effect of selank, noopept, and semax after i.n. administration in the BALB/c hippocampi may be associated with the mechanisms of nootropic and anxiolytic activities of these peptides manifested in that mice strain.

Opposite Modulation of the NMDA Receptor by Glycine and S-Ketamine and the Effects on Resting State EEG Gamma Activity: New Insights into the Glutamate Hypothesis of Schizophrenia.

NMDA-receptor hypofunction is increasingly considered to be an important pathomechanism in schizophrenia. However, to date, it has not been possible to identify patients with relevant NMDA-receptor hypofunction who would respond to glutamatergic treatments. Preclinical models, such as the ketamine model, could help identify biomarkers related to NMDA-receptor function that respond to glutamatergic modulation, for example, via activation of the glycine-binding site. We, therefore, aimed to investigate the effects of opposing modulation of the NMDA receptor on gamma activity (30-100 Hz) at rest, the genesis of which appears to be highly dependent on NMDA receptors. The effects of subanesthetic doses of S-ketamine and pretreatment with glycine on gamma activity at rest were examined in twenty-five healthy male participants using 64-channel electroencephalography. Psychometric scores were assessed using the PANSS and the 5D-ASC. While S-ketamine significantly increased psychometric scores and gamma activity at the scalp and in the source space, pretreatment with glycine did not significantly attenuate any of these effects when controlled for multiple comparisons. Our results question whether increased gamma activity at rest constitutes a suitable biomarker for the target engagement of glutamatergic drugs in the preclinical ketamine model. They might further point to a differential role of NMDA receptors in gamma activity generation.

Glutamate modulation for the treatment of levodopa induced dyskinesia: abrief review of the drugs tested in the clinic.

Levodopa is the standard treatment for Parkinson's disease, but its use is marred by the emergence of dyskinesia, for which treatment options remain limited. Here, we review the glutamatergic modulators that were assessed for their antidyskinetic potential in clinical trials, including N-methyl-D-aspartate (NMDA) antagonists, agonists at the glycine-binding site on NMDA receptors, metabotropic glutamate (mGlu) 4 agonists, mGlu5 antagonists, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonists and glutamate release inhibitors. Several agents that were investigated are not selective for their targets, raising uncertainty about the extent to which glutamatergic modulation contributed to their effects. Except for amantadine, the use of glutamatergic modulators for the treatment of dyskinesia in Parkinson's disease remains largely investigational, with promising results obtained with mGlu5 negative allosteric modulation.

D-serine metabolism in the medial prefrontal cortex, but not the hippocampus, is involved in AD/HD-like behaviors in SHRSP/Ezo

Attention-deficit/hyperactivity disorder (AD/HD) is a mild neurodevelopmental disorder with inattention, hyperactivity, and impulsivity as its core symptoms. We previously revealed that an AD/HD animal model, juvenile stroke-prone spontaneously hypertensive rats (SHRSP/Ezo) exhibited functional abnormalities in N-methyl-D-aspartate (NMDA) receptors in the prefrontal cortex. D-serine is an endogenous co-ligand that acts on the glycine-binding site of NMDA receptors, which is essential for the physiological activation of NMDA receptors. We herein performed neurochemical and pharmacological behavioral experiments to elucidate dysfunctions in D-serine metabolism (namely, biosynthesis and catabolism) associated to AD/HD.The serine enantiomers ratio (D-serine/D-serine + L-serine, DL ratio) in the medial prefrontal cortex (mPFC) and hippocampus (HIP) was lower in SHRSP/Ezo than in its genetic control. The level of D-amino acid oxidase (DAAO, D-serine degrading enzyme) was higher in the mPFC, and the level of serine racemase (SR, D-serine biosynthetic enzyme), was lower in the HIP in SHRSP/Ezo. Thus, changes in these enzymes may contribute to the lower DL ratio of SHRSP/Ezo. Moreover, a microinjection of a DAAO inhibitor into the mPFC in SHRSP/Ezo increased DL ratio and attenuated AD/HD-like behaviors, such as inattention and hyperactivity, in the Y-maze test. Injection into the HIP also increased the DL ratio, but had no effect on behaviors.These results suggest that AD/HD-like behaviors in SHRSP/Ezo are associated with an abnormal D-serine metabolism underlying NMDA receptor dysfunction in the mPFC. These results will contribute to elucidating the pathogenesis of AD/HD and the development of new treatment strategies for AD/HD.

Derivatives of (R)-3-(5-Furanyl)carboxamido-2-aminopropanoic Acid as Potent NMDA Receptor Glycine Site Agonists with GluN2 Subunit-Specific Activity.

NMDA receptors mediate glutamatergic neurotransmission and are therapeutic targets due to their involvement in a variety of psychiatric and neurological disorders. Here, we describe the design and synthesis of a series of (R)-3-(5-furanyl)carboxamido-2-aminopropanoic acid analogues 8a-s as agonists at the glycine (Gly) binding site in the GluN1 subunit, but not GluN3 subunits, of NMDA receptors. These novel analogues display highly variable potencies and agonist efficacies among the NMDA receptor subtypes (GluN1/2A-D) in a manner dependent on the GluN2 subunit. Notably, compound 8p is identified as a potent partial agonist at GluN1/2C (EC50 = 0.074 μM) with an agonist efficacy of 28% relative to activation by Gly and virtually no agonist activity at GluN1/2A, GluN1/2B, and GluN1/2D. Thus, these novel agonists can modulate the activity of specific NMDA receptor subtypes by replacing the full endogenous agonists Gly or d-serine (d-Ser), thereby providing new opportunities in the development of novel therapeutic agents.

Effect of the glycine transporter 1 inhibitor ALX-5407 on dyskinesia, psychosis-like behaviours and parkinsonism in the MPTP-lesioned marmoset

Dyskinesia and psychosis are complications encountered in advanced Parkinson's disease (PD) following long-term therapy with L-3,4-dihydroxyphenylalanine (L-DOPA). Disturbances in the glutamatergic system have been associated with both dyskinesia and psychosis, making glutamatergic modulation a potential therapeutic approach for these. Treatments thus far have sought to dampen glutamatergic transmission, for example through blockade of N-methyl-D-aspartate (NMDA) receptors or modulation of metabotropic glutamate receptors 5. In contrast, activation of the glycine-binding site on NMDA receptors is required for their physiological response. Here, we investigated whether indirectly enhancing glutamatergic transmission through inhibition of glycine re-uptake would be efficacious in diminishing both dyskinesia and psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset.Six marmosets were rendered parkinsonian by MPTP injection. Following repeated administration of L-DOPA to induce dyskinesia and PLBs, they underwent acute challenges of the glycine transporter 1 (GlyT1) inhibitor ALX-5407 (0.01, 0.1 and 1 mg/kg) or vehicle, in combination with L-DOPA, after which the severity of dyskinesia, PLBs and parkinsonian disability was evaluated.In combination with L-DOPA, ALX-5407 0.1 and 1 mg/kg significantly reduced the severity of dyskinesia, by 51% and 41% (both P < 0.001), when compared to vehicle. ALX-5407 0.01, 0.1 and 1 mg/kg also decreased the severity of global PLBs, by 25%, 51% and 38% (all P < 0.001), when compared to vehicle. The benefits on dyskinesia and PLBs were achieved without compromising the therapeutic effect of L-DOPA on parkinsonism.Our results suggest that GlyT1 inhibition may be a novel strategy to attenuate dyskinesia and PLBs in PD, without interfering with L-DOPA anti-parkinsonian action.

The Impact of NMDA Antagonists Ketamine and Prodrug 4-Chlorokynunerine (AV-101) in Subjects With Treatment-Resistant Mood Disorders

Glutamatergic dysfunction and immune system dysregulation are both thought to be involved in the pathophysiology of depression. One potential convergence point for these systems is the kynurenine (KYN) pathway. Notably, ketamine has rapid-acting and sustained antidepressant properties. 7-chlorokynurenic acid is a NMDA antagonist at glycine binding site Its prodrug, AV-101 is assumed to efficiently cross the blood-brain barrier and convert to 7-chlorokynurenic acid in the brain.

Converging Evidence on D-Amino Acid Oxidase-Dependent Enhancement of Hippocampal Firing Activity and Passive Avoidance Learning in Rats.

BackgroundN-methyl-D-aspartate (NMDA) receptor activation requires the binding of a co-agonist on the glycine-binding site. D-serine is the main endogenous co-agonist of NMDA receptors, and its availability significantly depends on the activity of the metabolic enzyme D-amino acid oxidase (DAAO). Inhibition of DAAO increases the brain levels of D-serine and modulates a variety of physiological functions, including cognitive behavior.MethodsHere, we examined the effects of a novel 4-hydroxypyridazin-3(2H)-one derivative DAAO inhibitor, Compound 30 (CPD30), on passive avoidance learning and on neuronal firing activity in rats.ResultsD-serine administration was applied as reference, which increased cognitive performance and enhanced hippocampal firing activity and responsiveness to NMDA after both local and systemic application. Similarly to D-serine, CPD30 (0.1 mg/kg) effectively reversed MK-801–induced memory impairment in the passive avoidance test. Furthermore, local iontophoretic application of CPD30 in the vicinity of hippocampal pyramidal neurons significantly increased firing rate and enhanced their responses to locally applied NMDA. CPD30 also enhanced hippocampal firing activity after systemic administration. In 0.1- to 1.0-mg/kg doses, CPD30 increased spontaneous and NMDA-evoked firing activity of the neurons. Effects of CPD30 on NMDA responsiveness emerged faster (at 10 minutes post-injection) when a 1.0-mg/kg dose was applied compared with the onset of the effects of 0.1 mg/kg CPD30 (at 30 minutes post-injection).ConclusionsThe present results confirm that the inhibition of DAAO enzyme is an effective strategy for cognitive enhancement. Our findings further facilitate the understanding of the cellular mechanisms underlying the behavioral effects of DAAO inhibition in the mammalian brain.

A Review of the Actions of D-cycloserine, a Putative Nootropic Agent, at the NMDA Receptor Complex-Associated Glycine Binding Site

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N,N-dimethylglycine prevents toluene-induced impairment in recognition memory and synaptic plasticity in mice

Toluene intoxication produces deleterious effects on cognitive function, which has been associated with the inhibition of N-methyl-d-aspartate receptor (NMDAR). The present study determined whether N,N-dimethylglycine (DMG), a nutrient supplement and a partial agonist for NMDAR glycine binding site, could counteract recognition memory deficits and hippocampal synaptic dysfunction after acute toluene exposure. Male ICR mice were treated with toluene (250−750 mg/kg) for monitoring the sociability and social novelty in three-chamber test and long-term potentiation (LTP) of hippocampal synaptic transmission. Moreover, the combined effects of DMG (30−100 mg/kg) pretreatment with toluene (750 mg/kg) on three-chamber test, novel location and object recognition test and synaptic function were determined. Toluene decreased the sociability, preference for social novelty, hippocampal synaptic transmission and LTP in a dose-dependent manner. DMG pretreatment significantly reduced the toluene-induced memory impairment in social recognition, object location and object recognition and synaptic dysfunction. Furthermore, NMDAR glycine binding site antagonist, 7-chlorokynurenic acid, abolished the protective effects of DMG. These results indicate that DMG could prevent toluene-induced recognition memory deficits and synaptic dysfunction and its beneficial effects might be associated with modulation of NMDAR. These findings suggest that DMG supplementation might be an effective approach to prevent memory problems for the workers at risk of high-level toluene exposure or toluene abusers.

Identification of the hypertension drug niflumic acid as a glycine receptor inhibitor

Glycine is one of the major neurotransmitters in the brainstem and the spinal cord. Glycine binds to and activates glycine receptors (GlyRs), increasing Cl− conductance at postsynaptic sites. This glycinergic synaptic transmission contributes to the generation of respiratory rhythm and motor patterns. Strychnine inhibits GlyR by binding to glycine-binding site, while picrotoxin blocks GlyR by binding to the channel pore. We have previously reported that bath application of strychnine to zebrafish embryos causes bilateral muscle contractions in response to tactile stimulation. To explore the drug-mediated inhibition of GlyRs, we screened a chemical library of ~ 1,000 approved drugs and pharmacologically active molecules by observing touch-evoked response of zebrafish embryos in the presence of drugs. We found that exposure of zebrafish embryos to nifedipine (an inhibitor of voltage-gated calcium channel) or niflumic acid (an inhibitor of cyclooxygenase 2) caused bilateral muscle contractions just like strychnine-treated embryos showed. We then assayed strychnine, picrotoxin, nifedipine, and niflumic acid for concentration-dependent inhibition of glycine-mediated currents of GlyRs in oocytes and calculated IC50s. The results indicate that all of them concentration-dependently inhibit GlyR in the order of strychnine > picrotoxin > nifedipine > niflumic acid.

Comparisons of Nociceptive Behavior and NMDA receptor‐Mediated Synaptic Transmission between Mice Lacking D‐Serine Production and Degradation Enzymes

D‐serine is the endogenous co‐agonist for the glycine‐binding site of the N‐methyl‐D‐aspartate (NMDA) glutamate receptor. D‐serine is produced by the enzyme serine racemase (SR) and is degraded by the enzyme D‐amino acid oxidase (DAO). Co‐activation of spinal NMDA receptors by D‐serine is known to play a significant role in the etiological mechanism of neuropathic and inflammatory pain. The present study aims to obtain further information on how D‐serine and its related enzymes (SR and DAO) are involved in the modulation of persistent pain.The experiments were performed on both SR knock‐out (SR‐KO) mice and the DAO‐mutant mice that lack the enzymatic activity of DAO. We have previously shown that SR‐KO mice have less than half of the D‐serine content in the spinal cord and that DAO‐mutant mice have a significantly elevated level of D‐serine.The DAO‐mutant and SR‐KO mice used in this study are kindly provided by R. Konno (International University of Health and Welfare, Tochigi, Japan).First, the nociceptive behavioral responses to formalin that is subcutaneously injected into a hind paw were analyzed. Results showed that the responses in the second phase, which are known be associated with NMDA receptor activation, were augmented both in SR‐KO mice and in DAO‐mutant mice.Second, tight‐seal whole‐cell recordings were made from neurons in the superficial dorsal horn (SDH) in the lumbar spinal slices that were prepared from SR‐KO mice or from DAO‐mutant mice. Non‐NMDA and NMDA receptor‐mediated excitatory postsynaptic currents (non‐NMDAEPSCs and NMDA‐EPSCs, respectively) were pharmacologically isolated. Results show that the ratio of the amplitudes of NMDA‐EPSCs to that of non‐NMDA‐EPSCs was significantly smaller in SR‐KO mice and larger in DAO‐mutant mice compared with each corresponding control group and that the time constant of decay time course of NMDA‐EPSCs was significantly longer in SR‐KO mice.Finally, quantitative real‐time RT‐PCR experiments were performed on RNA extracted from the SDH tissue. The results showed that the subunit composition of NMDA receptors altered in SR‐KO mice and DAO‐mutant mice. The most significant observation is that the expression level of the NR2B subunit of NMDA receptors increased in the SR‐KO mice.These observations might indicate that D‐serine and its related enzymes (SR and DAO) influence the activation level of NMDA receptors and their subunit composition and thus affect nociceptive synaptic transmission in the SDH of the spinal cord and influence nociceptive behavior.Support or Funding InformationThis work was supported by JSPS KAKENHI Grant Number JP18K16462 (EK).

Alterations of Astrocytes in the Context of Schizophrenic Dementia.

The levels of the astrocyte markers (GFAP, S100B) were increased unevenly in patients with schizophrenia. Reactive astrogliosis was found in approximately 70% of patients with schizophrenia. The astrocytes play a major role in etiology and pathogenesis of schizophrenia. Astrocytes produce the components that altered in schizophrenia extracellular matrix system which are involved in inflammation, functioning of interneurons, glio-, and neurotransmitter system, especially glutamate system. Astrocytes activate the interneurons through glutamate release and ATP. Decreased expression of astrocyte glutamate transporters was observed in patients with schizophrenia. Astrocytes influence on N-methyl-d-aspartate (NMDA) receptors via D-serine, an agonist of the glycine-binding site of NMDA receptors, and kynurenic acid, an endogenous antagonist. NMDA receptors, on its turn, control the impulses of dopamine neurons. Therefore following theories of schizophrenia are proposed. They are a) activation of astrocytes for neuroinflammation, b) glutamate and dopamine theory, as astrocyte products control the activity of NMDA receptors, which influence on the dopamine neurons.

The Role of the N-Methyl-D-Aspartate Receptors in Social Behavior in Rodents.

The appropriate display of social behaviors is essential for the well-being, reproductive success and survival of an individual. Deficits in social behavior are associated with impaired N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission. In this review, we describe recent studies using genetically modified mice and pharmacological approaches which link the impaired functioning of the NMDA receptors, especially of the receptor subunits GluN1, GluN2A and GluN2B, to abnormal social behavior. This abnormal social behavior is expressed as impaired social interaction and communication, deficits in social memory, deficits in sexual and maternal behavior, as well as abnormal or heightened aggression. We also describe the positive effects of pharmacological stimulation of the NMDA receptors on these social deficits. Indeed, pharmacological stimulation of the glycine-binding site either by direct stimulation or by elevating the synaptic glycine levels represents a promising strategy for the normalization of genetically-induced, pharmacologically-induced or innate deficits in social behavior. We emphasize on the importance of future studies investigating the role of subunit-selective NMDA receptor ligands on different types of social behavior to provide a better understanding of the underlying mechanisms, which might support the development of selective tools for the optimized treatment of disorders associated with social deficits.

Structural features in the glycine-binding sites of the GluN1 and GluN3A subunits regulate the surface delivery of NMDA receptors

N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors that play an essential role in mediating excitatory neurotransmission in the mammalian central nervous system (CNS). Functional NMDARs are tetramers composed of GluN1, GluN2A-D, and/or GluN3A-B subunits, giving rise to a wide variety of NMDAR subtypes with unique functional properties. Here, we examined the surface delivery and functional properties of NMDARs containing mutations in the glycine-binding sites in GluN1 and GluN3A subunits expressed in mammalian cell lines and primary rat hippocampal neurons. We found that the structural features of the glycine-binding sites in both GluN1 and GluN3A subunits are correlated with receptor forward trafficking to the cell surface. In addition, we found that a potentially clinically relevant mutation in the glycine-binding site of the human GluN3A subunit significantly reduces surface delivery of NMDARs. Taken together, these findings provide novel insight into how NMDARs are regulated by their glycine-binding sites and may provide important information regarding the role of NMDARs in both physiological and pathophysiological processes in the mammalian CNS.