Glycine Site Of NMDA Receptor Research Articles

Distinctive effects of NMDA receptor modulators on cerebral microcirculation in a schizophrenia mouse model

Substantial evidence demonstrates that schizophrenia patients have altered cerebral microcirculation. However, little is known regarding how cerebral microcirculatory blood flow (microCBF) changes in schizophrenia. Here, using time-lapse two-photon imaging of individual capillaries, we demonstrated a substantial decrease in cerebral microcirculation in a mouse model of schizophrenia. The involvement of NMDA receptor (NMDAR) functions was investigated to understand further the mechanism of microcirculation reduction in this animal model. Administration of D-serine, a selective full agonist at the glycine site of NMDAR, significantly increased the microCBF in the schizophrenia mouse. Interestingly, administration of GNE-8324, a GluN2A-selective positive allosteric modulator that selectively enhances NMDAR-mediated synaptic responses in inhibitory but not excitatory neurons, had no effect on the microCBF of the schizophrenia mice. Together, these data indicated that NMDAR participated in the regulation of microcirculation in schizophrenia using a mechanism dependent on the tonic NMDAR signaling and the selective modulation of inhibitory neuron activity. Further studies are warranted to establish NMDAR's role in modulating microcirculation in schizophrenia.

In vitro ADME characterization of a very potent 3-acylamino-2-aminopropionic acid-derived GluN2C-NMDA receptor agonist and its ester prodrugs.

The GluN2C subunit exists predominantly, but not exclusively in NMDA receptors within the cerebellum. Antagonists such as UBP1700 and positive allosteric modulators including PYD-106 and 3-acylamino-2-aminopropionic acid derivatives such as UA3-10 ((R)-2-amino-3-{[5-(2-bromophenyl)thiophen-2-yl]carboxamido}propionic acid) represent promising tool compounds to investigate the role of GluN2C-containing NMDA receptors in the signal transduction in the brain. However, due to its high polarity the bioavailability and CNS penetration of the amino acid UA3-10 are expected to be rather low. Herein, three ester prodrugs 12a-c of the NMDA receptor glycine site agonist UA3-10 were prepared and pharmacokinetically characterized. The esters 12a-c showed higher lipophilicity (higher logD 7.4 values) than the acid UA3-10 but almost the same binding at human serum albumin. The acid UA3-10 was rather stable upon incubation with mouse liver microsomes and NADPH, but the esters 12a-c were fast hydrolyzed to afford the acid UA3-10. Incubation with pig liver esterase and mouse serum led to rapid hydrolysis of the esters 12a-c. The isopropyl ester 12c showed a promising logD 7.4 value of 3.57 and the highest stability in the presence of pig liver esterase and mouse serum. These results demonstrate that ester prodrugs of UA3-10 can potentially afford improved bioavailability and CNS penetration.

Prolonged Febrile Seizures Impair Synaptic Plasticity and Alter Developmental Pattern of Glial Fibrillary Acidic Protein (GFAP)-Immunoreactive Astrocytes in the Hippocampus of Young Rats.

Prolonged neonatal febrile seizures (FSs) often lead to cognitive decline and increased risk of psychopathology in adulthood. However, the neurobiological mechanisms underlying the long-term adverse effects of FSs remain unclear. In this study, we exposed rat pups to hyperthermia and induced FSs lasting at least 15 min. We investigated the short-term (one day) and delayed (11–13 and 41–45 days) effects of FSs on some parameters of morphological and functional maturation in the hippocampus. We noticed that FSs altered the developmental pattern of glial fibrillary acidic protein (GFAP) immunoreactivity. In rats aged 21–23 days, GFAP-positive astrocytes covered a smaller area, and their morphological characteristics resembled those of rats at 11 days of age. In post-FS rats, the magnitude of long-term synaptic potentiation was reduced compared to control animals of the same age. Applying the gliotransmitter D-serine, an agonist of the glycine site of NMDA receptors, restored LTP to control values. A decrease in LTP amplitude was correlated with impaired spatial learning and memory in the Barnes maze task in post-FS rats. Our data suggest that impaired neuron–glia interactions may be an essential mechanism of the adverse effects of FS on the developing brain.

Neuroprotection against supra-lethal ‘stroke in a dish’ insults by an anti-excitotoxic receptor antagonist cocktail

The goal of this study was to identify cocktails of drugs able to protect cultured rodent cortical neurons against increasing durations of oxygen-glucose deprivation (OGD). As expected, a cocktail composed of an NMDA and AMPA receptor antagonists and a voltage gated Ca2+ channel blocker (MK-801, CNQX and nifedipine, respectively) provided complete neuroprotection against mild OGD. Increasingly longer durations of OGD necessitated increasing the doses of MK-801 and CNQX, until these cocktails ultimately failed to provide neuroprotection against supra-lethal OGD, even at maximal drug concentrations. Surprisingly, supplementation of any of these cocktails with blockers of TRPM7 channels for increasing OGD durations was not neuroprotective, unless these blockers possessed the ability to inhibit NMDA receptors. Supplementation of the maximally effective cocktail with other NMDA receptor antagonists augmented neuroprotection, suggesting insufficient NMDAR blockade by MK-801. Substitution of MK-801 in cocktails with high concentrations of a glycine site NMDA receptor antagonist caused the greatest improvements in neuroprotection, with the more potent SM-31900 superior to L689,560. Substitution of CQNX in cocktails with AMPA receptor antagonists at high concentrations also improved neuroprotection, particularly with the combination of SYM2206 and NBQX. The most neuroprotective cocktail was thus composed of SM-31900, SYM2206, NBQX, nifedipine and the antioxidant trolox. Thus, the cumulative properties of antagonist potency and concentration in a cocktail dictate neuroprotective efficacy. The central target of supra-lethal OGD is excitotoxicity, which must be blocked to the greatest extent possible to minimize ion influx.

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.

Improved functional biomechanics during squat following an exercise program targeting excessive anterior pelvic tilt in patients with symptomatic hip dysplasia

The goal of this study was to identify cocktails of drugs able to protect cultured rodent cortical neurons against increasing durations of oxygen-glucose deprivation (OGD). As expected, a cocktail composed of an NMDA and AMPA receptor antagonists and a voltage gated Ca2+ channel blocker (MK-801, CNQX and nifedipine, respectively) provided complete neuroprotection against mild OGD. Increasingly longer durations of OGD necessitated increasing the doses of MK-801 and CNQX, until these cocktails ultimately failed to provide neuroprotection against supra-lethal OGD, even at maximal drug concentrations. Surprisingly, supplementation of any of these cocktails with blockers of TRPM7 channels for increasing OGD durations was not neuroprotective, unless these blockers possessed the ability to inhibit NMDA receptors. Supplementation of the maximally effective cocktail with other NMDA receptor antagonists augmented neuroprotection, suggesting insufficient NMDAR blockade by MK-801. Substitution of MK-801 in cocktails with high concentrations of a glycine site NMDA receptor antagonist caused the greatest improvements in neuroprotection, with the more potent SM-31900 superior to L689,560. Substitution of CQNX in cocktails with AMPA receptor antagonists at high concentrations also improved neuroprotection, particularly with the combination of SYM2206 and NBQX. The most neuroprotective cocktail was thus composed of SM-31900, SYM2206, NBQX, nifedipine and the antioxidant trolox. Thus, the cumulative properties of antagonist potency and concentration in a cocktail dictate neuroprotective efficacy. The central target of supra-lethal OGD is excitotoxicity, which must be blocked to the greatest extent possible to minimize ion influx.

Facilitation of GluN2C-containing NMDA receptors in the external globus pallidus increases firing of fast spiking neurons and improves motor function in a hemiparkinsonian mouse model

Globus pallidus externa (GPe) is a nucleus in the basal ganglia circuitry involved in the control of movement. Recent studies have demonstrated a critical role of GPe cell types in Parkinsonism. Specifically increasing the function of parvalbumin (PV) neurons in the GPe has been found to facilitate motor function in a mouse model of Parkinson's disease (PD). The knowledge of contribution of NMDA receptors to GPe function is limited. Here, we demonstrate that fast spiking neurons in the GPe express NMDA receptor currents sensitive to GluN2C/GluN2D-selective inhibitors and glycine site agonist with higher efficacy at GluN2C-containing receptors. Furthermore, using a novel reporter model, we demonstrate the expression of GluN2C subunits in PV neurons in the GPe which project to subthalamic nuclei. GluN2D subunit was also found to localize to PV neurons in GPe. Ablation of GluN2C subunit does not affect spontaneous firing of fast spiking neurons. In contrast, facilitating the function of GluN2C-containing receptors using glycine-site NMDA receptor agonists, D-cycloserine (DCS) or AICP, increased the spontaneous firing frequency of PV neurons in a GluN2C-dependent manner. Finally, we demonstrate that local infusion of DCS or AICP into the GPe improved motor function in a mouse model of PD. Together, these results demonstrate that GluN2C-containing receptors and potentially GluN2D-containing receptors in the GPe may serve as a therapeutic target for alleviating motor dysfunction in PD and related disorders.

ВЛИЯНИЕ D-СЕРИНА НА ТРЕВОЖНО-ПОДОБНОЕ ПОВЕДЕНИЕ И СПОСОБНОСТЬ К ПРОСТРАНСТВЕННОМУ ОБУЧЕНИЮ КРЫС ЛИНИИ ГК, СЕЛЕКЦИОНИРОВАННЫХ НА ПРЕДРАСПОЛОЖЕННОСТЬ К КАТАТОНИЧЕСКИМ РЕАКЦИЯМ

Evidence is accumulating for an important role of D-serine, a co-agonist of the NMDA receptor glycine site, in the pathogenesis of psychiatric disorders. According to various literature sources, D-serine may contribute to correcting cognitive impairments and negative symptoms in schizophrenia. Given the therapeutic potential of D-serine, it seems important to investigate its effect on experimental models of pathological behavior. This study was carried out on GC rats, proposed as a model of catatonic disorders, and Wistar rats, undisposed to catatonic reactions. In numerous studies, D-serine is used at fairly high doses, although it has been established that high doses of D-serine elicit adverse side effects. The goal of this work was to investigate the effect of low D-serine doses on the behavior of both GC rats and control Wistar rats in the light-dark box and elevated plus maze tests, as well as on their learning ability in the Barnes maze. It was found that intraperitoneal injection of 50 mg/kg D-serine had both anxiolytic and procognitive effects on Wistar rats. In GC rats, a D-serine dose of 100 mg/kg reduced locomotor activity in the elevated plus maze test, while at 50 mg/kg, D-serine reduced locomotor activity in the Barnes maze, but did not affect the latency to escape.

A Study of the Participation of NMDA Glutamate Receptors in the Mechanisms of Specific Anterograde Amnesia Reversion

We studied the involvement of NMDA glutamate receptors in the mechanisms of anterograde amnesia. It was found that repeated training of amnestic animals treated with D-cycloserine, a potent agonist of the glycine site of NMDA receptors, did not lead to consolidation of long-term memory, while expression of short-term memory was more pronounced in comparison with control animals that received saline before repeated training. It was shown that D-cycloserine in amnestic snails did not affect the food reactions caused by the presentation of a conditioned stimulus during the reminder (without combination with the unconditioned stimulus). It is assumed that NMDA glutamate receptors in amnestic animals are involved in the neural plasticity mechanisms that underlie short-term memory, but their activation does not influence the anterograde amnesia processes and does not lead to the formation or recovery of long-term memory.

Rapastinel. NMDA receptor glycine site functional partial agonist, Treatment of major depressive disorder

Rapastinel. NMDA receptor glycine site functional partial agonist, Treatment of major depressive disorder

Modulating reconsolidation and extinction to regulate drug reward memory.

Drug addiction is an aberrant memory that shares the same memory processes as other memories. Brief exposure to drug-associated cues could result in reconsolidation, a hypothetical process during which original memory could be updated. In contrast, longer exposure times to drug-associated cues could trigger extinction, a process that decreases the conditioned responding. In this review, we discuss the pharmacological and non-pharmacological manipulations on the reconsolidation and extinction that could be used to interfere with drug reward memories. Pharmacological agents such as β-adrenergic receptor antagonist propranolol can interfere with reconsolidation to disrupt drug reward memory. Pharmacological agents such as the NMDA receptor glycine site agonists d-cycloserine and d-serine can facilitate extinction and then attenuate the expression of drug reward memory. Besides pharmacological interventions, drug-free behavioral approaches by utilizing the reconsolidation and extinction, such as 'post-retrieval extinction' and 'UCS-retrieval extinction', are also effective to erase or inhibit the recall of drug reward memory. Taken together, pharmacological modulation and non-pharmacological modulation of reconsolidation and extinction are promising approaches to regulate drug reward memory and prevent relapse.

GLYX-13, a NMDA Receptor Glycine-Site Functional Partial Agonist, Attenuates Cerebral Ischemia Injury In Vivo and Vitro by Differential Modulations of NMDA Receptors Subunit Components at Different Post-Ischemia Stage in Mice.

Excessive activation of NMDA receptors (NMDARs) is implicated in pathological synaptic plasticity also known as post-ischemic long-term potentiation (i-LTP) which was produced by glutamate mediated excitotoxicity after stroke. In the past decades, many NMDARs inhibitors failed in clinical investigations due to severe psychotomimetic side effects. GLYX-13 is a NMDAR modulator with glycine site partial agonist properties and has potential protective effects on ischemic neuronal death. However, the underlying molecular mechanism of GLYX-13 attenuating the ischemic neuronal damage remains elusive. Our study was conducted to examine the molecular, cellular and behavioral actions of GLYX-13 in stroke, and further characterize the mechanism underlying the neuroprotective actions via modulation of the NMDAR subunit composition. In present study we found that in vitro oxygen-glucose deprivation (OGD) stroke model, GLYX-13 blocked i-LTP and restored the ratio of NR2A/NR2B subunit composition. The glycine site of NMDARs full coagonist D-serine completely blocked the effects of GLYX-13 on i-LTP. Besides, in vivo middle cerebral artery occlusion (MCAO) model, GLYX-13 decreased the cerebral infarct volume and reduced injury of hippocampus. Western analysis showed that GLYX-13 down-regulated the expression of phosphorylated NR2B (Tyr1472) and up-regulated phosphorylated NR2A (Tyr1325). Furthermore, GLYX-13 treatment along with NR2B specific antagonist (Ro256981) failed to exhibit any additional neuro-protective effects, whereas the application of NR2A antagonist (NVP-AAM007) abolished the neuroprotective effects of GLYX-13, which suggested that the protective action of GLYX-13 should be by its regulation of NMDAR subunit components. Our study provides important insights on the potential protective mechanism of GLYX-13 in ischemia and proposes the glycine site of NMDARs as a novel target for developing therapeutic strategies to store synaptic function in stroke.

Subtype-Specific Agonists for NMDA Receptor Glycine Binding Sites.

A series of analogues based on serine as lead structure were designed, and their agonist activities were evaluated at recombinant NMDA receptor subtypes (GluN1/2A-D) using two-electrode voltage-clamp (TEVC) electrophysiology. Pronounced variation in subunit-selectivity, potency, and agonist efficacy was observed in a manner that was dependent on the GluN2 subunit in the NMDA receptor. In particular, compounds 15a and 16a are potent GluN2C-specific superagonists at the GluN1 subunit with agonist efficacies of 398% and 308% compared to glycine. This study demonstrates that subunit-selectivity among glycine site NMDA receptor agonists can be achieved and suggests that glycine-site agonists can be developed as pharmacological tool compounds to study GluN2C-specific effects in NMDA receptor-mediated neurotransmission.

(198) NYX-2925, a NMDA receptor glycine site functional partial agonist, shows efficacy in neuropathic pain that is NMDA and AMPA receptor dependent and appears to be driven through brain, but not spinal, circuitry

(198) NYX-2925, a NMDA receptor glycine site functional partial agonist, shows efficacy in neuropathic pain that is NMDA and AMPA receptor dependent and appears to be driven through brain, but not spinal, circuitry

SU93. Targeted Treatment of a Genetic Mutation in Glycine Decarboxylase With d-Cycloserine in Psychotic Disorders

Abstract Background: The identification of mutations in specific genes could enable personalized, “medically actionable” treatment interventions. We identified a potentially informative mutation, a rare structural rearrangement that includes a triplication of the glycine decarboxylase gene (GLDC). GLDC is the enzyme that catabolizes glycine, a precursor of d-serine, both of which are coagonists at the NMDA receptor (NMDAR). Four copies of GLDC would be expected to increase the degradation of glycine, resulting in low levels of brain glycine and NMDAR-mediated hypofunction, which has been strongly implicated in the pathophysiology of psychotic disorders. Carriers of this mutation may especially benefit from augmentation of psychotropic drug treatment with NMDAR coagonists. Methods: We carried out a double-blind placebo-controlled clinical trial (6 weeks per arm) of d-cycloserine (DCS), a partial agonist at the NMDAR glycine site, followed by 24 weeks of open-label DCS, in 2 related individuals who are carriers of the GLDC mutation, one with a diagnosis of bipolar disorder with psychotic features and the other with a diagnosis of schizo-affective disorder. Clinical assessments were carried out every 2 weeks using the PANSS, BPRS, YMRS, HAM-D, and CGI. The same individuals previously completed trials of acute and chronic glycine augmentation, which produced significant symptom improvement but caused problematic GI side effects. Results: Full trial results are still pending as the blind has not yet been broken. However, blinded analyses show significant changes in severity of clinical symptoms, indicating that DCS either produced dramatic clinical improvements or worsened symptom severity. Complete, unblinded results will be available and presented at the meeting. Conclusion: DCS may be an effective augmentation in psychotic individuals selected for being carriers of duplications or triplications of GLDC, or who are carriers of other genetic variants resulting in NMDAR hypofunction. If DCS reduced symptom severity, it is a preferable alternative to glycine as a targeted treatment in light of its clinical efficacy, ease of administration, and favorable side effect profile.

Fast-acting antidepressants rapidly stimulate ERK signaling and BDNF release in primary neuronal cultures

Recent preclinical and clinical studies demonstrate that three functionally different compounds, the NMDA receptor channel blocker ketamine, mGlu2/3 receptor antagonist LY341495, and NMDA receptor glycine site agent GLYX-13 produce rapid and long lasting antidepressant effects. Furthermore, these agents are reported to stimulate ERK and mTORC1 signaling in brain. Here we used rat primary cortical culture neurons to further examine the cellular actions of these agents. The results demonstrate that low concentrations of all three compounds rapidly increase levels of the phosphorylated and activated forms of ERK and a downstream target of mTORC1, p70S6 kinase, in a concentration and time dependent manner. In addition, each compound rapidly increases BDNF release into the culture media. Further studies demonstrate that induction of BDNF release, as well as stimulation of phospho-ERK is blocked by incubation with an AMPA receptor antagonist. The requirement for AMPA receptor stimulation suggests that the effects of these rapid agents are activity dependent. This possibility is supported by studies demonstrating that neuronal silencing, via incubation with the GABAA receptor agonist muscimol, completely blocks phospho-ERK and BDNF release by each agent. Finally, incubation with each drug for 24 h increases the number and length of neuronal branches. Together, the results demonstrate that these three different rapid acting antidepressant agents increase ERK signaling and BDNF release in an activity dependent manner that leads to increased neuronal complexity. Further studies will be required to determine the exact mechanisms underlying these effects in cultured neurons and in rodent models.

Anxiolytic effects of GLYX-13 in animal models of posttraumatic stress disorder-like behavior.

In the present study, we investigated the effectiveness of GLYX-13, an NMDA receptor glycine site functional partial agonist, to alleviate the enhanced anxiety and fear response in both a mouse and rat model of stress-induced behavioral changes that might be relevant to posttraumatic stress disorder (PTSD). Studies over the last decades have suggested that the hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis is one of the most consistent findings in stress-related disease. Herein, we used these animal models to further investigate the effect of GLYX-13 on the stress hormone levels and glucocorticoid receptor (GR) expression. We found that exposure to foot shock induced long-lasting behavioral deficiencies in mice, including freezing and anxiety-like behaviors, that were significantly ameliorated by the long-term administration of GLYX-13 (5 or 10 mg/kg). Our enzyme-linked immunosorbent assay results showed that long-term administration of GLYX-13 at behaviorally effective doses (5 or 10 mg/kg) significantly decreased the elevated serum levels of both corticosterone and its upstream stress hormone adrenocorticotropic hormone in rats subjected to the TDS procedure. These results suggest that GLYX-13 exerts a therapeutic effect on PTSD-like stress responding that is accompanied by (or associated with) modulation of the HPA axis, including inhibition of stress hormone levels and upregulation of hippocampal GR expression.

Altered kynurenine pathway metabolites in serum of chronic migraine patients.

BackgroundActivation of glutamate (Glu) receptors plays a key role in the pathophysiology of migraine. Both NMDA and metabotropic Glu receptors are activated or inhibited by metabolites of the kynurenine pathway, such as kynureninic acid (KYNA), quinolinic acid (QUINA), and xanthurenic acid (XA). In spite of the extensive research carried out on KYNA and other kynurenine metabolites in experimental models of migraine, no studies have ever been carried out in humans. Here, we measured all metabolites of the kynurenine pathway in the serum of patients affected by chronic migraine (CM) and age- and gender-matched healthy controls.MethodsWe assessed serum levels of tryptophan (Trp), L-kynurenine (KYN), KYNA, anthranilic acid (ANA), 3-hydroxyanthranilic acid (3-HANA), 3-hydroxykynirenine (3-HK), XA, QUINA, and 5-hydroxyindolacetic acid (5-HIAA) in 119 patients affected by CM (ICHD-3beta criteria) and 84 age-matched healthy subjects.Patients with psychiatric co-morbidities, systemic inflammatory, endocrine or neurological disorders, and mental retardation were excluded. Serum levels of all metabolites were assayed using liquid chromatography/tandem mass spectrometry (LC-MS/MS).ResultsLC-MS/MS analysis of kynurenine metabolites showed significant reductions in the levels of KYN (−32 %), KYNA (−25 %), 3-HK (−49 %), 3-HANA (−63 %), 5-HIAA (−36 %) and QUINA (−80 %) in the serum of the CM patients, as compared to healthy controls. Conversely, levels of Trp, ANA and XA were significantly increased in CM patients (+5 %, +339 % and +28 %, respectively).ConclusionsThese findings suggest that in migraine KYN is unidirectionally metabolized into ANA at expenses of KYNA and 3-HK. The reduction in the levels of KYNA, which behaves as a competitive antagonist of the glycine site of NMDA receptors, is consistent with the hypothesis that NMDA receptors are overactive in migraine. The increase in XA, a putative activator of Glu2 receptors, may represent a compensatory event aimed at reinforcing endogenous analgesic mechanisms. The large increase in the levels of ANA encourages research aimed at establishing whether ANA has any role in the regulation of nociceptive transmission.

D-Serine and Serine Racemase Are Associated with PSD-95 and Glutamatergic Synapse Stability

D-serine is an endogenous coagonist at the glycine site of synaptic NMDA receptors (NMDARs), synthesized by serine racemase (SR) through conversion of L-serine. It is crucial for synaptic plasticity and is implicated in schizophrenia. Our previous studies demonstrated specific loss of SR, D-serine-responsive synaptic NMDARs, and glutamatergic synapses in cortical neurons lacking α7 nicotinic acetylcholine receptors, which promotes glutamatergic synapse formation and maturation during development. We thus hypothesize that D-serine and SR (D-serine/SR) are associated with glutamatergic synaptic development. Using morphological and molecular studies in cortical neuronal cultures, we demonstrate that D-serine/SR are associated with PSD-95 and NMDARs in postsynaptic neurons and with glutamatergic synapse stability during synaptic development. Endogenous D-serine and SR colocalize with PSD-95, but not presynaptic vesicular glutamate transporter 1 (VGLUT1), in glutamatergic synapses of cultured cortical neurons. Low-density astrocytes in cortical neuronal cultures lack SR expression but contain enriched D-serine in large vesicle-like structures, suggesting possible synthesis of D-serine in postsynaptic neurons and storage in astrocytes. More interestingly, endogenous D-serine and SR colocalize with PSD-95 in the postsynaptic terminals of glutamatergic synapses during early and late synaptic development, implicating involvement of D-serine/SR in glutamatergic synaptic development. Exogenous application of D-serine enhances the interactions of SR with PSD-95 and NR1, and increases the number of VGLUT1- and PSD-95-positive glutamatergic synapses, suggesting that exogenous D-serine enhances postsynaptic SR/PSD-95 signaling and stabilizes glutamatergic synapses during cortical synaptic development. This is blocked by NMDAR antagonist 2-amino-5-phosphonopentanoic acid (AP5) and 7-chlorokynurenic acid (7-CK), a specific antagonist at the glycine site of NMDARs, demonstrating that D-serine effects are mediated through postsynaptic NMDARs. Conversely, exogenous application of glycine has no such effects, suggesting D-serine, rather than glycine, modulates postsynaptic events. Taken together, our findings demonstrate that D-serine/SR are associated with PSD-95 and NMDARs in postsynaptic neurons and with glutamatergic synapse stability during synaptic development, implicating D-serine/SR as regulators of cortical synaptic and circuit development.

D-Cycloserine reduces context specificity of sexual extinction learning

Backgroundd-Cycloserine (DCS) enhances extinction processes in animals. Although classical conditioning is hypothesized to play a pivotal role in the aetiology of appetitive motivation problems, no research has been conducted on the effect of DCS on the reduction of context specificity of extinction in human appetitive learning, while facilitation hereof is relevant in the context of treatment of problematic reward-seeking behaviors. MethodsFemale participants were presented with two conditioned stimuli (CSs) that either predicted (CS+) or did not predict (CS−) a potential sexual reward (unconditioned stimulus (US); genital vibrostimulation). Conditioning took place in context A and extinction in context B. Subjects received DCS (125mg) or placebo directly after the experiment on day 1 in a randomized, double-blind, between-subject fashion (Placebo n=31; DCS n=31). Subsequent testing for CS-evoked conditioned responses (CRs) in both the conditioning (A) and the extinction context (B) took place 24h later on day 2. Drug effects on consolidation were then assessed by comparing the recall of sexual extinction memories between the DCS and the placebo groups. ResultsPost learning administration of DCS facilitates sexual extinction memory consolidation and affects extinction’s fundamental context specificity, evidenced by reduced conditioned genital and subjective sexual responses, relative to placebo, for presentations of the reward predicting cue 24h later outside the extinction context. ConclusionsDCS makes appetitive extinction memories context-independent and prevents the return of conditioned response. NMDA receptor glycine site agonists may be potential pharmacotherapies for the prevention of relapse of appetitive motivation disorders with a learned component.