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N-methyl-D-aspartate (NMDA) receptors are heterotetrametric ion channels composed of two obligatory GluN1 subunits and two alternative GluN2 or GluN3 subunits, forming GluN1-N2, GluN1-N3, and GluN1-N2-N3 type of NMDA receptors. Extensive research has focused on the functional and structural properties of conventional GluN1–GluN2 NMDA receptors due to their early discovery and high expression levels. However, the knowledge of unconventional GluN1-N3 NMDA receptors remains limited. In this study, we modeled the GluN1-N3A, GluN1-N3B, and GluN1-N3A-N3B NMDA receptors using deep-learned protein-language predication algorithms AlphaFold and RoseTTAFold All-Atom. We then compared these structures with GluN1-N2 and GluN1-N3A receptor cryo-EM structures and found that GluN1-N3 receptors have distinct properties in subunit arrangement, domain swap, and domain interaction. Furthermore, we predicted the agonist- or antagonist-bound structures, highlighting the key molecular–residue interactions. Our findings shed new light on the structural and functional diversity of NMDA receptors and provide a new direction for drug development. This study uses advanced AI algorithms to model GluN1-N3 NMDA receptors, revealing unique structural properties and interactions compared to conventional GluN1-N2 receptors. By highlighting key molecular–residue interactions and predicting ligand-bound structures, our research enhances the understanding of NMDA receptor diversity and offers new insights for targeted drug development. [ABSTRACT FROM AUTHOR]

Synaptic dysfunction is an early feature in Alzheimer's disease (AD) pathogenesis and a major morphological correlate of memory deficits. Given the main synaptic location of N-methyl-D-aspartate receptors (NMDARs), their dysregulation has been implicated in these pathological effects. Here, to detect possible alterations in the expression and synaptic localisation of the GluN1 subunit in the brain of amyloidogenic APP/PS1 mice, we employed histoblot and SDS-digested freeze-fracture replica labelling (SDS-FRL) techniques. Histoblots showed that GluN1 expression was significantly reduced in the hippocampus in a layer-dependent manner, in the cortex and the caudate putamen of APP/PS1 transgenic mice at 12 months of age but was unaltered at 1 and 6 months. Using quantitative SDS-FRL, we unravelled the molecular organisation of GluN1 in seven excitatory synapse populations at a high spatial resolution in the CA1 and CA3 fields and the DG of the hippocampus in 12-month-old APP/PS1 mice. In the CA1 field, the labelling density for GluN1 in the excitatory synapses established on spines and interneurons, was significantly reduced in APP/PS1 mice compared to age-matched wild-type mice in the stratum lacunosum-moleculare but unaltered in the stratum radiatum. In the CA3 field, synaptic GluN1 was reduced in mossy fibre-CA3 pyramidal cell synapses but unaltered in the A/C-CA3 pyramidal cell synapses. In the DG, the density of GluN1 in granule cell-perforant pathway synapses was reduced in APP/PS1 mice. Altogether, our findings provide evidence of specific alterations of synaptic GluN1 in the trisynaptic circuit of the hippocampus in Aβ pathology. This differential vulnerability in the disruption of NMDARs may be involved in the mechanisms causing abnormal network activity of the hippocampal circuit and cognitive impairment characteristic of APP/PS1 mice. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that develops in patients with severe liver dysfunction and/or portocaval shunting. Despite more than a century of research into the relationship between liver damage and development of encephalopathy, pathogenetic mechanisms of hepatic encephalopathy have not yet been fully elucidated. It is generally recognized, however, that the main trigger of neurologic complications in hepatic encephalopathy is the neurotoxin ammonia/ammonium, concentration of which in the blood increases to toxic levels (hyperammonemia), when detoxification function of the liver is impaired. Freely penetrating into brain cells and affecting NMDA-receptor-mediated signaling, ammonia triggers a pathological cascade leading to the sharp inhibition of aerobic glucose metabolism, oxidative stress, brain hypoperfusion, nerve cell damage, and formation of neurological deficits. Brain hypoperfusion, in turn, could be due to the impaired oxygen transport function of erythrocytes, because of the disturbed energy metabolism that occurs in the membranes and inside erythrocytes and controls affinity of hemoglobin for oxygen, which determines the degree of oxygenation of blood and tissues. In our recent study, this causal relationship was confirmed and novel ammonium-induced pro-oxidant effect mediated by excessive activation of NMDA receptors leading to impaired oxygen transport function of erythrocytes was revealed. For a more complete evaluation of "erythrocytic" factors that diminish brain oxygenation and lead to encephalopathy, in this study, activity of the enzymes and concentration of metabolites of glycolysis and Rapoport–Lubering shunt, as well as morphological characteristics of erythrocytes from the rats with acute hyperammoniemia were determined. To elucidate the role of NMDA receptors in the above processes, MK-801, a non-competitive receptor antagonist, was used. Based on the obtained results it can be concluded that it is necessary to consider ammonium-induced morphofunctional disorders of erythrocytes and hemoglobinemia which can occur as a result of alterations in highly integrated networks of metabolic pathways may act as an additional systemic "erythrocytic" pathogenetic factor to prevent the onset and progression of cerebral hypoperfusion in hepatic encephalopathy accompanied by hyperammonemia. [ABSTRACT FROM AUTHOR]

NMDA-type glutamate receptors (NMDARs) are widely recognized as master regulators of synaptic plasticity, most notably for driving long-term changes in synapse size and strength that support learning. NMDARs are unique among neurotransmitter receptors in that they require binding of both neurotransmitter (glutamate) and co-agonist (e.g., D-serine) to open the receptor channel, which leads to the influx of calcium ions that drive synaptic plasticity. Over the past decade, evidence has accumulated that NMDARs also support synaptic plasticity via ion flux-independent (non-ionotropic) signaling upon the binding of glutamate in the absence of co-agonist, although conflicting results have led to significant controversy. Here, we hypothesized that a major source of contradictory results might be attributed to variable occupancy of the co-agonist binding site under different experimental conditions. To test this hypothesis, we manipulated co-agonist availability in acute hippocampal slices from mice of both sexes. We found that enzymatic scavenging of endogenous co-agonists enhanced the magnitude of long-term depression (LTD) induced by non-ionotropic NMDAR signaling in the presence of the NMDAR pore blocker MK801. Conversely, a saturating concentration of D-serine completely inhibited LTD and spine shrinkage induced by glutamate binding in the presence of MK801 or Mg2+. Using a Förster resonance energy transfer (FRET)-based assay in cultured neurons, we further found that D-serine completely blocked NMDA-induced conformational movements of the GluN1 cytoplasmic domains in the presence of MK801. Our results support a model in which D-serine availability serves to modulate NMDAR signaling and synaptic plasticity even when the NMDAR is blocked by magnesium. [ABSTRACT FROM AUTHOR]

N-Methyl-D-aspartate receptors (NMDARs), encoded by GRIN genes, are ionotropic glutamate receptors playing a critical role in synaptic transmission, plasticity, and synapse development. Genome sequence analyses have identified variants in GRIN genes in patients with neurodevelopmental disorders, but the underlying disease mechanisms are not well understood. Here, we have created and evaluated a transgenic mouse line carrying a missense variant Grin2bL825V, corresponding to a de novo GRIN2B variant encoding GluN2B(L825V) found in a patient with intellectual disability (ID) and autismspectrum disorder (ASD). We used HEK293T cells expressing recombinant receptors and primary hippocampal neurons prepared from heterozygous Grin2bL825V/+ (L825V/+) and wild-type (WT) Grin2b+/+ (+/+) male and female mice to assess the functional impact of the variant. Whole-cell NMDAR currents were reduced in neurons from L825V/+ compared with +/+ mice. The peak amplitude of NMDAR-mediated evoked excitatory postsynaptic currents (NMDAR-eEPSCs) was unchanged, but NMDAR-eEPSCs in L825V/+ neurons had faster deactivation compared with +/+ neurons and were less sensitive to a GluN2B-selective antagonist ifenprodil. Together, these results suggest a decreased functional contribution of GluN2B subunits to synaptic NMDAR currents in hippocampal neurons from L825V/+ mice. The analysis of the GluN2B(L825V) subunit surface expression and synaptic localization revealed no differences compared with WT GluN2B. Behavioral testing of mice of both sexes demonstrated hypoactivity, anxiety, and impaired sensorimotor gating in the L825V/+ strain, particularly affecting males, as well as cognitive symptoms. The heterozygous L825V/+ mouse offers a clinically relevant model of GRIN2B-related ID/ASD, and our results suggest synaptic-level functional changes that may contribute to neurodevelopmental pathology. [ABSTRACT FROM AUTHOR]

Alternative splicing of Grin1 exon 5 regulates induction of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses: LTP in mice lacking the GluN1 exon 5-encoded N1 cassette (GluN1a mice) is significantly increased compared with that in mice compulsorily expressing this exon (GluN1b mice). The mechanism underlying this difference is unknown. Here, we report that blocking the non-receptor tyrosine kinase Src prevents induction of LTP in GluN1a mice but not in GluN1b. We find that activating Src enhances pharmacologically isolated synaptic N-methyl-d-aspartate receptor (NMDAR) currents in GluN1a mice but not in GluN1b. Moreover, we observe that Src activation increases the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor component of Schaffer collateral-evoked excitatory post-synaptic potentials in GluN1a mice, but this increase is prevented by blocking NMDARs. We conclude that at these synapses, NMDARs in GluN1a mice are subject to upregulation by Src that mediates induction of LTP, whereas NMDARs in GluN1b mice are not regulated by Src, leading to Src-resistance of LTP. Thus, we have uncovered that a key regulatory mechanism for synaptic potentiation is gated by differential splicing of exon 5 of Grin1. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is an important global clinical issue, requiring not only prevention but also effective treatment. Following TBI, diverse parallel and intertwined pathological mechanisms affecting biochemical, neurochemical, and inflammatory pathways can have a severe impact on the patient's quality of life. The current review summarizes the evidence for the utility of amantadine in TBI in connection to its mechanism of action. Amantadine, the drug combining multiple mechanisms of action, may offer both neuroprotective and neuroactivating effects in TBI patients. Indeed, the use of amantadine in TBI has been encouraged by several clinical practice guidelines/recommendations. Amantadine is also available as an infusion, which may be of particular benefit in unconscious patients with TBI due to immediate delivery to the central nervous system and the possibility of precise dosing. In other situations, orally administered amantadine may be used. There are several questions that remain to be addressed: can amantadine be effective in disorders of consciousness requiring long-term treatment and in combination with drugs approved for the treatment of TBI? Do the observed beneficial effects of amantadine extend to disorders of consciousness due to factors other than TBI? Well-controlled clinical studies are warranted to ultimately confirm its utility in the TBI and provide answers to these questions. [ABSTRACT FROM AUTHOR]

Glycine plays a pivotal role in the Central Nervous System (CNS), being a major inhibitory neurotransmitter as well as a co-agonist of Glutamate at excitatory NMDA receptors. Interactions involving Glycine and other neurotransmitters are the subject of different studies. Functional interactions among neurotransmitters include the modulation of release through release-regulating receptors but also through transporter-mediated mechanisms. Many transporter-mediated interactions involve the amino acid transmitters Glycine, Glutamate, and GABA. Different studies published during the last two decades investigated a number of transporter-mediated interactions in depth involving amino acid transmitters at the nerve terminal level in different CNS areas, providing details of mechanisms involved and suggesting pathophysiological significances. Here, this evidence is reviewed also considering additional recent information available in the literature, with a special (but not exclusive) focus on glycinergic neurotransmission and Glycine–Glutamate interactions. Some possible pharmacological implications, although partly speculative, are also discussed. Dysregulations in glycinergic and glutamatergic transmission are involved in relevant CNS pathologies. Pharmacological interventions on glycinergic targets (including receptors and transporters) are under study to develop novel therapies against serious CNS pathological states including pain, schizophrenia, epilepsy, and neurodegenerative diseases. Although with limitations, it is hoped to possibly contribute to a better understanding of the complex interactions between glycine-mediated neurotransmission and other major amino acid transmitters, also in view of the current interest in potential drugs acting on "glycinergic" targets. [ABSTRACT FROM AUTHOR]

This document is a compilation of scientific articles and studies that explore the role of glycine transporters in schizophrenia and other psychiatric disorders. The articles discuss the mechanisms of glycine release and the potential therapeutic targets for treating schizophrenia. They also examine the effects of glycine augmentation on symptoms and explore the use of glycine transporter inhibitors as potential treatments for cognitive impairment and negative symptoms associated with schizophrenia. The document provides a comprehensive overview of current research in this field and may be useful for library patrons conducting research on schizophrenia and its treatment options. [Extracted from the article]

Introduction: Early social environment, either positive or negative, shapes the adult brain. Communal nesting (CN), a naturalistic setting in which 2-3 females keep their pups in a single nest sharing care-giving behavior, provides high level of peer interaction for pups. Early social isolation (ESI) from dam and siblings represents, instead, an adverse condition providing no peer interaction. Methods: We investigated whether CN (enrichment setting) might influence the response to ESI (impoverishment setting) in terms of social behavior and glutamate system in the medial prefrontal cortex (mPFC) of adult and adolescent male and female rats. Results: Pinning (a rewarding component of social play behavior) was significantly more pronounced in males than in females exposed to the combination of CN and ESI. CN sensitized the glutamate synapse in the mPFC of ESI-exposed male, but not female, rats. Accordingly, we observed (i) a potentiation of the glutamatergic neurotransmission in the mPFC of both adolescent and adult males, as shown by the recruitment of NMDA receptor subunits together with increased expression/activation of PSD95, SynCAM 1, Synapsin I and aCaMKII; (ii) a de-recruiting of NMDA receptors from active synaptic zones of same-age females, together with reduced expression/activation of the above-mentioned proteins, which might reduce the glutamate transmission. Whether similar sex-dependent glutamate homeostasis modulation occurs in other brain areas remains to be elucidated. Discussion: CN and ESI interact to shape social behavior and mPFC glutamate synapse homeostasis in an age- and sex-dependent fashion, suggesting that early-life social environment may play a crucial role in regulating the risk to develop psychopathology. [ABSTRACT FROM AUTHOR]

Astrocytic NMDA receptors (NMDARs) are heterotetramers, whose expression and properties are largely determined by their subunit composition. Astrocytic NMDARs are characterized by a low sensitivity to magnesium ions and low calcium conductivity. Their activation plays an important role in the regulation of various intracellular processes, such as gene expression and mitochondrial function. Astrocytic NMDARs are involved in calcium signaling in astrocytes and can act through the ionotropic and metabotropic pathways. Astrocytic NMDARs participate in the interactions of the neuroglia, thus affecting synaptic plasticity. They are also engaged in the astrocyte-vascular interactions and contribute to the regulation of vascular tone. Astrocytic NMDARs are involved in various pathologies, such as ischemia and hyperammonemia, and their blockade prevents negative changes in astrocytes during these diseases. [ABSTRACT FROM AUTHOR]

Alcohol use disorder (AUD) is a significant risk factor, accounting for approximately 13% of all deaths in the US. AUD not only destroys families but also causes economic losses due to reduced productivity, absenteeism, and healthcare expenses. Statistics revealing the sustained number of individuals affected by AUD over the years underscore the need for further understanding of the underlying pathophysiology to advance novel therapeutic strategies. Previous research has implicated the limbic brain regions N-methyl-D-aspartate glutamate receptors (NMDAR) in the emotional and behavioral effects of AUD. Given that aerobic exercise can modulate NMDAR activity and sensitivity to alcohol, this review presents a summary of clinical and basic science studies on NMDAR levels induced by alcohol consumption, as well as acute and protracted withdrawal, highlighting the potential role of aerobic exercise as an adjunctive therapy for AUD. Based on our findings, the utility of exercise in the modulation of reward-linked receptors and AUD may be mediated by its effects on NMDA signaling. These data support further consideration of the potential of aerobic exercise as a promising adjunctive therapy for AUD. [ABSTRACT FROM AUTHOR]

In this work the cryoprotective properties of the dipeptide L-carnosine (β-alanyl-L-histidine) on slices of the rat brain olfactory cortex are investigated. Changes in the activity of N-methyl-D-aspartate receptors, as the most vulnerable to the effects of cryopreservation (CP), were analyzed; for this purpose, the NMDA-synaptic component of the excitatory postsynaptic potential (abbreviated as NMDA potentials) was recorded extracellularly. The slices were incubated in a medium with L-carnosine (20 mM) and frozen at a slow rate (0.1°C/min) to –10°C, and after CP (30 days) they were warmed at the same rate (0.1°C/min) to 37°C. The effectiveness of L-carnosine for cryoprotection was determined by changes in the amplitudes of NMDA potentials after CP compared to before CP. The dipeptide restored the pH of the freezing medium (6.9, without L-carnosine) to optimal values (7.3–7.4), promoted the dehydration of free water from slices after CP, and inhibited the development of glutamate excitotoxicity in slices. The data obtained prove that L‑carnosine exhibits the properties of a non-toxic, effective cryoprotector in the nervous tissue of warm-blooded, non-hibernating animals. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder. While there are five FDA-approved drugs for treating this disease, each has only modest benefits. To design new and more effective therapies for ALS, particularly for sporadic ALS of unknown and diverse etiologies, we must identify key, convergent mechanisms of disease pathogenesis. This review focuses on the origin and effects of glutamate-mediated excitotoxicity in ALS (the cortical hyperexcitability hypothesis), in which increased glutamatergic signaling causes motor neurons to become hyperexcitable and eventually die. We characterize both primary and secondary contributions to excitotoxicity, referring to processes taking place at the synapse and within the cell, respectively. 'Primary pathways' include upregulation of calcium-permeable AMPA receptors, dysfunction of the EAAT2 astrocytic glutamate transporter, increased release of glutamate from the presynaptic terminal, and reduced inhibition by cortical interneurons—all of which have been observed in ALS patients and model systems. 'Secondary pathways' include changes to mitochondrial morphology and function, increased production of reactive oxygen species, and endoplasmic reticulum (ER) stress. By identifying key targets in the excitotoxicity cascade, we emphasize the importance of this pathway in the pathogenesis of ALS and suggest that intervening in this pathway could be effective for developing therapies for this disease. [ABSTRACT FROM AUTHOR]

Abstract—Glycoprotein N-cadherin (Neuronal cadherin) belongs to the family of calcium-dependent cell adhesion molecules, representing a key element that carries out intercellular contacts in brain neurons. However, it is involved not only in the mechanical connection of neurons but also influences the specifics of the further development and functional state of the neuron. This is due to the active interaction of N-cadherin with many proteins at the pre- and post-synapse, which initiates a cascade of reactions that provide processes such as long-term potentiation (underlying learning and memory), morphogenesis, neuronal recognition, activation of receptors (NMDA and AMPA types), and regulation of cytoskeleton formation. This polyfunctionality is necessary for specific neurons to connect to each other in a certain way, and such adhesion leads to the coordination of cell behavior through intercellular signaling and spatio-temporal control of differential gene expression. Mutations in the genes responsible for the expression of N-cadherin lead to various disorders of the functional activity of the synapse and the processes of spatial orientation and memory. Thus, involvement in important neuroplastic processes regulating cognitive functions and behavior determines interest in studying the effect of drugs on N-cadherin. In particular, N-cadherin deserves closer consideration by pharmacologists as a potential target in the mechanism of action of various psychoactive substances. [ABSTRACT FROM AUTHOR]

New adamantane-containing derivatives of edaravone, one of two drugs used to treat amyotrophic lateral sclerosis, were synthesized. The pyrazolone ring and adamantane moiety in the new edaravone derivatives were conjugated by alkyl and azetidine linkers via amination of the corresponding alcohol mesylates. Some of the new compounds were found to be effective blockers of the allosteric NMDA receptor binding site in rats but exhibited little activity against the intrachannel NMDA receptor binding site. The structure–activity relationship between the ability to block the ifenprodil binding site and the structure of the linkers and substituents on the molecule was analyzed. [ABSTRACT FROM AUTHOR]

1,1-Dibenzyl-3-(1-benzyl-1 1H-pyrazol-4-yl)-2-methylisothioureas containing structural elements both of known antioxidants and glutamate receptor modulators were proposed as compounds with a dual mode of biological action, namely the antioxidant activity and the ability to influence the glutamatergic signaling system. The target compounds were synthesized by the reaction of substituted 4-amino-1-benzylpyrazoles with thiophosgene followed by the condensation of the resulting 1-benzyl-4-isothiocyanato-1H-pyrazoles with dibenzylamine and the subsequent S-methylation of the resulting thioureas. 1,1-Dibenzyl-3-[1-(3,4-dichlorobenzyl)- and 1,1-dibenzyl-3-[1-(2,4-dichlorobenzyl)-1H-pyrazol-4-yl]-2-methylisothioureas were found to have a moderate ability to protect neuroblastoma cells against the toxic effect of hydrogen peroxide, making these compounds interesting for further study of the modulatory activity toward glutamate receptors. [ABSTRACT FROM AUTHOR]

Copyright of Headache: The Journal of Head & Face Pain is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Recently, a new signaling complex Death-Associated Protein Kinase 1 (DAPK1)—N-methyl D-aspartate receptor subtype 2B (NR2B) engaged in the neuronal death cascade was identified where it was found that after stroke injury, N-methyl-D-aspartate glutamate (NMDA) receptors interact with DAPK1 through NR2B subunit and lead to excitotoxicity via overactivation of NMDA receptors. In this study, we used ZINC-12 database to find out potential inhibitor of DAPK1 and found some natural compounds showing good binding affinity towards DAPK1. These natural compounds showed interactions with ATP-binding site residues as well as substrate-recognition motifs. Thus, it has been concluded that the ligands those are showing interactions with both the sites could be considered as potential inhibitors for DAPK1. [ABSTRACT FROM AUTHOR]

Glutamate is the major excitatory neurotransmitter in the central nervous system. Glutamatergic transmission can be mediated by ionotropic glutamate receptors (iGluRs), which mediate rapid synaptic depolarization that can be associated with Ca2+ entry and activity-dependent change in the strength of synaptic transmission, as well as by metabotropic glutamate receptors (mGluRs), which mediate slower postsynaptic responses through the recruitment of second messenger systems. A wealth of evidence reported over the last three decades has shown that this dogmatic subdivision between iGluRs and mGluRs may not reflect the actual physiological signaling mode of the iGluRs, i.e., α-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid (AMPA) receptors (AMPAR), kainate receptors (KARs), and N-methyl-D-aspartate (NMDA) receptors (NMDARs). Herein, we review the evidence available supporting the notion that the canonical iGluRs can recruit flux-independent signaling pathways not only in neurons, but also in brain astrocytes and cerebrovascular endothelial cells. Understanding the signaling versatility of iGluRs can exert a profound impact on our understanding of glutamatergic synapses. Furthermore, it may shed light on novel neuroprotective strategies against brain disorders. [ABSTRACT FROM AUTHOR]

Abnormalities in dopamine function might be related to psychiatric disorders such as schizophrenia. Even at the same concentration, dopamine exerts opposite effects on information processing in the prefrontal cortex depending on independent dopamine release modes known as tonic and phasic releases. This duality of dopamine prevents a blanket interpretation of the implications of dopamine abnormalities for diseases on the basis of absolute dopamine levels. Moreover, the mechanisms underlying the mode‐specific dopamine abnormalities are not clearly understood. Here, I show that the two modes of dopamine release in the prefrontal cortex of a schizophrenia‐like model are disrupted by different mechanisms. In the schizophrenia‐like model established by perinatal exposure to inflammatory cytokine, epidermal growth factor, tonic release was enhanced and phasic release was decreased in the prefrontal cortex. I examined the activity of dopamine neurons in the ventral tegmental area (VTA), which sends dopamine projections to the prefrontal cortex, under anaesthesia. The activation of VTA dopamine neurons during excitatory stimulation (local application of glutamate or N‐methyl‐d‐aspartic acid [NMDA]), which is associated with phasic activity, was blunt in this model. Dopaminergic neuronal activity in the resting state related to tonic release was increased by disinhibition of the dopamine neurons due to the impairment of 5HT2 (5HT2A) receptor‐regulated GABAergic inputs. Moreover, chronic administration of risperidone ameliorated this disinhibition of dopaminergic neurons. These results provide an idea about the mechanism of dopamine disturbance in schizophrenia and may be informative in explaining the effects of atypical antipsychotics as distinct from those of typical drugs. [ABSTRACT FROM AUTHOR]

Developmental neurogenesis is a tightly regulated spatiotemporal process with its dysregulation implicated in neurodevelopmental disorders. NMDA receptors are glutamate-gated ion channels that are widely expressed in the early nervous system, yet their contribution to neurogenesis is poorly understood. Notably, a variety of mutations in genes encoding NMDA receptor subunits are associated with neurodevelopmental disorders. To rigorously define the role of NMDA receptors in developmental neurogenesis, we used a mutant zebrafish line (grin1−/−) that lacks all NMDA receptors yet survives to 10 days post-fertilization, offering the opportunity to study post-embryonic neurodevelopment in the absence of NMDA receptors. Focusing on the forebrain, we find that these fish have a progressive supernumerary neuron phenotype confined to the telencephalon at the end of embryonic neurogenesis, but which extends to all forebrain regions during postembryonic neurogenesis. This enhanced neuron population does not arise directly from increased numbers or mitotic activity of radial glia cells, the principal neural stem cells. Rather, it stems from a lack of timely maturation of transit-amplifying neuroblasts into post-mitotic neurons, as indicated by a decrease in expression of the ontogenetically-expressed chloride transporter, KCC2. Pharmacological blockade with MK-801 recapitulates the grin1−/− supernumerary neuron phenotype, indicating a requirement for ionotropic signaling. Thus, NMDA receptors are required for suppression of indirect, transit amplifying cell-driven neurogenesis by promoting maturational termination of mitosis. Loss of suppression results in neuronal overpopulation that can fundamentally change brain circuitry and may be a key factor in pathogenesis of neurodevelopmental disorders caused by NMDA receptor dysfunction. [ABSTRACT FROM AUTHOR]

Aims: Basolateral amygdala (BLA), as a center for stress responses and emotional regulation, is involved in visceral hypersensitivity of irritable bowel syndrome (IBS) induced by stress. In the present study, we aimed to investigate the role of EphB2 receptor (EphB2) in BLA and explore the underlying mechanisms in this process. Methods: Visceral hypersensitivity was induced by water avoidance stress (WAS). Elevated plus maze test, forced swimming test, and sucrose preference test were applied to assess anxiety‐ and depression‐like behaviors. Ibotenic acid or lentivirus was used to inactivate BLA in either the induction or maintenance stage of visceral hypersensitivity. The expression of protein was determined by quantitative PCR, immunofluorescence, and western blot. Results: EphB2 expression was increased in BLA in WAS rats. Inactivation of BLA or downregulation of EphB2 in BLA failed to induce visceral hypersensitivity as well as anxiety‐like behaviors. However, during the maintenance stage of visceral pain, visceral hypersensitivity was only partially relieved but anxiety‐like behaviors were abolished by inactivation of BLA or downregulation of EphB2 in BLA. Chronic WAS increased the expression of EphB2, N‐methyl‐D‐aspartate receptors (NMDARs), and postsynaptic density protein (PSD95) in BLA. Downregulation of EphB2 in BLA reduced NMDARs and PSD95 expression in WAS rats. However, activation of NMDARs after the knockdown of EphB2 expression still triggered visceral hypersensitivity and anxiety‐like behaviors. Conclusions: Taken together, the results suggest that EphB2 in BLA plays an essential role in inducing visceral hypersensitivity. In the maintenance stage, the involvement of EphB2 is crucial but not sufficient. The increase in EphB2 induced by WAS may enhance synaptic plasticity in BLA through upregulating NMDARs, which results in IBS‐like symptoms. These findings may give insight into the treatment of IBS and related psychological distress. [ABSTRACT FROM AUTHOR]

Memories are stored into long-term representations through a process that depends on protein synthesis. However, a consolidated memory is not static and inflexible and can be reactivated under certain circumstances, the retrieval is able to reactivate memories and destabilize them engaging a process of restabilization known as reconsolidation. Although the molecular mechanisms that mediate fear memory reconsolidation are not entirely known, so here we investigated the molecular mechanisms in the hippocampus involved in contextual fear conditioning memory (CFC) reconsolidation in male Wistar rats. We demonstrated that the blockade of Src family kinases (SFKs), GluN2B-containing NMDA receptors and TrkB receptors (TrkBR) in the CA1 region of the hippocampus immediately after the reactivation session impaired contextual fear memory reconsolidation. These impairments were blocked by the neurotrophin BDNF and the NMDAR agonist, D-Serine. Considering that the study of the link between synaptic proteins is crucial for understanding memory processes, targeting the reconsolidation process may provide new ways of disrupting maladaptive memories, such as those seen in post-traumatic stress disorder. Here we provide new insights into the cellular mechanisms involved in contextual fear memory reconsolidation, demonstrating that SFKs, GluN2B-containing NMDAR, and TrkBR are necessary for the reconsolidation process. Our findings suggest a link between BDNF and SFKs and GluN2B-containing NMDAR as well as a link between NMDAR and SFKs and TrkBR in fear memory reconsolidation. These preliminary pharmacological findings provide new evidence of the mechanisms involved in the reconsolidation of fear memory and have the potential to contribute to the development of treatments for psychiatric disorders involving maladaptive memories. [ABSTRACT FROM AUTHOR]

Exposure to metal mixtures is recognized as a real-life scenario, needing novel studies that can assess their complex effects on brain development. There is still a significant public health concern associated with chronic low levels of metal exposure. In contrast to other metals, these three metals (As, Pb, and Mn) are commonly found in various environmental and industrial contexts. In addition to additive or synergistic interactions, concurrent exposure to this metal mixture may also have neurotoxic effects that differ from those caused by exposure to single components. The NMDA receptor and several important signaling proteins are involved in learning, memory, and synaptic plasticity in the hippocampus, including CaMKII, postsynaptic density protein-95 (PSD-95), synaptic Ras GTPase activating protein (SynGAP), a negative regulator of Ras-MAPK activity, and CREB. We hypothesized that alterations in the above molecular players may contribute to metal mixture developmental neurotoxicity. Thus, the aim of this study was to investigate the effect of these metals and their mixture at low doses (As 4 mg, Pb 4 mg, and Mn 10 mg/kg bw/p.o) on NMDA receptors and their postsynaptic signaling proteins during developing periods (GD6 to PD59) of the rat brain. Rats exposed to As, Pb, and Mn individually or at the same doses in a triple-metal mixture (MM) showed impairments in learning and memory functions in comparison to the control group rats. Declined protein expressions of NR2A, PSD-95, p- CaMKII, and pCREB were observed in the metal mix-exposed rats, while the expression of SynGAP was found to be enhanced in the hippocampus as compared to the controls on PD60. Thereby, our data suggest that alterations in the NMDA receptor complex and postsynaptic signaling proteins could explain the cognitive dysfunctions caused by metal-mixture-induced developmental neurotoxicity in rats. These outcomes indicate that incessant metal mixture exposure may have detrimental consequences on brain development. [ABSTRACT FROM AUTHOR]

Evidence supports the pathophysiological relevance of crosstalk between the neurotransmitters Glycine and Glutamate and their close interactions; some reports even support the possibility of Glycine–Glutamate cotransmission in central nervous system (CNS) areas, including the hippocampus. Functional studies with isolated nerve terminals (synaptosomes) permit us to study transporter-mediated interactions between neurotransmitters that lead to the regulation of transmitter release. Our main aims here were: (i) to investigate release-regulating, transporter-mediated interactions between Glycine and Glutamate in hippocampal nerve terminals and (ii) to determine the coexistence of transporters for Glycine and Glutamate in these terminals. Purified synaptosomes, analyzed at the ultrastructural level via electron microscopy, were used as the experimental model. Mouse hippocampal synaptosomes were prelabeled with [3H]D-Aspartate or [3H]Glycine; the release of radiolabeled tracers was monitored with the superfusion technique. The main findings were that (i) exogenous Glycine stimulated [3H]D-Aspartate release, partly by activation of GlyT1 and in part, unusually, through GlyT2 transporters and that (ii) D-Aspartate stimulated [3H]glycine release by a process that was sensitive to Glutamate transporter blockers. Based on the features of the experimental model used, it is suggested that functional transporters for Glutamate and Glycine coexist in a small subset of hippocampal nerve terminals, a condition that may also be compatible with cotransmission; glycinergic and glutamatergic transporters exhibit different functions and mediate interactions between the neurotransmitters. It is hoped that increased information on Glutamate–Glycine interactions in different areas, including the hippocampus, will contribute to a better knowledge of drugs acting at "glycinergic" targets, currently under study in relation with different CNS pathologies. [ABSTRACT FROM AUTHOR]

N-methyl-D-aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptors, are important in regulating sympathetic tone and cardiovascular function in the rostral ventrolateral medulla (RVLM). Amyloid-beta peptide (Aβ) is linked to the pathogenesis of Alzheimer's disease (AD). Cerebro- and cardiovascular diseases might be the risk factors for developing AD. The present study examines the acute effects of soluble Aβ on the function of NMDA receptors in rats RVLM. We used the magnitude of increases in the blood pressure (pressor responses) induced by microinjection of NMDA into the RVLM as an index of NMDA receptor function in the RVLM. Soluble Aβ was applied by intracerebroventricular (ICV) injection. Aβ1-40 at a lower dose (0.2 nmol) caused a slight reduction, and a higher dose (2 nmol) showed a significant decrease in NMDA-induced pressor responses 10 min after administration. ICV injection of Aβ1-42 (2 nmol) did not affect NMDA-induced pressor responses in the RVLM. Co-administration of Aβ1-40 with ifenprodil or memantine blocked the inhibitory effects of Aβ1-40. Immunohistochemistry analysis showed a significant increase in the immunoreactivity of phosphoserine 1480 of GluN2B subunits (pGluN2B-serine1480) in the neuron of the RVLM without significant changes in phosphoserine 896 of GluN1 subunits (pGluN1-serine896), GluN1 and GluN2B, 10 min following Aβ1-40 administration compared with saline. Interestingly, we found a much higher level of Aβ1-40 compared to that of Aβ1-42 in the cerebrospinal fluid (CSF) measured using enzyme-linked immunosorbent assay 10 min following ICV administration of the same dose (2 nmol) of the peptides. In conclusion, the results suggest that ICV Aβ1-40, but not Aβ1-42, produced an inhibitory effect on NMDA receptor function in the RVLM, which might result from changes in pGluN2B-serine1480 (regulated by casein kinase II). The different elimination of the peptides in the CSF might contribute to the differential effects of Aβ1-40 and Aβ1-42 on NMDA receptor function. [ABSTRACT FROM AUTHOR]

Recent findings suggest an important role for the dysregulation of stromal interaction molecule (STIM) proteins, activators of store-operated Ca2+ channels, and the prolonged activation of N-methyl-D-aspartate receptors (NMDARs) in the development of neurodegenerative diseases. We previously demonstrated that STIM silencing increases Ca2+ influx through NMDAR and STIM–NMDAR2 complexes are present in neurons. However, the interplay between NMDAR subunits (GluN1, GluN2A, and GluN2B) and STIM1/STIM2 with regard to intracellular trafficking remains unknown. Here, we found that the activation of NMDAR endocytosis led to an increase in STIM2–GluN2A and STIM2–GluN2B interactions in primary cortical neurons. STIM1 appeared to migrate from synaptic to extrasynaptic sites. STIM2 silencing inhibited post-activation NMDAR translocation from the plasma membrane and synaptic spines and increased NMDAR currents. Our findings reveal a novel molecular mechanism by which STIM2 regulates NMDAR synaptic trafficking by promoting NMDAR endocytosis after receptor overactivation, which may suggest protection against excessive uncontrolled Ca2+ influx through NMDARs. [ABSTRACT FROM AUTHOR]

Objective: N‐methyl‐d‐aspartate (NMDA) receptors are expressed at synaptic sites, where they mediate fast excitatory neurotransmission. NMDA receptors are critical to brain development and cognitive function. Natural variants to the GRIN1 gene, which encodes the obligatory GluN1 subunit of the NMDA receptor, are associated with severe neurological disorders that include epilepsy, intellectual disability, and developmental delay. Here, we investigated the pathogenicity of three missense variants to the GRIN1 gene, p. Ile148Val (GluN1‐3b[I481V]), p.Ala666Ser (GluN1‐3b[A666S]), and p.Tyr668His (GluN1‐3b[Y668H]). Methods: Wild‐type and variant‐containing NMDA receptors were expressed in HEK293 cells and primary hippocampal neurons. Patch‐clamp electrophysiology and pharmacology were used to profile the functional properties of the receptors. Receptor surface expression was evaluated using fluorescently tagged receptors and microscopy. Results: Our data demonstrate that the GluN1(I481V) variant is inhibited by the open pore blockers ketamine and memantine with reduce potency but otherwise has little effect on receptor function. By contrast, the other two variants exhibit gain‐of‐function molecular phenotypes. Glycine sensitivity was enhanced in receptors containing the GluN1(A666S) variant and the potency of pore block by memantine and ketamine was reduced, whereas that for MK‐801 was increased. The most pronounced functional deficits, however, were found in receptors containing the GluN1(Y668H) variant. GluN1(Y668H)/2A receptors showed impaired surface expression, were more sensitive to glycine and glutamate by an order of magnitude, and exhibited impaired block by extracellular magnesium ions, memantine, ketamine, and MK‐801. These variant receptors were also activated by either glutamate or glycine alone. Single‐receptor recordings revealed that this receptor variant opened to several conductance levels and activated more frequently than wild‐type GluN1/2A receptors. Significance: Our study reveals a critical functional locus of the receptor (GluN1[Y668]) that couples receptor gating to ion channel conductance, which when mutated may be associated with neurological disorder. [ABSTRACT FROM AUTHOR]

Introduction: The N-methyl-D-aspartate receptor (NMDAR) plays a critical role in synaptic transmission and is associated with various neurological and psychiatric disorders. Recently, a novel form of postsynaptic plasticity known as NMDAR- based short-term postsynaptic plasticity (STPP) has been identified. It has been suggested that long-lasting glutamate binding to NMDAR allows for the retention of input information in brain slices up to 500 ms, leading to response facilitation. However, the impact of STPP on the dynamics of neuronal populations remains unexplored. Methods: In this study, we incorporated STPP into a continuous attractor neural network (CANN) model to investigate its e [ABSTRACT FROM AUTHOR]

N-methyl-D-aspartate (NMDA) receptors are inhibited by many amidine and guanidine compounds. In this work, we studied the mechanisms of their inhibition by sepimostat—an amidine-containing serine protease inhibitor with neuroprotective properties. Sepimostat inhibited native NMDA receptors in rat hippocampal CA1 pyramidal neurons with IC50 of 3.5 ± 0.3 µM at −80 mV holding voltage. It demonstrated complex voltage dependence with voltage-independent and voltage-dependent components, suggesting the presence of shallow and deep binding sites. At −80 mV holding voltage, the voltage-dependent component dominates, and we observed pronounced tail currents and overshoots evidencing a "foot-in-the-door" open channel block. At depolarized voltages, the voltage-independent inhibition by sepimostat was significantly attenuated by the increase of agonist concentration. However, the voltage-independent inhibition was non-competitive. We further compared the mechanisms of the action of sepimostat with those of structurally-related amidine and guanidine compounds—nafamostat, gabexate, furamidine, pentamidine, diminazene, and DAPI—investigated previously. The action of all these compounds can be described by the two-component mechanism. All compounds demonstrated similar affinity to the shallow site, which is responsible for the voltage-independent inhibition, with binding constants in the range of 3–30 µM. In contrast, affinities to the deep site differed dramatically, with nafamostat, furamidine, and pentamidine being much more active. [ABSTRACT FROM AUTHOR]

The effect of preventive administration of a single intraperitoneal dose of dimethylsulfoxide (DMSO) at various concentrations (10, 30 and 50%; 10 mL/kg) on the nociceptive response in mice induced by local and systemic activation of TRPV1 ion channels by the TRPV1 agonist capsaicin was studied. DMSO (50%) significantly reduced (by 73.1%) the latency of the response to injection of capsaicin solution into the metatarsus. DMSO in the tail-flick test did not significantly affect the thermal pain threshold, which was elevated after a single subcutaneous injection (above the shoulder blades) of capsaicin at a dose of 1 mg/kg. However, DMSO (30 and 50%) per se raised the pain threshold of mice in the tail-flick test. Because externally applied DMSO enhanced the effect of capsaicin in the capsaicin test, the demonstrated analgesic effect of a single intraperitoneal injection of DMSO in the capsaicin test and tail-flick test in mice was due to its central action rather than to its effect on afferent innervation. [ABSTRACT FROM AUTHOR]

Positive and negative emotional states in rats can be studied by investigating ultrasonic vocalizations (USVs). Positive affect in rats is indexed by 50 kHz hedonic USVs, and negative affect is indexed by 22 kHz aversive calls. We examined the relationship of emotional states in rats using medial prefrontal cortex (MPFC) quantitative electroencephalograms (qEEG) and found that hedonic USVs were associated with active wake qEEG (high alpha/low delta power), and aversive USVs occurred with groggy wake qEEG (low alpha/high delta). Further, alpha frequency electrical stimulation of the MPFC induces hedonic calls and reward-seeking behavior, whereas delta frequency stimulation produces aversive calls and avoidance behavior. The brain region responsible for generating motor output for USVs, the periaqueductal gray (PAG), shows a motor-evoked potential that is temporally locked to the alpha (hedonic) and delta (aversive) motor-evoked potential. Closed-loop alpha frequency electrical stimulation could prevent delta qEEG and aversive USVs. At the neuronal circuit level, the alpha rhythm was associated with synaptic long-term potentiation (LTP) in the cortex, whereas the delta rhythm was associated with synaptic depotentiation (LTD) in the cortex. At the pharmacological level, NMDAR and growth factor modulation regulated these forms of neuroplasticity. At the single neuron level, excitatory neurons show increased activity in response to alpha frequencies and decreased activity during delta frequencies. In humans, the feeling of joy increased alpha and decreased delta power in frontal scalp qEEG, and the opposite response was seen for sadness. Thus, the synchronization of alpha/delta oscillations through the neuronal circuit responsible for emotional expression coordinates emotional behavior, and the switch between active wake/positive affect and groggy wake/negative affect is under the control of an LTP- LTD synaptic plasticity mechanism. [ABSTRACT FROM AUTHOR]

New hybrid structures based on memantine and edaravone molecules, in which the pyrazolone ring and adamantane fragments are linked by an alkyl linker, were synthesized. It was found that, in addition to the ability to block the intrachannel site of NMDA receptors, the new hybrid compounds exhibit the property of blockers of the allosteric site of NMDA receptors, which is not inherent in memantine and edaravone preparations. The most active hit compound was determined, which, along with the properties of a two-site blocker of the NMDA receptor, exhibits a pronounced activity as an inhibitor of lipid peroxidation, similarly to the drug edaravone. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy (HE), a neuropsychiatric disorder developing in patients with severe hepatic dysfunction, has been known for more than a century. However, pathogenetic mechanisms of cerebral dysfunction associated with liver disease are still poorly understood. There is a consensus that the primary cause of HE is accumulation of ammonia in the brain as a result of impaired liver detoxification capacity or the portosystemic shunt. Current evidence suggests that ammonia toxicity is mediated by hyperactivation of glutamate receptors, mainly N-methyl-D-aspartate receptors (NMDARs), and affects brain aerobic metabolism, which provides energy for multiple specific functions and neuronal viability. Recent reports on the presence of functional NMDARs in erythrocytes and the data on the deviations of blood parameters from their normal ranges indicate impaired hemodynamics and reduced oxygen-carrying capacity of erythrocytes in most patients with HE, thus suggesting a relationship between erythrocyte damage and cerebral dysfunction. In order to understand how hyperammonemia (HA)-induced disturbances in the energy metabolism in the brain (which needs a constant supply of large amounts of oxygen in the blood) lead to encephalopathy, it is necessary to reveal ammonia-induced impairments in the energy metabolism and antioxidant defense system of erythrocytes and to explore a potential role of ammonia in reduced brain oxygenation. To identify the said missing link, the activities of antioxidant enzymes and concentrations of reduced glutathione (GSH), oxidized glutathione (GSSG), and H2O2 were measured in the erythrocytes of rats with HA that were injected with the noncompetitive NMDAR antagonist MK-801. We found that in rats with HA, ammonia was accumulated in erythrocytes (cells lacking ammonia removal enzymes), which made them more susceptible to the prooxidant environment created during oxidative stress. This effect was completely or partially inhibited by MK-801. The data obtained might help to identify the risk factors in cognitive disorders and facilitate prediction of unfavorable outcomes of hypoperfusion in patients with a blood elevated ammonia concentration. [ABSTRACT FROM AUTHOR]

Objectives. To study the relationship between the expression activity of NMDA glutamate receptors and the proliferative activity and genetic properties of anaplastic astrocytomas, as well as the survival of patients with this disease. Materials and methods. This task was addressed by comparing the expression activity of NMDA glutamate receptors – which have been least studied in this context – as detected by immunofluorescence and the polymerase chain reaction, with data from histological and molecular studies, the proliferative activity of neoplasms, and patient survival. Results. The expression activity of NMDA glutamate receptors was found to be higher in grade 3 astrocytomas not carrying mutations in the IDH1 and IDH2 genes. NMDA receptor expression activity was also found to correlate directly with proliferative activity in tumors. NMDA receptor expression activity had a significant impact on the prognosis of relapse-free survival in patients. Conclusions. This work provides the first demonstration that NMDA glutamate receptors have a significant role in the progression of diffuse astrocytomas, which can become the basis for the creation of new approaches to treatment and diagnosis. [ABSTRACT FROM AUTHOR]

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The generation of appropriate behavioral responses involves dedicated neuronal circuits. The cortico-striatal- thalamo-cortical loop is especially important for the expression of motor routines and habits. Defects in this circuitry are closely linked to obsessive stereotypic behaviors, hallmarks of neuropsychiatric diseases including autism spectrum disorders (ASDs) and obsessive--compulsive disorders (OCDs). However, our knowledge of the essential synaptic machinery required to maintain balanced neurotransmission and plasticity within the cortico- striatal circuitry remains fragmentary. Mutations in the large synaptic scaffold protein intersectin1 (ITSN1) have been identified in patients presenting with ASD symptoms including stereotypic behaviors, although a causal relationship between stereotypic behavior and intersectin function has not been established. We report here that deletion of the two closely related proteins ITSN1 and ITSN2 leads to severe ASD/OCD-like behavioral alterations and defective cortico-striatal neurotransmission in knockout (KO) mice. Cortico-striatal function was compromised at multiple levels in ITSN1/2-depleted animals. Morphological analyses showed that the striatum of intersectin KO mice is decreased in size. Striatal neurons exhibit reduced complexity and an underdeveloped dendritic spine architecture. These morphological abnormalities correlate with defects in cortico-striatal neurotransmission and plasticity as well as reduced N-methyl-D-aspartate (NMDA) receptor currents as a consequence of postsynaptic NMDA receptor depletion. Our findings unravel a physiological role of intersectin in cortico-striatal neurotransmission to counteract ASD/OCD. Moreover, we delineate a molecular pathomechanism for the neuropsychiatric symptoms of patients carrying intersectin mutations that correlates with the observation that NMDA receptor dysfunction is a recurrent feature in the development of ASD/OCD-like symptoms. [ABSTRACT FROM AUTHOR]

Although amyloid-β (Aβ) is one of the neuropathological hallmarks of Alzheimer's Disease (AD), the mechanisms of Aβ neurotoxicity remain to be clarified. This study was aimed to evaluate the effect of Aβ on postsynaptic density-95 (PSD-95) tyrosine phosphorylation. Elucidating the regulatory mechanisms underlying it may be a promising therapy in AD. Aβ25–35 oligomers (20 μg/rat) were administered intracerebroventricularly in adult male Sprague-Dawley rats. PSD-95 tyrosine phosphorylation was assessed using immunoprecipitation followed by immunoblot analysis. Immunoblot was applied for measuring the protein levels of PSD-95 and β-actin. Following 3, 7, 14, 21 days after oligomeric Aβ25–35 treatment, the tyrosine phosphorylation of PSD-95 increased significantly, and peaked at 3 days after oligomeric Aβ25–35 treatment in hippocampal CA1 subfield. Src family protein tyrosine kinases (SrcPTKs) specific inhibitor PP2 attenuated the tyrosine phosphorylation of PSD-95 induced by Aβ25–35. Amantadine [N-methyl-D-aspartate (NMDA) receptor noncompetitive antagonist], NVP-AAM077 (GluN2A-containing NMDA receptor selective inhibitor) and Ro25-6981 (GluN2B-containing NMDA receptor selective inhibitor) also suppressed the Aβ25–35-induced PSD-95 tyrosine phosphorylation. These results suggest that Aβ oligomers induce the tyrosine phosphorylation of PSD-95 by SrcPTKs, which is mediated by the activation of GluN2A- and GluN2B-containing NMDA receptors. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common form of dementia worldwide, and it contributes up to 70% of cases. AD pathology involves abnormal amyloid beta (Aβ) accumulation, and the link between the Aβ1-42 structure and toxicity is of major interest. NMDA receptors (NMDAR) are thought to be essential in Aβ-affected neurons, but the role of this receptor in glial impairment is still unclear. In addition, there is insufficient knowledge about the role of Aβ species regarding mitochondrial redox states in neurons and glial cells, which may be critical in developing Aβ-caused neurotoxicity. In this study, we investigated whether different Aβ1-42 species—small oligomers, large oligomers, insoluble fibrils, and monomers—were capable of producing neurotoxic effects via microglial NMDAR activation and changes in mitochondrial redox states in primary rat brain cell cultures. Small Aβ1-42 oligomers induced a concentration- and time-dependent increase in intracellular Ca2+ and necrotic microglial death. These changes were partially prevented by the NMDAR inhibitors MK801, memantine, and D-2-amino-5-phosphopentanoic acid (DAP5). Neither microglial intracellular Ca2+ nor viability was significantly affected by larger Aβ1-42 species or monomers. In addition, the small Aβ1-42 oligomers caused mitochondrial reactive oxygen species (mtROS)-mediated mitochondrial depolarization, glutamate release, and neuronal cell death. In microglia, the Aβ1-42-induced mtROS overproduction was mediated by intracellular calcium ions and Aβ-binding alcohol dehydrogenase (ABAD). The data suggest that the pharmacological targeting of microglial NMDAR and mtROS may be a promising strategy for AD therapy. [ABSTRACT FROM AUTHOR]

The neuroinflammatory process characterizing multiple sclerosis (MS) is associated with changes in excitatory synaptic transmission and altered central concentrations of the primary excitatory amino acid, L‐glutamate (L‐Glu). Recent findings report that cerebrospinal fluid (CSF) levels of L‐Glu positively correlate with pro‐inflammatory cytokines in MS patients. However, to date, there is no evidence about the relationship between the other primary excitatory amino acid, L‐aspartate (L‐Asp), its derivative D‐enantiomer, D‐aspartate, and the levels of pro‐inflammatory and anti‐inflammatory cytokines in the CSF of MS. In the present study, we measured by HPLC the levels of these amino acids in the cortex, hippocampus, cerebellum, and spinal cord of mice affected by experimental autoimmune encephalomyelitis (EAE). Interestingly, in support of glutamatergic neurotransmission abnormalities in neuroinflammatory conditions, we showed reduced L‐Asp levels in the cortex and spinal cord of EAE mice and increased D‐aspartate/total aspartate ratio within the cerebellum and spinal cord of these animals. Additionally, we found significantly decreased CSF levels of L‐Asp in both relapsing–remitting (n = 157) MS (RR‐MS) and secondary progressive/primary progressive (n = 22) (SP/PP‐MS) patients, compared to control subjects with other neurological diseases (n = 40). Importantly, in RR‐MS patients, L‐Asp levels were correlated with the CSF concentrations of the inflammatory biomarkers G‐CSF, IL‐1ra, MIP‐1β, and Eotaxin, indicating that the central content of this excitatory amino acid, as previously reported for L‐Glu, reflects a neuroinflammatory environment in MS. In keeping with this, we revealed that CSF L‐Asp levels were positively correlated with those of L‐Glu, highlighting the convergent variation of these two excitatory amino acids under inflammatory synaptopathy occurring in MS. [ABSTRACT FROM AUTHOR]

Purpose: NMDA receptors (NMDARs) dysfunction plays a central role in the physiopathology of psychiatric and neurodegenerative disorders whose mechanisms are still poorly understood. The development of a PET (positron emission tomography) tracer able to selectively bind to the NMDARs intra-channel PCP site may make it possible to visualize NMDARs in an open and active state. We describe the in vitro pharmacological characterization of [18F]-fluoroethylnormemantine ([18F]-FNM) and evaluate its ability to localize activated NMDA receptors in a rat preclinical model of excitotoxicity. Procedures: The affinity of the non-radioactive analog for the intra-channel PCP site was determined in a radioligand competition assay using [3H]TCP ([3H]N-(1-[thienyl]cyclohexyl)piperidine) on rat brain homogenates. Selectivity was also investigated by the displacement of specific radioligands targeting various cerebral receptors. In vivo brain lesions were performed using stereotaxic quinolinic acid (QA) injections in the left motor area (M1) of seven Sprague Dawley rats. Each rat was imaged with a microPET/CT camera, 40 min after receiving a dose of 30 MBq + / − 20 of [18F]-FNM, 24 and 72 h after injury. Nine non-injured rats were also imaged using the same protocol. Results: FNM displayed IC50 value of 13.0 ± 8.9 µM in rat forebrain homogenates but also showed significant bindings on opioid receptors. In the frontal and left somatosensory areas, [18F]FNM PET detected a mean of 37% and 41% increase in [18F]FNM uptake (p < 0,0001) 24 and 72 h after QA stereotaxic injection, respectively, compared to the control group. Conclusions: In spite of FNM's poor affinity for NMDAR PCP site, this study supports the ability of this tracer to track massive activation of NMDARs in neurological diseases. [ABSTRACT FROM AUTHOR]

The non-competitive NMDA glutamate receptor antagonist memantine has neuroprotective properties and is the first non-cholinergic drug approved for the treatment of Alzheimer's disease. The purpose of this work was to test the hypothesis that injections of memantine to healthy animals can affect the subunit composition of NMDA receptors in the brain, which may explain the effects of its chronic administration. For this, the expression of subunits GluN1, GluN2A, GluN2B, and GluN2C was studied in the hippocampus and prefrontal cortex of rats after single or five subchronic injections of memantine. The results showed that the GluN2C subunit (GRIN2C) plays an important role in the effects of memantine; against the background of memantine treatment, the expression of this subunit markedly decreased in the prefrontal cortex, but not in the hippocampus, which significantly affected the excitation/inhibition balance in cortical structures. [ABSTRACT FROM AUTHOR]

Stroke and late-onset Alzheimer's disease (AD) are risk factors for each other; the comorbidity of these brain disorders in aging individuals represents a significant challenge in basic research and clinical practice. The similarities and differences between stroke and AD in terms of pathogenesis and pathophysiology, however, have rarely been comparably reviewed. Here, we discuss the research background and recent progresses that are important and informative for the comorbidity of stroke and late-onset AD and related dementia (ADRD). Glutamatergic NMDA receptor (NMDAR) activity and NMDAR-mediated Ca2+ influx are essential for neuronal function and cell survival. An ischemic insult, however, can cause rapid increases in glutamate concentration and excessive activation of NMDARs, leading to swift Ca2+ overload in neuronal cells and acute excitotoxicity within hours and days. On the other hand, mild upregulation of NMDAR activity, commonly seen in AD animal models and patients, is not immediately cytotoxic. Sustained NMDAR hyperactivity and Ca2+ dysregulation lasting from months to years, nevertheless, can be pathogenic for slowly evolving events, i.e. degenerative excitotoxicity, in the development of AD/ADRD. Specifically, Ca2+ influx mediated by extrasynaptic NMDARs (eNMDARs) and a downstream pathway mediated by transient receptor potential cation channel subfamily M member (TRPM) are primarily responsible for excitotoxicity. On the other hand, the NMDAR subunit GluN3A plays a "gatekeeper" role in NMDAR activity and a neuroprotective role against both acute and chronic excitotoxicity. Thus, ischemic stroke and AD share an NMDAR- and Ca2+-mediated pathogenic mechanism that provides a common receptor target for preventive and possibly disease-modifying therapies. Memantine (MEM) preferentially blocks eNMDARs and was approved by the Federal Drug Administration (FDA) for symptomatic treatment of moderate-to-severe AD with variable efficacy. According to the pathogenic role of eNMDARs, it is conceivable that MEM and other eNMDAR antagonists should be administered much earlier, preferably during the presymptomatic phases of AD/ADRD. This anti-AD treatment could simultaneously serve as a preconditioning strategy against stroke that attacks ≥ 50% of AD patients. Future research on the regulation of NMDARs, enduring control of eNMDARs, Ca2+ homeostasis, and downstream events will provide a promising opportunity to understand and treat the comorbidity of AD/ADRD and stroke. [ABSTRACT FROM AUTHOR]

In the cerebral cortex, glutamate activates NMDA receptors (NMDARs), localized in noradrenergic neurons, inducing noradrenaline release that may have a permissive effect on glutamatergic transmission, and therefore, on the modulation of long-term plasticity. ATP is co-released with noradrenaline, and with its metabolites (ADP and adenosine) is involved in the purinergic modulation of electrically-evoked noradrenaline release. However, it is not known if noradrenaline release evoked by activation of NMDARs is also under purinergic modulation. The present study aimed to investigate and to characterize the purinergic modulation of noradrenaline release evoked by NMDARs. Stimulation of rat cortical slices with 30 µM NMDA increased noradrenaline release, which was inhibited by ATP upon metabolization into ADP and adenosine and by the selective agonists of A1 and A2A receptors, CPA and CGS2680, respectively. It was also inhibited by UTP and UDP, which are mainly released under pathophysiological situations. Characterization of the effects mediated by these compounds indicated the involvement of P2Y1, P2Y6, A1 and A2A receptors. It is concluded that, in the rat brain cortex, NMDA-evoked noradrenaline release is modulated by several purinergic receptors that may represent a relevant mechanism to regulate the permissive effect of noradrenaline on NMDA-induced neuroplasticity. [ABSTRACT FROM AUTHOR]

Corticotropin-releasing hormone (CRH) is a neuropeptide regulating neuroendocrine and autonomic function. CRH mRNA and protein levels in the hypothalamic paraventricular nucleus (PVN) are increased in primary hypertension. However, the role of CRH in elevated sympathetic outflow in primary hypertension remains unclear. CRHR1 proteins were distributed in retrogradely labeled PVN presympathetic neurons with an increased level in the PVN tissue in adult spontaneously hypertensive rats (SHRs) compared with age-matched male Wistar--Kyoto (WKY) rats. CRH induced a more significant increase in the firing rate of PVN-rostral ventrolateral medulla (RVLM) neurons and sympathoexcitatory response in SHRs than in WKY rats, an effect that was blocked by preapplication of NMDA receptors (NMDARs) antagonist AP5 and PSD-95 inhibitor, Tat- N-dimer. Blocking CRHRs with astressin or CRHR1 with NBI35965 significantly decreased the firing rate of PVN-RVLM output neurons and reduced arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA) in SHRs but not in WKY, whereas blocking CRHR2 with antisauvagine-30 did not. Furthermore, Immunocytochemistry staining revealed that CRHR1 colocalized with NMDARs in PVN presympathetic neurons. Blocking CRHRs significantly decreased the NMDA currents in labeled PVN neurons. PSD-95-bound CRHR1 and PSD-95-bound GluN2A in the PVN were increased in SHRs. These data suggested that the upregulation of CRHR1 in the PVN is critically involved in the hyperactivity of PVN presympathetic neurons and elevated sympathetic outflow in primary hypertension. [ABSTRACT FROM AUTHOR]

Post-stroke depression (PSD), the most frequent psychiatric complication following stroke, could have a negative impact on the recuperation of stroke patients. Hyperhomocysteinemia (HHCY) has been reported to be a modifiable risk factor of stroke. The study tries to explore the effect of HHCY on PSD and the role of N-methyl-d-aspartate receptors (NMDARs)-mediated synaptic alterations. Forty-five adult male Sprague–Dawley rats were randomly allocated into five groups: sham operation group, middle cerebral artery occlusion group (MCAO), HCY-treated MCAO group HCY and MK-801 co-treated MCAO group and MK-801-treated MCAO group. 1.6 mg/kg/d D, L-HCY was administered by tail vein injection for 28 d prior to SHAM or MCAO operationand up to 14 d after surgery. The MK-801 (3 mg/kg) was administered by intraperitoneal injection 15 min prior to MCAO operation. HCY treatment aggravated depressive-like disorders of post-stroke rats by the open field test and sucrose preference test. Further, HCY significantly decreased central monoamines levels in the MCAO rats by HPLC. The transmission electron microscopy results showed that the number of synapses and the area of postsynaptic density decreased in the hippocampus of the HCY-treated MCAO rats. Additionally, HCY augmented ischemia-induced up-regulation of NMDARs, decreased the levels of synaptic structure-related marker PSD-95and the synaptic transmission-associated synaptic proteins (VGLUT1, SNAP-25 and Complexin Ι/ΙΙ). These effects of HCY were partly reversed by the NMDA antagonist MK-801. The current study suggested that NMDARs-mediated synaptic plasticity may be involved in the adverse effect of HCY on PSD. [ABSTRACT FROM AUTHOR]

Synaptic plasticity such as Long-term potentiation (LTP) is a key mechanism for learning in central synapses including the cortex. There are two least two major forms of LTPs: presynaptic LTP and postsynaptic LTP. For postsynaptic LTP, the potentiation of AMPA receptor-mediated responses through protein phosphorylation is thought to be a key mechanism. Silent synapses have been reported in the hippocampus, but it is thought to be mainly present in the cortex during early development, and may contribute to maturation of the cortical circuit. However, recent several lines of evidence demonstrate that silent synapses may exist in mature synapses of adult cortex, and they can be recruited by LTP-inducing protocols, as well as chemical-induced LTP. In pain-related cortical regions, silent synapses may not only contribute to cortical excitation after peripheral injury, but also the recruitment of new cortical circuits as well. Thus, it is proposed that silent synapses and modification of functional AMPA receptors and NMDA receptors may play important roles in chronic pain, including phantom pain. [ABSTRACT FROM AUTHOR]

Synaptic plasticity such as Long-term potentiation (LTP) is a key mechanism for learning in central synapses including the cortex. There are two least two major forms of LTPs: presynaptic LTP and postsynaptic LTP. For postsynaptic LTP, the potentiation of AMPA receptor-mediated responses through protein phosphorylation is thought to be a key mechanism. Silent synapses have been reported in the hippocampus, but it is thought to be mainly present in the cortex during early development, and may contribute to maturation of the cortical circuit. However, recent several lines of evidence demonstrate that silent synapses may exist in mature synapses of adult cortex, and they can be recruited by LTP-inducing protocols, as well as chemical-induced LTP. In pain-related cortical regions, silent synapses may not only contribute to cortical excitation after peripheral injury, but also the recruitment of new cortical circuits as well. Thus, it is proposed that silent synapses and modification of functional AMPA receptors and NMDA receptors may play important roles in chronic pain, including phantom pain. [ABSTRACT FROM AUTHOR]

N-methyl-D-aspartate receptors (NMDARs) play a critical role in excitotoxicity caused by ischemic stroke, but NMDAR antagonists have failed to be translated into clinical practice for treating stroke patients. Recent studies suggest that targeting the specific protein-protein interactions that regulate NMDARs may be an effective strategy to reduce excitotoxicity associated with brain ischemia. α2δ-1 (encoded by the Cacna2d1 gene), previously known as a subunit of voltage-gated calcium channels, is a binding protein of gabapentinoids used clinically for treating chronic neuropathic pain and epilepsy. Recent studies indicate that α2δ-1 is an interacting protein of NMDARs and can promote synaptic traffcking and hyperactivity of NMDARs in neuropathic pain conditions. In this review, we highlight the newly identified roles of α2δ-1-mediated NMDAR activity in the gabapentinoid effects and NMDAR excitotoxicity during brain ischemia as well as targeting a2d-1-bound NMDARs as a potential treatment for ischemic stroke. [ABSTRACT FROM AUTHOR]