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The free d-amino acid, d-aspartate, is abundant in the embryonic brain but significantly decreases after birth. Besides its intracellular occurrence, d-aspartate is also present at extracellular level and acts as an endogenous agonist for NMDA and mGlu5 receptors. These findings suggest that d-aspartate is a candidate signaling molecule involved in neural development, influencing brain morphology and behaviors at adulthood. To address this issue, we generated a knockin mouse model in which the enzyme regulating d-aspartate catabolism, d-aspartate oxidase (DDO), is expressed starting from the zygotic stage, to enable the removal of d-aspartate in prenatal and postnatal life. In line with our strategy, we found a severe depletion of cerebral d-aspartate levels (up to 95%), since the early stages of mouse prenatal life. Despite the loss of d-aspartate content, Ddo knockin mice are viable, fertile, and show normal gross brain morphology at adulthood. Interestingly, early d-aspartate depletion is associated with a selective increase in the number of parvalbumin-positive interneurons in the prefrontal cortex and also with improved memory performance in Ddo knockin mice. In conclusion, the present data indicate for the first time a biological significance of precocious d-aspartate in regulating mouse brain formation and function at adulthood.

Mitochondrial membrane potential regulation through the mitochondrial permeability transition pore (mPTP) is reportedly involved in the ischemic postconditioning (PostC) phenomenon. Melatonin is an endogenous hormone that regulates circadian rhythms. Its neuroprotective effects via mitochondrial melatonin receptors (MTs) have recently attracted attention. However, details of the neuroprotective mechanisms associated with PostC have not been clarified. Using hippocampal CA1 pyramidal cells from C57BL mice, we studied the involvement of MTs and the mPTP in melatonin-induced PostC mechanisms similar to those of ischemic PostC. We measured changes in spontaneous excitatory postsynaptic currents (sEPSCs), intracellular calcium concentration, mitochondrial membrane potential, and N-methyl-D-aspartate receptor (NMDAR) currents after ischemic challenge, using the whole-cell patch-clamp technique. Melatonin significantly suppressed increases in sEPSCs and intracellular calcium concentrations. The NMDAR currents were significantly suppressed by melatonin and the MT agonist, ramelteon. However, this suppressive effect was abolished by the mPTP inhibitor, cyclosporine A, and the MT antagonist, luzindole. Furthermore, both melatonin and ramelteon potentiated depolarization of mitochondrial membrane potentials, and luzindole suppressed depolarization of mitochondrial membrane potentials. This study suggests that melatonin-induced PostC via MTs suppressed the NMDAR that was induced by partial depolarization of mitochondrial membrane potential by opening the mPTP, reducing excessive release of glutamate and inducing neuroprotection against ischemia-reperfusion injury.

Glutamate N-methyl-D-aspartate receptor (NMDAR) is critical for promoting physiological synaptic plasticity and neuronal viability. As a major subpopulation of the NMDAR, the GluN2B subunit-containing NMDARs have distinct pharmacological properties, physiological functions, and pathological relevance to neurological diseases compared with other NMDAR subtypes. In mature neurons, GluN2B-containing NMDARs are likely expressed as both diheteromeric and triheteromeric receptors, though the functional importance of each subpopulation has yet to be disentangled. Moreover, the C-terminal region of the GluN2B subunit forms structural complexes with multiple intracellular signaling proteins. These protein complexes play critical roles in both activity-dependent synaptic plasticity and neuronal survival and death signaling, thus serving as the molecular substrates underlying multiple physiological functions. Accordingly, dysregulation of GluN2B-containing NMDARs and/or their downstream signaling pathways has been implicated in neurological diseases, and various strategies to reverse these deficits have been investigated. In this article, we provide an overview of GluN2B-containing NMDAR pharmacology and its key physiological functions, highlighting the importance of this receptor subtype during both health and disease states.

Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune central nervous system (CNS) disorder mediated by antibodies against the GluN1 subunit of the NMDA receptor. Sjögren’s disease (SjD) is a systemic autoimmune disorder that involves exocrine glands as a primary target. However, CNS manifestations, including the coexistence of other CNS diseases, may also occur. While antibodies against the NMDA receptor, targeting the GluN2 subunits, have been associated with SjD and neurological symptoms, the presence of GluN1 antibodies is rarely described, and the co-occurrence of these two disorders has been scarcely reported. Here, we present a case in which anti-NMDA receptor encephalitis and SjD were identified concurrently during the initial workup. The patient experienced three attacks over 13 months, each effectively treated with immunotherapy. No symptoms were reported during the final phone call (month 18). This case report illustrates the ‘unmasking’ of occult systemic autoimmunity by a non-specific neurological syndrome. A comprehensive diagnostic approach is essential to uncover polyautoimmunity and avoid premature diagnostic closure. Further studies may be required to determine whether the association between SjD and NMDA receptor autoimmunity extends beyond the GluN2 subunits to include the pathogenic GluN1 subunit antibodies.

Application of transcranial random noise stimulation (tRNS) between 0.1 and 640 Hz of the primary motor cortex (M1) for 10 min induces a persistent excitability increase lasting for at least 60 min. However, the mechanism of tRNS-induced cortical excitability alterations is not yet fully understood. The main aim of this study was to get first efficacy data with regard to the possible neuronal effect of tRNS. Single-pulse transcranial magnetic stimulation (TMS) was used to measure levels of cortical excitability before and after combined application of tRNS at an intensity of 1 mA for 10 min stimulation duration and a pharmacological agent (or sham) on eight healthy male participants. The sodium channel blocker carbamazepine showed a tendency toward inhibiting MEPs 5-60 min poststimulation. The GABA A agonist lorazepam suppressed tRNS-induced cortical excitability increases at 0-20 and 60 min time points. The partial NMDA receptor agonist D-cycloserine, the NMDA receptor antagonist dextromethorphan and the D2/D3 receptor agonist ropinirole had no significant effects on the excitability increases seen with tRNS. In contrast to transcranial direct current stimulation (tDCS), aftereffects of tRNS are seem to be not NMDA receptor dependent and can be suppressed by benzodiazepines suggesting that tDCS and tRNS depend upon different mechanisms.

N-methyl-D-aspartate receptors (NMDARs) are widely distributed in the central nervous system (CNS) and play critical roles in neuronal excitability in the CNS. Both clinical and preclinical studies have revealed that the abnormal expression or function of these receptors can underlie the pathophysiology of seizure disorders and epilepsy. Accordingly, NMDAR modulators have been shown to exert anticonvulsive effects in various preclinical models of seizures, as well as in patients with epilepsy. In this review, we provide an update on the pathologic role of NMDARs in epilepsy and an overview of the NMDAR antagonists that have been evaluated as anticonvulsive agents in clinical studies, as well as in preclinical seizure models.

Remifentanil, a widely used ultra-short-acting μ-opioid receptor agonist in clinical anesthesia, is strongly associated with postoperative hyperalgesia (remifentanil-induced hyperalgesia, RIH), posing significant challenges to postoperative pain management. RIH is characterized by an abnormally heightened pain perception following opioid withdrawal, and its underlying mechanisms are complex and multifactorial. Current research highlights the roles of central sensitization, peripheral sensitization, and multiple interacting molecular pathways. These include NMDA receptor activation, glial cell activation, neuroinflammation, disinhibition of inhibitory neurotransmission, and dysfunction of the descending pain modulation system. Additionally, alterations in ion channel expression, synaptic plasticity enhancement, and peripheral responses to inflammatory mediators contribute critically to RIH development. Individual factors such as age, sex, genetic polymorphisms, and surgical type significantly influence the risk of RIH. Although substantial progress has been made in elucidating the molecular mechanisms of RIH, a unified theoretical framework and effective clinical strategies remain lacking. Future studies should emphasize multi-omics approaches and clinically relevant experimental models to uncover key regulatory targets and provide a theoretical basis for individualized analgesic interventions.

Excessive activation of N-methyl- d -aspartic acid (NMDA) receptors after cerebral ischemia is a key cause of ischemic injury. For a long time, it was generally accepted that calcium influx is a necessary condition for ischemic injury mediated by NMDA receptors. However, recent studies have shown that NMDA receptor signaling, independent of ion flow, plays an important role in the regulation of ischemic brain injury. The purpose of this review is to better understand the roles of metabotropic NMDA receptor signaling in cerebral ischemia and to discuss the research and development directions of NMDA receptor antagonists against cerebral ischemia. This mini review provides a discussion on how metabotropic transduction is mediated by the NMDA receptor, related signaling molecules, and roles of metabotropic NMDA receptor signaling in cerebral ischemia. In view of the important roles of metabotropic signaling in cerebral ischemia, NMDA receptor antagonists, such as GluN2B-selective antagonists, which can effectively block both pro-death metabotropic and pro-death ionotropic signaling, may have better application prospects.

Expression of the N-methyl-D-aspartate receptor, particularly when containing the GluN2B subunit (NMDAR-GluN2B), varies across the prefrontal cortex (PFC). In humans, the subgenual cingulate cortex (SGC) contains among the highest levels of NMDAR-GluN2B expression, while the dorsolateral prefrontal cortex (dlPFC) exhibits a more moderate level of NMDAR-GluN2B expression. NMDAR-GluN2B are commonly associated with ionotropic synaptic function and plasticity and are essential to the neurotransmission underlying working memory in the macaque dlPFC in the layer III circuits, which in humans are afflicted in schizophrenia. However, NMDAR-GluN2B can also be found at extrasynaptic sites, where they may trigger distinct events, including some linked to neurodegenerative processes. The SGC is an early site of tau pathology in sporadic Alzheimer’s disease (sAD), which mirrors its high NMDAR-GluN2B expression. Additionally, the SGC is hyperactive in depression, which can be treated with NMDAR antagonists. Given the clinical relevance of NMDAR in the SGC and dlPFC, the current study used immunoelectron microscopy (immunoEM) to quantitatively compare the synaptic and extrasynaptic expression patterns of NMDAR-GluN2B across excitatory and inhibitory neuron dendrites in rhesus macaque layer III SGC and dlPFC. We found a larger population of extrasynaptic NMDAR-GluN2B in dendrites of putative pyramidal neurons in SGC as compared to the dlPFC, while the dlPFC had a higher proportion of synaptic NMDAR-GluN2B. In contrast, in putative inhibitory dendrites from both areas, extrasynaptic expression of NMDAR-GluN2B was far more frequently observed over synaptic expression. These findings may provide insight into varying cortical vulnerability to alterations in excitability and neurodegenerative forces.