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Opioid-seeking behaviors depend on glutamatergic plasticity in the nucleus accumbens core (NAcc). Here we investigated whether the behavioral and synaptic effects of opioids are influenced by acid-sensing ion channel 1A (ASIC1A). We tested the effects of ASIC1A on responses to several opioids and found that Asic1a−/− mice had elevated behavioral responses to acute opioid administration as well as opioid seeking behavior in conditioned place preference (CPP). Region-restricted restoration of ASIC1A in NAcc was sufficient to reduce opioid CPP, suggesting NAcc is an important site of action. We next tested the effects of oxycodone withdrawal on dendritic spines in NAcc. We found effects of oxycodone and ASIC1A that contrasted with changes previously described following cocaine withdrawal. Finally, we examined α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated and N-methyl-D-aspartic acid (NMDA) receptor-mediated synaptic currents in NAcc. Oxycodone withdrawal, like morphine withdrawal, increased the AMPAR/NMDAR ratio in Asic1a+/+ mice, whereas oxycodone withdrawal reduced the AMPAR/NMDAR ratio in Asic1a−/− mice. A single dose of oxycodone was sufficient to induce this paradoxical effect in Asic1a−/− mice, suggesting an increased sensitivity to oxycodone. We conclude that ASIC1A plays an important role in the behavioral and synaptic effects of opioids and may constitute a potential future target for developing novel therapies. [ABSTRACT FROM AUTHOR]

N-methyl-D-aspartate (NMDA) receptors are ionotropic glutamate receptors involved in learning and memory. NMDA receptors primarily comprise two GluN1 and two GluN2 subunits. The GluN2 subunit dictates biophysical receptor properties, including the extent of receptor activation and desensitization. GluN2A- and GluN2D-containing receptors represent two functional extremes. To uncover the conformational basis of their functional divergence, we utilize single-molecule fluorescence resonance energy transfer to probe the extracellular domains of these receptor subtypes under resting and ligand-bound conditions. We find that the conformational profile of the GluN2 amino-terminal domain correlates with the disparate functions of GluN2A- and GluN2D-containing receptors. Changes at the pre-transmembrane segments inversely correlate with those observed at the amino-terminal domain, confirming direct allosteric communication between these domains. Additionally, binding of a positive allosteric modulator at the transmembrane domain shifts the conformational profile of the amino-terminal domain towards the active state, revealing a bidirectional allosteric pathway between extracellular and transmembrane domains. NMDA receptors convert chemical signals into electrical signals in the brain, and function is fine-tuned by the subunit composition. Here the authors use smFRET to uncover a bi-directional communication pathway between different parts of the receptor. [ABSTRACT FROM AUTHOR]

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]

Background: Autoimmune encephalitis (AIE) encompasses a spectrum of rare autoimmune-mediated neurological disorders, which are characterized by brain inflammation and dysfunction. Autoantibodies targeting the N-methyld-aspartic acid receptor (NMDAR) and leucine-rich glioma-inactivated 1 (LGI1) are the most common subtypes of antibody-positive AIE. Currently, there are no approved therapies for AIE. Interleukin-6 (IL-6) signaling plays a role in the pathophysiology of AIE. Satralizumab, a humanized, monoclonal recycling antibody that specifically targets the IL-6 receptor and inhibits IL-6 signaling, has demonstrated efficacy and safety in another autoantibody-mediated neuroinflammatory disease, aquaporin-4 immunoglobulin G antibody-positive neuromyelitis optica spectrum disorder, and has the potential to be an evidencebased disease modifying treatment in AIE. Objectives: CIELO will evaluate the efficacy, safety, pharmacodynamics, and pharmacokinetics of satralizumab compared with placebo in patients with NMDAR-immunoglobulin G antibody-positive (IgG+) or LGI1-IgG+ AIE. Study design: CIELO (NCT05503264) is a prospective, Phase 3, randomized, double-blind, multicenter, basket study that will enroll approximately 152 participants with NMDAR-IgG+ or LGI1-IgG+ AIE. Prior to enrollment, participants will have received acute first-line therapy. Part 1 of the study will consist of a 52-week primary treatment period, where participants will receive subcutaneous placebo or satralizumab at Weeks 0, 2, 4, and every 4 weeks thereafter. Participants may continue to receive background immunosuppressive therapy, symptomatic treatment, and rescue therapy throughout the study. Following Part 1, participants can enter an optional extension period (Part 2) to continue the randomized, double-blind study drug, start open-label satralizumab, or stop study treatment and continue with follow-up assessments. Endpoints: The primary efficacy endpoint is the proportion of participants with a ≥1-point improvement in the modified Rankin Scale (mRS) score from study baseline and no use of rescue therapy at Week 24. Secondary efficacy assessments include mRS, Clinical Assessment Scale of Autoimmune Encephalitis (CASE), time to rescue therapy, sustained seizure cessation and no rescue therapy, Montreal Cognitive Assessment, and Rey Auditory Verbal Learning Test (RAVLT) measures. Safety, pharmacokinetics, pharmacodynamics, exploratory efficacy, and biomarker endpoints will be captured. Conclusion: The innovative basket study design of CIELO offers the opportunity to yield prospective, robust evidence, which may contribute to the development of evidence-based treatment recommendations for satralizumab in AIE. [ABSTRACT FROM AUTHOR]

Retinal neurodegeneration, characterized by retinal ganglion cell (RGC) death, is a leading cause of vision impairment and loss in blind diseases, such as glaucoma. Müller cells play crucial roles in maintaining retinal homeostasis. Thus, dysfunction of Müller cells has been implicated as one of the causes of retinal diseases. Yes-associated protein 1 (YAP), a nuclear effector of the Hippo pathway, regulates mammalian cell survival. In this study, we investigated the role of YAP in Müller cells during N-methyl-D-aspartic acid (NMDA)-induced excitotoxic RGC injury in rats. We found that YAP expression increased and was activated in Müller cells after NMDA-induced RGC injury. This YAP response was partly due to an increase in Yap mRNA levels, although it may be independent of the Hippo pathway and ß-TrCP-mediated YAP degradation. Morphological analysis revealed that verteporfin, a selective YAP inhibitor, exacerbated NMDA-induced RGC degeneration, suggesting that YAP activation in Müller cells contributes to RGC survival in NMDA-treated retinas. Studies in the rat Müller cell line (rMC-1) demonstrated that overexpression of YAP increased the levels of Bcl-xL, while verteporfin decreased the levels of Bcl-xL and cell viability and increased the levels of cytochrome c released from mitochondria and cleaved caspase-3. Finally, we found that Bcl-xL expression increased slightly in NMDA-treated retinas, whereas intravitreal injection of verteporfin suppressed this increase. Our findings suggest that activated YAP in Müller cells protects against NMDAinduced RGC injury by upregulating Bcl-xL expression. [ABSTRACT FROM AUTHOR]

Background: Ketamine has recently attracted considerable attention for its rapid effects on patients with major depressive disorder, including treatment-resistant depression (TRD). Despite ketamine's promising results in treating depression, a significant number of patients do not respond to the treatment, and predicting who will benefit remains a challenge. Although its antidepressant effects are known to be linked to its action as an antagonist of the N-methyl-D-aspartate (NMDA) receptor, the precise mechanisms that determine why some patients respond and others do not are still unclear. Objective: This study aims to understand the computational mechanisms underlying changes in the auditory mismatch negativity (MMN) response following treatment with intravenous ketamine. Moreover, we aim to link the computational mechanisms to their underlying neural causes and use the parameters of the neurocomputational model to make individual treatment predictions. Methods: This is a prospective study of 30 patients with TRD who are undergoing intravenous ketamine therapy. Prior to 3 out of 4 ketamine infusions, EEG will be recorded while patients complete the auditory MMN task. Depression, suicidality, and anxiety will be assessed throughout the study and a week after the last ketamine infusion. To translate the effects of ketamine on the MMN to computational mechanisms, we will model changes in the auditory MMN using the hierarchical Gaussian filter, a hierarchical Bayesian model. Furthermore, we will employ a conductance-based neural mass model of the electrophysiological data to link these computational mechanisms to their neural causes. Conclusion: The findings of this study may improve understanding of the mechanisms underlying response and resistance to ketamine treatment in patients with TRD. The parameters obtained from fitting computational models to EEG recordings may facilitate single-patient treatment predictions, which could provide clinically useful prognostic information. Trial registration: Clinicaltrials.gov NCT05464264. Registered June 24, 2022. [ABSTRACT FROM AUTHOR]

Synaptic plasticity is a key cellular model for learning, memory and chronic pain. Most previous studies were carried out in rats and mice, and less is known about synaptic plasticity in non-human primates. In the present study, we used integrative experimental approaches to study long-term potentiation (LTP) in the anterior cingulate cortex (ACC) of adult tree shrews. We found that glutamate is the major excitatory transmitter and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid (AMPA) receptors mediate postsynaptic responses. LTP in tree shrews was greater than that in adult mice and lasted for at least 5 h. N-methyl-d-aspartic acid (NMDA) receptors, Ca2+ influx and adenylyl cyclase 1 (AC1) contributed to tree shrew LTP. Our results suggest that LTP is a major form of synaptic plasticity in the ACC of primate-like animals. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'. [ABSTRACT FROM AUTHOR]

NMDA receptors (NMDARs) may be crucial to working memory (WM). Computational models predict that they sustain neural firing and produce associative memory, which may underpin maintaining and binding information, respectively. We test this in patients with antibodies to NMDAR (n = 10, female) and compare them with healthy control participants (n = 55, 20 male, 35 female). Patients were tested after recovery with a task that separates two aspects of WM: sustaining attention and feature binding. Participants had to remember two colored arrows. Then attention was directed to one of them. After a variable delay, they reported the direction of either the same arrow (congruent cue) or of the other arrow (incongruent cue). We asked how congruency affected recall precision and measured types of error. Patients had difficulty in both sustaining attention to an item over time and feature binding. Controls were less precise after longer delays and incongruent cues. In contrast, patients did not benefit from congruent cues at longer delays [group x congruency (long condition); p = 0.041], indicating they could not sustain attention. Additionally, patients reported the wrong item (misbinding errors) more than controls after congruent cues [group x delay (congruent condition), main effect of group; p≤0.001]. Our results suggest NMDARs are critical for both maintaining attention and feature binding. [ABSTRACT FROM AUTHOR]

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that has antidepressant and antisuicidal effects, as shown by multiple studies done over the past two decades, that can be used effectively in the management of treatment-resistant depression (TRD). The United States Food and Drug Administration has approved intranasal (S)-ketamine in combination with an oral antidepressant for TRD. Although research is promising with respect to ketamine's effect on depression and suicidality, the need for in-office administration and treatment monitoring limits the accessibility of treatment. Significant concerns remain regarding the risks of treatment and its abuse potential. Nonetheless, its potential efficacy in TRD and suicidality makes ketamine an effective treatment modality for this patient population. [Psychiatr Ann. 2024;54(6):e170–e176.] [ABSTRACT FROM AUTHOR]

Background: Transcranial magnetic stimulation (TMS) is a noninvasive neurostimulation modality that has been used to study human synaptic plasticity. Leveraging work in ex vivo preparations, mechanistically informed pharmacological adjuncts to TMS have been used to improve our fundamental understanding of TMS-induced synaptic plasticity. Methods: We systematically reviewed the literature pairing pharmacological adjuncts with TMS plasticity-induction protocols in humans. We searched MEDLINE, PsycINFO, and Embase from 2013 to Mar. 10, 2023. Studies published before 2013 were extracted from a previous systematic review. We included studies using repetitive TMS, theta-burst stimulation, paired associative stimulation, and quadripulse stimulation paradigms in healthy and clinical populations. Results: Thirty-six studies met our inclusion criteria (28 in healthy and 8 in clinical populations). Most pharmacological agents have targeted the glutamatergic N-methyl-D-aspartate (NMDA; 15 studies) or dopamine receptors (13 studies). The NMDA receptor is necessary for TMS-induced plasticity; however, sufficiency has not been shown across protocols. Dopaminergic modulation of TMSinduced plasticity appears to be dose-dependent. The GABAergic, cholinergic, noradrenergic, and serotonergic neurotransmitter systems have small evidence bases supporting modulation of TMS-induced plasticity, as do voltage-gated calcium and sodium channels. Studies in clinical populations suggest that pharmacological adjuncts to TMS may rescue motor cortex plasticity, with implications for therapeutic applications of TMS and a promising clinical trial in depression. Limitations: This review is limited by the predominance in the literature of studies with small sample sizes and crossover designs. Conclusion: Pharmacologically enhanced TMS largely parallels findings from ex vivo preparations. As this area expands and novel targets are tested, adequately powered samples in healthy and clinical populations will inform the mechanisms of TMS-induced plasticity in health and disease., Introduction Transcranial magnetic stimulation (TMS) is a noninvasive neurostimulation technique that induces electrical currents in underlying brain parenchyma through electromagnetic induction. (1) It is one of the most established noninvasive [...]

Background: The preservation of retinal ganglion cells (RGCs) and the facilitation of axon regeneration are crucial considerations in the management of various vision-threatening disorders. Therefore, we investigate the efficacy of interleukin-4 (IL-4), a potential therapeutic agent, in promoting neuroprotection and axon regeneration of retinal ganglion cells (RGCs) as identified through whole transcriptome sequencing in an in vitro axon growth model. Methods: A low concentration of staurosporine (STS) was employed to induce in vitro axon growth. Whole transcriptome sequencing was utilized to identify key target factors involved in the molecular mechanism underlying axon growth. The efficacy of recombinant IL-4 protein on promoting RGC axon growth was validated through in vitro experiments. The protective effect of recombinant IL-4 protein on somas of RGCs was assessed using RBPMS-specific immunofluorescent staining in mouse models with optic nerve crush (ONC) and N-methyl-D-aspartic acid (NMDA) injury. The protective effect on RGC axons was evaluated by anterograde labeling of cholera toxin subunit B (CTB), while the promotion of RGC axon regeneration was assessed through both anterograde labeling of CTB and immunofluorescent staining for growth associated protein-43 (GAP43). Results: Whole-transcriptome sequencing of staurosporine-treated 661 W cells revealed a significant upregulation in intracellular IL-4 transcription levels during the process of axon regeneration. In vitro experiments demonstrated that recombinant IL-4 protein effectively stimulated axon outgrowth. Subsequent immunostaining with RBPMS revealed a significantly higher survival rate of RGCs in the rIL-4 group compared to the vehicle group in both NMDA and ONC injury models. Axonal tracing with CTB confirmed that recombinant IL-4 protein preserved long-distance projection of RGC axons, and there was a notably higher number of surviving axons in the rIL-4 group compared to the vehicle group following NMDA-induced injury. Moreover, intravitreal delivery of recombinant IL-4 protein substantially facilitated RGC axon regeneration after ONC injury. Conclusion: The recombinant IL-4 protein exhibits the potential to enhance the survival rate of RGCs, protect RGC axons against NMDA-induced injury, and facilitate axon regeneration following ONC. This study provides an experimental foundation for further investigation and development of therapeutic agents aimed at protecting the optic nerve and promoting axon regeneration. [ABSTRACT FROM AUTHOR]

Dendritic structures play a pivotal role in the computational processes occurring within neurons. Signal propagation along dendrites relies on both passive conduction and active processes related to voltage-dependent ion channels. Among these channels, extrasynaptic N-methyl-D-aspartate channels (exNMDA) emerge as a significant contributor. Prior studies have mainly concentrated on interactions between synapses and nearby exNMDA (100 nm–10 µm from synapse), activated by presynaptic membrane glutamate. This study concentrates on the correlation between synaptic inputs and distal exNMDA (>100 µm), organized in clusters that function as signal amplifiers. Employing a computational model of a dendrite, we elucidate the mechanism underlying signal amplification in exNMDA clusters. Our findings underscore the pivotal role of the optimal spatial positioning of the NMDA cluster in determining signal amplification efficiency. Additionally, we demonstrate that exNMDA subunits characterized by a large conduction decay constant. Specifically, NR2B subunits exhibit enhanced effectiveness in signal amplification compared to subunits with steeper conduction decay. This investigation extends our understanding of dendritic computational processes by emphasizing the significance of distant exNMDA clusters as potent signal amplifiers. The implications of our computational model shed light on the spatial considerations and subunit characteristics that govern the efficiency of signal amplification in dendritic structures, offering valuable insights for future studies in neurobiology and computational neuroscience. [ABSTRACT FROM AUTHOR]

It is crucial to regulate N-methyl-D-aspartate (NMDA) function bivalently depending on the central nervous system (CNS) conditions. CNS disorders with NMDA hyperfunction are involved in the pathogenesis of neurotoxic and/or neurodegenerative disorders with elevated D-serine, one of the NMDA receptor co-agonists. On the contrary, NMDA-enhancing agents have been demonstrated to improve psychotic symptoms and cognition in CNS disorders with NMDA hypofunction. Serine racemase (SR), the enzyme regulating both D- and L-serine levels through both racemization (catalysis from L-serine to D-serine) and β-elimination (degradation of both D- and L-serine), emerges as a promising target for bidirectional regulation of NMDA function. In this study, we explored using dimethyl malonate (DMM), a pro-drug of the SR inhibitor malonate, to modulate NMDA activity in C57BL/6J male mice via intravenous administration. Unexpectedly, 400 mg/kg DMM significantly elevated, rather than decreased (as a racemization inhibitor), D-serine levels in the cerebral cortex and plasma. This outcome prompted us to investigate the regulatory effects of dodecagalloyl-α-D-xylose (α12G), a synthesized tannic acid analog, on SR activity. Our findings showed that α12G enhanced the racemization activity of human SR by about 8-fold. The simulated and fluorescent assay of binding affinity suggested a noncooperative binding close to the catalytic residues, Lys56 and Ser84. Moreover, α12G treatment can improve behaviors associated with major CNS disorders with NMDA hypofunction including hyperactivity, prepulse inhibition deficit, and memory impairment in animal models of positive symptoms and cognitive impairment of psychosis. In sum, our findings suggested α12G is a potential therapeutic for treating CNS disorders with NMDA hypofunction. [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]

BACKGROUND: Previous studies have shown that N-methyl-D-aspartic acid receptor (NMDA) receptors are associated with fluorine, but the role in fluorideinduced endoplasmic reticulum stress remains unclear. OBJECTIVE: To observe the changes of excitatory neurotransmitter NMDA receptor and endoplasmic reticulum stress IRE1α-ASK1-JNK pathway protein expression in brain tissue of rats with experimental fluorosis, and to investigate the pathogenesis of neurological injury in fluorosis by giving NMDA receptor inhibitor to SH-SY5Y cells. METHODS: (1) Animal model: 18 1-month-old SD rats were randomly divided into control group (drinking water fluoride content < 0.5 mg/L), low fluoride group (drinking water fluoride content 10.0 mg/L) and high fluoride group (drinking water fluoride content 100.0 mg/L), with 6 rats in each group, half of each sex. After 6 months of fluoride intake, the rats were observed for the occurrence of dental fluorosis, and the 24-hour urinary fluoride content was measured. After anesthesia and euthanasia, the brain tissue of rats was taken to observe the pathological changes. Western blot assay was used to detect NMDA receptors and IRE1α, ASK1 and JNK protein expression in the brain tissue. (2) Cell model: SH-SY5Y cells were cultured in vitro and treated with sodium fluoride at final concentrations of 0.3 mmol/L and 3 mmol/L. The fluoride-stained cells were interfered with 10 μmol/L NMDA receptor antagonists Ifenprodil and MK-801 to observe the relevant protein changes. RESULTS AND CONCLUSION: (1) The incidence of dental fluorosis and urinary fluoride level in rats in the high fluoride group were significantly higher than that in the control and low fluoride groups (P < 0.05). (2) Compared with the control group, the cytoplasm of neuronal cells in the CA3 area of the hippocampus in the low fluoride group was slightly more basophilic, while the neuronal cells in the CA3 area of the high fluoride group were disorganized, with increased basophilicity and some of the nuclei solidified. (3) In rat brain tissue, the expressions of NR2A in the high fluoride group and NR2B in the low fluoride group were significantly higher compared with the control group (P < 0.05), and NR2B, IRE1, ASK1, and p-JNK protein expression levels were increased in the high fluoride group compared with the control and low fluoride groups (P < 0.05). (4) In SH-SY5Y cells, NR1, NR2A and NR2B protein expressions were significantly increased in the high fluoride group compared to the control group (P < 0.05). The protein levels of NR1 and NR2A were significantly reduced in the high fluorine + Ifenprodil group and high fluorine + MK-801 group compared with the high fluorine group (P < 0.05). NR2B protein expression was significantly lower in the high fluorine + Ifenprodil group than that in the high fluorine group (P < 0.05). (5) In SH-SY5Y cells, IRE1, ASK1, and p-JNK protein expression was significantly higher in the high fluoride group compared with the control group (P < 0.05), while ASK1 and p-JNK protein expressions were significantly decreased in the high fluorine + Ifenprodil group and high fluorine + MK-801 group compared with the high fluorine group (P < 0.05). IRE1 protein level was significantly lower in the high fluorine + Ifenprodil group than that in the high fluorine group (P < 0.05). (6) It is concluded that excessive fluorine intake activates NMDA receptors in the central nervous system, causing increased expression of endoplasmic reticulum stress IRE1α, ASK1, and p-JNK proteins, and the use of NMDA receptor inhibitors has a mitigating effect on endoplasmic reticulum stress caused by fluorosis. [ABSTRACT FROM AUTHOR]

Ketamine induces a complex cascade of effects on diverse groups of brain cells through several receptors. In the cortex and hippocampus, the concomitant inhibition of interneurons and activation of excitatory neurons is triggered by rapid pharmacological effects and the subsequent engagement of signaling pathways that activate protein synthesis. The lasting effects of ketamine are sustained by the activation of neuronal plasticity mechanisms, including control of excitability and synaptogenesis in the cortex and hippocampus. Correlative evidence suggests the contribution of oligodendrocytes, astroglia, and microglia to the antidepressant effects of ketamine, but the casual involvement of these cell types has not been definitively tested. Over the past six decades, the use of ketamine has evolved from an anesthetic and recreational drug to the first non-monoaminergic antidepressant approved for treatment-resistant major depressive disorder (MDD). Subanesthetic doses of ketamine and its enantiomer (S)-ketamine (esketamine) directly bind to several neurotransmitter receptors [including N-methyl- d -aspartic acid receptor (NMDAR), κ and μ opioid receptor (KOR and MOR)] widely distributed in the brain and across different cell types, implicating several potential molecular mechanisms underlying the action of ketamine as an antidepressant. This review examines preclinical studies investigating cell-type-specific mechanisms underlying the effects of ketamine on behavior and synapses. Cell-type-specific approaches are crucial for disentangling the critical mechanisms involved in the therapeutic effect of ketamine. Over the past six decades, the use of ketamine has evolved from an anesthetic and recreational drug to the first non-monoaminergic antidepressant approved for treatment-resistant major depressive disorder (MDD). Subanesthetic doses of ketamine and its enantiomer (S)-ketamine (esketamine) directly bind to several neurotransmitter receptors [including N-methyl-d-aspartic acid receptor (NMDAR), κ and μ opioid receptor (KOR and MOR)] widely distributed in the brain and across different cell types, implicating several potential molecular mechanisms underlying the action of ketamine as an antidepressant. This review examines preclinical studies investigating cell-type-specific mechanisms underlying the effects of ketamine on behavior and synapses. Cell-type-specific approaches are crucial for disentangling the critical mechanisms involved in the therapeutic effect of ketamine. [ABSTRACT FROM AUTHOR]

Objective: Herpes simplex virus (HSV) infection triggered n-methyl-D-aspartate (NMDA) encephalitis can lead to varied neuropsychiatric manifestations, including movement disorders and manic symptoms. HSV is known to affect the same brain regions as in secondary mania. Method: We present a 35-year-old female diagnosed with recurrent depressive disorder (RDD) who developed NMDA encephalitis triggered by HSV infection. Result: HSV-triggered NMDA encephalitis led to a manic switch in a woman with RDD on antidepressants, along with the new onset of dyskinetic movements. Conclusion: A neurological insult predisposed our patient to the variable effects of antidepressant drugs. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) and N-methyl-D-aspartate (NMDA) receptors in the brain regulate metabolic homeostasis. In a paper published in Nature , Petersen et al. describe a bimodal molecule that conjugates a GLP-1 analog with MK-801 (NMDA receptor antagonist), which lowers feeding and body weight to a greater extent than the GLP-1R agonist alone. Glucagon-like peptide-1 (GLP-1) and N-methyl-D-aspartate (NMDA) receptors in the brain regulate metabolic homeostasis. In a paper published in Nature , Petersen et al. describe a bimodal molecule that conjugates a GLP-1 analog with MK-801 (NMDAR receptor antagonist), which lowers feeding and body weight to a greater extent than the GLP-1R agonist alone. [ABSTRACT FROM AUTHOR]

Ionotropic glutamate receptors (iGluRs) mediate excitatory signals between cells by binding neurotransmitters and conducting cations across the cell membrane. In the mammalian brain, most of these signals are mediated by two types of iGluRs: AMPA and NMDA (i.e. iGluRs sensitive to 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid and N-methyl-D-aspartic acid, respectively). Delta-type iGluRs of mammals also form neurotransmitter-binding channels in the cell membrane, but in contrast, their channel is not activated by neurotransmitter binding, raising biophysical questions about iGluR activation and biological questions about the role of delta iGluRs. We therefore investigated the divergence of delta iGluRs from their iGluR cousins using molecular phylogenetics, electrophysiology, and site-directed mutagenesis. We find that delta iGluRs are found in numerous bilaterian animals (e.g., worms, starfish, and vertebrates) and are closely related to AMPA receptors, both genetically and functionally. Surprisingly, we observe that many iGluRs of the delta family are activated by the classical inhibitory neurotransmitter, γ-aminobutyric acid (GABA). Finally, we identify nine amino acid substitutions that likely gave rise to the inactivity of today’s mammalian delta iGluRs, and these mutations abolish activity when engineered into active invertebrate delta iGluRs, partly by inducing receptor desensitization. These results offer biophysical insight into iGluR activity and point to a role for GABA in excitatory signaling in invertebrates. [ABSTRACT FROM AUTHOR]

Glaucoma and other optic neuropathies lead to progressive and irreversible vision loss by damaging retinal ganglion cells (RGCs) and their axons. Cell replacement therapy is a potential promising treatment. However, current methods to obtain RGCs have inherent limitations, including time‐consuming procedures, inefficient yields and complex protocols, which hinder their practical application. Here, we have developed a straightforward, rapid and efficient approach for directly inducing RGCs from mouse embryonic fibroblasts (MEFs) using a combination of triple transcription factors (TFs): ASCL1, BRN3B and PAX6 (ABP). We showed that on the 6th day following ABP induction, neurons with molecular characteristics of RGCs were observed, and more than 60% of induced neurons became iRGCs (induced retinal ganglion cells) in the end. Transplanted iRGCs had the ability to survive and appropriately integrate into the RGC layer of mouse retinal explants and N‐methyl‐D‐aspartic acid (NMDA)‐damaged retinas. Moreover, they exhibited electrophysiological properties typical of RGCs, and were able to regrow dendrites and axons and form synaptic connections with host retinal cells. Together, we have established a rapid and efficient approach to acquire functional RGCs for potential cell replacement therapy to treat glaucoma and other optic neuropathies. [ABSTRACT FROM AUTHOR]

Background: Attention provides the foundation for cognitions, which was shown to be affected by microwave (MW) radiation. With the ubiquitous of microwaves, public concerns regarding the impact of MW radiation on attention has hence been increased. Our study aims to investigate the potential effect and mechanism of acute microwave exposure on attention. Results: We identified obvious impairment of attention in mice by the five-choice serial reaction time (5-CSRT) task. Proteomic analysis of the cerebrospinal fluid (CSF) revealed neuroinflammation and microglial activation potentially due to acute MW exposure. Moreover, biochemical analysis further confirmed microglial activation in the prefrontal cortex (PFC) of mice subjected to acute MW exposure. Finally, minocycline, a commercially available anti-inflammatory compound, attenuated neuroinflammation, inhibited the upregulation of N-methyl-D-aspartic acid receptor (NMDAR) including NR2A and NR2B, and also accelerated the attentional recovery after MW exposure. Conclusions: We believe that microglial activation and NMDAR upregulation likely contribute to inattention induced by acute MW exposure, and we found that minocycline may be effective in preventing such process. [ABSTRACT FROM AUTHOR]

Background: Antibodies against N-methyl-D-aspartate receptors are the most commonly identified cause of autoimmune encephalitis. While predominantly associated with malignancies, cases of anti-N-methyl-D-aspartate receptor autoimmune encephalitis have been reported after infections with the herpessimplex virus or, more recently, in patients with severe COVID-19 disease. Case presentation: A previously healthy 17-year-old male adolescent acutely developed psychosis with auditory and visual hallucinations, fluctuating mental status, and an isolated seizure 5  weeks after a mildly symptomatic COVID-19 infection. The symptoms continued to worsen, accompanied by catatonia, and additional neurological symptoms developed during the initial antipsychotic treatment. A diagnostic workup revealed antibodies against N-methyl-Daspartate receptors in the cerebrospinal fluid without other major abnormalities. After establishing the diagnosis, initiation of immunomodulatory therapy stopped the symptom progression and led to full recovery within 2  months. Conclusion: The case is remarkable in that anti-N-methyl-D-aspartate receptor autoimmune encephalitis developed shortly after a COVID-19 infection in an adolescent, despite the individual experiencing only mild COVID symptoms. The diagnosis should be considered in cases of acute-onset psychotic symptoms during or after COVID-19 infection, particularly in individuals without a prior psychiatric history, who present with atypical psychiatric or neurological features. [ABSTRACT FROM AUTHOR]

Epigenetics is a biological process that modifies and regulates gene expression, affects neuronal function, and contributes to pain. However, the mechanism by which epigenetics facilitates and maintains chronic pain is poorly understood. We aimed to determine whether [N.sup.6]-methyladenosine (m6A) specifically modified by methyltransferase-like 14 (METTL14) alters neuronal activity and governs pain by sensitizing the GluN2A subunit of the N-methyl-D-aspartate receptor (NMDAR) in the dorsal root ganglion (DRG) neurons in a model of chemotherapy-induced neuropathic pain (CINP). Using dot blotting, immunofluorescence, gain/loss-of-function, and behavioral assays, we found that m6A levels were upregulated in L4-L6 DRG neurons in CINP in a DBP/METTL14-dependent manner, which was also confirmed in human DRGs. Blocking METTL14 reduced m6A methylation and attenuated pain hypersensitivity. Mechanistically, METTL14-mediated m6A modification facilitated the synaptic plasticity of DRG neurons by enhancing the GluN2A subunit of NMDAR, and inhibiting METTL14 blocked this effect. In contrast, overexpression of METTL14 upregulated m6A modifications, enhanced presynaptic NMDAR activity in DRG neurons, and facilitated pain sensation. Our findings reveal a previously unrecognized mechanism of METTL14-mediated m6A modification in DRG neurons to maintain neuropathic pain. Targeting these molecules may provide a new strategy for pain treatment., Introduction Chemotherapy-induced neuropathic pain (CINP) is a debilitating complication caused by damage to the peripheral nervous system by chemotherapeutic agents, including paclitaxel (1). CINP occurs in approximately 50% to 90% [...]

The olfactory system of insects regulates the processes of insect feeding, mating, and egg laying through the participation of various olfactory proteins, hence it plays a key role in insect survival and reproduction. The tea leafhopper, Empoasca onukii Matsuda, is one of the most devastating pests in Chinese tea plantations. Transcriptome sequencing experiments were conducted to detect chemoreceptor genes including odorant receptors/co-receptors (ORs/Orco), ionotropic receptors (IRs), N-methyl-D-aspartic acid receptors (NMDAs), gustatory receptors (GRs), and sensory neuron membrane proteins (SNMPs). Phylogenetic analysis of chemoreceptor genes and the expression levels of the identified genes in four different tissues of E. onukii, including antennae, heads, bodies, and legs were also analyzed. In total, 12 ORs, five IRs, three NMDAs, three GRs, and two SNMPs were annotated in the E. onukii transcriptome data. The number of chemoreceptor genes in E. onukii was considerably lower than that in other hemiptera insects. Phylogenetic analysis was conducted to compare ORs, IRs, NMDAs, GRs, and SNMPs among the hemiptera insects, and showed that chemoreceptor genes in E.onukii were clustered into ten clades with other hemiptera insects, respectively. The results of RT-qPCR showed that seven EonuORs, three EonuIRs, and one EonuGRs were highly expressed in the antennae of E. onukii. The function of chemoreceptor genes in E. onukii in sensing the volatile compounds remains to be elucidated. [ABSTRACT FROM AUTHOR]

Objective • Generally autoimmune encephalitis (AE) cases present with central nervous system symptoms. Many types of autoantibodies are associated with autoimmune encephalitis, with anti-N-methyl-D-aspartate receptor being the most commonly reported. However, autoimmune encephalitis cases with autoantibodies targeting unknown epitopes are increasingly recognized. This article aims to summarize the clinical experience and assess the feasibility of modified electroconvulsive therapy (MECT) as an adjunctive treatment method for autoimmune encephalitis patients with poor response to first-line immunotherapy and mainly displaying psychiatric symptoms. Methods • This work reports three cases of which two have been diagnosed as autoantibodies targeting unknown epitope autoimmune encephalitis while one has been diagnosed as anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and all were effectively treated with MECT. Results • All three cases that otherwise failed to respond to standard immunotherapy for controlling psychiatric symptoms exhibited excellent clinical outcomes following MECT. The underlying mechanism of action of MECT is unclear and whether such an effect involves a neurotransmitter rebalance in the brain remains uncertain. At present, we have observed only a small number of clinical cases, warranting further research among a larger number of clinical cases and more systematic multicenter retrospective analysis. Conclusions • It should be noted that, while our experience supports the utility of MECT in the treatment of certain cases of AE, this option should be regarded as an adjuvant therapy after standard immunosuppressive therapy. Clinicians must be aware that patients should be provided with psychiatric or neurological services for timely diagnosis along with timely and appropriate treatment. [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]

Ifenprodil has been known to reduce cardiac contractility and cerebral vasodilation by antagonizing α1-adrenergic and N-methyl D-aspartate receptor-mediated intracellular signals. This study aimed to investigate the direct effect of ifenprodil on the human voltage-gated Kv1.5 channel (hKv1.5) by using a Xenopus oocyte expression system and a two-microelectrode voltage clamp technique. The amplitudes of hKv1.5 currents, including peak and steady state, were suppressed in a concentration-dependent manner (IC50; 43.1 and 35.5 μM, respectively) after 6 min of ifenprodil treatment. However, these effects were ~ 80% reversed by washout, suggesting that ifenprodil directly inhibited the hKv1.5 independent of membrane receptors or intracellular signals. The inhibition rate of steady state showed voltage dependence, wherein the rates increased according to test voltage depolarization. Ifenprodil reduced the time constants of hKv1.5 inactivation but has higher effects on activation. hKv1.5 inhibition by ifenprodil showed use dependency because the drug more rapidly reduced the current at the higher activation frequencies, and subsequent reduction in frequency after high activation frequency caused a partial channel block relief. Therefore, ifenprodil directly blocked the hKv1.5 in an open state and accelerated the time course of the channel inactivation, which provided a biophysical mechanism for the hKv1.5 blocking effects of ifenprodil. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a common neurodegenerative disorder of middle-aged and elderly people, clinically characterized by resting tremor, myotonia, reduced movement, and impaired postural balance. Clinically, patients with PD are often administered levodopa (L-DOPA) to improve their symptoms. However, after years of L-DOPA treatment, most patients experience complications of varying severity, including the "on-off phenomenon", decreased efficacy, and levodopa-induced dyskinesia (LID). The development of LID can seriously affect the quality of life of patients, but its pathogenesis is unclear and effective treatments are lacking. Glutamic acid (Glu)-mediated changes in synaptic plasticity play a major role in LID. The N-methyl-D-aspartic acid receptor (NMDAR), an ionotropic glutamate receptor, is closely associated with synaptic plasticity, and neuroinflammation can modulateNMDAR activation or expression; in addition, neuroinflammation may be involved in the development of LID. However, it is not clear whether NMDA receptors are co-regulated with neuroinflammation during LID formation. Here we review how neuroinflammation mediates the development of LID through the regulation of NMDA receptors, and assess whether common anti-inflammatory drugs and NMDA receptor antagonistsmay be able to mitigate the development of LID through the regulation of central neuroinflammation, thereby providing a new theoretical basis for finding new therapeutic targets for LID. [ABSTRACT FROM AUTHOR]

Narcolepsy is a chronic and underrecognized sleep disorder characterized by excessive daytime sleepiness and cataplexy. Furthermore, narcolepsy type 1 (NT1) has serious negative impacts on an individual's health, society, and the economy. Currently, many sleep centers lack the means to measure orexin levels in the cerebrospinal fluid. We aimed to analyze the characteristics of metabolite changes in patients with NT1, measured by ultra-performance liquid chromatography–tandem mass spectrometry. A principal component analysis (PCA), an orthogonal partial least square discriminant analysis (OPLS-DA), t tests, and volcano plots were used to construct a model of abnormal metabolic pathways in narcolepsy. We identified molecular changes in serum specimens from narcolepsy patients and compared them with control groups, including dehydroepiandrosterone, epinephrine, N-methyl-D-aspartic acid, and other metabolites, based on an OPLS-loading plot analysis. Nine metabolites yielded an area under the receiver operating curve > 0.75. Meanwhile, seven abnormal metabolic pathways were correlated with differential metabolites, such as metabolic pathways; neuroactive ligand‒receptor interaction; and glycine, serine, and threonine metabolism. To our knowledge, this is the first study to reveal the characteristic metabolite changes in sera from NT1 patients for the selection of potential blood biomarkers and the elucidation of NT1 pathogenesis. [ABSTRACT FROM AUTHOR]

Neonatal hypoxic-ischemic encephalopathy (HIE) is a disease caused by insufficient blood supply in the brain in newborns during the perinatal period. Severe HIE leads to patient death, and patients with mild HIE are at increased risk of cognitive deficits and behavioral abnormalities. The NMDA receptor is an important excitatory receptor in the central nervous system, and in adult hypoxic-ischemic injury both subtypes of the NMDA receptor play important but distinct roles. The GluN2Acontaining NMDA receptor (GluN2A-NMDAR) could activate neuronal protective signaling pathway, while the GluN2B-NMDAR subtype is coupled to the apoptosis-inducing signaling pathway and leads to neuronal death. However, the expression level of GluN2B is higher in newborns than in adults, while the expression of GluN2A is lower. Therefore, it is not clear whether the roles of different NMDA receptor subtypes in HIE are consistent with those in adults. We investigated this issue in this study and found that in HIE, GluN2B plays a protective role by mediating the protective pathway through binding with PSD95, which is quite different to that in adults. The results of this study provided new theoretical support for the clinical treatment of neonatal hypoxic ischemia. [ABSTRACT FROM AUTHOR]

The lateral habenula (LHb) has received special attention due to its role in modulating motivated behavior, stress response, and rewarding and aversive stimuli through monoamine transmission. In the present study, the involvement of the N‐methyl‐d‐aspartate (NMDA) receptors of the LHb in the expression and acquisition phases of morphine‐induced conditioned place preference (CPP) was studied in male rats. Bilateral injections of agonist/antagonist (MK‐801) of NMDA receptor were performed during the conditioning sessions of the acquisition phase. In other separate groups, drugs were also injected into the LHb before the test session during the expression phase of CPP. A 5‐day CPP bias paradigm was used to study the effect of injections of NMDA and MK‐801 into the LHb on morphine reward‐related behavior. Different doses of NMDA plus morphine reduced the CPP score during the acquisition phase, whereas MK‐801 significantly increased conditioning scores during the acquisition phase of CPP. The injection of agonists and antagonists of NMDA receptors in LHb had no significant effect on CPP scores and locomotion during the expression phase of CPP, whereas the motor activity in the acquisition phase was affected by the drugs. The reduction effect of NMDA on the CPP scores during the acquisition phase was blocked by pretreatment with MK‐801. Our findings also suggest that NMDA receptors in the LHb may be involved in the acquisition phase of morphine‐induced CPP. [ABSTRACT FROM AUTHOR]

While sensory representations in the brain depend on context, it remains unclear how such modulations are implemented at the biophysical level, and how processing layers further in the hierarchy can extract useful features for each possible contextual state. Here, we demonstrate that dendritic N-Methyl-D-Aspartate spikes can, within physiological constraints, implement contextual modulation of feedforward processing. Such neuron-specific modulations exploit prior knowledge, encoded in stable feedforward weights, to achieve transfer learning across contexts. In a network of biophysically realistic neuron models with context-independent feedforward weights, we show that modulatory inputs to dendritic branches can solve linearly nonseparable learning problems with a Hebbian, error-modulated learning rule. Wealso demonstrate that local prediction of whether representations originate either from different inputs, or from different contextual modulations of the same input, results in representation learning of hierarchical feedforward weights across processing layers that accommodate a multitude of contexts. [ABSTRACT FROM AUTHOR]

Adenosine A1 receptors (AA1R) have been shown to counteract N-methyl- D -aspartate (NMDA)–mediated glutamatergic excitotoxicity. In the present study, we investigated the role of AA1R in neuroprotection by trans -resveratrol (TR) against NMDA-induced retinal injury. In total, 48 rats were divided into the following four groups: normal rats pretreated with vehicle; rats that received NMDA (NMDA group); rats that received NMDA after pretreatment with TR; and rats that received NMDA after pretreatment with TR and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), an AA1R antagonist. Assessment of general and visual behaviour was performed using the open field test and two-chamber mirror test, respectively, on Days 5 and 6 post NMDA injection. Seven days after NMDA injection, animals were euthanized, and eyeballs and optic nerves were harvested for histological parameters, whereas retinae were isolated to determine the redox status and expression of pro- and anti-apoptotic proteins. In the present study, the retinal and optic nerve morphology in the TR group was protected from NMDA-induced excitotoxic damage. These effects were correlated with the lower retinal expression of proapoptotic markers, lipid peroxidation, and markers of nitrosative/oxidative stress. The general and visual behavioural parameters in the TR group showed less anxiety-related behaviour and better visual function than those in the NMDA group. All the findings observed in the TR group were abolished by administration of DPCPX. • Adenosine A1 receptors (AA1R) involves in retinal protection by trans-resveratrol (TR). • TR improves visual behaviour in rats with NMDA-induced retinal injury. • AA1R-mediated neuroprotection by TR is associated with reduced oxidative stress. • AA1R-mediated neuroprotection by TR is associated with reduced nitrosative stress. • AA1R-mediated neuroprotection by TR is associated with reduced apoptosis. [ABSTRACT FROM AUTHOR]