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Ionotropic glutamate receptors are expressed in mouse and human spermatozoa. However, the possible role of these receptors has not been reported in the sperm acrosome reaction. This study was conducted to demonstrate the function of N‐methyl‐D‐aspartate (NMDA) glutamate receptors in the acrosome reaction of mouse spermatozoa. Epididymal spermatozoa from adult mice were release in a culture medium. The sperm suspension was then divided into six groups: (1) spermatozoa at 0 min, (2) spermatozoa at 60 min (control), (3) spermatozoa treated with NMDA glutamate receptor agonist (L‐glutamate, LG), (4) spermatozoa treated with α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA)/kainite glutamate receptor agonist (kainic acid), (5) spermatozoa treated with NMDA glutamate receptor antagonist (MK‐801)+LG and (6) spermatozoa treated with ethylene glycol tetraacetic acid (EGTA, as a calcium chelator)+LG. The sperm samples were examined for the acrosome reaction and intracellular calcium concentration. After 60 min, LG but not kainic acid significantly increased both the acrosome reaction and intracellular calcium levels in the spermatozoa compared with the control group. Co‐administration of MK‐801 or EGTA+LG could significantly reverse the effect of LG in the acrosome reaction and the level of intracellular calcium as compared to the LG group. The possibility that LG induced the acrosome reaction and elevated inter‐cellular calcium concentration in mouse spermatozoa and that MK‐801 could reverse the effects of LG, may suggest the involvement of NMDA glutamate receptors, at least in the initiation of the acrosome reaction in vitro. [ABSTRACT FROM AUTHOR]

Introduction: Memantine as N-Methyl-D-Aspartic Acid (NMDA) receptor antagonist is used in some neurological disorders. Moreover, memantine presents modulatory effects on the somatosensory information processing in healthy subjects. This study investigated the effects of memantine on electrophysiological properties of barrel cortex neurons in male rats. Methods: Single unit recording was used to evaluate the electrophysiological properties of barrel cortex neurons. The neural responses to the Principal Whisker (PW), Adjacent Whisker (AW), and combined displacement of two whiskers [20 ms Inter-Stimulus Intervals (ISIs)] were recorded before and 2 hours after memantine gavage (10 mg/kg). A Condition Test Ratio (CTR) was calculated for assessing inhibitory interactions. Results: Two hours after memantine gavage, neuronal ON and OFF responses to PW deflection were decreased. Furthermore, CTR for both ON and OFF responses was decreased following memantine administration. Conclusion: The current study demonstrated that memantine modified neural response properties in the rat barrel cortex. [ABSTRACT FROM AUTHOR]

Two coordination polymers, that is [Zn(pdc)(im)(H2O)]n (1) and [Cu(pdc)(im)2]n·n(H2pdc) (2) (H2pdc = terephthalic acid, im = imidazole), were hydrothermally synthesized via the reactions of H2pdc and im in combination with Zn(II) or Cu(II) ions. Compound 1 shows intense blue luminescence and compound 2 shows good photocatalytic activity for the methyl violet degradation under the irradiation of ultraviolet light. In addition, the assessment of the two compounds' application values against Parkinson's disease were carried out and their specific mechanism was tested simultaneously. First of all, the real time RT-PCR was implemented and the relative expression levels of N-methyl-D-aspartic acid receptor receptor on neurons were measured. Besides, the Annexin V-FITC/PI apoptosis assay was utilized for the assessment of the influence of the compounds on the dopaminergic neuron death rate. The hemolysis toxicity detection was conducted to detect the biocompatible of the compounds. [ABSTRACT FROM AUTHOR]

Background: Recently, antibodies against the alpha isoform of the glial-fibrillary-acidic-protein (GFAPa) were identified in a small series of patients with encephalomyelitis. Coexisting autoantibodies (NMDA receptor, GAD65 antibodies) have been described in a few of these patients. We describe a patient with rapidly progressive encephalomyeloradiculitis and a combination of anti-ITPR1, anti-GFAP and anti-MOG antibodies. Case presentation and literature review: A 44-year old caucasian woman with a flu-like prodrome presented with meningism, progressive cerebellar signs and autonomic symptoms, areflexia, quadriplegia and respiratory insufficiency. MRI showed diffuse bilateral T2w-hyperintense brain lesions in the cortex, white matter, the corpus callosum as well as a longitudinal lesion of the medulla oblongata and the entire spinal cord. Anti-ITPR1, anti-GFAP and anti-MOG antibodies were detected in cerebrospinal fluid along with lymphocytic pleocytosis. Borderline tumor of the ovary was diagnosed. Thus, the disease of the patient was deemed to be paraneoplastic. The patient was treated by surgical removal of tumor, steroids, immunoglobulins, plasma exchange and rituximab. Four months after presentation, the patient was still tetraplegic, reacted with mimic expressions to pain or touch and could phonate solitary vowels. An extensive literature research was performed. Conclusion: Our case and the literature review illustrate that multiple glial and neuronal autoantibodies can cooccur, that points to a paraneoplastic etiology, above all ovarian teratoma or thymoma. Clinical manifestation can be a mixture of typically associated syndromes, e.g. ataxia associated with anti-ITPR1 antibodies, encephalomyelitis with anti-GFAPa antibodies and longitudinal extensive myelitis with anti-MOG antibodies. [ABSTRACT FROM AUTHOR]

We present a new multistage method to study the N-Methyl-D-Aspartate (NMDA) neuroreceptor starting from the reconstruction of its crystallographic structure. Thanks to the combination of Homology Modelling, Molecular Dynamics and Lattice Boltzmann simulations, we analyse the allosteric transition of NDMA upon ligand binding and compute the receptor response to ionic passage across the membrane. [ABSTRACT FROM AUTHOR]

Background and Purpose: Neurosteroids influence neuronal function and have multiple promising clinical applications. Direct modulation of postsynaptic neurotransmitter receptors by neurosteroids is well characterized, but presynaptic effects remain poorly understood. Here, we report presynaptic glutamate release potentiation by neurosteroids pregnanolone and pregnanolone sulfate and compare their mechanisms of action to phorbol 12,13‐dibutyrate (PDBu), a mimic of the second messenger DAG. Experimental Approach We use whole‐cell patch‐clamp electrophysiology and pharmacology in rat hippocampal microisland cultures and total internal reflection fluorescence (TIRF) microscopy in HEK293 cells expressing GFP‐tagged vesicle priming protein Munc13‐1, to explore the mechanisms of neurosteroid presynaptic modulation. Key Results: Pregnanolone sulfate and pregnanolone potentiate glutamate release downstream of presynaptic Ca2+ influx, resembling the action of a phorbol ester PDBu. PDBu partially occludes the effect of pregnanolone, but not of pregnanolone sulfate. Calphostin C, an inhibitor that disrupts DAG binding to its targets, reduces the effect PDBu and pregnanolone, but not of pregnanolone sulfate, suggesting that pregnanolone might interact with a well‐known DAG/phorbol ester target Munc13‐1. However, TIRF microscopy experiments found no evidence of pregnanolone‐induced membrane translocation of GFP‐tagged Munc13‐1, suggesting that pregnanolone may regulate Munc13‐1 indirectly or interact with other DAG targets. Conclusion and Implications: We describe a novel presynaptic effect of neurosteroids pregnanolone and pregnanolone sulfate to potentiate glutamate release downstream of presynaptic Ca2+ influx. The mechanism of action of pregnanolone, but not of pregnanolone sulfate, partly overlaps with that of PDBu. Presynaptic effects of neurosteroids may contribute to their therapeutic potential in the treatment of disorders of the glutamate system. [ABSTRACT FROM AUTHOR]

Alzheimer's Disease (AD) is one of the most prevalent neurodegenerative chronic diseases. As it progresses, patients become increasingly dependent, and their caregivers are burdened with the increasing demand for managing their care. Mobile health (mHealth) technology, such as smartphone applications, can support the need of these caregivers. This paper examines the published academic literature of mHealth applications that support the caregivers of AD patients. Following the PRISMA for scoping reviews, we searched published literature in five electronic databases between January 2014 and January 2021. Twelve articles were included in the final review. Six themes emerged based on the functionalities provided by the reviewed applications for caregivers. They are tracking, task management, monitoring, caregiver mental support, education, and caregiver communication platform. The review revealed that mHealth applications for AD patients' caregivers are inadequate. There is an opportunity for industry, government, and academia to fill the unmet need of these caregiver. [ABSTRACT FROM AUTHOR]

Background: The pond snail, Lymnaea stagnalis (L. stagnalis), has served as a valuable model organism for neurobiology studies due to its simple and easily accessible central nervous system (CNS). L. stagnalis has been widely used to study neuronal networks and recently gained popularity for study of aging and neurodegenerative diseases. However, previous transcriptome studies of L. stagnalis CNS have been exclusively carried out on adult L. stagnalis only. As part of our ongoing effort studying L. stagnalis neuronal growth and connectivity at various developmental stages, we provide the first age-specific transcriptome analysis and gene annotation of young (3 months), adult (6 months), and old (18 months) L. stagnalis CNS. Results: Using the above three age cohorts, our study generated 55–69 millions of 150 bp paired-end RNA sequencing reads using the Illumina NovaSeq 6000 platform. Of these reads, ~ 74% were successfully mapped to the reference genome of L. stagnalis. Our reference-based transcriptome assembly predicted 42,478 gene loci, of which 37,661 genes encode coding sequences (CDS) of at least 100 codons. In addition, we provide gene annotations using Blast2GO and functional annotations using Pfam for ~ 95% of these sequences, contributing to the largest number of annotated genes in L. stagnalis CNS so far. Moreover, among 242 previously cloned L. stagnalis genes, we were able to match ~ 87% of them in our transcriptome assembly, indicating a high percentage of gene coverage. The expressional differences for innexins, FMRFamide, and molluscan insulin peptide genes were validated by real-time qPCR. Lastly, our transcriptomic analyses revealed distinct, age-specific gene clusters, differentially expressed genes, and enriched pathways in young, adult, and old CNS. More specifically, our data show significant changes in expression of critical genes involved in transcription factors, metabolisms (e.g. cytochrome P450), extracellular matrix constituent, and signaling receptor and transduction (e.g. receptors for acetylcholine, N-Methyl-D-aspartic acid, and serotonin), as well as stress- and disease-related genes in young compared to either adult or old snails. Conclusions: Together, these datasets are the largest and most updated L. stagnalis CNS transcriptomes, which will serve as a resource for future molecular studies and functional annotation of transcripts and genes in L. stagnalis. [ABSTRACT FROM AUTHOR]

Attention-deficit/hyperactivity disorder (ADHD) is a common neuropsychiatric disorder in children. Although animal models and human brain imaging studies indicate a significant role for glutamatergic dysfunction in ADHD, there is no direct evidence that glutamatergic dysfunction is sufficient to induce ADHD-like symptoms. The glial glutamate transporter GLT1 plays a critical role in glutamatergic neurotransmission. We report here the generation of mice expressing only 20% of normal levels of the GLT1. Unlike conventional GLT1 knockout mice, these mice survive to adulthood and exhibit ADHD-like phenotypes, including hyperactivity, impulsivity and impaired memory. These findings indicate that glutamatergic dysfunction due to GLT1 deficiency, a mechanism distinct from the dopaminergic deficit hypothesis of ADHD, underlies ADHD-like symptoms. • We generate mice expressing 20% of normal levels of the glutamate transporter GLT1. • Unlike GLT1 knockout mice, two thirds of GLT1 hypomorph mice survived to adulthood. • GLT1 hypomorph mice show attention-deficit/hyperactivity disorder-like phenotypes. • GLT1 hypomorph mice serve as a new model to study glutamatergic dysfunction in ADHD. [ABSTRACT FROM AUTHOR]

The neuron-specific tyrosine phosphatase striatal-enriched phosphatase (STEP) is emerging as a key regulator of excitotoxicity, which is involved in the pathogenesis of both acute and chronic neurological diseases. However, the intracellular mechanisms that are regulated by STEP to confer neuroprotection against excitotoxic insults are not well understood. The present study investigates the role of STEP in regulating neuronal release of the proinflammatory prostanoid prostaglandin E2 (PGE2), which is associated with a wide range of pathological conditions. The findings show that glutamate-mediated activation of the N-methyl-D-aspartic acid receptor in STEP-deficient neurons leads to rapid and sustained increase in the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), a signaling molecule involved in the production of inflammatory mediators. Such sustained p38 MAPK activation increases the activity of cytosolic phospholipase A2, which catalyzes the release of arachidonic acid, the initial substrate for PGE2 biosynthesis. Sustained p38 MAPK activation also induces nuclear factor-κB-mediated increase in expression of cyclooxygenase-2 that is involved in the conversion of arachidonic acid to prostanoids, resulting in enhanced biosynthesis and release of PGE2 from neurons. Restoration of STEP function with a STEP mimetic (TAT-STEP-myc peptide) significantly decreases the activation of p38 MAPK-mediated cytosolic phospholipase A2/cyclooxygenase-2/PGE2 signaling cascade. This study identifies an important mechanism involved in the neuronal release of the proinflammatory mediator PGE2 after excitotoxic insult and highlights for the first time the immunomodulatory ability of a neuronal tyrosine phosphatase. [ABSTRACT FROM AUTHOR]

The surface of astrocyte processes that often surround excitatory synapses is packed with high-affinity glutamate transporters, largely preventing extrasynaptic glutamate escape. The shape and prevalence of perisynaptic astroglia vary among brain regions, in some cases providing a complete isolation of synaptic connections from the surrounding tissue. The perception has been that the geometry of perisynaptic environment is therefore essential to preventing extrasynaptic glutamate escape. To understand to what degree this notion holds, we modelled brain neuropil as a space filled with a scatter of randomly sized, overlapping spheres representing randomly shaped cellular elements and intercellular lumen. Simulating release and diffusion of glutamate molecules inside the interstitial gaps in this medium showed that high-affinity transporters would efficiently constrain extrasynaptic spread of glutamate even when diffusion passages are relatively open. We thus estimate that, in the hippocampal or cerebellar neuropil, the bulk of glutamate released by a synaptic vesicle is rapidly bound by transporters (or high-affinity target receptors) mainly in close proximity of the synaptic cleft, whether or not certain physiological or pathological events change local tissue geometry. [ABSTRACT FROM AUTHOR]

Memantine is NMDA (N Methyl D Aspartate) antagonist used to manage dementia, it works by blocking the glutamate receptors that stimulate excite-toxic neuronal death that results from excessive calcium influx into the neurons which in turn causes mitochondrial suffocation and neuronal death. Memantine is an uncompetitive, low affinity, open-channel blocker that reduces the glutamate induced overstimulation of the receptors that results in neuronal damage. It is unlike potential neuroprotective agents that block virtually all NMDA receptor activity including blockade of those essential for normal neuronal functioning. On the other hand, the pathology of dementia we are tackling here appears several years and may be decades earlier in structural and functional MRI studies before the development of the full-blown clinical picture of Alzheimer's Dementia. The use of Meantime in this paper is targeting the excite-toxic etiology mainly and the development of Alzheimer's Dementia. We used the term and definitions of critical numbers in a synonymous way to talk about brain reserve and to hypothesize the potential mechanism of Memantine in delaying the onset of symptoms of Alzheimer's Dementia if used as a monotherapy irrespective of other pathologies such as the neurofibrillary tangles and plaques formation. Meanwhile, in the same hypothesis we left a room for using memantine and other disease modifying agents to be combined and used to tackle more than one etiological factor in those individuals with genetic risk to develop Alzheimer's Dementia with and without cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

This study presents development and characterization of a radiotracer, [125I]iodonefiracetam ([125I]iodoNEF). Labeling with high yield and radiochemical purity was achieved through the formation of a [125I]iodoNEF radiotracer after investigating many factors like oxidizing agent content (chloramines-T (Ch-T)), substrate amount (Nefiracetam (NEF)), pH of reaction mixture, reaction time and temperature. Nefiracetam (NEF) is known as nootropic agent, acting as N-methyl-d-aspartic acid receptor ligand (NMDA). The radiolabeled compound was stable, and exhibited the logarithm of the partition coefficient (log p) value of [125I]iodonefiracetam as 1.85 (lipophilic). Biodistribution studies in normal mice confirmed the suitability of the [125I]iodoNEF radiotracer as a novel tracer for brain imaging. High uptake of 8.61 ± 0.14 percent injected dose/g organ was observed in mice [ABSTRACT FROM AUTHOR]

Striatal circuits must be modulated for behavioral flexibility, the ability to adapt to environmental changes. Striatal astrocytes contribute to circuit neuromodulation by controlling the activity of ambient neurotransmitters. In particular, extracellular glutamate levels are tightly controlled by the astrocytic glutamate transporter EAAT2, influencing synaptic functioning and neural network activity. However, it remains unclear if EAAT2 responds to environmental cues to specifically shape action control. To investigate the relationship between behavioral flexibility and experience-dependent regulation of EAAT2 expression in the dorsal striatum, mice were trained on an instrumental task. We manipulated EAAT2 expression using chemogenetic activation of astrocytic Gq signaling or in vivo morpholinos and determined the ability to adapt to novel environmental contingencies. The loss of behavioral flexibility with task overtraining is associated with the upregulation of EAAT2, which results in enhanced glutamate clearance and altered modulation of glutamatergic neurotransmission in the lateral part of the dorsal striatum. Interfering with EAAT2 upregulation in this striatal area preserves behavioral flexibility. Astrocytes are emerging as critical regulators of striatal functions. This work demonstrates that plasticity of EAAT2 expression in the lateral part of the dorsal striatum shapes behavior, thus providing novel mechanistic insights into how flexibility in action control is regulated. [ABSTRACT FROM AUTHOR]

MiRNAs are small, non‐coding RNAs that can silence the expression of various target genes by binding their mRNAs and thus regulate a wide range of crucial bodily functions. However, the miRNA expression profile of schizophrenia after antipsychotic mediation is largely unknown. Non‐competitive N‐methyl‐D‐aspartic acid (NMDA) receptor antagonists such as MK‐801 have provided useful animal models to investigate the effects of schizophrenia‐like symptoms in rodent animals. Herein, the hippocampal miRNA expression profiles of Sprague‐Dawley rats pretreated with MK‐801 were examined after antipsychotic clozapine (CLO) treatment. Total hippocampal RNAs from three groups were subjected to next‐generation sequencing (NGS), and bioinformatics analyses, including differential expression and enrichment analyses, were performed. Eight miRNAs were differentially expressed between the MK‐801 and vehicle (VEH) control groups. Interestingly, 14 miRNAs were significantly differentially expressed between the CLO + MK‐801 and MK‐801 groups, among which rno‐miR‐184 was the most upregulated. Further analyses suggested that these miRNAs modulate target genes that are involved in endocytosis regulation, ubiquitin‐mediated proteolysis, and actin cytoskeleton regulation and thus might play important roles in the pathogenesis of schizophrenia. Our results suggest that differentially expressed miRNAs play important roles in the complex pathophysiology of schizophrenia and subsequently impact brain functions. [ABSTRACT FROM AUTHOR]

Introduction: Obsessive-compulsive disorder (OCD) is a chronic condition characterized by time-consuming and distressing obsessions and/or compulsions, often accompanied by avoidance behaviours. It is a highly prevalent and incident disorder that results in considerable disability and quality of life reduction. Current pharmacological treatments are hindered by their delayed onset and the limited evidence on how to approach first and second line treatment-resistant patients. Recent research showcased the involvement of glutamatergic pathways in the pathophysiology of OCD prompting research into the potential therapeutic use of ketamine, which binds to the N-methyl-D-aspartic acid receptor and acts as a non-competitive antagonist of glutamate. Objectives: The aim of this study is to conduct a literature review on the use of ketamine and its enantiomers as a treatment for OCD and report a clinical case involving an OCD patient who experienced significant improvement following ketamine use. Methods: A search was performed on PubMed using a combination of keywords and Medical Subject Headings terms, including "Ketamine", "Esketamine" and "Obsessive-Compulsive Disorder". Only studies that involved patients with OCD aged ≥18 years who had received ketamine or its enantiomers as an intervention and that reported treatment response using a validated scale were included. Results: Nine studies were included, 4 case reports, 3 open-label trials and 2 randomized controlled trials, totalling 71 patients. Ketamine was administered intravenously in 7 studies and intranasally in the remaining 2. The results were heterogeneous, with some studies reporting no effect on obsessive-compulsive (OC) symptoms and others demonstrating significant and rapid improvement, albeit some only transitorily. We present the case of a 42-year-old man who experienced OC symptoms since the age of 20 but was only formally diagnosed with OCD 3 years ago. During his first consultation, the patient described obsessive thoughts related to contamination and dirtiness, accompanied by handwashing rituals and avoidance behaviours (e.g., avoiding touching handles and switches). His Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score was 29. Escitalopram was initiated with a progressive dose titration, resulting in partial improvement (Y-BOCS 23). In a follow-up appointment, the patient disclosed that he had purchased and self-administered a single intravenous dose of 2g of ketamine 2 months earlier for recreational use. This led to an immediate and significant improvement of his OC symptoms. Subsequent re-evaluation 4 months later confirmed that he remained asymptomatic (Y-BOCS 2). Conclusions: Ketamine may be a therapeutic alternative for OCD patients who are treatment resistant due to its rapid anti-obsessional effect. Further studies with improved designs and larger sample sizes are warranted to better assess the efficacy of ketamine in OCD treatment. Disclosure of Interest: None Declared [ABSTRACT FROM AUTHOR]

Dizocilpine (MK-801), a non-competitive N-methyl-D-aspartic acid receptor (NMDA-R) antagonist, can induce schizophrenia-like symptoms in healthy individuals, implicating NMDA-R hypofunction in disease pathogenesis. Brain-derived neurotrophic factor (BDNF) is also implicated in schizophrenia, and expression is regulated by NMDA-R activity, suggesting a functional link. We previously found that BDNF signaling was upregulated by MK-801 in cultured hippocampal astrocytes, but the underlying mechanism is not clear. To address this issue, the levels of BDNF expression and secretion were evaluated in hippocampal astrocytes incubated with MK-801 by ELISA and qPCR, with and without NMDA co-incubation or pretreatment of either the ERK1/2 inhibitor, PD98059 or the PI3K inhibitor, LY294002. The apoptosis, viability, and proliferation of the astrocytes were also examined. In the current study, we demonstrate that MK-801 treatment (20 μM for 5 days) enhances the proliferation of rat cultured hippocampal astrocytes. Expression of BDNF mRNA was enhanced after 24 h in MK-801, but returned to near baseline over the next 24 h in the continued presence of MK-801. However, two successive 24-h treatments enhanced BDNF expression. These application regimens had no effect on apoptosis or proliferation rate. Co-addition of NMDA significantly inhibited MK-801-induced upregulation of BDNF. Similarly, MK-801-induced BDNF upregulation was blocked by pretreatment with inhibitors of PI3K and ERK1/2, but not by inhibitors of p38 and JNK. These findings suggested that astrocytes may contribute to the acute neurological and behavioral response to MK-801 treatment via a transient increase in BDNF expression involving NMDA-R–PI3K–ERK signaling. [ABSTRACT FROM AUTHOR]

Stress is a biologically relevant signal and can modulate hippocampal synaptic plasticity. The subiculum is the major output station of the hippocampus and serves as a critical hub in the stress response network. However, stress-associated synaptic plasticity in the ventral subiculum has not been adequately addressed. Therefore, we investigated the impact of a single exposure to an inherently stressful two-way active avoidance conditioning on the induction of long-term potentiation (LTP) at CA1—subiculum synapses in ventral hippocampal slices from young adult rats 1 day after stressor exposure. We found that acute stress enhanced LTP and lowered the induction threshold for a late-onset LTP at excitatory CA1 to subicular burst-spiking neuron synapses. This late-onset LTP was dependent on the activation of β-adrenergic and glutamatergic N -methyl-D-aspartate receptors and independent of D1/D5 dopamine receptor activation. Thereby, we present a cellular mechanism that might contribute to behavioral stress adaptation after acute stressor exposure. [ABSTRACT FROM AUTHOR]

In this study, while presenting a clinical case with early psychiatric manifestations, we emphasized the need to pay attention to neurological diagnoses such as Anti N‐Methyl‐D‐Aspartate Receptor (NMDAR) encephalitis at the time of manifestation of these common symptoms. [ABSTRACT FROM AUTHOR]

Brain on fire, an unusual phrase used for the deadliest autoimmune ailment, called anti-NMDA (N-methyl-D-aspartate) receptor encephalitis, characterizing extreme psychiatric and neurotic signs. Though being the deadliest one, still it can be treated with the help of various therapeutic approaches such as Corticosteroids, Intravenous immunoglobulin (IVIG) and plasmapheresis or plasma exchange. Although the prevalence of encephalitis can be observed in both the sexes, however the majority of ailment (95%) is seen in women with teratoma ovaries or different neoplasms. Recognition of anti-NMDA receptor encephalitis could be very essential to avoid any misconception regarding incorrect interpretation of various psychotic disorders. However, various treatment options are available still further investigation should be required to carried out to find out other clinically beneficial drugs. [ABSTRACT FROM AUTHOR]

In the present study, we identified L-erythro-β-hydroxyasparagine (L-β-EHAsn) found abundantly in human urine, as a novel substrate of Zn2+-dependent D-serine dehydratase (DSD). L-β-EHAsn is an atypical amino acid present in large amounts in urine but rarely detected in serum or most organs/tissues examined. Quantitative analyses of urinary L-β-EHAsn in young healthy volunteers revealed significant correlation between urinary L-β-EHAsn concentration and creatinine level. Further, for in-depth analyses of L-β-EHAsn, we developed a simple three-step synthetic method using trans-epoxysuccinic acid as the starting substance. In addition, our research revealed a strong inhibitory effect of L-β-EHAsn on mammalian serine racemase, responsible for producing D-serine, a co-agonist of the N-methyl-D-aspartate (NMDA) receptor involved in glutamatergic neurotransmission. [ABSTRACT FROM AUTHOR]

The pathophysiology of Alzheimer's disease (AD) is related to neuroinflammatory responses mediated by microglia. Memantine, an antagonist of N-methyl-d-aspartate (NMDA) receptors used as an anti-Alzheimer's drug, protects from neuronal death accompanied by suppression of proliferation and activation of microglial cells in animal models of AD. However, it remains to be tested whether memantine can directly affect microglial cell function. In this study, we examined whether pretreatment with memantine affects intracellular NO and Ca2+ mobilization using DAF-2 and Fura-2 imaging, respectively, and tested the effects of memantine on phagocytic activity by human β-Amyloid (1–42) phagocytosis assay in rodent microglial cells. Pretreatment with memantine did not affect production of NO or intracellular Ca2+ elevation induced by TNF in rodent microglial cells. Pretreatment with memantine also did not affect the mRNA expression of pro-inflammatory (TNF, IL-1β, IL-6 and CD45) or anti-inflammatory (IL-10, TGF-β and arginase) phenotypes in rodent microglial cells. In addition, pretreatment with memantine did not affect the amount of human β-Amyloid (1–42) phagocytosed by rodent microglial cells. Moreover, we observed that pretreatment with memantine did not affect 11 major proteins, which mainly function in the phagocytosis and degradation of β-Amyloid (1–42), including TREM2, DAP12 and neprilysin in rodent microglial cells. To the best of our knowledge, this is the first report to suggest that memantine does not directly modulate intracellular NO and Ca2+ mobilization or phagocytic activity in rodent microglial cells. Considering the neuroinflammation hypothesis of AD, the results might be important to understand the effect of memantine in the brain. [ABSTRACT FROM AUTHOR]

Background: d -glutamate, which is involved in N-methyl- d -aspartate receptor modulation, may be associated with cognitive ageing. Aims: This study aimed to use peripheral plasma d -glutamate levels to differentiate patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) from healthy individuals and to evaluate its prediction ability using machine learning. Methods: Overall, 31 healthy controls, 21 patients with MCI and 133 patients with AD were recruited. Serum d -glutamate levels were measured using high-performance liquid chromatography (HPLC). Cognitive deficit severity was assessed using the Clinical Dementia Rating scale and the Mini-Mental Status Examination (MMSE). We employed four machine learning algorithms (support vector machine, logistic regression, random forest and naïve Bayes) to build an optimal predictive model to distinguish patients with MCI or AD from healthy controls. Results: The MCI and AD groups had lower plasma d -glutamate levels (1097.79 ± 283.99 and 785.10 ± 720.06 ng/mL, respectively) compared to healthy controls (1620.08 ± 548.80 ng/mL). The naïve Bayes model and random forest model appeared to be the best models for determining MCI and AD susceptibility, respectively (area under the receiver operating characteristic curve: 0.8207 and 0.7900; sensitivity: 0.8438 and 0.6997; and specificity: 0.8158 and 0.9188, respectively). The total MMSE score was positively correlated with d -glutamate levels (r = 0.368, p < 0.001). Multivariate regression analysis indicated that d -glutamate levels were significantly associated with the total MMSE score (B = 0.003, 95% confidence interval 0.002–0.005, p < 0.001). Conclusions: Peripheral plasma d -glutamate levels were associated with cognitive impairment and may therefore be a suitable peripheral biomarker for detecting MCI and AD. Rapid and cost-effective HPLC for biomarkers and machine learning algorithms may assist physicians in diagnosing MCI and AD in outpatient clinics. [ABSTRACT FROM AUTHOR]

Background: Dysfunction of the N -methyl- D -aspartate glutamate receptor is involved in the putative pathology of schizophrenia. There is growing interest in the potential of N -methyl- D -aspartate receptor modulators to improve the symptoms of schizophrenia, but the evidence for the use of glutamatergic agents for augmenting schizophrenia remains inconclusive. Aims: We conducted a meta-analysis to test the efficacy and safety of N -methyl- D -aspartate receptor modulator supplements in patients with schizophrenia. Methods: Following a systemic search in MEDLINE, Embase, Cochrane and Scopus, 40 double-blinded, randomised, placebo-controlled trials involving 4937 patients with schizophrenia were included in this meta-analysis. The change in the severity of symptoms among patients with schizophrenia was defined as the primary outcome, whereas the safety profiles of the intervention, including the discontinuation rate and adverse events, were defined as secondary outcomes. Results: When added to antipsychotic treatments, N -methyl- D -aspartate receptor modulators improved multiple schizophrenia symptoms, particularly negative symptoms, and had satisfactory side effects and safety profile. Among the seven glutamatergic agents analysed, glycine, D-serine and sarcosine had better treatment profiles than other agents, and NMDA receptor co-agonists, as a group, provided a reduction in schizophrenia symptoms compared to antipsychotic treatments without supplementation. Augmentation with N -methyl- D -aspartate receptor modulators was only effective among patients treated with antipsychotics other than clozapine. Conclusions: The results indicate that N -methyl- D -aspartate receptor modulators, particularly with glycine, D-serine and sarcosine, are more beneficial than the placebo in treating schizophrenia, and the effects extended to both positive and negative symptoms, when augmented with antipsychotics other than clozapine. [ABSTRACT FROM AUTHOR]

• Chicken embryo CGNs can be used to evaluate effects on developmental neurotoxicity. • Either POP mixture or PFOS alone induced toxicity on their own. • Either POP mixture or PFOS alone aggravated glutamate-induced excitotoxicity. • These effects of the pollutants could be blocked by NMDA receptor antagonists. • PFOS alone cannot explain the effects seen with the total POP mixture. Primary cultures of cerebellar granule neurons (CGNs) derived from chicken embryos were used to explore the effects on developmental neurotoxicity by a complex defined mixture of persistent organic pollutants (POPs). Its chemical composition and concentrations were based on blood levels in the Norwegian/Scandinavian population. Perfluorooctane sulfonic acid (PFOS) alone, its most abundant compound was also evaluated. Different stages of CGNs maturation, between day in vitro (DIV) 1, 3, and 5 were exposed to the POP mixture, or PFOS alone. Their combination with glutamate, an excitatory endogenous neurotransmitter important in neurodevelopment, also known to cause excitotoxicity was evaluated. Outcomes with the mixture at 500x blood levels were compared to PFOS at its corresponding concentration of 20 μM. The POP mixture reduced tetrazolium salt (MTT) conversion at earlier stages of maturation, compared to PFOS alone. Glutamate-induced excitotoxicity was enhanced above the level of that induced by glutamate alone, especially in mature CGNs at DIV5. Glutathione (GSH) concentrations seemed to set the level of sensitivity for the toxic insults from exposures to the pollutants. The role of N-methyl-D-aspartate receptor (NMDA-R) mediated calcium influx in pollutant exposures was investigated using the non-competitive and competitive receptor antagonists MK-801 and CGP 39551. Observations indicate a calcium-independent, but still NMDA-R dependent mechanism in the absence of glutamate, and a calcium- and NMDA-R dependent one in the presence of glutamate. The outcomes for the POP mixture cannot be explained by PFOS alone, indicating that other chemicals in the mixture contribute its overall effect. [ABSTRACT FROM AUTHOR]

Introduction: Environmental noise stress affects non-auditory brain regions such as the hippocampus; an area of the brain implicated in cognition and emotion. Recent experimental data indicate that dysfunction of the blood-brain barrier (BBB) and overexpression of NMDA receptors may cause anxiety. In this experiment, we evaluated the effect of nanocurcumin on anxiety-like behavior and the expression of tight junctions and NMDA receptor subunits in the hippocampus of rats exposed to traffic noise. Methods and Materials: Forty rats were assigned to control (CON), stress (ST), nanocurcumin (NC), and nanocurcumin+stress (NC+ST) groups. Anxiety-like behavior was evaluated through an elevated zero maze apparatus. The gene expression of tight junctions and NMDA receptor subunits was examined by real-time PCR in the hippocampus. Results: Statistical analysis showed that noise exposure developed anxiety-like behavior and elevated the corticosterone level in the ST group compared to the CON group. The nanocurcumin administration decreased the stress and anxiety in the NC+ST group compared to the ST animals. While the noise stress reduced the gene expression of tight junctions occludin, claudin-5, and ZO-1, the nanocurcumin administration increased them in the NC+ST animals. Furthermore, the noise stress elevated the gene expression of the NMDA receptor subunits GRIN1 and GRIN2B. The NC+ST animals showed a modification of these subunits compared to the ST animals. Conclusions: Our findings showed that noise exposure promotes stress and anxiety and impairs the NMDA receptor structure and BBB integrity. The nanocurcumin treatment partly restores the destructive effects of noise exposure [ABSTRACT FROM AUTHOR]

This Editorial highlights a remarkable study in the current issue of the Journal of Neurochemistry in which Hascup and coworkers provide novel data showing that riluzole, an anti‐glutamatergic drug, may be a promising early intervention strategy for Alzheimer's disease (AD), aimed at restoring glutamate neurotransmission prior to amyloid beta (Aβ) plaque accumulation and cognitive decline. The mice APP/PS1, a model of AD, initially are cognitively normal but have elevated glutamate release in the hippocampus at 2–4 months of age. They begin showing cognitive decline and Aβ plaque accumulation at approximately 6–8 months of age, and show obvious AD neuropathology and cognitive impairment at 10–12 months. The riluzole treatment over 4 months (at 2–6 months of age) targeting early changes in glutamatergic neurotransmission prevents cognitive decline observed at 12 months of age and restores glutamatergic neurotransmission. This is one of the most convincing preclinical evidence supporting the idea of targeting glutamate neurotransmission in patients at risk for AD and to use riluzole for this purpose. [ABSTRACT FROM AUTHOR]

Background: Excitotoxicity is a common pathological process in neurodegenerative diseases associated with overactivity of N-methyl-D-aspartate (NMDA) and P/Q type voltage-gated calcium (Cav2.1) channels. Omega-lycotoxin-Gsp2671g is a therapeutic tool to modulate overactive Cav2.1 (P/Q type) channels. Omega-lycotoxin binds to Cav2.1 channels with high affinity and selectivity. This study aimed to investigate the effects of Omega-lycotoxin on the cognitive impairment induced by kainic acid in rats. Methods: The effect of pre-treatment and post-treatment trials of intra-hippocampal Cornu Ammonis-3 administration of omega-lycotoxin (0.5, 1 or 2μg) was studied on the cognitive impairment induced by kainic acid in rats. The rats' learning and memory were assessed by the passive avoidance and a single-day testing version of the Morris water maze method. Results: Omega-lycotoxin caused a significant increase in the latency of the passive avoidance test and the duration of their presence in the target area of the Morris water maze test compared to the groups treated with kainic acid (P<0.0001). There were statistically significant differences for the effects of various doses of omega-lycotoxin. The post-treatment groups showed a greater improvement than those in the pretreatment groups. Conclusion: The findings demonstrated that a single dose of omega-lycotoxin can prevent or revert the memory impairment caused by kainic acid in rats. [ABSTRACT FROM AUTHOR]

Ketamine, a phencyclidine derivative and N-methyl-D-aspartate (NMDA) receptor antagonist, is widely used as an anesthetic, analgesic, and sedative agent in daily pediatric practice. Experimental studies have suggested that early prenatal or postnatal exposure to ketamine can induce neuroapoptosis, and establish neurobehavioral deficits that are evident in adulthood. However, most of the currently available clinical evidence is derived from retrospective and observational clinical studies. We, herein, attempt a brief review of the cellular and molecular mechanisms suggested to mediate ketamine-induced developmental neurotoxicity, utilizing a selected number of recent in vivo experimental evidence. [ABSTRACT FROM AUTHOR]

Bivalve metamorphosis is a developmental transition from a free-living larva to a benthic juvenile (spat), regulated by a complex interaction of neurotransmitters and neurohormones such as L-DOPA and epinephrine (catecholamine). We recently suggested an N -Methyl-D-aspartate (NMDA) receptor pathway as an additional and previously unknown regulator of bivalve metamorphosis. To explore this theory further, we successfully induced metamorphosis in the Pacific oyster, Crassostrea gigas , by exposing competent larvae to L-DOPA, epinephrine, MK-801 and ifenprodil. Subsequently, we cloned three NMDA receptor subunits CgNR1 , CgNR2A and CgNR2B , with sequence analysis suggesting successful assembly of functional NMDA receptor complexes and binding to natural occurring agonists and the channel blocker MK-801. NMDA receptor subunits are expressed in competent larvae, during metamorphosis and in spat, but this expression is neither self-regulated nor regulated by catecholamines. In-situ hybridisation of CgNR1 in competent larvae identified NMDA receptor presence in the apical organ/cerebral ganglia area with a potential sensory function, and in the nervous network of the foot indicating an additional putative muscle regulatory function. Furthermore, phylogenetic analyses identified molluscan-specific gene expansions of key enzymes involved in catecholamine biosynthesis. However, exposure to MK-801 did not alter the expression of selected key enzymes, suggesting that NMDA receptors do not regulate the biosynthesis of catecholamines via gene expression. • Three NMDA receptor subunits cloned in the Pacific oyster, Crassostrea gigas. • NMDA receptor in apical/cerebral ganglia and foot nerve structure of pediveliger. • NMDA receptor antagonists (MK-801, ifenprodil) induced metamorphosis in oysters. • Enzymes expression for catecholamine biosynthesis not regulated by NMDA receptors. • NMDA receptor pathway as part of the regulatory mechanism of oyster metamorphosis. [ABSTRACT FROM AUTHOR]

Background: Previous studies suggested that Cg1 area of the cingulate cortex of rats controls glutamate-mediated fear-induced defensive behaviour and antinociception organised at the posterior hypothalamus. In turn, microinjection of the nitric oxide donor SIN-1 into the anterior hypothalamus of mice produced defensive behaviours and fear-induced antinociception. However, it remains unknown whether Cg1 also modulates the latter mechanisms in mice. Aims: The present study examined the influence of Cg1 on SIN1-evoked fear-induced defensive behaviour and antinociception organised at the anterior hypothalamus of mice. Methods: The fear-like behavioural and antinociceptive responses to the microinjection of SIN-1 (300 nmol) into the anterior hypothalamus were evaluated after the microinjection of either N-methyl-D-aspartic acid receptor agonist (0.1, 1 and 10 nmol) or physiological saline into the cingulate cortex of C57BL/6 male mice. In addition, neurotracing and immunohistochemistry were used to characterise Cg1-anterior hypothalamus glutamatergic pathways. Results: The data showed that activation of Cg1 N-methyl-D-aspartic acid receptors increased escape while reducing freezing and antinociceptive responses to SIN-1 microinjections into the anterior hypothalamus. Anterograde neural tract tracer co-localised with VGLUT2-labelled fibres suggests these responses are mediated by glutamatergic synapses at the anterior hypothalamus. Conclusions: In contrast with previous studies showing that Cg1 facilitates both escape and antinociception to chemical stimulation of the posterior hypothalamus in rats, the present data suggest that Cg1 facilitates escape while inhibiting defensive antinociception produced by the microinjection of SIN-1 in the anterior hypothalamus of mice. Accordingly, Cg1 may have opposite effects on antinociceptive responses organised in the anterior and posterior hypothalamus of mice and rats, respectively. [ABSTRACT FROM AUTHOR]

Rationale: Risky choice can be measured using the risky decision task (RDT). In the RDT, animals choose between a large, risky option that is paired with probabilistic foot shock and a small, safe option that is never paired with shock. To date, studies examining the neurochemical basis of decision-making in the RDT have focused primarily on the dopaminergic system but have not focused on the glutamatergic system, which has been implicated in risky decision-making. Objectives: Because glutamate is known to play a critical role in decision-making, we wanted to determine the contribution of the glutamatergic system to performance in the RDT. Methods: In the experiment, 32 rats (16 male; 16 female) were tested in the RDT. The probability of receiving a foot shock increased across the session (ascending schedule) for half of the rats but decreased across the session (descending schedule) for half of the rats. Following training, rats received injections of the N-methyl-d-aspartate (NMDA) receptor competitive antagonist CGS 19755 (0, 1.0, 2.5, 5.0 mg/kg; s.c.) and the GluN2B-selective antagonist Ro 63-1908 (0, 0.1, 0.3, 1.0 mg/kg; s.c.). Results: CGS 19755 (2.5 and 5.0 mg/kg) increased risky choice in males and females trained on the ascending schedule. Ro 63-1908 (1.0 mg/kg) decreased risky choice, but only in male rats trained on the ascending schedule. Conclusions: Although NMDA receptor antagonists differentially alter risky choice in the RDT, the current results show that NMDA receptors are an important mediator of decision-making involving probabilistic delivery of positive punishment. [ABSTRACT FROM AUTHOR]

Ketamine produces immediate antidepressant effects and has inspired research into next-generation treatments. Ketamine also has short term dissociative effects, in which individuals report altered consciousness and perceptions of themselves and their environment. However, whether ketamine's dissociative side effects are necessary for its antidepressant effects remains unclear. This perspective examines the relationship between dissociative effects and acute and longer-lasting antidepressant response to ketamine and other N-methyl-D-aspartate (NMDA) receptor antagonists. Presently, the literature does not support the conclusion that dissociation is necessary for antidepressant response to ketamine. However, further work is needed to explore the relationship between dissociation and antidepressant response at the molecular, biomarker, and psychological levels. Ketamine is associated with rapid antidepressant effects and temporary dissociative experiences, and this review examines whether these dissociative symptoms are necessary for antidepressant efficacy. Although the current literature does not support this relationship, further work is needed to explore possible associations at the molecular, biomarker, and psychological levels. [ABSTRACT FROM AUTHOR]

The present study was aimed to evaluate the anticonvulsant activity of acteoside and explore its mechanism of action. Initially, the acteoside was evaluated in maximal electroshock (MES) and pentylenetetrazole (PTZ)–induced convulsions, and later it was evaluated against N-methyl-d-aspartic acid (NMDA)–induced mortality in Swiss albino mice. Based on the response in these models, further evaluations were performed to explore the mechanism of action. In the results, the acteoside (10, 25, and 50 mg/kg) has shown significant anticonvulsant activity in the PTZ model (p < 0.01 for all doses); however, there was no protection observed in MES and NMDA models. Therefore, further mechanism-based studies were performed on the PTZ model, and the outcomes have revealed that there was a significant reduction in GABA (p < 0.01 for both regions) and elevation of glutamate (p < 0.01 for both regions) in the cortex and hippocampus regions of PTZ-treated animals. Further, the antioxidant levels (SOD, catalase, GPx, GR, GSH, LPO) were altered significantly (p < 0.01 for all parameters), with reduced GABAA mRNA levels (p < 0.01) in the PTZ control compared with the normal control. Interestingly, co-administration of acteoside (25 mg/kg) (p < 0.01 for all parameters) has restored all the PTZ-induced alterations compared to PTZ-control. Moreover, the anti-PTZ action of acteoside was completely blocked in the presence of flumazenil, and thus confirmed the GABAergic mechanism behind the anticonvulsant activity of acteoside. Besides, actophotometer and rotarod tests have confirmed that the acteoside is free from central side effects like motor incoordination and locomotor deficits. [ABSTRACT FROM AUTHOR]