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Introduction: Neurodevelopmental disorders (NDDs) are diverse and can be explained by either genomic aberrations or single nucleotide variants. Most likely due to methodological approaches and/or disadvantages, the concurrence of both genetic events in a single patient has hardly been reported and even more rarely the pathogenic variant has been regarded as the cause of the phenotype when a chromosomal alteration is initially identified. Case Presentation: Here, we describe a NDD patient with a 6p nonpathogenic paracentric inversion paternally transmitted and a de novo pathogenic variant in the GRIN2B gene. Molecular-cytogenetic studies characterized the familial 6p inversion and revealed a paternal 9q inversion not transmitted to the patient. Subsequent whole-genome sequencing in the patient-father dyad corroborated the previous findings, discarded inversions-related cryptic genomic rearrangements as causative of the patient's phenotype, and unveiled a novel heterozygous GRIN2B variant (p.(Ser570Pro)) only in the proband. In addition, Sanger sequencing ruled out such a variant in her mother and thereby confirmed its de novo origin. Due to predicted disturbances in the local secondary structure, this variant may alter the ion channel function of the M1 transmembrane domain. Other pathogenic variants in GRIN2B have been related to the autosomal dominant neurodevelopmental disorder MRD6 (intellectual developmental disorder, autosomal dominant 6, with or without seizures), which presents with a high variability ranging from mild intellectual disability (ID) without seizures to a more severe encephalopathy. In comparison, our patient's clinical manifestations include, among others, mild ID and brain anomalies previously documented in subjects with MRD6. Conclusion: Occasionally, gross chromosomal abnormalities can be coincidental findings rather than a prime cause of a clinical phenotype (even though they appear to be the causal agent). In brief, this case underscores the importance of comprehensive genomic analysis in unraveling the wide-ranging genetic causes of NDDs and may bring new insights into the MRD6 variability. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to examine the potential influence of RS4680 (COMT), RS16965628 (SLC6A4), and RS1019385 (GRIN2B) polymorphisms on the therapeutic response to repetitive transcranial magnetic stimulation (rTMS) and selective serotonin reuptake inhibitors (SSRIs) in individuals with obsessivecompulsive disorder (OCD). Patients and methods: Thirty-six untreated outpatients diagnosed with OCD were recruited and allocated to active or sham rTMS groups for two weeks. The mean age of the participants was 31.61, with 17 males (47.22%) and 19 females (52.78%). Peripheral blood samples (5 mL) were collected from each participant using ethylenediaminetetraacetic acid (EDTA) vacuum tubes for genotyping purposes, clinical evaluation was taken place at baseline and second week. Results: The A allele of RS4680, C allele of RS16965628, and GG allele of RS1019385 were identified as potential bio-markers for predicting treatment response to OCD treatments (rTMS & SSRIs). Conclusion: Those genes may serve as bio-markers for the combined treatment of rTMS and SSRIs in OCD. The finding hold promise for further research and the potential implementation of precision treatment of OCD. Clinical trial registration: https://www.chictr.org.cn, identifier ChiCTR1900023641. [ABSTRACT FROM AUTHOR]

N-methyl-D-aspartate receptors (NMDARs emerging from GRIN genes) are tetrameric receptors that form diverse channel compositions in neurons, typically consisting of two GluN1 subunits combined with two GluN2(A-D) subunits. During prenatal stages, the predominant channels are di-heteromers with two GluN1 and two GluN2B subunits due to the high abundance of GluN2B subunits. Postnatally, the expression of GluN2A subunits increases, giving rise to additional subtypes, including GluN2A-containing di-heteromers and tri-heteromers with GluN1, GluN2A, and GluN2B subunits. The latter emerge as the major receptor subtype at mature synapses in the hippocampus. Despite extensive research on purely di-heteromeric receptors containing two identical GRIN variants, the impact of a single variant on the function of other channel forms, notably tri-heteromers, is lagging. In this study, we systematically investigated the effects of two de novo GRIN2B variants (G689C and G689S) in pure, mixed di- and tri-heteromers. Our findings reveal that incorporating a single variant in mixed di-heteromers or tri-heteromers exerts a dominant negative effect on glutamate potency, although 'mixed' channels show improved potency compared to pure variant-containing di-heteromers. We show that a single variant within a receptor complex does not impair the response of all receptor subtypes to the positive allosteric modulator pregnenolone-sulfate (PS), whereas spermine completely fails to potentiate tri-heteromers containing GluN2A and -2B-subunits. We examined PS on primary cultured hippocampal neurons transfected with the variants, and observed a positive impact over current amplitudes and synaptic activity. Together, our study supports previous observations showing that mixed di-heteromers exhibit improved glutamate potency and extend these findings towards the exploration of the effect of Loss-of-Function variants over tri-heteromers. Notably, we provide an initial and crucial demonstration of the beneficial effects of GRIN2B-relevant potentiators on tri-heteromers. Our results underscore the significance of studying how different variants affect distinct receptor subtypes, as these effects cannot be inferred solely from observations made on pure di-heteromers. Overall, this study contributes to ongoing efforts to understand the pathophysiology of GRINopathies and provides insights into potential treatment strategies. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is an irreversible and neurodegenerative disorder. Its etiology is not clear, but the involvement of genetic components plays a central role in the onset of the disease. In the present study, the expression of 10 genes (APP , PS1 and PS2 , APOE , APBA2 , LRP1 , GRIN2B , INSR , GJB1 , and IDE) involved in the main pathways related to AD were analyzed in auditory cortices and cerebellum from 29 AD patients and 29 healthy older adults. Raw analysis revealed tissue-specific changes in genes LRP1 , INSR , and APP. A correlation analysis showed a significant effect also tissue-specific AD in APP , GRIN2B , INSR , and LRP1. Furthermore, the E4 allele of the APOE gene revealed a significant correlation with change expression tissue-specific in ABPA2 , APP , GRIN2B , LRP1 , and INSR genes. To assess the existence of a correction between changes in target gene expression and a probability of AD in each tissue (auditory cortices and cerebellum) an analysis of the effect of expressions was realized and showed that the reduction in the expression of the APP in auditory cortex and GRIN2B cerebellum had a significant effect in increasing the probability of AD, in the same logic, our result also suggesting that increased expression of the LRP1 and INSR genes had a significant effect on increasing the probability of AD. Our results showed tissue-specific gene expression alterations associated with AD and certainly opened new perspectives to characterize factors involved in gene regulation and to obtain possible biomarkers for AD. [ABSTRACT FROM AUTHOR]

Autism spectrum disorders (ASDs) are described as generalized developmental disorders, with an average age of onset of 36 months. Genetic and environmental factors may contribute to this multifactorial disorder. The present study aimed to investigate the association of three GRIN2B polymorphisms, including rs1019385, rs1024893, and rs3764028, with ASDs. Based on the results, there was a significant difference regarding the genotype frequency of rs3764028 polymorphism between the control and case (ASD) groups (P = 0.027). According to the recessive model, this variant was associated with ASDs (P = 0.23). None of the eight haplotype models with frequencies above 0.5 showed significant differences between the case and control groups in terms of allelic frequency. The present results showed that the rs376028 variant was directly related to the phenotypic symptoms of ASDs. [ABSTRACT FROM AUTHOR]

Attention-deficit hyperactivity disorder is a highly inherited neurodevelopmental disorder. Previous genetic research has linked ADHD to certain genes in the dopaminergic synaptic pathway. Nonetheless, research on this relationship has produced varying results across various populations. China is a multi-ethnic country with its own unique genetic characteristics. Therefore, such a population can provide useful information about the relationship between gene polymorphisms in dopaminergic synaptic pathways and ADHD. This study looked at the genetic profiles of 284 children in China's Xinjiang. In total, 142 ADHD children and 142 control subjects were enrolled. Following the extraction of DNA from oral mucosal cells, 13 SNPs for three candidate genes (SLC6A3, DRD2, and GRIN2B) in the dopaminergic synaptic pathway of ADHD were screened. Based on the results of single nucleotide polymorphism (SNP) analyses, we found that the DRD2 gene variants rs6277 and rs6275, and the SLC6A3 gene variant rs2652511, were significantly associated with ADHD in boys and girls, respectively, after adjusting for false discovery rate (FDR) in terms of allele frequencies. Furthermore, our generalized multifactorial downscaling approach identified a significant association between rs6275 and rs1012586. These findings suggest that DRD2 and SLC6A3 genes have a crucial role in ADHD susceptibility. Additionally, we observed that the interaction between GRIN2B and DRD2 genes may contribute to the susceptibility of Chinese children with ADHD. [ABSTRACT FROM AUTHOR]

Selective breeding has been utilized to study the genetic basis of exercise behavior, but research suggests that epigenetic mechanisms, such as DNA methylation, also contribute to this behavior. In a previous study, we demonstrated that the brains of mice from a genetically selected high runner (HR) line have sex‐specific changes in DNA methylation patterns in genes known to be genomically imprinted compared to those from a non‐selected control (C) line. Through cross‐fostering, we also found that maternal upbringing can modify the DNA methylation patterns of additional genes. Here, we identify an additional set of genes in which DNA methylation patterns and gene expression may be altered by selection for increased wheel‐running activity and maternal upbringing. We performed bisulfite sequencing and gene expression assays of 14 genes in the brain and found alterations in DNA methylation and gene expression for Bdnf, Pde4d and Grin2b. Decreases in Bdnf methylation correlated with significant increases in Bdnf gene expression in the hippocampus of HR compared to C mice. Cross‐fostering also influenced the DNA methylation patterns for Pde4d in the cortex and Grin2b in the hippocampus, with associated changes in gene expression. We also found that the DNA methylation patterns for Atrx and Oxtr in the cortex and Atrx and Bdnf in the hippocampus were further modified by sex. Together with our previous study, these results suggest that DNA methylation and the resulting change in gene expression may interact with early‐life influences to shape adult exercise behavior. [ABSTRACT FROM AUTHOR]

• Novel GRIN2B mutation (c.3272A > C) in a patient with epilepsy and intellectual disability. • p.K1091T serves as a phosphorylation site for Casein kinase 2. • GluN2B-K1091T variant decreases surface NMDA receptors expression and dendritic density. • GluN2B-K1091T mutant suppresses glutamate affinity and excitatory synaptic transmission. Epilepsy, a neurological condition, is widely prevalent among individuals with intellectual disability (ID). It is well established that N-methyl-D-aspartate (NMDA) receptors play an important role in both epilepsy and ID. Autosomal dominant mutations in the GRIN2B gene, which encodes the GluN2B subunit of the NMDA receptor, have been reported to be associated with epilepsy and ID. However, the underlying mechanism of this association is not well-understood. In this study, we identified a novel GRIN2B mutation (c.3272A > C, p.K1091T) in a patient with epilepsy and ID. The proband was a one year and ten months old girl. GRIN2B variant was inherited from her mother. We further investigated the functional consequences of this mutation. Our findings revealed that the p.K1091T mutation created a Casein kinase 2 phosphorylation site. Using recombinant NMDA receptors containing the GluN2B-K1091T along with GluN1 in HEK 293T cells, we observed significant defects in its interactions with postsynaptic density 95. It is accompanied by reduced delivery of the receptors to the cell membrane and a decrease in glutamate affinity. Moreover, primary neurons expressing GluN2B-K1091T also exhibited impaired surface expression of NMDA receptors, a reduction in dendritic spine number and excitatory synaptic transmission. In summary, our study reports a novel GRIN2B mutation and provides functional characteristics of this mutation in vitro , thereby contributing to the understanding of GRIN2B variants in epilepsy and ID. [ABSTRACT FROM AUTHOR]

The glutamatergic system may be central to the neurobiology and treatment of major depressive disorder (MDD) and psychosis. Despite the success of N-methyl-D-aspartate receptor (NMDAR) antagonists for the treatment of MDD, little is known regarding the expression of these glutamate receptors in MDD. In this study we measured gene expression, via qRT-PCR, of the major NMDAR subunits, in the anterior cingulate cortex (ACC) in MDD subjects with and without psychosis, and non-psychiatric controls. Overall, GRIN2B mRNA was increased in both MDD with (+32%) and without psychosis (+40%) compared to controls along with a trend increase in GRIN1 mRNA in MDD overall (+24%). Furthermore, in MDD with psychosis there was a significant decrease in the GRIN2A:GRIN2B mRNA ratio (−19%). Collectively these results suggest dysfunction of the glutamatergic system at the gene expression level in the ACC in MDD. Increased GRIN2B mRNA in MDD, along with an altered GRIN2A:GRIN2B ratio in psychotic depression, suggests a disruption to NMDAR composition could be present in the ACC in MDD; this could lead to enhanced signalling via GluN2B-containing NMDARs and greater potential for glutamate excitotoxicity in the ACC in MDD. These results support future research into GluN2B antagonist-based treatments for MDD. [ABSTRACT FROM AUTHOR]

Background: Personal variations in genetic risk for schizophrenia relate to its phenotypic heterogeneity—both in disorder development and clinical manifestations. Abnormal glutamatergic neurotransmitter system functioning is integrated in the pathogenesis of schizophrenia. Methods: A sample of 805 Russian schizophrenia patients from the Siberian Federal region was investigated. We examined the association of 39 single nucleotide polymorphisms in eight genes (GRIN2A, GRIN2B, SLC1A2, SLC1A3, SLC17A7, GRM3, GRM7, and GRM8) involved in the glutamatergic system with the development of clinical heterogeneity of schizophrenia. The MassARRAY Analyzer 4 was used for genotyping. Results: GRIN2A rs11644461, rs8057394 and GRIN2B rs7313149 are associated with the continuous type of schizophrenia. The GRIN2A rs8057394*G allele is a relative risk factor (p = 0.019) for developing the continuous type of schizophrenia. We found a nominally significant association between negative symptoms of schizophrenia and SLC17A7 rs62126236. The SLC17A7 rs62126236*T allele has a protective effect (p = 0.039) against predominant negative symptoms in schizophrenia. The total Positive and Negative Syndrome Scale (PANSS) scores were significantly associated with GRIN2A rs9788936 after adjusting for multiple testing (p = 0.001). Conclusions: In this study the contribution of the glutamatergic gene polymorphisms to the clinical heterogeneity of schizophrenia has been demonstrated. [ABSTRACT FROM AUTHOR]

Antihistamines have potent efficacy to alleviate COVID-19 (Coronavirus disease 2019) symptoms such as anti-inflammation and as a pain reliever. However, the pharmacological mechanism(s), key target(s), and drug(s) are not documented well against COVID-19. Thus, we investigated to decipher the most significant components and how its research methodology was utilized by network pharmacology. The list of 32 common antihistamines on the market were retrieved via drug browsing databases. The targets associated with the selected antihistamines and the targets that responded to COVID-19 infection were identified by the Similarity Ensemble Approach (SEA), SwissTargetPrediction (STP), and PubChem, respectively. We described bubble charts, the Pathways-Targets-Antihistamines (PTA) network, and the protein–protein interaction (PPI) network on the RPackage via STRING database. Furthermore, we utilized the AutoDock Tools software to perform molecular docking tests (MDT) on the key targets and drugs to evaluate the network pharmacological perspective. The final 15 targets were identified as core targets, indicating that Neuroactive ligand–receptor interaction might be the hub-signaling pathway of antihistamines on COVID-19 via bubble chart. The PTA network was constructed by the RPackage, which identified 7 pathways, 11 targets, and 30 drugs. In addition, GRIN2B, a key target, was identified via topological analysis of the PPI network. Finally, we observed that the GRIN2B-Loratidine complex was the most stable docking score with −7.3 kcal/mol through molecular docking test. Our results showed that Loratadine might exert as an antagonist on GRIN2B via the neuroactive ligand–receptor interaction pathway. To sum up, we elucidated the most potential antihistamine, a key target, and a key pharmacological pathway as alleviating components against COVID-19, supporting scientific evidence for further research.

Background: Network biology approaches have emerged as a promising tool to study disease mechanisms and explain comorbidities. Network biology approaches can be applied to integrate the complex neural networks that can help in understanding the molecular mechanisms of neurodevelopmental disorders and hence provide an insight into the diagnosis and treatment of these disorders. Aim: To identify priority genes involved in ADHD through multiple system biology approach and its subsequent treatment through molecular interaction studies. Methodology: In the present study, genes related to the neurodevelopmental disorders associated with ADHD were identified. STRING plugin on cytoscape was used to construct network and identify the hub genes. Further, expression, mutational, and regulatory analysis of the identified priority genes was done to evaluate its expression in brain. Computational drug designing approaches were further applied to identify the natural drug that can target the identified priority gene for the treatment of neurodevelopmental disorders. Objective: The present study is an attempt to identify the priority genes and thereby explain the molecular mechanism of neurodevelopmental disorders using computational network biology approaches in integration with other in-silico tools. Result: Our study concludes that GRIN2B can be a potential target in the mechanism of different neurodevelopmental disorders. The docking of GRIN2B receptor with neuroprotectant phytochemicals revealed that Asiatic acid, a naturally occurring pentacyclic triterpenoid, extracted from Centella asiatica can be used as a potential phytocompound for the treatment of Neurodevelopmental Disorders. Conclusion: Asiatic acid can be used as a therapeutic agent against GRIN2B receptor for treatment of ADHD.

The GRIN2B-related neurodevelopmental disorder is a rare disease caused by mutations in the GRIN2B gene, which encodes the GluN2B subunit of NMDA receptors. Most individuals with GRIN2B-related neurodevelopmental disorder present with intellectual disability and developmental delay. Motor impairments, autism spectrum disorder, and epilepsy are also common. A large number of pathogenic de novo mutations have been identified in GRIN2B. However, it is not yet known how these variants lead to the clinical symptoms of the disease. Recent research has begun to address this issue. Here, we describe key experimental approaches that have been used to better understand the pathophysiology of this disease. We discuss the impact of several distinct pathogenic GRIN2B variants on NMDA receptor properties. We then critically review pivotal studies examining the synaptic and neurodevelopmental phenotypes observed when disease-associated GluN2B variants are expressed in neurons. These data provide compelling evidence that various GluN2B mutants interfere with neuronal differentiation, dendrite morphogenesis, synaptogenesis, and synaptic plasticity. Finally, we identify important open questions and considerations for future studies aimed at understanding this complex disease. Together, the existing data provide insight into the pathophysiological mechanisms that underlie GRIN2B-related neurodevelopmental disorder and emphasize the importance of comparing the effects of individual, disease-associated variants. Understanding the molecular, cellular and circuit phenotypes produced by a wide range of GRIN2B variants should lead to the identification of core neurodevelopmental phenotypes that characterize the disease and lead to its symptoms. This information could help guide the development and application of effective therapeutic strategies for treating individuals with GRIN2B-related neurodevelopmental disorder.

Background: Environmental factors contribute to autism spectrum disorder. Fentanyl, one of the most widely used opioid analgesics in anaesthesia, can induce neurotoxicity, but its role in autism remains unknown. We determined whether fentanyl induced autism-like behaviours in young mice and the underlying mechanisms.Methods: Young male and female mice received fentanyl at postnatal days 6, 8, and 10, and performed behavioural tests, including three-chamber social preference, elevated plus maze, grooming behaviour, and open-field test, from postnatal days 30-32. Expression of Grin2b, the gene encoding the GluN2B subunit of the N-methyl-d-aspartate receptor, was assessed in the anterior cingulate cortex of male mice using fluorescence in situ hybridisation histochemistry. We used bisulfite target sequencing to determine Grin2b hypermethylation sites after fentanyl treatment. In the specific activation and rescue experiments, we injected the mu opioid receptor agonist [D-Ala,2 N-MePhe,4 Gly-ol]-enkephalin (DAMGO) or Grin2b overexpression lentivirus into the anterior cingulate cortex of male mice.Results: Fentanyl induced autism-like behaviours in both young male and female mice, and downregulated Grin2b expression (0.49-fold [0.08] vs 1.00-fold [0.09]; P<0.01) and GluN2B protein amounts (0.38-fold [0.07] vs 1.00-fold [0.12]; P<0.01) in the anterior cingulate cortex through hypermethylation of Grin2b. The mu-opioid receptor antagonist naloxone and overexpression of Grin2b in anterior cingulate cortex attenuated the fentanyl-induced effects, whereas DAMGO injection into the anterior cingulate cortex induced autism-like behaviours.Conclusions: These data suggest that fentanyl induces autism-like behaviours in young mice via an epigenetic mechanism. Further research is required to determine possible clinical relevance to autism risk. [ABSTRACT FROM AUTHOR]

The GluN2B subunit of N-methyl-D-aspartate receptors plays an important role in the physiology of different neurodevelopmental diseases. Genetic variations in the GluN2B coding gene (GRIN2B) have consistently been linked to West syndrome, intellectual impairment with focal epilepsy, developmental delay, macrocephaly, corticogenesis, brain plasticity, as well as infantile spasms and Lennox–Gastaut syndrome. It is unknown, however, how GRIN2B genetic variation impacts protein function. We determined the cumulative pathogenic impact of GRIN2B variations on healthy participants using a computational approach. We looked at all of the known mutations and calculated the impact of single nucleotide polymorphisms on GRIN2B, which encodes the GluN2B protein. The pathogenic effect, functional impact, conservation analysis, post-translation alterations, their driving residues, and dynamic behaviors of deleterious nsSNPs on protein models were then examined. Four polymorphisms were identified as phylogenetically conserved PTM drivers and were related to structural and functional impact: rs869312669 (p.Thr685Pro), rs387906636 (p.Arg682Cys), rs672601377 (p.Asn615Ile), and rs1131691702 (p.Ser526Pro). The combined impact of protein function is accounted for by the calculated stability, compactness, and total globularity score. GluN2B hydrogen occupancy was positively associated with protein stability, and solvent-accessible surface area was positively related to globularity. Furthermore, there was a link between GluN2B protein folding, movement, and function, indicating that both putative high and low local movements were linked to protein function. Multiple GRIN2B genetic variations are linked to gene expression, phylogenetic conservation, PTMs, and protein instability behavior in neurodevelopmental diseases. These findings suggest the relevance of GRIN2B genetic variations in neurodevelopmental problems. [ABSTRACT FROM AUTHOR]

Patients with de novo pathogenic mutations in the I GRIN2B i gene usually present with various neurodevelopmental disorders that include epilepsy, such as epileptic encephalopathy, autistic spectrum disorders, developmental delay, and intellectual disability [3] In our study, we have found a heterozygous missense mutation in the I GRIN2B i gene at exon I 12 i c.2452A > T (p.Met818Leu). Stosser et al had reported a similar missense mutation in GRIN2B c.2452 A > C;p.met818Leu [8] Memantine is an uncompetitive NMDAR antagonist that binds preferentially to the NMDAR-operated cation channels. Keywords: GRIN2B; memantine; epileptic encephalopathy; epileptic spasms EN GRIN2B memantine epileptic encephalopathy epileptic spasms 287 290 4 09/07/22 20220701 NES 220701 Conflict of Interest None declared. [Extracted from the article]

Abstract Objective In order to assess the applicability of a direct-to-consumer (DTC) genetic testing to translational research for obtaining new knowledge on relationships between drug target genes and diseases, we examined possibility of these data by associating SNPs and disease related phenotype information collected from healthy individuals. Results A total of 12,598 saliva samples were collected from the customers of commercial service for SNPs analysis and web survey were conducted to collect phenotype information. The collected dataset revealed similarity to the Japanese data but distinguished differences to other populations of all dataset of the 1000 Genomes Project. After confirmation of a well-known relationship between ALDH2 and alcohol-sensitivity, Phenome-Wide Association Study (PheWAS) was performed to find association between pre-selected drug target genes and all the phenotypes. Association was found between GRIN2B and multiple phenotypes related to depression, which is considered reliable based on previous reports on the biological function of GRIN2B protein and its relationship with depression. These results suggest possibility of using SNPs and phenotype information collected from healthy individuals as a translational research tool for drug discovery to find relationship between a gene and a disease if it is possible to extract individuals in pre-disease states by properly designed questionnaire.

We have shown that deficiency of neutral sphingomyelinase 2 (nSMase2), an enzyme generating the sphingolipid ceramide, improves memory in adult mice. Here, we performed sphingolipid and RNA-seq analyses on the cortex from 10-month-old nSMase2-deficient (fro/fro) and heterozygous (+ /fro) mice. fro/fro cortex showed reduced levels of ceramide, particularly in astrocytes. Differentially abundant transcripts included several functionally related groups, with decreases in mitochondrial oxidative phosphorylation and astrocyte activation transcripts, while axon guidance and synaptic transmission and plasticity transcripts were increased, indicating a role of nSMase2 in oxidative stress, astrocyte activation, and cognition. Experimentally induced oxidative stress decreased the level of glutathione (GSH), an endogenous inhibitor of nSMase2, and increased immunolabeling for ceramide in primary + /fro astrocytes, but not in fro/fro astrocytes. β-galactosidase activity was lower in 5-week-old fro/fro astrocytes, indicating delayed senescence due to nSMase2 deficiency. In fro/fro cortex, levels of the senescence markers C3b and p27 and the proinflammatory cytokines interleukin 1β, interleukin 6, and tumor necrosis factor α were reduced, concurrent with twofold decreased phosphorylation of their downstream target, protein kinase Stat3. RNA and protein levels of the ionotropic glutamate receptor subunit 2B (Grin2b/NR2B) were increased by twofold, which was previously shown to enhance cognition. This was consistent with threefold reduced levels of exosomes carrying miR-223-3p, a micro-RNA downregulating NR2B. In summary, our data show that nSMase2 deficiency prevents oxidative stress-induced elevation of ceramide and secretion of exosomes by astrocytes that suppress neuronal function, indicating a role of nSMase2 in the regulation of neuroinflammation and cognition. [ABSTRACT FROM AUTHOR]

Objective: Rolandic epilepsy (RE) is among the most common focal epilepsies in childhood. For the majority of patients with RE and atypical RE (ARE), the etiology remains elusive. We thus screened patients with RE/ARE in order to detect disease-causing variants.. Methods: A trios-based whole-exome sequencing approach was performed in a cohort of 28 patients with RE/ARE. Clinical data and EEGs were reviewed. Variants were validated by Sanger sequencing. Results: Two compound heterozygous missense variants p.Val272Ile/p.Asn3028Ser and p.Ala3657Val/p.Met4419Val of ADGRV1 were identified in two unrelated familial cases of RE/ARE. All the variants were in the calcium exchanger β domain and were suggested to be damaging by at least one web-based prediction tool. These variants are not present or are present at a very low minor allele frequency in the gnomAD database. Previously, biallelic ADGRV1 variants (p.Gly2756Arg and p.Glu4410Lys) have been observed in RE, consistent with the observation in this study and supporting the association between ADGRV1 variants and RE. Additionally, a de novo mutation, p.Asp668Asn, in GRIN2B was identified in a sporadic case of ARE, and a missense variant, p.Asn1551Ser, in RyR2 was identified in a family with RE with incomplete penetrance. These genes are all calcium homeostasis associated genes, suggesting the potential effect of calcium homeostasis in RE/ARE. Conclusions: The results from the present study suggest that the genes ADGRV1, GRIN2B, and RyR2 are associated with RE/ARE. These data link defects in neuronal intracellular calcium homeostasis to RE/ARE pathogenesis implicating that these defects plays an important role in the development of these conditions. [ABSTRACT FROM AUTHOR]

The article discusses a new hypothesis that autoimmune diseases of the thyroid gland can lead to depression and neurological complications. It is believed that the neuronal N-methyl-D-aspartate receptor plays a significant role in depression pathophysiology and neurological and mental diseases, respectively. The study involved 153 patients with various forms of thyroid pathology. GRIN2B levels in the sera of the patients and healthy individuals were quantified using enzyme-linked immunosorbent assay with highly sensitive Human GRIN2B (Glutamate Receptor, Ionotropic, N-Methyl-D-Aspartate 2B) ELISA Kit. Genotyping of the glutamate ionotropic receptor NMDA type subunit 1, GRIN1 (rs4880213) gene polymorphism. The CT genotype of the NMDA gene (rs4880213) was predominant in the surveyed population. The C allele of the NMDA gene was more frequent than the T allele among patients with thyroid disease. GRIN2B levels were significantly decreased in patients with postoperative hypothyroidism 3.45 times, and in patients with AIT-induced hypothyroidism, there was a probable increase in GRIN2B levels by 1.58 times compared with controls. GRIN2B levels were significantly different in patients of different groups depending on thyroid pathology. Our study showed direct close correlation (r=0.635) between GRIN2B and anti-TPO levels (p<0.001), a significant direct close correlation (r=0.527) between GRIN2B and anti-TG levels in the blood (p<0.001). Our results allow us to consider the GRIN2B level as an important prognostic minimally invasive marker of neurological complications in endocrine pathology. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence suggests that prenatal chemical exposure triggers epigenetic modifications that could influence health outcomes later in life. In this study, we investigated whether DNA methylation (DNAm) levels at the glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B) gene underlies the association between prenatal exposure to an endocrine disrupting chemical (EDC), bisphenol F (BPF), and lower cognitive functions in 7-year-old children. Methods: Data from 799 children participating in the Swedish Environmental Longitudinal Mother and child Asthma and allergy (SELMA) pregnancy cohort was analyzed. Prenatal BPF exposure was assessed by measuring BPF levels in maternal urine. At age 7, DNAm of three CpG sites in a regulatory region of the GRIN2B gene was analyzed from buccal swabs using bisulfite-Pyrosequencing. Cognitive functions, including full-scale IQ and four subscales, were evaluated using the Wechsler Intelligence Scale for Children (WISC-IV). Associations between prenatal BPF exposure and GRIN2B DNAm, as well as between GRIN2B DNAm and cognitive functions, were determined using regression models adjusted for potential confounders. Generalized structural equation models (gSEM) were used to evaluate if GRIN2B DNAm mediates the association between prenatal BPF exposure and cognitive functions at 7 years of age. Results: Prenatal BPF exposure was positively associated with GRIN2B DNAm levels at the third CpG site (CpG3), while CpG3 methylation was inversely associated with cognitive test scores. Mediation analyses showed that CpG3 methylation exerted 6–9% of the association between BPF exposure and full-scale IQ, as well as verbal comprehension and perceptual reasoning in boys, while not significant in girls. Conclusions: This study is the first to identify locus-specific DNAm as a mediating factor underlying an epidemiological association between prenatal EDC exposure and cognitive functions in childhood. It also confirms previous findings, that GRIN2B DNAm is responsive to environmental exposures.

Introduction: Autism spectrum disorder is a genetically and phenotypically heterogeneous group. Genetic studies carried out to date have suggested that both common and rare genetic variants play a role in the etiology of this disorder. In our study, we aimed to investigate the effect of FOXP2, GRIN2B, KATNAL2 and GABRA4 gene variants in the pathogenesis of autism spectrum disorder. Method: In our prospectively planned study, all exons and exon-intron junctions of FOXP2, GRIN2B, KATNAL2 and GABRA4 genes were screened by next generation sequencing analysis in 96 patients who diagnosed with autism spectrum disorder. Results: In our study, the average age was 10.1 and the male/female ratio was 75/21. Pathogenic or likely pathogenic variants were not detected in FOXP2, GRIN2B, KATNAL2 and GABRA4 genes, however, 69 intronic variants of unknown clinical significance were detected in 50 cases (52%). Among those, 26 were in the GABRA4 gene, 22 in the FOXP2 gene, 13 in the KATNAL2 gene, and 8 in the GRIN2B gene. Twenty three of these 69 variants were novel that were not previously reported in the literature. Conclusion: In our study, we could not identify a relationship between the autism spectrum disorder and FOXP2, GRIN2B, KATNAL2 and GABRA4 genes. Identifying genetic risk factors that play a role in the etiopathogenesis of autism spectrum disorder will contribute significantly to understanding the molecular mechanisms of the disease and the development of new treatment strategies. In this context, comprehensive molecular genetic studies such as whole exome or whole genome sequencing are required with higher number of cases in different populations. [ABSTRACT FROM AUTHOR]

Objective: In order to assess the applicability of a direct-to-consumer (DTC) genetic testing to translational research for obtaining new knowledge on relationships between drug target genes and diseases, we examined possibility of these data by associating SNPs and disease related phenotype information collected from healthy individuals. Results: A total of 12,598 saliva samples were collected from the customers of commercial service for SNPs analysis and web survey were conducted to collect phenotype information. The collected dataset revealed similarity to the Japanese data but distinguished differences to other populations of all dataset of the 1000 Genomes Project. After confirmation of a well-known relationship between ALDH2 and alcohol-sensitivity, Phenome-Wide Association Study (PheWAS) was performed to find association between pre-selected drug target genes and all the phenotypes. Association was found between GRIN2B and multiple phenotypes related to depression, which is considered reliable based on previous reports on the biological function of GRIN2B protein and its relationship with depression. These results suggest possibility of using SNPs and phenotype information collected from healthy individuals as a translational research tool for drug discovery to find relationship between a gene and a disease if it is possible to extract individuals in pre-disease states by properly designed questionnaire. [ABSTRACT FROM AUTHOR]

Accruing evidence supports the hypothesis that memory deficits in early Alzheimer Disease (AD) might be due to synaptic failure caused by accumulation of intracellular amyloid beta (Aβ) oligomers, then secreted to the extracellular media. Transgenic mouse AD models provide valuable information on AD pathology. However, the failure to translate these findings to humans calls for models that better recapitulate the human pathology. McGill-R-Thy1-APP transgenic (Tg) rat expresses the human amyloid precursor protein (APP751) with the Swedish and Indiana mutations (of familial AD), leading to an AD-like slow-progressing brain amyloid pathology. Therefore, it offers a unique opportunity to investigate learning and memory abilities at early stages of AD, when Aβ accumulation is restricted to the intracellular compartment, prior to plaque deposition. Our goal was to further investigate early deficits in memory, particularly long-term memory in McGill-R-Thy1-APP heterozygous (Tg+/–) rats. Short-term- and long-term habituation to an open field were preserved in 3-, 4-, and 6-month-old (Tg+/–). However, long-term memory of inhibitory avoidance to a foot-shock, novel object-recognition and social approaching behavior were seriously impaired in 4-month-old (Tg+/–) male rats, suggesting that they are unable to either consolidate and/or evoke such associative and discriminative memories with aversive, emotional and spatial components. The long-term memory deficits were accompanied by increased transcript levels of genes relevant to synaptic plasticity, learning and memory processing in the hippocampus, such as Grin2b, Dlg4, Camk2b , and Syn1. Our findings indicate that in addition to the previously well-documented deficits in learning and memory, McGill-R-Thy1-APP rats display particular long-term-memory deficits and deep social behavior alterations at pre-plaque early stages of the pathology. This highlights the importance of Aβ oligomers and emphasizes the validity of the model to study AD-like early processes, with potentially predictive value. [ABSTRACT FROM AUTHOR]

NMDA receptors (NMDARs) are glutamate‐gated ion channels that contribute to nearly all brain processes. Not surprisingly then, genetic variations in the genes encoding NMDAR subunits can be associated with neurodevelopmental, neurological and psychiatric disorders. These disease‐associated variants (DAVs) present challenges, such as defining how DAV‐induced alterations in receptor function contribute to disease progression and how to treat the affected individual clinically. As a starting point to overcome these challenges, we need to refine our understanding of the complexity of NMDAR structure function. In this regard, DAVs have expanded our knowledge of NMDARs because they do not just target well‐known structure‐function motifs, but rather give an unbiased view of structural elements that are important to the biology of NMDARs. Indeed, established NMDAR structure‐function motifs have been validated by the appearance of disorders in patients where these motifs have been altered, and DAVs have identified novel structural features in NMDARs such as gating triads and hinges in the gating machinery. Still, the majority of DAVs remain unexplored and occur at sites in the protein with unidentified function or alter receptor properties in multiple and unanticipated ways. Detailed mechanistic and structural investigations are required of both established and novel motifs to develop a highly refined pathomechanistic model that accounts for the complex machinery that regulates NMDARs. Such a model would provide a template for rational drug design and a starting point for personalized medicine. [ABSTRACT FROM AUTHOR]

Childhood adversity is an early life stressor associated with increased risk of several psychiatric disorders such as depression. Epigenetic changes, primarily DNA methylation, can be affected by early life stress, which in turn might contribute to altered disease susceptibility later in life. One plausible biomarker of early life stress is methylation of the ionotropic glutamate receptor NMDA type subunit 2B (GRIN2B) gene, which has been previously shown to be epigenetically affected by prenatal environmental stressors. Here, we set out to investigate if stress-inducing adversity during childhood is associated with changes in methylation of GRIN2B in adulthood. We studied 186 individuals from a Swedish naturalistic population-based cohort who had provided saliva samples (DNA) as well as information regarding both childhood adversity (CA) and depressive symptoms (dep) (n CA,dep = 41, n CA,no-dep = 56, n no-CA,dep = 40, N no-CA,no-dep = 49). Methylation at four CpG sites in a regulatory region of GRIN2B was analysed using bisulfite pyrosequencing. Associations for methylation status to childhood adversity and to depression status were investigated using linear regression models. Our study shows that childhood adversity is associated with increased methylation levels of GRIN2B in adulthood, for three of the measured CpGs (p = 0.007, 0.006 and 5 × 10−14). This indicates that GRIN2B methylation is susceptible to early life stress, and that methylation at this gene is persistent over time. No association was found between GRIN2B methylation and depression status. Yet, this does not rule out a role for alterations in GRIN2B methylation for other neuropsychological outcomes not studied here. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to examine the potential influence of RS4680 ( COMT ), RS16965628 ( SLC6A4 ), and RS1019385 ( GRIN2B ) polymorphisms on the therapeutic response to repetitive transcranial magnetic stimulation (rTMS) and selective serotonin reuptake inhibitors (SSRIs) in individuals with obsessive-compulsive disorder (OCD)., Patients and Methods: Thirty-six untreated outpatients diagnosed with OCD were recruited and allocated to active or sham rTMS groups for two weeks. The mean age of the participants was 31.61, with 17 males (47.22%) and 19 females (52.78%). Peripheral blood samples (5 mL) were collected from each participant using ethylenediaminetetraacetic acid (EDTA) vacuum tubes for genotyping purposes, clinical evaluation was taken place at baseline and second week., Results: The A allele of RS4680, C allele of RS16965628, and GG allele of RS1019385 were identified as potential bio-markers for predicting treatment response to OCD treatments (rTMS & SSRIs)., Conclusion: Those genes may serve as bio-markers for the combined treatment of rTMS and SSRIs in OCD. The finding hold promise for further research and the potential implementation of precision treatment of OCD., Clinical Trial Registration: https://www.chictr.org.cn, identifier ChiCTR1900023641., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chu, Wu, Yin, Zhang, Zhong, Fan and Wang.)

Background and Objectives: We examined the allelic variants of N-methyl- d-aspartate receptor 2B (GRIN2B) and analyzed the associations between GRIN2B gene polymorphism with ketamine use conditions and psychopathological symptoms in chronic ketamine users.Methods: A total of 231 subjects were recruited. Four single nucleotide polymorphisms of GRIN2B, rs1805502, rs7301328, rs890, and rs1806201 were examined in 151 male chronic ketamine users and 80 controls. Psychopathological symptoms in chronic ketamine users were evaluated using the Positive and Negative Syndrome Scale, the Beck Depression Inventory, and the Beck Anxiety Inventory.Results: The genotype CC of rs1806201 had a lower frequency in ketamine users than that in control subjects (χ2  = 8.167, P = .004) and the T allele frequency of rs1806201 in ketamine users was higher than that in the control subjects (P = .009, odds ratio = 2.019 [1.196-3.410]). Ketamine users of genotype TT and CC of rs1806201 had an earlier onset of ketamine use than subjects of genotype TC (P = .038, P = .049, respectively). The dose of ketamine consumption per day of use was higher in genotype GG of rs7301328 than that in those with CG in ketamine users (P = .026). There were no significant differences of the severity of psychopathologic symptoms among different genotypes tested.Conclusion and Scientific Significance: GRIN2B gene polymorphism may play a role in ketamine abuse. (Am J Addict 2020;29:105-110). [ABSTRACT FROM AUTHOR]

Rapid advances in sequencing technology have led to an explosive increase in the number of genetic variants identified in patients with neurological disease and have also enabled the assembly of a robust database of variants in healthy individuals. A surprising number of variants in the GRIN genes that encode N-methyl-D-aspartate (NMDA) glutamatergic receptor subunits have been found in patients with various neuropsychiatric disorders, including autism spectrum disorders, epilepsy, intellectual disability, attention-deficit/hyperactivity disorder, and schizophrenia. This review compares and contrasts the available information describing the clinical and functional consequences of genetic variations in GRIN2A and GRIN2B. Comparison of clinical phenotypes shows that GRIN2A variants are commonly associated with an epileptic phenotype but that GRIN2B variants are commonly found in patients with neurodevelopmental disorders. These observations emphasize the distinct roles that the gene products serve in circuit function and suggest that functional analysis of GRIN2A and GRIN2B variation may provide insight into the molecular mechanisms, which will allow more accurate subclassification of clinical phenotypes. Furthermore, characterization of the pharmacological properties of variant receptors could provide the first opportunity for translational therapeutic strategies for these GRIN-related neurological and psychiatric disorders.

Background: Schizophrenia is a complex mental disorder with a high heritability. Dysfunction of the N-methyl-D-aspartate (NMDA)-type glutamate receptors may be involved in the pathogenesis of schizophrenia. In this study, we examined the contribution of GRIN2A and GRIN2B (Glutamate Ionotropic Receptor NMDA Type Subunit 2A/2B) polymorphisms to the clinical features of schizophrenia, such as the leading symptoms, the type of course, and the age of onset. Methods: A population of 402 Russian patients with schizophrenia from the Siberian region was investigated. Genotyping of seventeen single-nucleotide polymorphisms (SNPs) in GRIN2A and GRIN2B was performed using QuantStudio™ 3D Digital PCR System Life Technologies amplifier using TaqMan Validated SNP Genotyping Assay kits (Applied Biosystems). The results were analyzed using Chi-square and the Fisher’s exact tests. Results: We found an association of GRIN2A rs7206256 and rs11644461 and GRIN2B rs7313149 with the early onset (before the age of 18 years old) schizophrenia. We did not reveal any associations of GRIN2A and GRIN2B polymorphisms with leading (positive vs. negative) symptoms or type of course (continuous vs. episodic) of schizophrenia. Conclusions: In the study, we confirmed the involvement of the GRIN2A and GRIN2B genes in the early onset of schizophrenia in a Russian population of the Siberian region.

Supplemental Digital Content is available in the text. Background: Several lines of evidence support the hypothesis that impaired functioning of the glutamatergic N -methyl- d -aspartate receptor (NMDAR) might be involved in the etiology of schizophrenia. NMDAR is activated by phosphorylation by Fyn, and there is also some evidence to suggest that abnormalities in Fyn functionality could also be involved in susceptibility to schizophrenia. In a recent weighted burden analysis of exome-sequenced schizophrenia cases and controls, we noted modest statistical evidence for an enrichment of rare, functional variants in FYN , GRIN1 , and GRIN2B in schizophrenia cases. Aim: To test the plausibility of the hypothesis that schizophrenia susceptibility might be associated with genetic variants predicted to cause impaired functioning of NMDAR, either directly or indirectly through impairment of the kinases that phosphorylate it. Methods: In an exome-sequenced sample of 4225 schizophrenia cases and 5834 controls, rare variants occurring in genes for the NMDAR subunits and for the kinases acting on it were annotated. The counts of disruptive and damaging variants were compared between cases and controls, and the distribution of amino acids affected by damaging variants was visualised in ProteinPaint and the RCSB Protein Data Bank. Special attention was paid to tyrosine residues subject to phosphorylation. Results: There was no suggestion that abnormalities of the serine–threonine kinases or of Src were associated with schizophrenia. Overall, three cases and no controls had a disruptive variant in GRIN2A and two cases and no controls had a disruptive variant in FYN. Moreover, 14 cases and three controls had damaging variants in FYN , and all the variants in controls affected amino acid residues in the N-terminal region outside of any known functional domains. By contrast, 10 variants in cases affected amino acids in functional domains, and in the 3D structure of Fyn, two of the amino acid substitutions, A376T and Q517E, were adjacent to each other. A total of eight cases and one control had damaging variants in GRIN1 , but there was no obvious pattern with respect to particular functional domains being affected in this or other genes. A single case had a variant in GRIN2A affecting a well-supported phosphorylation site, Y943C, and three cases had a variant in FYN which produces an amino acid change, T216S, which lies two residues away from two adjacent well-supported phosphorylation sites. Aside from this, there was no suggestion that tyrosine phosphorylation sites in Fyn or NMDAR were affected. Conclusion: The numbers of variants involved are too small for firm conclusions to be drawn. The results are consistent with the hypothesis that ∼0.5% of patients with schizophrenia have disruptive or damaging genetic variants, which could plausibly impair functioning of NMDAR directly or indirectly through impairing Fyn function. [ABSTRACT FROM AUTHOR]

Objectives. To seek the genetic mechanisms of impairments to the recognition of emotions, which is a sign of schizophrenia which degrades social adaptation of patients. This search was based on the view that the interaction between the dopaminergic and glutamatergic systems has a role in the pathogenesis of schizophrenia. The effects of the interaction between the polymorphic C366G locus in the gene encoding the NR2B subunit of the NMDA receptor - GRIN2B - the polymorphic loci in the dopamine receptor genes ANKK1/DRD2 Taq1A and DRD4 48-VNTR on the recognition of emotional expressions were studied. Materials and methods. The effects of the interaction between GRIN2B and DRD2 were studied in cohorts of 237 patients and 235 healthy subjects; those between GRIN2B and DRD4 were studied in cohorts of 268 and 208, respectively. Results and conclusions. Both effects reached significance in the combined cohorts of patients and healthy subjects (GRIN2B × DRD2, F = 4.12, p = 0.043; GRIN2B × DRD4, F = 6.43, p = 0.012). The effect of the interaction between the polymorphic loci in the GRIN2B and DRD2 genes on the recognition of expressed emotions in schizophrenia patients was confirmed. In patients with the less effective allele of the DRD2 gene and not bearing the minor allele of the GRIN2B gene, results were close to normal, while the genotype containing the minor alleles of both genes produced the worst results. This result is consistent with concepts of the possible role of the hypofunction of NMDA receptors and D2-mediated regulation of their activity in the production of schizophrenia endotypes such as the recognition of expressed emotions. [ABSTRACT FROM AUTHOR]

A genetically valid animal model could transform our understanding of schizophrenia (SCZ) disease mechanisms. Rare heterozygous loss-of-function (LoF) mutations in GRIN2A , encoding a subunit of the NMDA receptor, greatly increase the risk of SCZ. By transcriptomic, proteomic, and behavioral analyses, we report that heterozygous Grin2a mutant mice show (1) large-scale gene expression changes across multiple brain regions and in neuronal (excitatory and inhibitory) and non-neuronal cells (astrocytes and oligodendrocytes), (2) evidence of hypoactivity in the prefrontal cortex (PFC) and hyperactivity in the hippocampus and striatum, (3) an elevated dopamine signaling in the striatum and hypersensitivity to amphetamine-induced hyperlocomotion (AIH), (4) altered cholesterol biosynthesis in astrocytes, (5) a reduction in glutamatergic receptor signaling proteins in the synapse, and (6) an aberrant locomotor pattern opposite of that induced by antipsychotic drugs. These findings reveal potential pathophysiologic mechanisms, provide support for both the "hypo-glutamate" and "hyper-dopamine" hypotheses of SCZ, and underscore the utility of Grin2a -deficient mice as a genetic model of SCZ. [Display omitted] • Mice lacking Grin2a , a human risk gene, model several aspects of schizophrenia • Grin2a +/− mice show prefrontal cortex hypoactivity and hippocampal hyperactivity • Hyperdopaminergic state in striatum and amphetamine hypersensitivity in Grin2a +/− mice • Astrocytes, oligodendrocytes, and diverse neuronal types are affected in Grin2a +/− mice Farsi et al. show that heterozygous mouse mutants of Grin2a , a human schizophrenia risk gene, display major changes at the transcriptomic, proteomic, behavioral, and neurophysiological levels, affecting widespread brain regions, diverse cell types, and multiple signaling pathways, with several abnormal features that resemble schizophrenia patients. [ABSTRACT FROM AUTHOR]

Epilepsy is a brain disorder with a global prevalence of 1%. It has been attributed to genetics and environmental factors. Despite efforts to identify the molecular pathology of epilepsy, the underlying mechanism is not understood yet. This study was carried out to compare GRIN2B, BDNF, and IL-1β gene expressions in 50 patients suffering from generalized epilepsy with tonic-colonic seizures and 50 age- and sex-matched healthy subjects using TaqMan Real-time PCR. Our results demonstrated significant upregulation of these genes in people with epilepsy compared with healthy subjects. We also found a positive correlation between GRIN2B and BDNF expression (r2=0.4619, p < 0.0001), BDNF and IL-1β expression (r2 = 0.515, p < 0.0001), and GRIN2B and IL-1β gene expressions (r2 = 0.666, p < 0.0001) which implies the possibility to estimate the expression level of these genes by assessment of expression of one of them. Considering the results of the previous animal studies which showed upregulation of these genes in brain tissues of epileptic animals, the expression levels of GRIN2B, BDNF, and IL-1β in blood samples might be related to their expression in brain samples. Future studies are needed to assess the role of these genes in the pathogenesis of epilepsy and evaluate whether altered expression of these genes along with imaging methods can facilitate subtyping the epilepsy. [ABSTRACT FROM AUTHOR]

Evidences have indicated a high degree of comorbidity of alcoholism and depression. N-acetylcysteine (NAC) has shown its clinical efficiency in the treatment of several psychiatric disorders and is identified as a multi-target acting drug. The ability of NAC to prevent alcohol abstinence-induced depression-like effects and underlying mechanism(s) have not been adequately addressed. This study was aimed to investigate the beneficial effects of NAC in the alcohol abstinence-induced depression developed following long-term voluntary alcohol intake. For evaluation of the effects of NAC, Sprague–Dawley rats were enabled to voluntary drinking of 4.5%, 7.5% and 9% v/v alcohol for fifteen days. NAC (25, 50, and 100 mg/kg) and fluoxetine (5 mg/kg) were injected intraperitoneally for three consecutive days during the alcohol abstinence period on the days 16, 17, 18. The behavioral studies were conducted employing forced swim test (FST), and tail suspension test (TST) on day 18 to determine the effects of N-acetylcysteine and fluoxetine in the ethanol withdrawal induced-depression. Blood alcohol concentration, alcohol biomarkers like SGPT, SGOT, ALP, GGT, and MCV were estimated by using commercially available kits. Serotonin concentrations were measured in the plasma, hippocampus and pre-frontal cortex using the rat ELISA kit. The expression of GRIN1 , GRIN2A , GRIN2B genes for the N-methyl d -aspartate receptors (NMDAR) subunits in the hippocampus and the prefrontal cortex were also examined by reverse-transcription quantitative polymerase chain reaction. The results revealed that alcohol abstinence group depicted increased immobility time in FST and TST. Further, NAC exerted significant protective effect at the doses 50 mg/kg and 100 mg/kg, but 25 mg/kg showed insignificant protection against alcohol abstinence-induced depression. The increased level of biochemical parameters following ethanol abstinence were also reversed by NAC at the dose of 100 mg/kg. The significant reversal effect of NAC on the serotonin level following alcohol abstinence was greater in the hippocampus as compared to the third-day alcohol withdrawal group. The increased expression levels of GRIN2A and GRIN2B following ethanol abstinence were reversed with a higher dose of NAC (100 mg/kg) treatment. In conclusion, the results of the study reveal that NAC has remarkable protective effects in the alcohol abstinence-induced depression by modulating alcohol markers, serotonin levels and GRIN2A , GRIN2B gene expression of NMDAR signaling pathway in rats. [ABSTRACT FROM AUTHOR]

Drug dependence is a chronic brain disease with harmful consequences for both individual users and society. Glutamate is a primary excitatory neurotransmitter in the brain, and both in vivo and in vitro experiments have implicated N-methyl-D-aspartate (NMDA) receptor, a glutamate receptor, as an element in various types of addiction. Recent findings from genetics-based approaches such as genome-wide linkage, candidate gene association, genome-wide association (GWA), and next-generation sequencing have demonstrated the significant association of NMDA receptor subunit genes such as GluN3A, GluN2B, and GluN2A with various addiction-related phenotypes. Of these genes, GluN3A has been the most studied, and it has been revealed to play crucial roles in the etiology of addictions. In this communication, we provide an updated view of the genetic effects of NMDA receptor subunit genes and their functions in the etiology of addictions based on the findings from investigation of both common and rare variants as well as SNP-SNP interactions. To better understand the molecular mechanisms underlying addiction-related behaviors and to promote the development of specific medicines for the prevention and treatment of addictions, current efforts aim not only to identify more causal variants in NMDA receptor subunits by using large independent samples but also to reveal the molecular functions of these variants in addictions. [ABSTRACT FROM AUTHOR]

Stressing events in the early period of life affect neuronal plasticity and cognitive functions in adulthood. A key role in the mechanisms of formation of memory and attention is played by the glutamatergic system. However, there has been virtually no systematic study on the effect of early postnatal stress on the expression of glutamatergic system genes in various regions of the brain in mice. In this study, we used two types of early postnatal stress: prolonged separation of pups from mothers (for 3 hours per day) and shortterm separation (15 minutes per day) during the first 2 weeks of life. We used an object recognition test to evaluate attention and memory to assess cognitive abilities in adults. We found that prolonged maternal separation reduced the ability to recognize a novel object and also disrupted motor and exploratory activities in adult animals, while short-term separation did not affect the studied parameters. We assessed the expression of the major genes of the glutamatergic system (AMPA receptor subunits Gria1, Gria2; NMDA subunits Grin1, Grin2a, and Grin2b; metabotropic receptor subunits Grm1, Grm2, and Grm3; glutamate transporters Vglut2, Eaat2, and Rab4a) in the frontal cortex, hippocampus, and hypothalamus. In the group with prolonged maternal separation, we found a decrease in the expression of Grin2b in the hypothalamus in comparison with the control, which led to a decrease in the mRNA ratio of this subunit to Grin2a mRNA, and possibly to a change in the ratio of these subunits in the NMDA receptor. In spite of the revealed cognitive impairments, we did not find significant changes in the expression of genes in the frontal cortex and hippocampus. Shortterm daily separation from mothers did not lead to changes in cognitive abilities and expression of genes of the glutamatergic system in mice. Thus, our results show that prolonged maternal separation may lead to a redistribution of the receptor subunits in the hypothalamus, which can modify the activity of the HPAA and determine the response to stress in these mice. [ABSTRACT FROM AUTHOR]