297 results on '"GRIN1"'
Search Results
2. Foxg1 regulates translation of neocortical neuronal genes, including the main NMDA receptor subunit gene, Grin1.
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Artimagnella, Osvaldo, Maftei, Elena Sabina, Esposito, Mauro, Sanges, Remo, and Mallamaci, Antonello
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TRANSCRIPTION factors , *GENETIC translation , *METHYL aspartate receptors , *HISTOGENESIS , *GENES - Abstract
Background: Mainly known as a transcription factor patterning the rostral brain and governing its histogenesis, FOXG1 has been also detected outside the nucleus; however, biological meaning of that has been only partially clarified. Results: Prompted by FOXG1 expression in cytoplasm of pallial neurons, we investigated its implication in translational control. We documented the impact of FOXG1 on ribosomal recruitment of Grin1-mRNA, encoding for the main subunit of NMDA receptor. Next, we showed that FOXG1 increases GRIN1 protein level by enhancing the translation of its mRNA, while not increasing its stability. Molecular mechanisms underlying this activity included FOXG1 interaction with EIF4E and, possibly, Grin1-mRNA. Besides, we found that, within murine neocortical cultures, de novo synthesis of GRIN1 undergoes a prominent and reversible, homeostatic regulation and FOXG1 is instrumental to that. Finally, by integrated analysis of multiple omic data, we inferred that FOXG1 is implicated in translational control of hundreds of neuronal genes, modulating ribosome engagement and progression. In a few selected cases, we experimentally verified such inference. Conclusions: These findings point to FOXG1 as a key effector, potentially crucial to multi-scale temporal tuning of neocortical pyramid activity, an issue with profound physiological and neuropathological implications. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Foxg1 regulates translation of neocortical neuronal genes, including the main NMDA receptor subunit gene, Grin1
- Author
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Osvaldo Artimagnella, Elena Sabina Maftei, Mauro Esposito, Remo Sanges, and Antonello Mallamaci
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Foxg1 ,Translation ,Grin1 ,NMDAR ,Neuronal activity ,Biology (General) ,QH301-705.5 - Abstract
Abstract Background Mainly known as a transcription factor patterning the rostral brain and governing its histogenesis, FOXG1 has been also detected outside the nucleus; however, biological meaning of that has been only partially clarified. Results Prompted by FOXG1 expression in cytoplasm of pallial neurons, we investigated its implication in translational control. We documented the impact of FOXG1 on ribosomal recruitment of Grin1-mRNA, encoding for the main subunit of NMDA receptor. Next, we showed that FOXG1 increases GRIN1 protein level by enhancing the translation of its mRNA, while not increasing its stability. Molecular mechanisms underlying this activity included FOXG1 interaction with EIF4E and, possibly, Grin1-mRNA. Besides, we found that, within murine neocortical cultures, de novo synthesis of GRIN1 undergoes a prominent and reversible, homeostatic regulation and FOXG1 is instrumental to that. Finally, by integrated analysis of multiple omic data, we inferred that FOXG1 is implicated in translational control of hundreds of neuronal genes, modulating ribosome engagement and progression. In a few selected cases, we experimentally verified such inference. Conclusions These findings point to FOXG1 as a key effector, potentially crucial to multi-scale temporal tuning of neocortical pyramid activity, an issue with profound physiological and neuropathological implications.
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- 2024
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4. Quantitative proteomic and phosphoproteomic analyses of the hippocampus reveal the involvement of NMDAR1 signaling in repetitive mild traumatic brain injury.
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Zhicheng Tian, Zixuan Cao, Erwan Yang, Juan Li, Dan Liao, Fei Wang, Taozhi Wang, Zhuoyuan Zhang, Haofuzi Zhang, Xiaofan Jiang, Xin Li, and Peng Luo
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- 2023
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5. An experimental study of the effects of SNPs in the TATA boxes of the GRIN1, ASCL3 and NOS1 genes on interactions with the TATA-binding protein
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E. B. Sharypova, I. A. Drachkova, I. V. Chadaeva, M. P. Ponomarenko, and L. K. Savinkova
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grin1 ,ascl3 ,nos1 ,tata-binding protein ,affinity ,tbp/tata interaction ,Genetics ,QH426-470 - Abstract
The GRIN1, ASCL3, and NOS1 genes are associated with various phenotypes of neuropsychiatric disorders. For instance, these genes contribute to the development of schizophrenia, Alzheimer’s and Parkinson’s diseases, and epilepsy. These genes are also associated with various cancers. For example, ASCL3 is overexpressed in breast cancer, and NOS1, in ovarian cancer cell lines. Based on our findings and literature data, we had previously obtained results suggesting that the single-nucleotide polymorphisms (SNPs) that disrupt erythropoiesis are highly likely to be associated with cognitive and neuropsychiatric disorders in humans. In the present work, using SNP_TATA_Z-tester, we investigated the influence of unannotated SNPs in the TATA boxes of the promoters of the GRIN1, ASCL3, and NOS1 genes (which are involved in neuropsychiatric disorders and cancers) on the interaction of the TATA boxes with the TATA-binding protein (TBP). Double-stranded oligodeoxyribonucleotides identical to the TATA-containing promoter regions of the GRIN1, ASCL3, and NOS1 genes (reference and minor alleles) and recombinant human TBP were employed to study in vitro (by an electrophoretic mobility shift assay) kinetic characteristics of the formation of TBP–TATA complexes and their affinity. It was found, for example, that allele A of rs1402667001 in the GRIN1 promoter increases TBP–TATA affinity 1.4-fold, whereas allele C in the TATA box of the ASCL3 promoter decreases the affinity 1.4-fold. The lifetime of the complexes in both cases decreased by ~20 % due to changes in the rates of association and dissociation of the complexes (ka and kd, respectively). Our experimental results are consistent with the literature showing GRIN1 underexpression in schizophrenic disorders as well as an increased risk of cervical, bladder, and kidney cancers and lymphoma during ASCL3 underexpression. The effect of allele A of the –27G>A SNP (rs1195040887) in the NOS1 promoter is suggestive of an increased risk of ischemic damage to the brain in carriers. A comparison of experimental TBP–TATA affinity values (KD) of wild-type and minor alleles with predicted ones showed that the data correlate well (linear correlation coefficient r = 0.94, p < 0.01).
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- 2022
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6. Oculogyric crisis induced by risperidone in a child with GRIN1 variant
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Ali Mir, Montaha Almudhry, Shahid Bashir, and Hamoud Khallaf
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GRIN1 ,Risperidone ,Oculogyric crisis ,NMDA ,Dopamine ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
The GluN1 subunit of the N-methyl-d-aspartate (NMDA) receptor is encoded by GRIN1 gene. Mutations in this gene can cause neurodevelopmental disorders with or without hyperkinetic movements and seizures. It can be inherited as either autosomal dominant (NDHMSD) or autosomal recessive (NDHMSR). Patients can present with severe psychomotor delay, seizures, behavioral problems, stereotypies, and oculogyric crisis (OGC). There is emerging evidence regarding the molecular interaction between dopamine and NMDA receptors, cross-talk between dopamine and glutamate signaling, and mutations in GRIN1 could affect both glutamatergic and dopaminergic synaptic transmission. Dopamine antagonists, such as risperidone, which is used to treat behavioral problems, can cause extrapyramidal side effects, including OGC. Here, we present a case of an 8-year-old boy with a GRIN1 variant who was treated with risperidone for severe behavioral problems and experienced an OGC for approximately 30 h. The child had no prior history of such event and experienced no re-occurrences after discontinuing risperidone. This case highlights the importance of exercising extra caution while prescribing dopamine antagonists for patients with GRIN1 mutations and reports the efficacy of memantine in treating seizures and behavioral side effects in such patients. In the era of precision medicine, this case represents a good example of how patient's genetic makeup should be considered in prescribing the right medication for the right patient.
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- 2023
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7. TFAP2A is involved in neuropathic pain by regulating Grin1 expression in glial cells of the dorsal root ganglion.
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Yuan, Bao-Tong, Li, Meng-Na, Zhu, Lin-Peng, Xu, Meng-Lin, Gu, Jun, Gao, Yong-Jing, and Ma, Ling-Jie
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DORSAL root ganglia , *GENE expression , *TRANSCRIPTION factors , *INTRATHECAL injections , *SATELLITE cells - Abstract
[Display omitted] Neuropathic pain is a highly prevalent and refractory condition, yet its mechanism remains poorly understood. While NR1, the essential subunit of NMDA receptors, has long been recognized for its pivotal role in nociceptive transmission, its involvement in presynaptic stimulation is incompletely elucidated. Transcription factors can regulate the expression of both pro-nociceptive and analgesic factors. Our study shows that transcription factor TFAP2A was up-regulated in the dorsal root ganglion (DRG) neurons, satellite glial cells (SGCs), and Schwann cells following spinal nerve ligation (SNL). Intrathecal injection of siRNA targeting Tfap2a immediately or 7 days after SNL effectively alleviated SNL-induced pain hypersensitivity and reduced Tfap2a expression levels. Bioinformatics analysis revealed that TFAP2A may regulate the expression of the Grin1 gene, which encodes NR1. Dual-luciferase reporter assays confirmed TFAP2A's positive regulation of Grin1 expression. Notably, both Tfap2a and Grin1 were expressed in the primary SGCs and upregulated by lipopolysaccharides. The expression of Grin1 was also down-regulated in the DRG following Tfap2a knockdown. Furthermore, intrathecal injection of siRNA targeting Grin1 immediately or 7 days post-SNL effectively alleviated SNL-induced mechanical allodynia and thermal hyperalgesia. Finally, intrathecal Tfap2a siRNA alleviated SNL-induced neuronal hypersensitivity, and incubation of primary SGCs with Tfap2a siRNA decreased NMDA-induced upregulation of proinflammatory cytokines. Collectively, our study reveals the role of TFAP2A- Grin1 in regulating neuropathic pain in peripheral glia, offering a new strategy for the development of novel analgesics. [ABSTRACT FROM AUTHOR]
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- 2024
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8. Subtype-specific conformational landscape of NMDA receptor gating.
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Bleier, Julia, Furtado de Mendonca, Philipe Ribeiro, Habrian, Chris H., Stanley, Cherise, Vyklicky, Vojtech, and Isacoff, Ehud Y.
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N-methyl-D-aspartate receptors are ionotropic glutamate receptors that mediate synaptic transmission and plasticity. Variable GluN2 subunits in diheterotetrameric receptors with identical GluN1 subunits set very different functional properties. To understand this diversity, we use single-molecule fluorescence resonance energy transfer (smFRET) to measure the conformations of the ligand binding domain and modulatory amino-terminal domain of the common GluN1 subunit in receptors with different GluN2 subunits. Our results demonstrate a strong influence of the GluN2 subunits on GluN1 rearrangements, both in non-agonized and partially agonized activation intermediates, which have been elusive to structural analysis, and in the fully liganded state. Chimeric analysis reveals structural determinants that contribute to these subtype differences. Our study provides a framework for understanding the conformational landscape that supports highly divergent levels of activity, desensitization, and agonist potency in receptors with different GluN2s and could open avenues for the development of subtype-specific modulators. [Display omitted] • smFRET reveals conformational differences between NMDA receptors with different GluN2s • Low-P o receptors are more splayed at rest and more compact when fully agonized • Interaction between the GluN1 LBD and GluN2 NTD contributes to these differences Bleier et al. use single-molecule fluorescence resonance energy transfer (smFRET) in NMDA receptors to compare conformations and rearrangements of receptor subtypes with different GluN2 subunits. They find that low-open-probability receptors are more splayed and dynamic at rest, more compact when fully agonized, and show distinct subunit interactions. [ABSTRACT FROM AUTHOR]
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- 2024
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9. Berberis vulgaris extract-based Fe3O4 nanocomposites affect NMDA1 function and physical activity: Analysis of Grin1 expression in Syrian mice model of Experimental autoimmune encephalomyelitis
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Fatemeh Noruzifard, Amaneh Javid, and Seyed Mohsen Miresmaeili
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nmda ,neuroprotection ,grin1 ,syrian mice ,berberis vulgaris ,Medicine ,Science - Abstract
Background: Ionotropic glutamate NMDA receptors are multi-subunit proteins with few selective pharmacological ligands and are tentatively implicated in MS and other neurodegenerative disorders. The present study was aimed at evaluating the antioxidant properties of Berberis vulgaris extract-loaded magnetite nanoparticles on the Grin1 gene expression in NMDA receptor in EAE Syrian mice. Methods: EAE mice models were generated through active immunization with MBP and PTx and kept for days 9-14 until EAE signs appeared followed by administration of barberry extract loaded magnetic nanoparticles. Results: Pure BE concentrations did not show recovery signs until days 7-9, but partial recovery in tail movement was seen on days 11 and 14, which was significant as compared to the control group in terms of improvement of the clinical scores. Meanwhile bare nanoparticles had neither disease recovery/progression properties nor EAE mice mortality as compared to controls, but 1 mg BE + Fe3O4 reduced EAE symptom severity and resulted in significant improvement of hind limb sensitivity to toe pinching and improved tail movements. Meanwhile 2 mg Be + Fe3O4 showed much better sensitivity to toe pinching and complete tail recovery. qRT-PCR analysis showed a significant decrease in relative Grin1 expression in female mice after treatment with 0.2 and 1 mg BE. However, a profound decrease in Grin1 expression was seen at 0.2, 1 and 2 mg BE + Fe3O4 treated groups in a dose-dependent manner. Conclusion: The results indicated that Fe3O4+ BE could alleviate the EAE severity and progression
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- 2021
10. Characteristic features of electroencephalogram in a pediatric patient with GRIN1 encephalopathy
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Naohiro Yamamoto, Masataka Fukuoka, Ichiro Kuki, Naomi Tsuchida, Naomichi Matsumoto, and Shin Okazaki
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GRIN1 ,Electroencephalogram ,Paroxysmal fast activity ,N-methyl-D-aspartate receptor ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Background: The number of reports on GRIN1 variants associated with neurodevelopmental phenotypes has increased in recent years. However, there are only two detailed reports on electroencephalography findings. Case study: We had a case with severe global developmental delay, and exome sequencing revealed a novel de novo heterozygous variant of GRIN1. The patient's electroencephalography showed unique findings: paroxysmal fast activity—20–30 Hz beta waves, independently in the bilateral occipital regions, sometimes in a continuous manner—and prolonged alpha activity in the bilateral frontal regions, observed mainly during sleep, those findings were observed persistently. Discussion: The electroencephalography findings of our case have not been reported in the past. Receptor hypofunction due to the GRIN1 variant and imbalance in excitatory/inhibitory transmission owing to the dysfunction of the N-methyl-D-aspartate receptors may be the mechanism for the global developmental delay, stereotyped movements, and development of paroxysmal fast activity in our case. Accumulation of additional case reports is needed to confirm the reproducibility of the electroencephalography findings for disease specificity.
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- 2022
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11. Abnormal sensory perception masks behavioral performance of Grin1 knockdown mice.
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Lipina, Tatiana, Men, Xiaoyu, Blundell, Matisse, Salahpour, Ali, and Ramsey, Amy J.
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SENSORY perception , *EXECUTIVE function , *AUTISM spectrum disorders , *VISUAL perception , *DEPTH perception , *COGNITIVE ability - Abstract
The development and function of sensory systems require intact glutamatergic neurotransmission. Changes in touch sensation and vision are common symptoms in autism spectrum disorders, where altered glutamatergic neurotransmission is strongly implicated. Further, cortical visual impairment is a frequent symptom of GRIN disorder, a rare genetic neurodevelopmental disorder caused by pathogenic variants of GRIN genes that encode NMDA receptors. We asked if Grin1 knockdown mice (Grin1KD), as a model of GRIN disorder, had visual impairments resulting from NMDA receptor deficiency. We discovered that Grin1KD mice had deficient visual depth perception in the visual cliff test. Since Grin1KD mice are known to display robust changes in measures of learning, memory, and emotionality, we asked whether deficits in these higher‐level processes could be partly explained by their visual impairment. By changing the experimental conditions to improve visual signals, we observed significant improvements in the performance of Grin1KD mice in tests that measure spatial memory, executive function, and anxiety. We went further and found destabilization of the outer segment of retina together with the deficient number and size of Meissner corpuscles (mechanical sensor) in the hind paw of Grin1KD mice. Overall, our findings suggest that abnormal sensory perception can mask the expression of emotional, motivational and cognitive behavior of Grin1KD mice. This study demonstrates new methods to adapt routine behavioral paradigms to reveal the contribution of vision and other sensory modalities in cognitive performance. [ABSTRACT FROM AUTHOR]
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- 2022
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12. A homozygous GRIN1 null variant causes a more severe phenotype of early infantile epileptic encephalopathy.
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Blakes, Alexander J. M., English, Joel, Banka, Siddharth, and Basu, Helen
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Pathogenic variants in glutamate receptor, ionotropic, NMDA‐1 (GRIN1) cause an autosomal dominant or recessive neurodevelopmental disorder with global developmental delay, with or without seizures (AD or AR GRIN1‐NDD). Here, we describe a novel homozygous canonical splice site variant in GRIN1 in a 12‐month‐old boy with early infantile epileptic encephalopathy and severe global developmental delay. This represents only the second family with a homozygous predicted‐null variant in GRIN1 reported to date. We review the published literature on AR GRIN1‐NDD and find that the phenotype in our patient is much more severe than those seen with homozygous missense variants. A similarly severe phenotype of intractable epilepsy and infantile death has only been reported in one other family with a homozygous nonsense variant in GRIN1. We, therefore, propose that biallelic predicted‐null variants in GRIN1 can cause a markedly more severe clinical phenotype than AR GRIN1‐NDD caused by missense variants. [ABSTRACT FROM AUTHOR]
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- 2022
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13. Potential Ago2/miR-3068-5p Cascades in the Nucleus Accumbens Contribute to Methamphetamine-Induced Locomotor Sensitization of Mice.
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Liu, Dan, Liang, Min, Zhu, Li, Zhou, Ting-ting, Wang, Yu, Wang, Rui, Wu, Fei-fei, Goh, Eyleen L. K., and Chen, Teng
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MICE ,DRUG addiction ,METHAMPHETAMINE ,MICRORNA ,NUCLEUS accumbens - Abstract
Dysregulation of microRNA (miRNA) biogenesis is involved in drug addiction. Argonaute2 (Ago2), a specific splicing protein involved in the generation of miRNA, was found to be dysregulated in the nucleus accumbens (NAc) of methamphetamine (METH)-sensitized mice in our previous study. Here, we determined whether Ago2 in the NAc regulates METH sensitization in mice and identified Ago2-dependent miRNAs involved in this process. We found a gradual reduction in Ago2 expression in the NAc following repeated METH use. METH-induced hyperlocomotor activity in mice was strengthened by knocking down NAc neuronal levels of Ago2 but reduced by overexpressing Ago2 in NAc neurons. Surprisingly, miR-3068-5p was upregulated following overexpression of Ago2 and downregulated by silencing Ago2 in the NAc. Knocking down miR-3068-5p, serving as an Ago2-dependent miRNA, strengthened the METH sensitization responses in mice. These findings demonstrated that dysregulated Ago2 in neurons in the NAc is capable of regulating METH sensitization and suggested a potential role of Ago2-dependent miR-3068-5p in METH sensitization. [ABSTRACT FROM AUTHOR]
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- 2021
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14. Accumulation of NMDA receptors in accumbal neuronal ensembles mediates increased conditioned place preference for cocaine after prolonged withdrawal.
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Huai, Ziqing, Huang, Bing, He, Guanhong, Li, Haibo, Liu, Yonghui, Le, Qiumin, Wang, Feifei, Ma, Lan, and Liu, Xing
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METHYL aspartate receptors , *COCAINE-induced disorders , *TREATMENT of drug addiction , *COCAINE , *DOPAMINE receptors - Abstract
Cue-induced cocaine craving gradually intensifies following abstinence, a phenomenon known as the incubation of drug craving. Neuronal ensembles activated by initial cocaine use, are critically involved in this process. However, the mechanisms by which neuronal changes occurring in the ensembles after withdrawal contribute to incubation remain largely unknown. Here we labeled neuronal ensembles in the shell of nucleus accumbens (NAcSh) activated by cocaine conditioned place preference (CPP) training. NAcSh ensembles showed an increasing activity induced by CPP test after 21-day withdrawal. Inhibiting synaptic transmission of NAcSh ensembles suppressed the preference for cocaine paired-side after 21-day withdrawal, demonstrating a critical role of NAcSh ensembles in increased preference for cocaine. The density of dendritic spines in dopamine D1 receptor expressing ensembles was increased after 21-day withdrawal. Moreover, the expression of Grin1 , a subunit of the N-methyl-D-aspartate (NMDA) receptor, specifically increased in the NAcSh ensembles after cocaine withdrawal in both CPP and self-administration (SA) mouse models. Targeted knockdown or dysfunction of Grin1 in NAcSh ensembles significantly suppressed craving for cocaine. Our results suggest that the accumulation of NMDA receptors in NAcSh ensembles mediates increased craving for cocaine after prolonged withdrawal, thereby providing potential molecular targets for treatment of drug addiction. [Display omitted] ● Activity of NAcSh ensembles is enhanced by CPP test after prolonged withdrawal, alongside enhanced preference for cocaine. ● Inhibition of synaptic transmission of NAcSh ensembles decreases preference for cocaine side after prolonged withdrawal. ● Dendritic spine density is increased in NAcSh D1-ensembles after prolonged withdrawal. ● Grin1 expression is up-regulated in NAcSh neuronal ensembles after prolonged withdrawal. ● Down-regulation or dysfunction of Grin1 in NAcSh neuronal ensembles decreases preference for cocaine. [ABSTRACT FROM AUTHOR]
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- 2024
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15. Overlapping cortical malformations in patients with pathogenic variants in GRIN1 and GRIN2B
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Stefanie Brock, Annie Laquerriere, Florent Marguet, Scott J Myers, Yuan Hongjie, Diana Baralle, Tim Vanderhasselt, Katrien Stouffs, Kathelijn Keymolen, Sukhan Kim, James Allen, Gil Shaulsky, Jamel Chelly, Pascale Marcorelle, Jacqueline Aziza, Laurent Villard, Elise Sacaze, Marie C Y de Wit, Martina Wilke, Grazia Maria Simonetta Mancini, Ute Hehr, Derek Lim, Sahar Mansour, Stephen F Traynelis, Claire Beneteau, Marie Denis-Musquer, Anna C Jansen, Andrew E Fry, Nadia Bahi-Buisson, Neurology, Clinical Genetics, Internal Medicine, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], and Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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NMDAR ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,nervous system ,GRIN1 ,[SDV]Life Sciences [q-bio] ,Genetics ,polymicrogyria ,Human medicine ,malformations of cortical development ,GRIN2B ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Genetics (clinical) - Abstract
BackgroundMalformations of cortical development (MCDs) have been reported in a subset of patients with pathogenic heterozygous variants inGRIN1orGRIN2B, genes which encode for subunits of the N-methyl-D-aspartate receptor (NMDAR). The aim of this study was to further define the phenotypic spectrum of NMDAR-related MCDs.MethodsWe report the clinical, radiological and molecular features of 7 new patients and review data on 18 previously reported individuals with NMDAR-related MCDs. Neuropathological findings for two individuals with heterozygous variants inGRIN1are presented. We report the clinical and neuropathological features of one additional individual with homozygous pathogenic variants inGRIN1.ResultsHeterozygous variants inGRIN1andGRIN2Bwere associated with overlapping severe clinical and imaging features, including global developmental delay, epilepsy, diffuse dysgyria, dysmorphic basal ganglia and hippocampi. Neuropathological examination in two fetuses with heterozygousGRIN1variants suggests that proliferation as well as radial and tangential neuronal migration are impaired. In addition, we show that neuronal migration is also impaired by homozygousGRIN1variants in an individual with microcephaly with simplified gyral pattern.ConclusionThese findings expand our understanding of the clinical and imaging features of the ‘NMDARopathy’ spectrum and contribute to our understanding of the likely underlying pathogenic mechanisms leading to MCD in these patients.
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- 2023
16. From bedside‐to‐bench: What disease‐associated variants are teaching us about the NMDA receptor.
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Amin, Johansen B., Moody, Gabrielle R., and Wollmuth, Lonnie P.
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METHYL aspartate receptors , *DRUG design , *ION channels , *NEUROLOGICAL disorders , *INDIVIDUALIZED medicine - Abstract
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]
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- 2021
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17. Conformational basis of subtype-specific allosteric control of NMDA receptor gating.
- Author
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Bleier J, de Mendonca PRF, Habrian C, Stanley C, Vyklicky V, and Isacoff EY
- Abstract
N-methyl-D-aspartate receptors are ionotropic glutamate receptors that are integral to synaptic transmission and plasticity. Variable GluN2 subunits in diheterotetrameric receptors with identical GluN1 subunits set very different functional properties, which support their individual physiological roles in the nervous system. To understand the conformational basis of this diversity, we assessed the conformation of the common GluN1 subunit in receptors with different GluN2 subunits using single-molecule fluorescence resonance energy transfer (smFRET). We established smFRET sensors in the ligand binding domain and modulatory amino-terminal domain to study an apo-like state and partially liganded activation intermediates, which have been elusive to structural analysis. Our results demonstrate a strong, subtype-specific influence of apo and glutamate-bound GluN2 subunits on GluN1 rearrangements, suggesting a conformational basis for the highly divergent levels of receptor activity, desensitization and agonist potency. Chimeric analysis reveals structural determinants that contribute to the subtype differences. Our study provides a framework for understanding GluN2-dependent functional properties and could open new avenues for subtype-specific modulation., Competing Interests: Declaration of Interests The authors declare no competing interests.
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- 2024
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18. Methionine mediates resilience to chronic social defeat stress by epigenetic regulation of NMDA receptor subunit expression.
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Bilen, Maria, Ibrahim, Pascal, Barmo, Nour, Abou Haidar, Edwina, Karnib, Nabil, El Hayek, Lauretta, Khalifeh, Mohamad, Jabre, Vanessa, Houbeika, Rouba, Stephan, Joseph S., and Sleiman, Sama F.
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METHYL aspartate receptors , *METHIONINE , *HISTONE methylation , *AMINO acids , *HISTONES , *WESTERN immunoblotting , *SOCIAL defeat - Abstract
Rationale: Previous studies suggested that methionine (Met) levels are decreased in depressed patients. However, whether the decrease in this amino acid is important for phenotypic behaviors associated with depression has not been deciphered. Objective: The response of individuals to chronic stress is variable, with some individuals developing depression and others becoming resilient to stress. In this study, our objective was to examine the effect of Met on susceptibility to stress. Methods: Male C57BL/6J mice were subjected to daily defeat sessions by a CD1 aggressor, for 10 days. On day 11, the behavior of mice was assessed using social interaction and open-field tests. Mice received Met 4 h before each defeat session. Epigenetic targets were assessed either through real-rime RTPCR or through Western Blots. Results: Met did not modulate anxiety-like behaviors, but rather promoted resilience to chronic stress, rescued social avoidance behaviors and reversed the increase in the cortical expression levels of N-methyl-d-aspartate receptor (NMDAR) subunits. Activating NMDAR activity abolished the ability of Met to promote resilience to stress and to rescue social avoidance behavior, whereas inhibiting NMDAR did not show any synergistic or additive protective effects. Indeed, Met increased the cortical levels of the histone methyltransferase SETDB1, and in turn, the levels of the repressive histone H3 lysine (K9) trimethylation (me3). Conclusions: Our data indicate that Met rescues susceptibility to stress by inactivating cortical NMDAR activity through an epigenetic mechanism involving histone methylation. [ABSTRACT FROM AUTHOR]
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- 2020
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19. Progressive neuroanatomical changes caused by Grin1 loss-of-function mutation
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Katheron Intson, Matthijs C. van Eede, Rehnuma Islam, Marija Milenkovic, Yuanye Yan, Ali Salahpour, R. Mark Henkelman, and Amy J. Ramsey
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GRIN1 ,GluN1 ,NR1 ,NMDA ,Encephalopathy ,Autism ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
NMDA receptor dysfunction is central to the encephalopathies caused by missense mutations in the NMDA receptor subunit genes. Missense variants of GRIN1, GRIN2A, and GRIN2B cause similar syndromes with varying severity of intellectual impairment, autism, epilepsy, and motor dysfunction. To gain insight into possible biomarkers of NMDAR hypofunction, we asked whether a loss-of-function variant in the Grin1 gene would cause structural changes in the brain that could be detected by MRI. We also studied the developmental trajectory of these changes to determine whether structural changes coincided with reported cognitive impairments in the mice. We performed magnetic resonance imaging in male Grin1−/− knockdown mice (GluN1KD) that were three, six, or twelve weeks old. Deformation-based morphometry was used to assess neuroanatomical differences. Volumetric reductions were detected in substantia nigra and striatum of GluN1KD mice at all ages. Changes in limbic structures were only evident at six weeks of age. Reductions in white matter volumes were first evident at three weeks, and additional deficits were detected at six and twelve weeks. FluoroJade immunofluorescence revealed degenerating neurons in twelve-week old GluN1KD mice. We conclude that Grin1 loss-of-function mutations cause volume reductions in dopaminergic structures early in development, while changes to limbic and white matter structures are delayed and are more pronounced in post-adolescent ages. The evidence of degenerating neurons in the mature brain indicates an ongoing process of cell loss as a consequence of NMDAR hypofunction.
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- 2019
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20. Rett and Rett‐like syndrome: Expanding the genetic spectrum to KIF1A and GRIN1 gene
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Jiaping Wang, Qingping Zhang, Yan Chen, Shujie Yu, Xiru Wu, and Xinhua Bao
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GRIN1 ,KIF1A ,Rett ,Rett‐like ,Genetics ,QH426-470 - Abstract
Abstract Background This study aimed to investigate the new genetic etiologies of Rett syndrome (RTT) or Rett‐like phenotypes. Methods Targeted next‐generation sequencing (NGS) was performed on 44 Chinese patients with RTT or Rett‐like phenotypes, in whom genetic analysis of MECP2, CDKL5, and FOXG1 was negative. Results The detection rate was 31.8% (14/44). A de novo pathogenic variant (c.275_276ins AA, p. Cys92*) of KIF1A was identified in a girl with all core features of typical RTT. A patient with atypical RTT was detected having de novo GRIN1 pathogenic variant (c.2337C > A, p. Val793Phe). Additionally, compound heterozygous pathogenic variants of PPT1 gene were detected in a girl, who initially displayed typical RTT features, but progressed into neuronal ceroid lipofuscinoses (NCL) afterwards. Pathogenic variants in KCNQ2, MEF2C, WDR45, TCF4, IQSEC2, and SDHA were also found in our cohort. Conclusions It is the first time that pathogenic variants of GRIN1 and KIF1A were linked to RTT and Rett‐like profiles. Our findings expanded the genetic heterogeneity of Chinese RTT or Rett‐like patients, and also suggest that some patients with genetic metabolic disease such as NCL, might displayed Rett features initially, and clinical follow‐up is essential for the diagnosis.
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- 2019
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21. 二甲双胍对精神分裂症模型小鼠行为和候选基因表达的影响.
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卢梦楠, 陈黄韬, 陶志炜, 魏欣怡, 赵董步甲, 武姗姗, and 马 捷
- Abstract
Objective To explore the effects of different doses of metformin hydrochloride on behavior and candidate gene expression in mouse model of schizophrenia so as to provide new ideas and clues for clinical treatment of schizophrenia. Methods First, 50 C57 BL/6 J mice of the same batch were randomly divided into five groups as blank control group, negative control group, and three metformin hydrochloride experimental groups(low dose 200 mg/kg, medium dose 400 mg/kg, and high dose 800 mg/kg), with 10 mice in each group. In addition, except the blank control group, all the other groups were injected intraperitoneally with dizocepin maleate(MK-801), N-methyl-D-aspartate glutamate(NMDA) receptor non-competitive antagonist. Meanwhile, metformin hydrochloride was given prophylactically at the same time in the three metformin hydrochloride experimental groups. Then, the five groups of mice were subjected to ethology experiments such as elevated plus maze, open field test, and Morris water maze. Finally, the mice’s brain tissues were extracted as soon as they were killed for detection of the expressions of AMPK,GRIN1,HDAC1 and DGCR8 at the mRNA level by RT-qPCR.Results In all the ethologic experiments,significant differences were found between the blank control group and the negative control group(P<0.05),which suggested that the experimental animal model had been successfully constructed.In the elevated plus maze test and open field test,there was a major disparity between the high-dose metformin hydrochloride experimental group and the negative control group(P <0.01),which indicated that high-dose metformin hydrochloride had a great alleviating effect on anxiety symptoms of schizophrenia induced by MK-801.At the same time,RT-qPCR results showed that high-dose metformin could proportionally increase the expression levels of AMPK and GRIN1(P<0.001),thus reversing the trend of decreased expressions of these genes in the negative control group.Conclusion High-dose metformin hydrochloride can alleviate abnormal behavior in schizophrenic model mice,and it may play an important role through AMPK and GRIN1 related signal pathways,thus providing new ideas and clues for the clinical treatment of schizophrenia. [ABSTRACT FROM AUTHOR]
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- 2020
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22. Memantine Prevents the WIN 55,212-2 Evoked Cross-Priming of Ethanol-Induced Conditioned Place Preference (CPP)
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Marta Marszalek-Grabska, Irena Smaga, Paulina Surowka, Pawel Grochecki, Tymoteusz Slowik, Malgorzata Filip, and Jolanta H. Kotlinska
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cannabinoid ,glutamate ,CNR1 ,GRIN1 ,GRIN2A ,ethanol relapse ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The activation of the endocannabinoid system controls the release of many neurotransmitters involved in the brain reward pathways, including glutamate. Both endocannabinoid and glutamate systems are crucial for alcohol relapse. In the present study, we hypothesize that N-methyl-D-aspartate (NMDA) glutamate receptors regulate the ability of a priming dose of WIN 55,212-2 to cross-reinstate ethanol-induced conditioned place preference (CPP). To test this hypothesis, ethanol-induced (1.0 g/kg, 10% w/v, i.p.) CPP (unbiased method) was established using male adult Wistar rats. After CPP extinction, one group of animals received WIN 55,212-2 (1.0 and 2.0 mg/kg, i.p.), the cannabinoid receptor 1 (CB1) agonist, or ethanol, and the other group received memantine (3.0 or 10 mg/kg, i.p.), the NMDA antagonist and WIN 55,212-2 on the reinstatement day. Our results showed that a priming injection of WIN 55,212-2 (2.0 mg/kg, i.p.) reinstated (cross-reinstated) ethanol-induced CPP with similar efficacy to ethanol. Memantine (3.0 or 10 mg/kg, i.p.) pretreatment blocked this WIN 55,212-2 effect. Furthermore, our experiments indicated that ethanol withdrawal (7 days withdrawal after 10 days ethanol administration) down-regulated the CNR1 (encoding CB1), GRIN1/2A (encoding GluN1 and GluN2A subunit of the NMDA receptor) genes expression in the prefrontal cortex and dorsal striatum, but up-regulated these in the hippocampus, confirming the involvement of these receptors in ethanol rewarding effects. Thus, our results show that the endocannabinoid system is involved in the motivational properties of ethanol, and glutamate may control cannabinoid induced relapse into ethanol seeking behavior.
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- 2021
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23. Quantitative proteomic and phosphoproteomic analyses of the hippocampus reveal the involvement of NMDAR1 signaling in repetitive mild traumatic brain injury.
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Tian Z, Cao Z, Yang E, Li J, Liao D, Wang F, Wang T, Zhang Z, Zhang H, Jiang X, Li X, and Luo P
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The cumulative damage caused by repetitive mild traumatic brain injury can cause long-term neurodegeneration leading to cognitive impairment. This cognitive impairment is thought to result specifically from damage to the hippocampus. In this study, we detected cognitive impairment in mice 6 weeks after repetitive mild traumatic brain injury using the novel object recognition test and the Morris water maze test. Immunofluorescence staining showed that p-tau expression was increased in the hippocampus after repetitive mild traumatic brain injury. Golgi staining showed a significant decrease in the total density of neuronal dendritic spines in the hippocampus, as well as in the density of mature dendritic spines. To investigate the specific molecular mechanisms underlying cognitive impairment due to hippocampal damage, we performed proteomic and phosphoproteomic analyses of the hippocampus with and without repetitive mild traumatic brain injury. The differentially expressed proteins were mainly enriched in inflammation, immunity, and coagulation, suggesting that non-neuronal cells are involved in the pathological changes that occur in the hippocampus in the chronic stage after repetitive mild traumatic brain injury. In contrast, differentially expressed phosphorylated proteins were mainly enriched in pathways related to neuronal function and structure, which is more consistent with neurodegeneration. We identified N-methyl-D-aspartate receptor 1 as a hub molecule involved in the response to repetitive mild traumatic brain injury , and western blotting showed that, while N-methyl-D-aspartate receptor 1 expression was not altered in the hippocampus after repetitive mild traumatic brain injury, its phosphorylation level was significantly increased, which is consistent with the omics results. Administration of GRP78608, an N-methyl-D-aspartate receptor 1 antagonist, to the hippocampus markedly improved repetitive mild traumatic brain injury-induced cognitive impairment. In conclusion, our findings suggest that N-methyl-D-aspartate receptor 1 signaling in the hippocampus is involved in cognitive impairment in the chronic stage after repetitive mild traumatic brain injury and may be a potential target for intervention and treatment., Competing Interests: None
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- 2023
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24. Chronic Alcohol Use Induces Molecular Genetic Changes in the Dorsomedial Thalamus of People with Alcohol-Related Disorders
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Andreas-Christian Hade, Mari-Anne Philips, Ene Reimann, Toomas Jagomäe, Kattri-Liis Eskla, Tanel Traks, Ele Prans, Sulev Kõks, Eero Vasar, and Marika Väli
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alcoholism ,alcohol use disorder ,autopsy ,mediodorsal thalamus ,GRIN1 ,FTO ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The Mediodorsal (MD) thalamus that represents a fundamental subcortical relay has been underrepresented in the studies focusing on the molecular changes in the brains of subjects with alcohol use disorder (AUD). In the current study, MD thalamic regions from AUD subjects and controls were analyzed with Affymetrix Clariom S human microarray. Long-term alcohol use induced a significant (FDR ≤ 0.05) upregulation of 2802 transcripts and downregulation of 1893 genes in the MD thalamus of AUD subjects. A significant upregulation of GRIN1 (glutamate receptor NMDA type 1) and FTO (alpha-ketoglutarate dependent dioxygenase) was confirmed in western blot analysis. Immunohistochemical staining revealed similar heterogenous distribution of GRIN1 in the thalamic nuclei of both AUD and control subjects. The most prevalent functional categories of upregulated genes were related to glutamatergic and GABAergic neurotransmission, cellular metabolism, and neurodevelopment. The prevalent gene cluster among down-regulated genes was immune system mediators. Forty-two differentially expressed genes, including FTO, ADH1B, DRD2, CADM2, TCF4, GCKR, DPP6, MAPT and CHRH1, have been shown to have strong associations (FDR p < 10−8) with AUD or/and alcohol use phenotypes in recent GWA studies. Despite a small number of subjects, we were able to detect robust molecular changes in the mediodorsal thalamus caused by alcohol emphasizing the importance of deeper brain structures such as diencephalon, in the development of AUD-related dysregulation of neurocircuitry.
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- 2021
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25. Acute D-Serine Co-Agonism of β-Cell NMDA Receptors Potentiates Glucose-Stimulated Insulin Secretion and Excitatory β-Cell Membrane Activity
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Amber Lockridge, Eric Gustafson, Alicia Wong, Robert F. Miller, and Emilyn U. Alejandro
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β-cell ,D-serine ,glucose homeostasis ,insulin secretion ,mice ,Grin1 ,Cytology ,QH573-671 - Abstract
Insulin-secreting pancreatic β-cells express proteins characteristic of D-serine regulated synapses, but the acute effect of D-serine co-agonism on its presumptive β-cell target, N-methyl D-aspartate receptors (NMDARs), is unclear. We used multiple models to evaluate glucose homeostasis and insulin secretion in mice with a systemic increase in D-serine (intraperitoneal injection or DAAO mutants without D-serine catabolism) or tissue-specific loss of Grin1-encoded GluN1, the D-serine binding NMDAR subunit. We also investigated the effects of D-serine ± NMDA on glucose-stimulated insulin secretion (GSIS) and β-cell depolarizing membrane oscillations, using perforated patch electrophysiology, in β-cell-containing primary isolated mouse islets. In vivo models of elevated D-serine correlated to improved blood glucose and insulin levels. In vitro, D-serine potentiated GSIS and β-cell membrane excitation, dependent on NMDAR activating conditions including GluN1 expression (co-agonist target), simultaneous NMDA (agonist), and elevated glucose (depolarization). Pancreatic GluN1-loss females were glucose intolerant and GSIS was depressed in islets from younger, but not older, βGrin1 KO mice. Thus, D-serine is capable of acute antidiabetic effects in mice and potentiates insulin secretion through excitatory β-cell NMDAR co-agonism but strain-dependent shifts in potency and age/sex-specific Grin1-loss phenotypes suggest that context is critical to the interpretation of data on the role of D-serine and NMDARs in β-cell function.
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- 2021
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26. Abnormal circadian rhythm in patients with GRIN1-related developmental epileptic encephalopathy.
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Scala, Marcello, Amadori, Elisabetta, Fusco, Lucia, Marchese, Francesca, Capra, Valeria, Minetti, Carlo, Vari, Maria Stella, and Striano, Pasquale
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CIRCADIAN rhythms ,GENETIC disorders ,ANTI-NMDA receptor encephalitis ,ADENOSYLMETHIONINE ,CHILDREN with epilepsy ,AMINO acid residues ,EYE movements - Abstract
GRIN1 encodes the obligate subunit (GluN1) of glutamate N-methyl- d -aspartate receptor (NMDAr). Pathogenic variants in GRIN1 are a well-known cause of infantile encephalopathy characterized by profound developmental delay (DD), variable epileptic phenotypes, and distinctive behavioral abnormalities. Recently, GRIN1 has also been implicated in the pathogenesis of polymicrogyria (PMG). We investigated two patients presenting with severe intellectual disability (ID), epilepsy, stereotyped movements, and abnormal ocular movements. They showed distinctive circadian rhythm alterations and sleep-wake patterns anomalies characterized by recurrent cyclic crying or laughing spells. Genetic analysis led to the identification of two distinct de novo variants in GRIN1 affecting the same amino acid residue of an important functional protein domain. Recent advances in circadian rhythm and sleep regulation suggest that abnormal GluN1 function might play a relevant pathogenetic role for the peculiar behavioral abnormalities observed in GRIN1 patients. Our cases highlight the relevance of circadian rhythm abnormalities in epileptic children as a clue toward GRIN1 encephalopathy and expand the complex phenotypic spectrum of this severe genetic disorder. • GRIN1 encodes the obligate subunit of glutamate N-methyl- d -aspartate receptor (NMDAr). • GRIN1 deficiency causes a severe early-onset epileptic encephalopathy. • This study describes distinctive circadian rhythm alterations in GRIN1 patients. • Sleep-wake anomalies and cyclic crying or laughing spells might foster early diagnosis. • Manipulating glutamate metabolism might be a therapeutic approach in GRIN1 patients. [ABSTRACT FROM AUTHOR]
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- 2019
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27. Comparative analyses of the neurobehavioral, molecular, and enzymatic effects of organophosphates on embryo-larval zebrafish (Danio rerio).
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Schmitt, Cassandra, McManus, Michelle, Kumar, Naveen, Awoyemi, Olushola, and Crago, Jordan
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ZEBRA danio , *ORGANOPHOSPHORUS pesticides , *BRACHYDANIO , *MALATHION , *DIAZINON , *FISH larvae - Abstract
Organophosphates insecticides (OPs) are common surface water contaminants in both urban and agricultural landscapes. Neurobehavioral effects on larval fish are known to occur at concentrations higher than those reported in the environment. The aim of this study was to perform a comparative analysis of neurobehavioral, molecular, and biochemical responses of four OPs (diazinon, dichlorvos, malathion, methyl-parathion) via the following endpoint measurements: distance traveled, velocity, gene expression (AChE, c-Fos, LINGO-1B, GRIN-1B), enzymatic acetylcholinesterase (AChE) activity, and carboxylesterase (CES) activity. OP exposures (5 hpf - 120 dpf) on embryo-larval zebrafish (Danio rerio) were assessed using a larval zebrafish behavior assay at concentrations: 0.01, 0.1, 10, and 100 μg/L. Individual OPs had varying degrees of neurotoxicity. Significant hypoactivity was observed in the 100 μg/L treatments for diazinon and malathion (p < 0.05) as compared to the controls. Diazinon-exposed larvae exhibited a 26% locomotor decrease, and hypoactivity was observed in malathion-exposed larvae at a reduction of 22% and 29% for distance traveled and velocity, respectively. Gene regulation and enzymatic activity changes were measured for both 0.1 and 100 μg/L exposures across OP treatments. Increased CES activity was observed for the 0.1 μg/L treatments of diazinon and methyl-parathion as well as the 100 μg/L treatment of dichlorvos; meanwhile, decreased CES activity was observed for 100 μg/L treatments of diazinon and malathion. Relative enzymatic activity of AChE was inhibited as compared to the control for the 0.1 μg/L diazinon. No other treatment group exhibited a significant effect on biochemical AChE activity; however, AChE upregulation was observed in the 0.1 μg/L exposure for diazinon, dichlorvos, and malathion. Methyl-parathion was observed to downregulate c-Fos at 0.1 μg/L exposure. Malathion upregulated LINGO-1B at 100 μg/L, a gene associated with neuronal regeneration; meanwhile, downregulation of LINGO-1B was observed for 0.1 μg/L exposure of methyl-parathion. Additional downregulation was observed for GRIN-1B in the 100 μg/L diazinon, 100 μg/L dichlorvos, and 0.1 μg/L methyl-parathion treatments. Exposure of ZF embryos to independent concentrations of 100 μg/L concentrations of diazinon and malathion resulted in hypoactivity and decreased CES activity at 5 dfp. No changes in swimming behavior were observed for either the 0.1 μg/L or 100 μg/L dichlorvos or methyl-parathion treatments. Observations from this study indicate that AChE inhibition may not be the most sensitive biomarker of OP pesticide exposure in zebrafish. Rather, the enzyme CES demonstrated higher sensitivity as a biomarker of OP toxicity. • Carboxylesterase is an efficient biomarker of organophosphate exposure • Diazinon and malathion induce hypoactivity of zebrafish at 100 μg/L exposure • Neurodegenerative gene changes observed at 0.1 and 100 μg/L concentrations • No behavioral, biochemical, or molecular changes of methyl-parathion at 100 μg/L [ABSTRACT FROM AUTHOR]
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- 2019
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28. In-silico investigation of coding variants potentially affecting the functioning of the glutamatergic N-methyl-d-aspartate receptor in schizophrenia.
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Tsavou, Antonia and Curtis, David
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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]
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- 2019
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29. Identification of Hub Gene GRIN1 Correlated with Histological Grade and Prognosis of Glioma by Weighted Gene Coexpression Network Analysis
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Yang Hong, Xinhuan Wang, Chao Shang, Yaofeng Hu, and Aoran Yang
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Article Subject ,Human Protein Atlas ,Nerve Tissue Proteins ,Kaplan-Meier Estimate ,Computational biology ,Receptors, N-Methyl-D-Aspartate ,General Biochemistry, Genetics and Molecular Biology ,Transcriptome ,Glioma ,Databases, Genetic ,Protein Interaction Mapping ,Biomarkers, Tumor ,medicine ,Humans ,Gene Regulatory Networks ,Protein Interaction Maps ,KEGG ,Gene ,Survival analysis ,General Immunology and Microbiology ,biology ,Brain Neoplasms ,Gene Expression Profiling ,Brain ,Computational Biology ,GRIN1 ,General Medicine ,Prognosis ,medicine.disease ,Immunohistochemistry ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,biology.protein ,Medicine ,Research Article - Abstract
The function of glutamate ionotropic receptor NMDA type subunit 1 (GRIN1) in neurodegenerative diseases has been widely reported; however, its role in the occurrence of glioma remains less explored. We obtained clinical data and transcriptome data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Hub gene’s expression differential analysis and survival analysis were conducted by browsing the Gene Expression Profiling Interactive Analysis (GEPIA) database, Human Protein Atlas database, and LOGpc database. We conducted a variation analysis of datasets obtained from GEO and TCGA and performed a weighted gene coexpression network analysis (WGCNA) using the R programming language (3.6.3). Kaplan-Meier (KM) analysis was used to calculate the prognostic value of GRIN1. Finally, we conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Using STRING, we constructed a protein–protein interaction (PPI) network. Cytoscape software, a prerequisite of visualizing core genes, was installed, and CytoHubba detected the 10 most tumor-related core genes. We identified 185 differentially expressed genes (DEGs). GO and KEGG enrichment analyses illustrated that the identified DEGs are imperative in different biological functions and ascertained the potential pathways in which the DEGs may be enriched. The overall survival calculated by KM analysis showed that patients with lower expression of GRIN1 had worse prognoses than patients with higher expression of GRIN1 ( p = 0.004 ). The GEPIA and LOGpc databases were used to verify the expression difference of GRIN1 among GBM, LGG, and normal brain tissues. Ultimately, immunohistochemical assay results showed that GRIN1 was detected in normal tissue and not in the tumor specimens. Our results highlight a potential target for glioma treatment and will further our understanding of the molecular mechanisms underlying the treatment of glioma.
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- 2021
30. A homozygous <scp> GRIN1 </scp> null variant causes a more severe phenotype of early infantile epileptic encephalopathy
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Joel English, Alexander J M Blakes, Siddharth Banka, and Helen Basu
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N-Methylaspartate ,GRIN1 ,media_common.quotation_subject ,Nonsense ,Nerve Tissue Proteins ,Receptors, N-Methyl-D-Aspartate ,splicing ,Epilepsy ,Neurodevelopmental disorder ,Genetics ,Humans ,Medicine ,Missense mutation ,Global developmental delay ,developmental disorder ,Genetics (clinical) ,media_common ,biology ,business.industry ,Infant ,medicine.disease ,Phenotype ,Developmental disorder ,biology.protein ,epilepsy ,business ,Spasms, Infantile ,null variant - Abstract
Pathogenic variants in glutamate receptor, ionotropic, NMDA-1 (GRIN1) cause an autosomal dominant or recessive neurodevelopmental disorder with global developmental delay, with or without seizures (AD or AR GRIN1-NDD). Here, we describe a novel homozygous canonical splice site variant in GRIN1 in a 12-month-old boy with early infantile epileptic encephalopathy and severe global developmental delay. This represents only the second family with a homozygous predicted-null variant in GRIN1 reported to date. We review the published literature on AR GRIN1-NDD and find that the phenotype in our patient is much more severe than those seen with homozygous missense variants. A similarly severe phenotype of intractable epilepsy and infantile death has only been reported in one other family with a homozygous nonsense variant in GRIN1. We, therefore, propose that biallelic predicted-null variants in GRIN1 can cause a markedly more severe clinical phenotype than AR GRIN1-NDD caused by missense variants.
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- 2021
31. Recurrent seizure‐related GRIN1 variant: Molecular mechanism and targeted therapy
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Hongjie Yuan, Stephen F. Traynelis, Guojun Zhang, Daniel W. Shrey, Wenjuan Chen, Satyanarayana Gedela, Katie L. Strong, Yuchen Xu, and Rui Song
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Male ,Agonist ,Adolescent ,medicine.drug_class ,Mutation, Missense ,Nerve Tissue Proteins ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Pharmacology ,Receptors, N-Methyl-D-Aspartate ,Protein Structure, Secondary ,Xenopus laevis ,Epilepsy ,Recurrence ,Seizures ,Exome Sequencing ,Animals ,Humans ,Medicine ,Missense mutation ,Amino Acid Sequence ,Excitatory Amino Acid Agents ,RC346-429 ,Research Articles ,Exome sequencing ,Dose-Response Relationship, Drug ,biology ,business.industry ,General Neuroscience ,HEK 293 cells ,Memantine ,Genetic Variation ,GRIN1 ,medicine.disease ,Pedigree ,HEK293 Cells ,Child, Preschool ,biology.protein ,NMDA receptor ,Anticonvulsants ,Female ,Neurology. Diseases of the nervous system ,Neurology (clinical) ,business ,Research Article ,RC321-571 ,medicine.drug - Abstract
Objective Genetic variants in the GRIN genes that encode N‐methyl‐D‐aspartate receptor (NMDAR) subunits have been identified in various neurodevelopmental disorders, including epilepsy. We identified a GRIN1 variant from an individual with early‐onset epileptic encephalopathy, evaluated functional changes to NMDAR properties caused by the variant, and screened FDA‐approved therapeutic compounds as potential treatments for the patient. Methods Whole exome sequencing identified a missense variant in GRIN1. Electrophysiological recordings were made from Xenopus oocytes and transfected HEK cells to determine the NMDAR biophysical properties as well as the sensitivity to agonists and FDA‐approved drugs that inhibit NMDARs. A beta‐lactamase reporter assay in transfected HEK cells evaluated the effects of the variant on the NMDAR surface expression. Results A recurrent de novo missense variant in GRIN1 (c.1923G>A, p.Met641Ile), which encodes the GluN1 subunit, was identified in a pediatric patient with drug‐resistant seizures and early‐onset epileptic encephalopathy. In vitro analysis indicates that GluN1‐M641I containing NMDARs showed enhanced agonist potency and reduced Mg2+ block, which may be associated with the patient’s phenotype. Results from screening FDA‐approved drugs suggested that GluN1‐M641I containing NMDARs are more sensitive to the NMDAR channel blockers memantine, ketamine, and dextromethorphan compared to the wild‐type receptors. The addition of memantine to the seizure treatment regimen significantly reduced the patient’s seizure burden. Interpretation Our finding contributes to the understanding of the phenotype–genotype correlations of patients with GRIN1 gene variants, provides a molecular mechanism underlying the actions of this variant, and explores therapeutic strategies for treating GRIN1‐related neurological conditions.
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- 2021
32. Under the mask of Kabuki syndrome: Elucidation of genetic-and phenotypic heterogeneity in patients with Kabuki-like phenotype.
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Paderova, Jana, Drabova, Jana, Holubova, Andrea, Vlckova, Marketa, Havlovicova, Marketa, Gregorova, Andrea, Pourova, Radka, Romankova, Vera, Moslerova, Veronika, Geryk, Jan, Norambuena, Patricia, Krulisova, Veronika, Krepelova, Anna, Sr.Macek, Milan, and Jr.Macek, Milan
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KABUKI syndrome , *GENETICISTS , *MOLECULAR genetics , *EXOMES , *GENETIC code - Abstract
Kabuki syndrome is mainly caused by dominant de-novo pathogenic variants in the KMT2D and KDM6A genes. The clinical features of this syndrome are highly variable, making the diagnosis of Kabuki-like phenotypes difficult, even for experienced clinical geneticists. Herein we present molecular genetic findings of causal genetic variation using array comparative genome hybridization and a Mendeliome analysis, utilizing targeted exome analysis focusing on regions harboring rare disease-causing variants in Kabuki-like patients which remained KMT2D/KDM6A -negative. The aCGH analysis revealed a pathogenic CNV in the 14q11.2 region, while targeted exome sequencing revealed pathogenic variants in genes associated with intellectual disability ( HUWE1, GRIN1 ), including a gene coding for mandibulofacial dysostosis with microcephaly ( EFTUD2 ). Lower values of the MLL2-Kabuki phenotypic score are indicative of Kabuki-like phenotype (rather than true Kabuki syndrome), where aCGH and Mendeliome analyses have high diagnostic yield. Based on our findings we conclude that for new patients with Kabuki-like phenotypes it is possible to choose a specific molecular testing approach that has the highest detection rate for a given MLL2-Kabuki score, thus fostering more precise patient diagnosis and improved management in these genetically- and phenotypically heterogeneous clinical entities. [ABSTRACT FROM AUTHOR]
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- 2018
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33. De novo mutations in GRIN1 cause extensive bilateral polymicrogyria.
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Fry, Andrew E., Fawcett, Katherine A., Zelnik, Nathanel, Hongjie Yuan, Thompson, Belinda A. N., Shemer-Meiri, Lilach, Cushion, Thomas D., Mugalaasi, Hood, Sims, David, Stoodley, Neil, Seo-Kyung Chung, Rees, Mark I., Patel, Chirag V., Brueton, Louise A., Layet, Valérie, Giuliano, Fabienne, Kerr, Michael P., Banne, Ehud, Meiner, Vardiella, and Lerman-Sagie, Tally
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MISSENSE mutation , *METHYL aspartate receptors , *GENE expression , *BRAIN diseases , *CELL lines , *PATIENTS , *NEURAL development , *CELL receptors , *DEVELOPMENTAL disabilities , *EPILEPSY , *GENETIC mutation , *NERVE tissue proteins , *VISION disorders , *CEREBRAL cortex abnormalities , *DISEASE risk factors - Abstract
Polymicrogyria is a malformation of cortical development. The aetiology of polymicrogyria remains poorly understood. Using whole-exome sequencing we found de novo heterozygous missense GRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine further de novo missense GRIN1 mutations in additional cortical malformation patients. Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy. GRIN1 encodes GluN1, the essential subunit of the N-methyl-d-aspartate receptor. The polymicrogyria-associated GRIN1 mutations tended to cluster in the S2 region (part of the ligand-binding domain of GluN1) or the adjacent M3 helix. These regions are rarely mutated in the normal population or in GRIN1 patients without polymicrogyria. Using two-electrode and whole-cell voltage-clamp analysis, we showed that the polymicrogyria-associated GRIN1 mutations significantly alter the in vitro activity of the receptor. Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor. These results are striking because previous GRIN1 mutations have generally caused loss of function, and because N-methyl-d-aspartate receptor agonists have been used for many years to generate animal models of polymicrogyria. Overall, our results expand the phenotypic spectrum associated with GRIN1 mutations and highlight the important role of N-methyl-d-aspartate receptor signalling in the pathogenesis of polymicrogyria. [ABSTRACT FROM AUTHOR]
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- 2018
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34. West syndrome with hyperkinesia and cortical visual impairment: A case report of GRIN1 encephalopathy
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Seul A Choi and Young Ok Kim
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medicine.medical_specialty ,biology ,Blindness ,business.industry ,Encephalopathy ,Glutamate receptor ,GRIN1 ,West Syndrome ,Cortical visual impairment ,medicine.disease ,Hyperkinesis ,Internal medicine ,medicine ,biology.protein ,Cardiology ,medicine.symptom ,business ,Hyperkinesia - Published
- 2021
35. Association of Polymorphisms in Neurotransmitter Genes and the TMEM18 Gene with Eating Behavior in Obese Patients
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Gulnaz F. Korytina, V. V. Victorov, D. S. Avzaletdinova, L. Z. Akhmadishina, T. V. Victorova, Z. A. Shangareeva, and O. V. Kochetova
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Genetics ,biology ,GRIK5 ,biology.protein ,GRIN1 ,GRIN2B ,Locus (genetics) ,GABBR2 ,Emotional eating ,Allele ,GRIA1 - Abstract
Obesity and related complications are caused by eating disorders. The complex pathogenesis of the formation of food dependence has a genetic basis. This paper investigates the relationship between polymorphic variants of genes coding for glutamate receptors (GRIK5 rs8099939, GRIK3 rs534131, GRIA1 rs2195450, GRIN2B rs7301328, rs2268132, rs1805476, GRIN1 rs6293), (GABA) B receptor (GABBR2 rs3750344), serotonin receptor (HTR2A rs6313, rs6311), brain-derived neurotrophic factor (BDNF rs925946, rs11030107), and transmembrane protein 18 (TMEM18 rs2860323, rs6548238) with eating disorders in overweight and obese patients. BMI is shown to be associated with genotype GG of locus rs6293 of gene GRIN1, CC-AC of GRIK5 rs8099939, CC-CT of TMEM18 rs6548238, and CT-TT of GRIA1 rs2195450. Disorder of restrained eating behavior was identified in AC-AA genotype carriers at locus rs1805476 of gene GRIN2B (P = 0.04) and GG genotype carriers at locus rs6293 of gene GRIN1 (P = 0.028). Upset of emotional eating was characteristic of A allele carriers at locus rs1805476 of gene GRIN2B (P = 0.005) and AC-CC genotype carriers. Extern eating disorder was observed for carriers of genotypes AA and AC at the polymorphic locus rs1805476 of gene GRIN2B (P = 0.0003). Thus, polymorphisms of the glutamate and serotonin receptor genes, as well as the transmembrane protein 18 gene, are important factors in the development of eating disorders and obesity.
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- 2021
36. Decreased DNA methylation at promoters and gene-specific neuronal hypermethylation in the prefrontal cortex of patients with bipolar disorder
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Kazuya Iwamoto, Junko Ueda, Yutaka Nakachi, Tadafumi Kato, Kiyoto Kasai, and Miki Bundo
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Cell type ,Bipolar Disorder ,DNMT3B ,Prefrontal Cortex ,Genome-wide association study ,Article ,Epigenesis, Genetic ,Cellular and Molecular Neuroscience ,Genetics ,medicine ,Humans ,Bipolar disorder ,Prefrontal cortex ,Molecular Biology ,Gene ,Neurons ,biology ,GRIN1 ,Promoter ,DNA Methylation ,medicine.disease ,Molecular biology ,Psychiatry and Mental health ,DNA methylation ,biology.protein ,Genome-Wide Association Study - Abstract
Bipolar disorder (BD) is a severe mental disorder characterized by repeated mood swings. Although genetic factors are collectively associated with the etiology of BD, the underlying molecular mechanisms, particularly how environmental factors affect the brain, remain largely unknown. We performed promoter-wide DNA methylation analysis of neuronal and nonneuronal nuclei in the prefrontal cortex of patients with BD (N = 34) and controls (N = 35). We found decreased DNA methylation at promoters in both cell types in the BD patients. Gene Ontology (GO) analysis of differentially methylated region (DMR)-associated genes revealed enrichment of molecular motor-related genes in neurons, chemokines in both cell types, and ion channel- and transporter-related genes in nonneurons. Detailed GO analysis further revealed that growth cone- and dendrite-related genes, including NTRK2 and GRIN1, were hypermethylated in neurons of BD patients. To assess the effect of medication, neuroblastoma cells were cultured under therapeutic concentrations of three mood stabilizers. We observed that up to 37.9% of DMRs detected in BD overlapped with mood stabilizer-induced DMRs. Interestingly, mood stabilizer-induced DMRs showed the opposite direction of changes in DMRs, suggesting the therapeutic effects of mood stabilizers. Among the DMRs, 12 overlapped with loci identified in a genome-wide association study (GWAS) of BD. We also found significant enrichment of neuronal DMRs in the loci reported in another GWAS of BD. Finally, we performed qPCR of DNA methylation-related genes and found that DNMT3B was overexpressed in BD. The cell-type-specific DMRs identified in this study will be useful for understanding the pathophysiology of BD.
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- 2021
37. Exposure to anandamide on young rats causes deficits in learning, temporal perception and induces changes in NMDA receptor expression.
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Hernández-Guerrero, César, García-Salcedo, Verónica, Buenrostro-Jauregui, Mario, Sanchez-Castillo, Hugo, Aguilera-Reyes, Ulises, Martínez-Castro, Noemi, and Galicia-Castillo, Oscar
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METHYL aspartate receptors , *ANANDAMIDE , *GENE expression , *NEURAL development , *STIMULUS & response (Psychology) , *CONTEXTUAL learning - Abstract
Human use of marijuana at an early age has been reported to lead to cognitive impairment. However, researchers have not yet clearly determined whether this impairment is due to marijuana-induced alterations in the developing nervous system and whether this deficit persists into adulthood after marijuana use has ceased. We administered anandamide to developing rats to assess the effect of cannabinoids on development. We subsequently evaluated learning and performance on a temporal bisection task in adulthood and assessed the expression of genes encoding principal subunits of NMDA receptors (Grin1, Grin2A, and Grin2B) in the hippocampus and prefrontal cortex. Rats in two age groups, namely, 21-day-old and 150-day-old rats, received intraperitoneal injections of anandamide or the vehicle for 14 days. Both groups performed a temporal bisection test, which included listening to tones of different durations and classifying them as short or long. The expression of the Grin1, Grin2A and Grin2B mRNAs was evaluated using quantitative PCR in both age groups after extracting mRNA from the hippocampus and prefrontal cortex. We observed a learning impairment in the temporal bisection task (p < 0.05) and changes in the response latency (p < 0.05) in rats that received anandamide. Furthermore, these rats exhibited decreased expression of Grin2b (p = 0.001) compared to those that received the vehicle. In human subjects, the use of cannabinoids during development induces a long-term deficit, but this deficit is not observed in subjects who use cannabinoids in adulthood. Rats treated with anandamide earlier in development took longer to learn the task, suggesting that anandamide exerts a harmful effect on cognition in developing rats. Administration of anandamide during early stages of development induced deficits in learning and other cognitive processes that depend on an adequate estimation of time. The cognitive demands of the environment must be considered when evaluating the cognitive effects of cannabinoids on developing or mature brains. High cognitive demands might induce differential expression of NMDA receptors that improves cognitive capacity, overcoming altered glutamatergic function • Administration of cannabinoids during early stages of development induced permanent deficits in learning and other cognitive processes. • Cannabinoids induce a different expression of NMDA subunits in Young subjects in comparation to the adults rats. • Cognitive processes depend on an adequate estimation of time, the observed deficit could be related to increase in temporal perception by cannabinoids. [ABSTRACT FROM AUTHOR]
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- 2023
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38. Aconiti lateralis Radix Praeparata inhibits Alzheimer’s disease by regulating the complex regulation network with the core of GRIN1 and MAPK1
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Wang Yutao, Zhang Huixiang, Yan Shan, You Dingyun, Ming Yu, Cao Xue, Wu Hongxiang, Jing Wang, Lihuan Zhang, Zhang Qianqian, Wang Limei, and Shi Lanlan
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aminophenol ,Cell ,Pharmaceutical Science ,Context (language use) ,Traditional Chinese medicine ,Pharmacology ,030226 pharmacology & pharmacy ,01 natural sciences ,03 medical and health sciences ,0302 clinical medicine ,Fuzi ,Drug Discovery ,Medicine ,Radix ,Viability assay ,MAPK1 ,therapy ,biology ,business.industry ,GRIN1 ,APP cells ,General Medicine ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,medicine.anatomical_structure ,Complementary and alternative medicine ,Apoptosis ,biology.protein ,Molecular Medicine ,business ,Research Article - Abstract
Context Current medicine for Alzheimer's disease (AD) cannot effectively reverse or block nerve injury. Traditional Chinese Medicine practice and research imply Aconiti lateralis Radix Praeparata (Fuzi) may meet this goal. Objective Analysing the anti-AD effect of Fuzi and its potential molecular mechanism. Materials and methods AD model cells were treated with Fuzi in 0-300 mg/mL for 24 h in 37 °C. The cell viability (CV) and length of cell projections (LCP) for each group were observed, analysed, and standardised using control as a baseline (CVs and LCPs). The Fuzi and AD relevant genes were identified basing on databases, and the molecular mechanism of Fuzi anti-AD was predicted by network analysis. Results Experiment results showed that Fuzi in 0.4 mg/mL boosted LCP (LCPs = 1.2533, p ≤ 0.05), and in 1.6-100 mg/mL increased CV (CVs from 1.1673 to 1.3321, p ≤ 0.05). Bioinformatics analysis found 17 Fuzi target genes (relevant scores ≥ 20), showing strong AD relevant signals (RMS_p ≤ 0.05, related scores ≥ 5), enriched in the pathways regulating axon growth, synaptic plasticity, cell survival, proliferation, apoptosis, and death (p ≤ 0.05). Especially, GRIN1 and MAPK1 interacted with APP protein and located in the key point of the "Alzheimer's disease" pathway. Discussion and conclusions These results suggest that Fuzi may have therapeutic and prevention potential in AD, and GRIN1 and MAPK1 may be the core of the pathways of the Fuzi anti-AD process. Fuzi should be studied more extensively, especially for the prevention of AD.
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- 2021
39. The NMDA Receptor Subunit (GluN1 and GluN2A) Modulation Following Different Conditions of Cocaine Abstinence in Rat Brain Structures
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Lucia Caffino, Marek Sanak, Fabio Fumagalli, Małgorzata Filip, Małgorzata Frankowska, Karolina Wydra, Irena Smaga, and Agata Suder
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Male ,medicine.medical_specialty ,Infralimbic cortex ,Drug-Seeking Behavior ,Self Administration ,Biology ,Environment ,Toxicology ,Receptors, N-Methyl-D-Aspartate ,Extinction, Psychological ,03 medical and health sciences ,Glutamatergic ,Cocaine-Related Disorders ,0302 clinical medicine ,Cocaine ,Dopamine Uptake Inhibitors ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Cocaine abstinence ,Environmental enrichment ,General Neuroscience ,GRIN1 ,Brain ,NMDA receptor subunit ,Extinction (psychology) ,030227 psychiatry ,Cocaine self-administration ,Rats ,Endocrinology ,medicine.anatomical_structure ,Social Isolation ,biology.protein ,NMDA receptor ,GRIN2A ,Original Article ,Postsynaptic density ,030217 neurology & neurosurgery - Abstract
Different neuronal alterations within glutamatergic system seem to be crucial for developing of cocaine-seeking behavior. Cocaine exposure provokes a modulation of the NMDA receptor subunit expression in rodents, which probably contributes to cocaine-induced behavioral alterations. The aim of this study was to examine the composition of the NMDA receptor subunits in the brain structures in rats with the history of cocaine self-administration after cocaine abstinence (i) in an enriched environment, (ii) in an isolated condition, (iii) with extinction training, or (iv) without instrumental task, as well as the Grin1 (encoding GluN1) and Grin2A (encoding GluN2A) gene expression were evaluated after 10-day extinction training in rat brain structures. In the present study, we observed changes only following cocaine abstinence with extinction training, when the increased GluN2A subunit levels were seen in the postsynaptic density fraction but not in the whole homogenate of the prelimbic cortex (PLC) and dorsal hippocampus (dHIP) in rats previously self-administered cocaine. At the same time, extinction training did not change the Grin1 and Grin2A gene expression in these structures. In conclusion, NMDA receptor subunit modulation observed following cocaine abstinence with extinction training may represent a potential target in cocaine-seeking behavior.
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- 2021
40. Экспрессия генов глутаматных рецепторов в гиппокампе и лобной коре у крыс линии ГК с генетической кататонией
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medicine.medical_specialty ,biology ,Glutamate receptor ,GRIN1 ,Kainate receptor ,General Medicine ,AMPA receptor ,Endocrinology ,Internal medicine ,biology.protein ,medicine ,GRIN2A ,NMDA receptor ,GRIN2B ,GRIA1 - Abstract
The GC rat strain (the abbreviation of the words «genetic» and «catatonia») was obtained in the Institute of Cytology and Genetics of the SB RAS by breeding to enhance the passive-defensive freezing reaction in response to a weak stress stimulus. GC rats have a predisposition to catatonic reactions, as well as a number of behavioral and biochemical features corresponding to the homologous characteristics of patients with schizophrenia and depression. At the basis of the catatonic syndrome, as in schizophrenia, is believed to be the presence of a complex disturbance in functioning brain’s neurotransmitter systems, with special attention having been recently paid to glutamatergic system dysfunction, proposing the glutamate hypothesis of psychopathologies. Glutamate is the main excitatory mediator in the central nervous system and realize physiological effects through ionotropic (AMPA-, NMDA-, kainate) and metabotropic (mGlu) glutamate receptors. There are many studies indicating a change in the expression of glutamate receptor genes and the composition of their subunits in schizophrenia and bipolar disorders, as well as indicating the involvement of NMDA glutamate receptors in the manifestation of catatonic syndrome. In this regard, the aim of the work was to study the expression of the genes of glutamate system in the hippocampus and the frontal cortex of GC rats. Real-time PCR showed low expression of Grm3 gene encoding the metabotropic glutamate autoreceptor in the hippocampus of rats with genetic catatonia. The expression of Grin1, Grin2A, Grin2B, Gria1, Grm2, Slc17a6 in the frontal cortex and the hippocampus, as well as the Grm3 gene in the frontal cortex, did not differ from the control. Thus, the revealed low expression of mRNA of the Grm3 gene in the hippocampus can affect the neurotransmission of glutamate in this structure, and, among other things, contribute to an increase in nervous excitability in GC rats.
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- 2021
41. Expression of Glutamate Receptor Genes in the Hippocampus and Frontal Cortex in GC Rat Strain with Genetic Catatonia
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M. A. Ryazanova and V. S. Plekanchuk
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0301 basic medicine ,biology ,Physiology ,Glutamate receptor ,GRIN1 ,Kainate receptor ,AMPA receptor ,Biochemistry ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,biology.protein ,GRIN2A ,NMDA receptor ,GRIN2B ,Neuroscience ,GRIA1 ,030217 neurology & neurosurgery ,Ecology, Evolution, Behavior and Systematics - Abstract
The GC (genetic catatonia) rat strain was bred by selection aimed at enhancing the passive-defensive freezing response to a weak stressful stimulus. GC rats have a genetic predisposition to develop catatonic responses, as well as a number of behavioral and biochemical features corresponding to the homologous characteristics of patients with schizophrenia and depression. The catatonic syndrome, like schizophrenia, is believed to be based on a complex disturbance of the brain neurotransmitter systems. Since recently, special attention is being paid to the dysfunction of the glutamatergic system within the glutamate hypothesis of psychopathologies. Glutamate is the major excitatory neurotransmitter in the central nervous system; it mediates its physiological effects through ionotropic (AMPA-, NMDA-, kainate) and metabotropic (mGlu) glutamate receptors. Numerous studies indicate a change in the expression of glutamate receptor genes and the composition of receptor subunits in schizophrenia and bipolar disorders, as well as the involvement of NMDA glutamate receptors in the manifestation of the catatonic syndrome. In this regard, the aim of the work was to study the expression of glutamate system genes in the hippocampus and frontal cortex of GC rats. Real-time PCR showed low expression of the Grm3 gene (encoding a metabotropic glutamate autoreceptor) in the hippocampus of rats with genetic catatonia. The expression of Grin1, Grin2A, Grin2B, Gria1, Grm2 and Slc17a6 genes in the frontal cortex and hippocampus, as well as of the Grm3 gene in the frontal cortex, was indistinguishable from the control. Thus, the revealed low expression of Grm3 mRNA in the hippocampus may affect glutamate neurotransmission in this brain structure and, specifically, contribute to increased nervous excitability in GC rats.
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- 2021
42. Exploratory study of selected nucleotide variants in GRIN1, GRIN2A and GRIN2B encoding subunits of the NMDA receptor in a targeted group of schizophrenia patients with chronic cognitive impairment
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Krzystanek, Marek, Asman, Marek, Witecka, Joanna, Pałasz, Artur, and Wiaderkiewicz, Ryszard
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Adult ,Male ,Genotype ,Population ,Nerve Tissue Proteins ,Bioinformatics ,Polymorphism, Single Nucleotide ,Receptors, N-Methyl-D-Aspartate ,Article ,Humans ,Medicine ,Prefrontal cortex ,education ,Aged ,Pharmacology ,education.field_of_study ,biology ,business.industry ,Cognitive deficits ,Genetic Variation ,GRIN1 ,Cognition ,DNA ,General Medicine ,Middle Aged ,NMDA receptor ,medicine.disease ,Single nucleotide variants ,Schizophrenia ,Case-Control Studies ,biology.protein ,GRIN2A ,Female ,Schizophrenic Psychology ,GRIN2B ,Cognition Disorders ,business ,Negative Results - Abstract
Background Schizophrenia is a mental disease that affects approximately 1% of the population. Despite over 100 years of research, its pathomechanism has still not been clarified. Cognitive deficits, which are one of the symptomatic dimensions of schizophrenia, usually appear a few years before the first psychotic episode. Therefore, this is why they are probably the clinical manifestation of the primary pathomechanism of schizophrenia. It is also supposed that N-methyl-d-aspartate receptor (NMDA-R) insufficiency in the prefrontal cortex is responsible for cognitive deficits in schizophrenia. The study aimed to examine whether four selected single nucleotide variants in GRIN1, GRIN2A and GRIN2B encoding NMDA-R subunits, of which two have not been tested before, are linked with the selected clinical phenotype of cognitive dysfunction in schizophrenia. Methods The study included the targeted group of 117 patients diagnosed with schizophrenia, all with cognitive deficits and in symptomatic remission. DNA fragments including the studied polymorphisms of the NMDA receptors subunit genes were amplified by polymerase chain reaction and subjected to sequencing. Results The study did not confirm the presence of any of the four selected single nucleotide variants in GRIN1, GRIN2A and GRIN2B subunits of NMDA-R. Conclusions The finding indicates that selected single nucleotide variants in GRIN2A and GRIN2B encoding subunits of the NMDA receptor are not associated with the presence of cognitive deficits in schizophrenia.
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- 2020
43. Epigenetic-mediated N-methyl-D-aspartate receptor changes in the brain of isolated reared rats
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Paulo Louzada-Junior, Camila Marcelino Loureiro, Rosana Shuhama, Cristina Marta Del-Ben, Gavin P. Reynolds, Helene A Fachim, Sâmia R.L. Joca, Paulo Rossi Menezes, Caroline F. Dalton, and Fabiana Corsi-Zuelli
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0301 basic medicine ,Cancer Research ,glutamate receptor ,hippocampus ,03 medical and health sciences ,0302 clinical medicine ,Gene expression ,Genetics ,Epigenetics ,protein expression ,prefrontal cortex ,Messenger RNA ,DNA methylation ,biology ,GRIN1 ,Molecular biology ,Reverse transcriptase ,NMDAR ,schizophrenia ,030104 developmental biology ,nervous system ,early stress ,isolation rearing from weaning ,gene expression ,biology.protein ,GRIN2A ,GRIN2B ,030217 neurology & neurosurgery - Abstract
Aim: We investigated: Grin1, Grin2a, Grin2b DNA methylation; NR1 and NR2 mRNA/protein in the prefrontal cortex (PFC); and hippocampus of male Wistar rats exposed to isolation rearing. Materials & methods: Animals were kept isolated or grouped (n = 10/group) from weaning for 10 weeks. Tissues were dissected for RNA/DNA extraction and N-methyl-D-aspartate receptor subunits were analyzed using quantitative reverse transcription (RT)-PCR, ELISA and pyrosequencing. Results: Isolated-reared animals had: decreased mRNA in PFC for all markers, increased NR1 protein in hippocampus and hypermethylation of Grin1 in PFC and Grin2b in hippocampus, compared with grouped rats. Associations between mRNA/protein and DNA methylation were found for both brain areas. Conclusion: This study indicates that epigenetic DNA methylation may underlie N-methyl-D-aspartate receptor mRNA/protein expression alterations caused by isolation rearing.
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- 2020
44. Changes in Behavior and the Expression of Ionotropic Glutamate Receptor Genes in the Brains of Adult Rats after Neonatal Administration of Bacterial Lipopolysaccharide
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O. E. Zubareva, A. Yu. Rotov, Alexander P. Schwarz, Ekaterina Veniaminova, K. Fomalont, and Alexander N. Trofimov
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0301 basic medicine ,medicine.medical_specialty ,biology ,General Neuroscience ,GRIN1 ,Hippocampus ,AMPA receptor ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,Internal medicine ,biology.protein ,medicine ,GRIN2A ,Ionotropic glutamate receptor ,NMDA receptor ,GRIN2B ,030217 neurology & neurosurgery ,Ionotropic effect - Abstract
Many studies have shown that early experience, particularly of neonatal infections, has a role in forming high anxiety levels in later life. One of the mechanisms of these changes may consist of impairments to the functional activity of ionotropic glutamate receptors associated with rearrangements in their subunit composition. The aim of the present work was to study measures of anxiety and levels of expression of genes for NMDA receptor (Grin1, Grin2a, Grin2b) and AMPA receptor (Gria1, Gria2) subunits in the medial prefrontal cortex, ventral and dorsal parts of the hippocampus in adult rats which at an early age had received bacterial lipopolysaccharide (LPS) at doses inducing the development of neuroinflammatory processes. Gene expression was studied by real-time reverse transcription PCR (qRT-PCR). Administration of LPS at doses of 25 and 50 μg/kg to male Wistar rats on days 15, 18, and 21 of life induced increases in the expression of genes for proinflammatory cytokines IL-1β and tumor necrosis factor in parts of the hippocampus. Increases in the expression of the Grin2b, Gria1, and Gria2 genes in the ventral parts of the hippocampus were seen three months after LPS administration (after injection of 50 μg/kg LPS), as were increases in expression of the Gria2 gene in the dorsal part of the hippocampus (after injection of 25 μg/kg LPS). These changes were accompanied by impairment to exploratory behavior in the open field test and decreased anxiety levels in the elevated plus maze. These studies showed that administration of bacterial LPS in early postnatal ontogeny leads to time-delayed changes in the expression of genes for NMDA and AMPA receptor subunits in the hippocampus and the associated forms of behavior.
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- 2020
45. Selected single-nucleotide variants in GRIN1, GRIN2A, and GRIN2B encoding subunits of the NMDA receptor are not biomarkers of schizophrenia resistant to clozapine: exploratory study
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Krzystanek, Marek, Asman, Marek, Witecka, Joanna, Pałasz, Artur, and Wiaderkiewicz, Ryszard
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Adult ,Male ,0301 basic medicine ,Genotype ,Short Communication ,Drug Resistance ,Nerve Tissue Proteins ,Polymorphism, Single Nucleotide ,Receptors, N-Methyl-D-Aspartate ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Single-nucleotide variants ,medicine ,Humans ,Receptor ,Clozapine ,Gene ,Clozapine-resistant schizophrenia ,Aged ,Pharmacology ,Genetics ,biology ,Cognitive deficits ,GRIN1 ,DNA ,General Medicine ,Middle Aged ,NMDA receptor ,medicine.disease ,030104 developmental biology ,Schizophrenia ,Case-Control Studies ,biology.protein ,GRIN2A ,Female ,GRIN2B ,Biomarkers ,030217 neurology & neurosurgery ,Antipsychotic Agents ,medicine.drug - Abstract
Background Schizophrenia is a common mental illness whose pathogenesis is still unknown. The vulnerability and stress model in schizophrenia assume that susceptibility to the disease is mainly associated with genes. Of the five symptomatic dimensions of schizophrenia, cognitive impairment appears to be most associated with the pathogenesis of schizophrenia. The aim of the study was to explore whether selected nucleotide variants in GRIN1, GRIN2A, and GRIN2B encoding subunits of the N-methyl-d-aspartate receptor (NMDA-R) receptor occur in a selected group of patients with treatment resistant schizophrenia with cognitive impairment. Methods The study included 45 patients diagnosed with super refractory schizophrenia, all with cognitive deficits and chronically psychotic. DNA fragments including the studied polymorphisms of the NMDA receptors subunit genes were amplified by polymerase chain reaction and subjected to sequencing. Results The study did not confirm the presence of any of the four selected single-nucleotide variants in GRIN1, GRIN2A, and GRIN2B subunits of NMDA-R in the study group. Conclusion Results of the study indicated that the selected single-nucleotide variants are not associated both with resistance to clozapine and the presence of cognitive deficits in schizophrenia. It is possible, however, that a more extensive sequencing along with analyzing the expression of these genes may reveal different single-nucleotide variants than those assumed in the study.
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- 2020
46. Functional Analysis of the 3ʹ Untranslated Region of the Human GRIN1 Gene in Regulating Gene Expression in vitro
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Yong-ping Liu, Jing-hua Meng, Bao-jie Wang, Xue Wu, and Jun Yao
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biology ,Three prime untranslated region ,business.industry ,GRIN1 ,Molecular biology ,Stop codon ,030227 psychiatry ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Cell culture ,law ,Gene expression ,microRNA ,biology.protein ,Recombinant DNA ,Medicine ,Receptor ,business ,030217 neurology & neurosurgery - Abstract
Purpose Abnormal expression of the NR1 subunit of the N-methyl-d-aspartate (NMDA) receptor may potentially increase the susceptibility to neuropsychiatric diseases. The purpose of this study was to investigate the functional sequence of the 3'UTR of the human GRIN1 gene, which encodes the GluN1 receptor to determine the effect on the expression of GluN1 receptor. Methods We transferred seven recombinant pmirGLO recombinant vectors containing the 3'UTR truncated fragment of the GRIN1 gene into HEK-293, SK-N-SH, and U87 cell lines and compared the relative fluorescence intensity of adjacent length fragments. The TargetScan database was used to predict miRNAs. Then, miRNA mimics/inhibitors were co-transfected into the three cell lines with the 3'UTR of GRIN1 (pmirGLO - GRIN1), to investigate their influence on GRIN1 gene expression. Results Compared with the pmirGLo-Basic vector, the relative fluorescence intensity of the complete GRIN1 gene 3'UTR recombinant sequence -27 bp - +1284 bp (the next base of the stop codon is +1) was significantly decreased in all three cell lines. The relative fluorescence intensities were significantly different between -27 bp - +294 bp and -27 bp - +497 bp regions, and between -27 bp - +708 bp and -27 bp - +907 bp regions. According to the prediction of the TargetScan database and analysis, miR-212-5p, miR-324-3p and miR-326 may bind to +295 bp - +497 bp, while miR-491-5p may bind to +798 bp - +907 bp. After co-transfection of miRNA mimic/inhibitor or mimic/inhibitor NC with a recombinant vector in the 3'UTR region of GRIN1 gene, we found that has-miR-491-5p inhibited GRIN1 expression significantly in all three cell lines, while has-miR-326 inhibitor upregulated GRIN1 expression in HEK-293 and U87 cells. Conclusion miR-491-5p may bind to the 3'UTR of the GRIN1 gene (+799 bp - +805 bp, the next base of the stop codon is +1) and down-regulate gene expression in HEK-293, SK-N-SH, and U87 cell lines, which implicates a potential role of miR-491-5p in central nervous system diseases.
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- 2020
47. Differential alternative splicing in brain regions of rats selected for aggressive behavior.
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Babenko, V., Bragin, A., Chadaeva, I., Markel, A., and Orlov, Y.
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ALTERNATIVE RNA splicing , *MESSENGER RNA , *BRAIN physiology , *GENETICS of aggression , *GENE expression , *GENE ontology , *METHYL aspartate - Abstract
Profiles of alternative mRNA isoforms have been determined in three brain regions of rats from an aggressive and a tame line selected for 74 generations. Among 2319 genes with alternatively spliced exons, approximately 84% were confirmed by analyzing public databases. Based on Gene Ontology-guided clustering of alternatively spliced genes, it has been found that the sample was enriched in synapse-specific genes (FDR < 10). Patterns of gene expression in the brains of animals with genetically determined high or low aggression were more frequently found to differ in the use of alternatively spliced exons than in animals environmentally conditioned for increased or lowered propensity to aggression. For the Adcyap1r1 gene, five alternatively spliced mRNA isoforms have been represented differentially in aggressive animals. A detailed analysis of the gene that encodes glutamate ionotropic receptor NMDA type subunit 1 ( Grin1) has confirmed significant differences in the levels of its alternatively spliced isoforms in certain brain regions of tame and aggressive rats. These differences may affect the behavior in rats genetically selected for aggression levels. [ABSTRACT FROM AUTHOR]
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- 2017
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48. De novo GRIN1 mutations: An emerging cause of severe early infantile encephalopathy.
- Author
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Zehavi, Yoav, Mandel, Hanna, Zehavi, Arie, Rashid, Muhammad Abu, Straussberg, Rachel, Jabur, Banan, Shaag, Avraham, Elpeleg, Orly, and Spiegel, Ronen
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GENETIC mutation , *BRAIN diseases , *MUSCLE hypotonia , *HYPERKINETIC dysarthria , *METHYL aspartate receptors - Abstract
De novo GRIN1 mutations have recently been shown to cause severe intellectual disability, hypotonia, hyperkinetic and stereotyped movements, and epilepsy. We report two new cases of severe early onset encephalopathy associated with hyperkinetic and oculogyric-like movements, caused by mutations in the GRIN1 gene; both were identified by whole exome sequencing. One of the patients harbored the novel mutation p.Ser688Tyr and the other patient harbored the p.Gly827Arg mutation, which was previously reported in three patients. In silico studies suggested that the p.Se688Tyr mutation results in disruption of NMDA ligand binding and the p.Gly827Arg mutation results in disrupted gating of the ion channel. Our study highlights the importance of GRIN1 mutations in the etiology of isolated cases of early onset encephalopathy, and the valuable role of whole exome sequencing in identifying these mutations. [ABSTRACT FROM AUTHOR]
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- 2017
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49. Glutamate ionotropic receptor NMDA type subunit 1: A novel potential protein target of dapagliflozin against renal interstitial fibrosis.
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Liu, Yuyuan, Wang, Yanzhe, Chen, Sijia, Bai, Linnan, Li, Fengqin, Wu, Yue, Zhang, Ling, and Wang, Xiaoxia
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SODIUM-glucose cotransporters , *RENAL fibrosis , *GLUTAMATE receptors , *METHYL aspartate receptors , *TRANSFORMING growth factors-beta , *DAPAGLIFLOZIN , *MOLECULAR dynamics - Abstract
Renal interstitial fibrosis (RIF) is the final pathway for chronic kidney diseases (CKD) to end-stage renal disease, with no ideal therapy at present. Previous studies indicated that sodium glucose co-transporter-2 inhibitor (SGLT2i) dapagliflozin had the effect of anti-RIF, but the mechanism remains elusive and the renal protective effect could not be fully explained by singly targeting SGLT2. In this study, we aimed to explore the mechanism of dapagliflozin against RIF and identify novel potential targets. Firstly, dapagliflozin treatment improved pro-fibrotic indicators in unilateral ureteral obstruction mice and transforming growth factor beta 1 induced human proximal tubular epithelial cells. Then, transcriptomics and bioinformatics analysis were performed, and results revealed that dapagliflozin against RIF by regulating inflammation and oxidative stress related signals. Subsequently, targets prediction and analysis demonstrated that glutamate ionotropic receptor NMDA type subunit 1 (GRIN1) was a novel potential target of dapagliflozin, which was related to inflammation and oxidative stress related signals. Moreover, molecular dynamics simulation revealed that dapagliflozin could stably bind to GRIN1 protein and change its spatial conformation. Furthermore, human renal samples and Nephroseq data were used for GRIN1 expression evaluation, and the results showed that GRIN1 expression were increased in renal tissues of CKD and RIF patients than controls. Additionally, further studies demonstrated that dapagliflozin could reduce intracellular calcium influx in renal tubular cells, which depended on regulating GRIN1 protein but not gene. In conclusion, GRIN1 is probably a novel target of dapagliflozin against RIF. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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50. Arthrogryposis multiplex congenita with polymicrogyria and infantile encephalopathy caused by a novel GRIN1 variant
- Author
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Katsuaki Toyoshima, Kenji Kurosawa, Kaoru Katsumata, Hiroaki Murakami, Yumi Enomoto, Naoto Nishimura, and Tatsuro Kumaki
- Subjects
Infantile encephalopathy ,Pathology ,medicine.medical_specialty ,Arthrogryposis multiplex congenita ,Epilepsy ,biology ,lcsh:QH426-470 ,business.industry ,lcsh:Life ,GRIN1 ,medicine.disease ,Biochemistry ,Paediatric neurological disorders ,Transmembrane domain ,lcsh:Genetics ,lcsh:QH501-531 ,Genetics ,biology.protein ,Polymicrogyria ,Data Report ,Medicine ,business ,Molecular Biology - Abstract
Variants of GRIN1, which encodes GluN1, are associated with developmental delay, epilepsy, and cortical malformation. Here, we report a case of arthrogryposis multiplex congenita with polymicrogyria and infantile encephalopathy caused by a heterozygous variant, c.1949A>C, p.(Asn650Thr) of GRIN1, which could result in the disruption of the third transmembrane domain (M3) of GluN1. This case expands our understanding of the known phenotypes of GRIN1-related neurodevelopmental disorders.
- Published
- 2020
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