149 results on '"GRIN1"'
Search Results
2. Foxg1 regulates translation of neocortical neuronal genes, including the main NMDA receptor subunit gene, Grin1.
- Author
-
Artimagnella, Osvaldo, Maftei, Elena Sabina, Esposito, Mauro, Sanges, Remo, and Mallamaci, Antonello
- Subjects
- *
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]
- Published
- 2024
- Full Text
- View/download PDF
3. Foxg1 regulates translation of neocortical neuronal genes, including the main NMDA receptor subunit gene, Grin1
- Author
-
Osvaldo Artimagnella, Elena Sabina Maftei, Mauro Esposito, Remo Sanges, and Antonello Mallamaci
- Subjects
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.
- Published
- 2024
- Full Text
- View/download PDF
4. Quantitative proteomic and phosphoproteomic analyses of the hippocampus reveal the involvement of NMDAR1 signaling in repetitive mild traumatic brain injury.
- Author
-
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
- Published
- 2023
- Full Text
- View/download PDF
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
- Author
-
E. B. Sharypova, I. A. Drachkova, I. V. Chadaeva, M. P. Ponomarenko, and L. K. Savinkova
- Subjects
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).
- Published
- 2022
- Full Text
- View/download PDF
6. Oculogyric crisis induced by risperidone in a child with GRIN1 variant
- Author
-
Ali Mir, Montaha Almudhry, Shahid Bashir, and Hamoud Khallaf
- Subjects
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.
- Published
- 2023
- Full Text
- View/download PDF
7. TFAP2A is involved in neuropathic pain by regulating Grin1 expression in glial cells of the dorsal root ganglion.
- Author
-
Yuan, Bao-Tong, Li, Meng-Na, Zhu, Lin-Peng, Xu, Meng-Lin, Gu, Jun, Gao, Yong-Jing, and Ma, Ling-Jie
- Subjects
- *
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]
- Published
- 2024
- Full Text
- View/download PDF
8. Subtype-specific conformational landscape of NMDA receptor gating.
- Author
-
Bleier, Julia, Furtado de Mendonca, Philipe Ribeiro, Habrian, Chris H., Stanley, Cherise, Vyklicky, Vojtech, and Isacoff, Ehud Y.
- Abstract
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]
- Published
- 2024
- Full Text
- View/download PDF
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
- Author
-
Fatemeh Noruzifard, Amaneh Javid, and Seyed Mohsen Miresmaeili
- Subjects
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
- Published
- 2021
10. Characteristic features of electroencephalogram in a pediatric patient with GRIN1 encephalopathy
- Author
-
Naohiro Yamamoto, Masataka Fukuoka, Ichiro Kuki, Naomi Tsuchida, Naomichi Matsumoto, and Shin Okazaki
- Subjects
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.
- Published
- 2022
- Full Text
- View/download PDF
11. Abnormal sensory perception masks behavioral performance of Grin1 knockdown mice.
- Author
-
Lipina, Tatiana, Men, Xiaoyu, Blundell, Matisse, Salahpour, Ali, and Ramsey, Amy J.
- Subjects
- *
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]
- Published
- 2022
- Full Text
- View/download PDF
12. A homozygous GRIN1 null variant causes a more severe phenotype of early infantile epileptic encephalopathy.
- Author
-
Blakes, Alexander J. M., English, Joel, Banka, Siddharth, and Basu, Helen
- 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. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
13. Potential Ago2/miR-3068-5p Cascades in the Nucleus Accumbens Contribute to Methamphetamine-Induced Locomotor Sensitization of Mice.
- Author
-
Liu, Dan, Liang, Min, Zhu, Li, Zhou, Ting-ting, Wang, Yu, Wang, Rui, Wu, Fei-fei, Goh, Eyleen L. K., and Chen, Teng
- Subjects
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]
- Published
- 2021
- Full Text
- View/download PDF
14. Accumulation of NMDA receptors in accumbal neuronal ensembles mediates increased conditioned place preference for cocaine after prolonged withdrawal.
- Author
-
Huai, Ziqing, Huang, Bing, He, Guanhong, Li, Haibo, Liu, Yonghui, Le, Qiumin, Wang, Feifei, Ma, Lan, and Liu, Xing
- Subjects
- *
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]
- Published
- 2024
- Full Text
- View/download PDF
15. Overlapping cortical malformations in patients with pathogenic variants in GRIN1 and GRIN2B
- Author
-
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)
- Subjects
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.
- Published
- 2023
16. From bedside‐to‐bench: What disease‐associated variants are teaching us about the NMDA receptor.
- Author
-
Amin, Johansen B., Moody, Gabrielle R., and Wollmuth, Lonnie P.
- Subjects
- *
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]
- Published
- 2021
- Full Text
- View/download PDF
17. Conformational basis of subtype-specific allosteric control of NMDA receptor gating.
- Author
-
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.
- Published
- 2024
- Full Text
- View/download PDF
18. Methionine mediates resilience to chronic social defeat stress by epigenetic regulation of NMDA receptor subunit expression.
- Author
-
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.
- Subjects
- *
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]
- Published
- 2020
- Full Text
- View/download PDF
19. Progressive neuroanatomical changes caused by Grin1 loss-of-function mutation
- Author
-
Katheron Intson, Matthijs C. van Eede, Rehnuma Islam, Marija Milenkovic, Yuanye Yan, Ali Salahpour, R. Mark Henkelman, and Amy J. Ramsey
- Subjects
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.
- Published
- 2019
- Full Text
- View/download PDF
20. Rett and Rett‐like syndrome: Expanding the genetic spectrum to KIF1A and GRIN1 gene
- Author
-
Jiaping Wang, Qingping Zhang, Yan Chen, Shujie Yu, Xiru Wu, and Xinhua Bao
- Subjects
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.
- Published
- 2019
- Full Text
- View/download PDF
21. Memantine Prevents the WIN 55,212-2 Evoked Cross-Priming of Ethanol-Induced Conditioned Place Preference (CPP)
- Author
-
Marta Marszalek-Grabska, Irena Smaga, Paulina Surowka, Pawel Grochecki, Tymoteusz Slowik, Malgorzata Filip, and Jolanta H. Kotlinska
- Subjects
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.
- Published
- 2021
- Full Text
- View/download PDF
22. Quantitative proteomic and phosphoproteomic analyses of the hippocampus reveal the involvement of NMDAR1 signaling in repetitive mild traumatic brain injury.
- Author
-
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
- Abstract
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
- Published
- 2023
- Full Text
- View/download PDF
23. Chronic Alcohol Use Induces Molecular Genetic Changes in the Dorsomedial Thalamus of People with Alcohol-Related Disorders
- Author
-
Andreas-Christian Hade, Mari-Anne Philips, Ene Reimann, Toomas Jagomäe, Kattri-Liis Eskla, Tanel Traks, Ele Prans, Sulev Kõks, Eero Vasar, and Marika Väli
- Subjects
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.
- Published
- 2021
- Full Text
- View/download PDF
24. Acute D-Serine Co-Agonism of β-Cell NMDA Receptors Potentiates Glucose-Stimulated Insulin Secretion and Excitatory β-Cell Membrane Activity
- Author
-
Amber Lockridge, Eric Gustafson, Alicia Wong, Robert F. Miller, and Emilyn U. Alejandro
- Subjects
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.
- Published
- 2021
- Full Text
- View/download PDF
25. Abnormal circadian rhythm in patients with GRIN1-related developmental epileptic encephalopathy.
- Author
-
Scala, Marcello, Amadori, Elisabetta, Fusco, Lucia, Marchese, Francesca, Capra, Valeria, Minetti, Carlo, Vari, Maria Stella, and Striano, Pasquale
- Subjects
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]
- Published
- 2019
- Full Text
- View/download PDF
26. Comparative analyses of the neurobehavioral, molecular, and enzymatic effects of organophosphates on embryo-larval zebrafish (Danio rerio).
- Author
-
Schmitt, Cassandra, McManus, Michelle, Kumar, Naveen, Awoyemi, Olushola, and Crago, Jordan
- Subjects
- *
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]
- Published
- 2019
- Full Text
- View/download PDF
27. In-silico investigation of coding variants potentially affecting the functioning of the glutamatergic N-methyl-d-aspartate receptor in schizophrenia.
- Author
-
Tsavou, Antonia and Curtis, David
- Abstract
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]
- Published
- 2019
- Full Text
- View/download PDF
28. Under the mask of Kabuki syndrome: Elucidation of genetic-and phenotypic heterogeneity in patients with Kabuki-like phenotype.
- Author
-
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
- Subjects
- *
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]
- Published
- 2018
- Full Text
- View/download PDF
29. De novo mutations in GRIN1 cause extensive bilateral polymicrogyria.
- Author
-
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
- Subjects
- *
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]
- Published
- 2018
- Full Text
- View/download PDF
30. Exposure to anandamide on young rats causes deficits in learning, temporal perception and induces changes in NMDA receptor expression.
- Author
-
Hernández-Guerrero, César, García-Salcedo, Verónica, Buenrostro-Jauregui, Mario, Sanchez-Castillo, Hugo, Aguilera-Reyes, Ulises, Martínez-Castro, Noemi, and Galicia-Castillo, Oscar
- Subjects
- *
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]
- Published
- 2023
- Full Text
- View/download PDF
31. Aconiti lateralis Radix Praeparata inhibits Alzheimer’s disease by regulating the complex regulation network with the core of GRIN1 and MAPK1
- Author
-
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
- Subjects
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.
- Published
- 2021
32. The NMDA Receptor Subunit (GluN1 and GluN2A) Modulation Following Different Conditions of Cocaine Abstinence in Rat Brain Structures
- Author
-
Lucia Caffino, Marek Sanak, Fabio Fumagalli, Małgorzata Filip, Małgorzata Frankowska, Karolina Wydra, Irena Smaga, and Agata Suder
- Subjects
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.
- Published
- 2021
33. Differential alternative splicing in brain regions of rats selected for aggressive behavior.
- Author
-
Babenko, V., Bragin, A., Chadaeva, I., Markel, A., and Orlov, Y.
- Subjects
- *
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]
- Published
- 2017
- Full Text
- View/download PDF
34. De novo GRIN1 mutations: An emerging cause of severe early infantile encephalopathy.
- Author
-
Zehavi, Yoav, Mandel, Hanna, Zehavi, Arie, Rashid, Muhammad Abu, Straussberg, Rachel, Jabur, Banan, Shaag, Avraham, Elpeleg, Orly, and Spiegel, Ronen
- Subjects
- *
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]
- Published
- 2017
- Full Text
- View/download PDF
35. Glutamate ionotropic receptor NMDA type subunit 1: A novel potential protein target of dapagliflozin against renal interstitial fibrosis.
- Author
-
Liu, Yuyuan, Wang, Yanzhe, Chen, Sijia, Bai, Linnan, Li, Fengqin, Wu, Yue, Zhang, Ling, and Wang, Xiaoxia
- Subjects
- *
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
- View/download PDF
36. Arthrogryposis multiplex congenita with polymicrogyria and infantile encephalopathy caused by a novel GRIN1 variant
- Author
-
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
37. The GluN3 subunit regulates ion selectivity within native N-methyl-d-aspartate receptors
- Author
-
Thomas Sullenberger, Sanjay Kumar, and Stephen Beesley
- Subjects
0301 basic medicine ,Protein subunit ,GluN3 ,Triheteromeric NMDA receptors ,Article ,lcsh:RC321-571 ,03 medical and health sciences ,Glutamatergic ,0302 clinical medicine ,mental disorders ,Ion selectivity ,Binding site ,Receptor ,Ion-substitution experiments ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Entorhinal cortex ,chemistry.chemical_classification ,biology ,General Neuroscience ,musculoskeletal, neural, and ocular physiology ,Glutamate receptor ,GRIN1 ,Somatosensory cortex ,Amino acid ,Electrophysiology ,030104 developmental biology ,chemistry ,nervous system ,Glycine ,biology.protein ,Biophysics ,030217 neurology & neurosurgery - Abstract
Highlights • The GluN3 subunit is the least understood of all subunits that make up functional NMDARs in the brain. • We show through ion substitution experiments that NMDARs containing GluN3 are more permeable to Ca2+ than those containing just GluN1 and GluN2. • We attribute these differences to their ability to screen for Ca2+ over Na+. • Subunit-dependent cation selectivity represents a hitherto unrealized mechanism for finer control of Ca2+ influx enhancing the repertoire of synaptic NMDARs., Glutamatergic N-methyl-d-aspartate receptors (NMDARs) are heterotetrameric proteins whose subunits are derived from three gene families, GRIN1 (codes for GluN1), GRIN2 (GluN2) and GRIN3 (GluN3). In addition to providing binding sites for glutamate and the co-agonist glycine, these subunits in their di (d-) and tri (t-) heteromeric configurations regulate various aspects of receptor function in the brain. For example, the decay kinetics of NMDAR-mediated synaptic currents depend on the type of GluN2 subunit (GluN2A-GluN2D) in the receptor subunit composition. While much is known about the contributions of GluN1 and GluN2 to d-NMDAR function, we know comparatively little about how GluN3 influences the function of t-NMDARs composed of one or more subunits from each of the three gene families. We report here that in addition to altering kinetics and voltage-dependent properties, the GluN3 subunit endows these receptors with ion selectivity wherein influx of Ca2+ is preferred over Na+. This became apparent in the process of assessing Ca2+ permeability through these receptors and is of significance given that NMDARs are generally believed to be nonselective to cations and increased selectivity can lead to enhanced permeability. This was true of two independent brain regions where t-NMDARs are expressed, the somatosensory cortex, where both receptor subtypes are expressed at separate inputs onto single neurons, and the entorhinal cortex, where they are co-expressed at individual synaptic inputs. Based on this data and the sequence of amino acids lining selectivity filters within these subunits, we propose GluN3 to be a regulatory subunit for ion selectivity in t-NMDARs.
- Published
- 2020
38. Control of Long-Term Synaptic Potentiation and Learning by Alternative Splicing of the NMDA Receptor Subunit GluN1
- Author
-
Ameet S. Sengar, P. Joel Ross, James Ellis, Michael Brudno, Wen-Bo Zhang, Michael W. Salter, Celeste Leung, Yongqian Wang, Stephen W. Scherer, Ner Mu Nar Saw, Hongbin Li, Arun K. Ramani, YuShan Tu, and Zhengping Jia
- Subjects
0301 basic medicine ,Autism Spectrum Disorder ,Induced Pluripotent Stem Cells ,Long-Term Potentiation ,Primary Cell Culture ,Hippocampus ,Nerve Tissue Proteins ,Biology ,Receptors, N-Methyl-D-Aspartate ,Synaptic Transmission ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,Exon ,Long-term synaptic potentiation ,0302 clinical medicine ,Animals ,Humans ,lcsh:QH301-705.5 ,Spatial Memory ,Mice, Knockout ,Neurons ,Cell Death ,Alternative splicing ,Excitatory Postsynaptic Potentials ,GRIN1 ,Cell Differentiation ,Long-term potentiation ,Exons ,Alternative Splicing ,Protein Subunits ,030104 developmental biology ,nervous system ,lcsh:Biology (General) ,Synapses ,Synaptic plasticity ,biology.protein ,NMDA receptor ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Summary: NMDA receptors (NMDARs) are critical for physiological synaptic plasticity, learning, and memory and for pathological plasticity and neuronal death. The GluN1 subunit is encoded by a single gene, GRIN1, with 8 splice variants, but whether the diversity generated by this splicing has physiological consequences remains enigmatic. Here, we generate mice lacking from the GluN1 exon 5-encoded N1 cassette (GluN1a mice) or compulsorily expressing this exon (GluN1b mice). Despite no differences in basal synaptic transmission, long-term potentiation in the hippocampus is significantly enhanced in GluN1a mice compared with that in GluN1b mice. Furthermore, GluN1a mice learn more quickly and have significantly better spatial memory performance than do GluN1b mice. In addition, in human iPSC-derived neurons in autism spectrum disorder NMDARs show characteristics of N1-lacking GluN1. Our findings indicate that alternative splicing of GluN1 is a mechanism for controlling physiological long-lasting synaptic potentiation, learning, and memory. : NMDA receptors (NMDARs) are critical for synaptic plasticity, learning, and memory and for pathological plasticity and neuronal death. Sengar et al. report that alternative splicing of exon 5 of the obligatory GluN1 subunit of the NMDAR controls the gain of long-lasting synaptic potentiation, learning, and memory in mice. Keywords: GluN1, NMDA Receptor, long-term potentiation, N1 cassette, autism, splicing
- Published
- 2019
39. Cre-activation in ErbB4-positive neurons of floxed Grin1/NMDA receptor mice is not associated with major behavioral impairment
- Author
-
Peter Gass, Rolf Sprengel, Dragos Inta, Sabine Chourbaji, Miriam A. Vogt, Anne S. Mallien, and Natascha Pfeiffer
- Subjects
Psychosis ,Population ,RC435-571 ,glutamate ,Genetic model ,mental disorders ,Medicine ,Pharmacology (medical) ,Neuregulin 1 ,education ,ERBB4 ,Biological Psychiatry ,Original Research ,Pharmacology ,Psychiatry ,education.field_of_study ,biology ,neurodevelopment ,business.industry ,musculoskeletal, neural, and ocular physiology ,GRIN1 ,medicine.disease ,NMDA receptor ,post-adolescent ,neuregulin-1 ,schizophrenia ,Psychiatry and Mental health ,Neurology ,nervous system ,Schizophrenia ,biology.protein ,pharmacogenetic ,Neurology (clinical) ,biological phenomena, cell phenomena, and immunity ,business ,Neuroscience ,psychological phenomena and processes - Abstract
Extensive evidence suggests a dysfunction of the glutamate NMDA receptor (NMDAR) in schizophrenia, a severe psychiatric disorder with putative early neurodevelopmental origins, but clinical onset mainly during late adolescence. On the other hand, pharmacological models using NMDAR antagonists and the clinical manifestation of anti-NMDAR encephalitis indicate that NMDAR blockade/hypofunction can trigger psychosis also at adult stages, without any early developmental dysfunction. Previous genetic models of NMDAR hypofunction restricted to parvalbumin-positive interneurons indicate the necessity of an early postnatal impairment to trigger schizophrenia-like abnormalities, whereas the cellular substrates of NMDAR-mediated psychosis at adolescent/adult stages are unknown. Neuregulin 1 (NRG1) and its receptor ErbB4 represent schizophrenia-associated susceptibility factors that closely interact with NMDAR. To determine the neuronal populations implicated in “late” NMDAR-driven psychosis, we analyzed the effect of the inducible ablation of NMDARs in ErbB4-expressing cells in mice during late adolescence using a pharmacogenetic approach. Interestingly, the tamoxifen-inducible NMDAR deletion during this late developmental stage did not induce behavioral alterations resembling depression, schizophrenia or anxiety. Our data indicate that post-adolescent NMDAR deletion, even in a wider cell population than parvalbumin-positive interneurons, is also not sufficient to generate behavioral abnormalities resembling psychiatric disorders. Other neuronal substrates that have to be revealed by future studies, may underlie post-adolescent NMDAR-driven psychosis.
- Published
- 2021
40. Association of CaMK2A and MeCP2 signaling pathways with cognitive ability in adolescents
- Author
-
Ming Tsan Su, Li-Ching Lee, Ting Kuang Yeh, Chun-Yen Chang, Ying-Chun Cho, and Hsing-Ying Huang
- Subjects
Male ,Adolescent ,Methyl-CpG-Binding Protein 2 ,Psychology, Adolescent ,Taiwan ,Glutamic Acid ,Receptors, Ionotropic Glutamate ,Polymorphism, Single Nucleotide ,MECP2 ,Single-nucleotide variant (SNV) ,Cellular and Molecular Neuroscience ,Glutamatergic ,Neuroblastoma ,Cognition ,Reference Values ,Cell Line, Tumor ,CAMK2A ,Humans ,GRIN3A ,Phosphorylation ,RC346-429 ,Promoter Regions, Genetic ,Molecular Biology ,GRIA1 ,Glutamatergic signaling pathway ,Feedback, Physiological ,Methyl-CpG binding protein 2 (MeCP2) ,biology ,Research ,GRIN1 ,Enzyme Activation ,HEK293 Cells ,biology.protein ,Calcium/calmodulin-dependent protein kinase IIα (CaMK2A) ,GRIN2B ,Female ,Neurology. Diseases of the nervous system ,Cognitive function ,Signal transduction ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,Neuroscience ,Protein Processing, Post-Translational ,Signal Transduction - Abstract
The glutamatergic signaling pathway is involved in molecular learning and human cognitive ability. Specific single variants (SNVs, formerly single-nucleotide polymorphisms) in the genes encoding N-methyl-d-aspartate receptor subunits have been associated with neuropsychiatric disorders by altering glutamate transmission. However, these variants associated with cognition and mental activity have rarely been explored in healthy adolescents. In this study, we screened for SNVs in the glutamatergic signaling pathway to identify genetic variants associated with cognitive ability. We found that SNVs in the subunits of ionotropic glutamate receptors, including GRIA1, GRIN1, GRIN2B, GRIN2C, GRIN3A, GRIN3B, and calcium/calmodulin-dependent protein kinase IIα (CaMK2A) are associated with cognitive function. Plasma CaMK2A level was correlated positively with the cognitive ability of Taiwanese senior high school students. We demonstrated that elevating CaMK2A increased its autophosphorylation at T286 and increased the expression of its downstream targets, including GluA1 and phosphor- GluA1 in vivo. Additionally, methyl-CpG binding protein 2 (MeCP2), a downstream target of CaMK2A, was found to activate the expression of CaMK2A, suggesting that MeCP2 and CaMK2A can form a positive feedback loop. In summary, two members of the glutamatergic signaling pathway, CaMK2A and MeCP2, are implicated in the cognitive ability of adolescents; thus, altering the expression of CaMK2A may affect cognitive ability in youth.
- Published
- 2021
41. Potential Ago2/miR-3068-5p Cascades in the Nucleus Accumbens Contribute to Methamphetamine-Induced Locomotor Sensitization of Mice
- Author
-
Dan Liu, Min Liang, Li Zhu, Ting-ting Zhou, Yu Wang, Rui Wang, Fei-fei Wu, Eyleen L. K. Goh, Teng Chen, Lee Kong Chian School of Medicine (LKCMedicine), and National Neuroscience Institute
- Subjects
Ago2 ,media_common.quotation_subject ,Locomotor Sensitization ,miR-3068-5p ,RM1-950 ,Pharmacology ,Nucleus accumbens ,Methamphetamine ,chemistry.chemical_compound ,Downregulation and upregulation ,Grin1 ,microRNA ,medicine ,Gene silencing ,Medicine [Science] ,Pharmacology (medical) ,methamphetamine ,Sensitization ,Original Research ,media_common ,Chemistry ,Addiction ,Meth ,locomotor sensitization ,medicine.anatomical_structure ,Therapeutics. Pharmacology ,medicine.drug - 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. Ministry of Education (MOE) Published version This work was supported by grants from the National Natural Science Foundation of China given to TC (Grant no. 81772034) and LZ (Grant no. 81701870); the Natural Science Foundation of Shaanxi Province to LZ (2020JQ-081); the Ministry of Education (MOE) Tier 3 grant to EG (Grant no. MOE2017-T3-1-002).
- Published
- 2021
- Full Text
- View/download PDF
42. Memantine Prevents the WIN 55,212-2 Evoked Cross-Priming of Ethanol-Induced Conditioned Place Preference (CPP)
- Author
-
Małgorzata Filip, Jolanta Kotlinska, Tymoteusz Słowik, Pawel Grochecki, Paulina Surówka, Marta Marszalek-Grabska, and Irena Smaga
- Subjects
Male ,Cannabinoid receptor ,Pharmacology ,GRIN2A ,0302 clinical medicine ,Conditioning, Psychological ,Biology (General) ,WIN 55,212-2 ,Spectroscopy ,ethanol relapse ,0303 health sciences ,CNR1 ,Chemistry ,Memantine ,Glutamate receptor ,General Medicine ,cannabinoid ,Endocannabinoid system ,Computer Science Applications ,NMDA receptor ,psychological phenomena and processes ,medicine.drug ,Agonist ,QH301-705.5 ,medicine.drug_class ,Morpholines ,GRIN1 ,glutamate ,Naphthalenes ,Article ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,medicine ,Animals ,Rats, Wistar ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,030304 developmental biology ,Motivation ,Ethanol ,Organic Chemistry ,Conditioned place preference ,Benzoxazines ,rats ,nervous system ,030217 neurology & neurosurgery - 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.
- Published
- 2021
- Full Text
- View/download PDF
43. Sex differences in the neuroadaptations associated with incubated cocaine-craving: A focus on the dorsomedial prefrontal cortex.
- Author
-
Towers EB, Kilgore M, Bakhti-Suroosh A, Pidaparthi L, Williams IL, Abel JM, and Lynch WJ
- Abstract
Introduction: Women have a shorter course from initial cocaine use to meeting the criteria for cocaine use disorder as compared to men. Preclinical findings similarly indicate that females develop key features of an addiction-like phenotype faster than males, including an enhanced motivation for cocaine and compulsive use, indicating that this phenomenon is biologically based. The goals of this study were to determine whether cocaine-craving, another key feature of addiction, also develops sooner during withdrawal in females than males and to determine whether there are sex differences in the molecular mechanisms associated with its development focusing on markers known to mediate cocaine-craving in males (i.e., dorsomedial prefrontal cortex, dmPFC, expression of brain-derived neurotrophic factor exon-IV, Bdnf-IV , and NMDA receptor subunits, Grin2a, Grin2b , and Grin1 )., Methods: Cocaine-craving was assessed following extended-access cocaine self-administration and 2, 7, or 14 days of withdrawal using an extinction/cue-induced reinstatement procedure. Tissue was obtained from the dmPFC immediately after reinstatement testing and gene expression changes were analyzed using real-time qPCR., Results: In males, cocaine-craving (total extinction and cue-induced reinstatement responding) progressively increased from early to later withdrawal time-points whereas in females, cocaine-craving was already elevated during early withdrawal (after 2 days) and did not further increase at later withdrawal time-points. Levels of cocaine-craving, however, were similar between the sexes. Gene expression changes differed markedly between the sexes such that males showed the expected relapse- and withdrawal-associated changes in Bdnf-IV, Grin2a, Grin2b , and Grin1 expression, but females only showed a modest increase Grin1 expression at the intermediate withdrawal timepoint., Discussion: These findings indicate that cocaine-craving is similarly expressed in males and females although the time-course for its incubation appears to be accelerated in females; the molecular mechanisms also likely differ in females versus males., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Towers, Kilgore, Bakhti-Suroosh, Pidaparthi, Williams, Abel and Lynch.)
- Published
- 2023
- Full Text
- View/download PDF
44. APROXIMACIONES COMPUTACIONALES PARA LA IDENTIFICACIÓN DE PROMOTORES EUCARIOTAS TIPO II
- Author
-
M. Mejía-Guerra and L. Lareo
- Subjects
Genes ,GRIN1 ,NMDA ,promotores ,reguladores ,Science (General) ,Q1-390 - Abstract
La identificación de segmentos funcionales dentro del DNA es uno de los campos más estudiados en la actualidad, debido a la generación de grandes volúmenes de información a partir de los proyectosgenómicos, las predicciones computacionales han atraído la atención de la comunidad científica en general.En este marco la identificación de secuencias reguladoras se erige como un importante campo del análisis de genomas; sin embargo, dada la enorme complejidad del proceso de regulación de la transcripciónaunque promisorios el problema de la predicción de las zonas reguladoras no se ha solucionado en su totalidad.Este artículo presenta una descripción de algunas aproximaciones desarrolladas para la identificación de promotores y sus elementos cis-reguladores, también se describen las estructuras de señales funcionales y estructurales que son diana de reconocimiento de algunos de estos programas de predicción aplicados al gen que codifica para la subunidad NR1 del receptor de glutamato sensible a N-metil-D-aspartato (iGluR-NMDA) el cual ha sido objeto de estudio desde la década de los noventa.
- Published
- 2006
45. A 16-year-old girl with anti-NMDA-receptor encephalitis and family history of psychotic disorders.
- Author
-
Cleland, Neil, Lieblich, Samuel, Schalling, Martin, and Rahm, Christoffer
- Subjects
- *
METHYL aspartate receptors , *ANTI-NMDA receptor encephalitis , *ENCEPHALITIS , *BRAIN diseases , *PSYCHOSES - Abstract
BackgroundAutoimmune NMDA-R encephalitis (ANRE) shares clinical features with schizophrenia. Recent research also indicates that both disorders are associated with dysfunction of the N-Methyl-D-Aspartate glutamate receptors (NMDA-R) subunit 1.MethodsWe present the case of Ms A, 16 years old. Ms A presented with acute personality change, bizarre behaviour, delusional ideas and atypical seizures. She had a family history of psychotic disorders, and autistic traits diagnosed in childhood. She was initially diagnosed with a psychotic disorder. Delayed testing of CSF indicated ANRE. As the patient was a Jehovah's witness the treating team was unable to use gammaglobulin therapy; they instead relied on combined plasmapheresis and rituximab. To exclude the possibility that the affected members of this family shared a gene coding for an abnormal configuration of the NMDA receptor subunit 1 we sequenced the region of the GRIN1 gene in DNA extracted from blood in both Ms A and her grandmother.ResultsMs A’s condition improved dramatically, though her long-term memory is still demonstrably impaired. No genetic abnormality was detected.ConclusionsThis case emphasizes how important it is, for a first episode psychosis, to exclude ANRE and other autoimmune synaptic encephalitides, even in the face of significant family history, and if seronegative, the importance of testing for CSF autoantibodies. [ABSTRACT FROM PUBLISHER]
- Published
- 2015
- Full Text
- View/download PDF
46. Genetic basis of depressive disorders
- Author
-
Yu. D. Davydova, R. F. Enikeeva, A. V. Kazantseva, R. N. Mustafin, A. R. Romanova, S. B. Malykh, and E. K. Khusnutdinov
- Subjects
0301 basic medicine ,Candidate gene ,medicine.medical_specialty ,Genome-wide association study ,Biology ,QH426-470 ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,depressive disorder ,Internal medicine ,medicine ,Genetics ,whole-exome sequencing ,Exome sequencing ,Genetic association ,TPH2 ,neurotrophin ,apoptosis ,GRIN1 ,PSMD9 ,gwas ,cytokines ,serotonin ,030104 developmental biology ,Endocrinology ,Methylenetetrahydrofolate reductase ,biology.protein ,hypothalamic-pituitary adrenal axis ,General Agricultural and Biological Sciences ,030217 neurology & neurosurgery - Abstract
Depression is a common mental disorder being one of the main causes of disability and mortality worldwide. Despite an intensive research during the past decades, the etiology of depressive disorders (DDs) remains incompletely understood; however, genetic factors are significantly involved in the liability to depression. The present review is focused on the studies based on a candidate gene approach, genome-wide association studies (GWAS) and whole exome sequencing (WES), which previously demonstrated associations between gene polymorphisms and DDs. According to the first approach, DD development is affected by serotonergic (TPH1, TPH2, HTR1A, HTR2A, and SLC6A4), dopaminergic (DRD4, SLC6A3) and noradrenergic (SLC6A2) system genes, and genes of enzymatic degradation (MAOA, COMT). In addition, there is evidence of the involvement of HPA-axis genes (OXTR, AVPR1A, and AVPR1B), sex hormone receptors genes (ESR1, ESR2, and AR), neurotrophin (BDNF) and methylenetetrahydrofolate reductase (MTHFR) genes, neuronal apoptosis (CASP3, BCL-XL, BAX, NPY, APP, and GRIN1) and inflammatory system (TNF, CRP, IL6, IL1B, PSMB4, PSMD9, and STAT3) genes in DD development. The results of the second approach (GWAS and WES) revealed that the PCLO, SIRT1, GNL3, GLT8D1, ITIH3, MTNR1A, BMP5, FHIT, KSR2, PCDH9, and AUTS2 genes predominantly responsible for neurogenesis and cell adhesion are involved in liability to depression. Therefore, the findings discussed suggest that genetic liability to DD is a complex process, which assumes simultaneous functioning of multiple genes including those reported previously, and requires future research in this field.
- Published
- 2019
47. Chronic Alcohol Use Induces Molecular Genetic Changes in the Dorsomedial Thalamus of People with Alcohol-Related Disorders
- Author
-
Mari-Anne Philips, Toomas Jagomäe, Sulev Kõks, Ene Reimann, Marika Väli, Tanel Traks, Kattri-Liis Eskla, Andreas-Christian Hade, Eero Vasar, and Ele Prans
- Subjects
medicine.medical_specialty ,Microarray ,GRIN1 ,Thalamus ,Alcohol use disorder ,alcohol use disorder ,Article ,lcsh:RC321-571 ,03 medical and health sciences ,Diencephalon ,Glutamatergic ,0302 clinical medicine ,autopsy ,Downregulation and upregulation ,Internal medicine ,medicine ,mediodorsal thalamus ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,030304 developmental biology ,0303 health sciences ,biology ,alcoholism ,General Neuroscience ,ADH1B ,medicine.disease ,Endocrinology ,biology.protein ,FTO ,030217 neurology & neurosurgery - 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.
- Published
- 2021
48. Acute D-Serine Co-Agonism of β-Cell NMDA Receptors Potentiates Glucose-Stimulated Insulin Secretion and Excitatory β-Cell Membrane Activity
- Author
-
Alicia Wong, Robert F. Miller, Eric C. Gustafson, Emilyn U. Alejandro, and Amber D Lockridge
- Subjects
Agonist ,Blood Glucose ,Male ,medicine.medical_specialty ,insulin secretion ,mice ,N-Methylaspartate ,medicine.drug_class ,medicine.medical_treatment ,Context (language use) ,D-serine ,Nerve Tissue Proteins ,Models, Biological ,Receptors, N-Methyl-D-Aspartate ,Article ,Grin1 ,Internal medicine ,Insulin-Secreting Cells ,Glucose Intolerance ,medicine ,Serine ,Glucose homeostasis ,glucose homeostasis ,Animals ,Homeostasis ,Receptor ,lcsh:QH301-705.5 ,Mice, Knockout ,Sex Characteristics ,Chemistry ,Insulin ,Depolarization ,General Medicine ,NMDA receptor ,β-cell ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,Glucose ,Phenotype ,lcsh:Biology (General) ,Excitatory postsynaptic potential ,Female - Abstract
Insulin-secreting pancreatic &beta, cells express proteins characteristic of D-serine regulated synapses, but the acute effect of D-serine co-agonism on its presumptive &beta, 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 &beta, cell depolarizing membrane oscillations, using perforated patch electrophysiology, in &beta, 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 &beta, 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, &beta, Grin1 KO mice. Thus, D-serine is capable of acute antidiabetic effects in mice and potentiates insulin secretion through excitatory &beta, 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 &beta, cell function.
- Published
- 2021
49. GRIN1 mutations cause encephalopathy with infantile-onset epilepsy, and hyperkinetic and stereotyped movement disorders.
- Author
-
Ohba, Chihiro, Shiina, Masaaki, Tohyama, Jun, Haginoya, Kazuhiro, Lerman‐Sagie, Tally, Okamoto, Nobuhiko, Blumkin, Lubov, Lev, Dorit, Mukaida, Souichi, Nozaki, Fumihito, Uematsu, Mitsugu, Onuma, Akira, Kodera, Hirofumi, Nakashima, Mitsuko, Tsurusaki, Yoshinori, Miyake, Noriko, Tanaka, Fumiaki, Kato, Mitsuhiro, Ogata, Kazuhiro, and Saitsu, Hirotomo
- Subjects
- *
DRUG therapy for convulsions , *ANTICONVULSANTS , *EPILEPSY , *GENETIC mutation , *PHENOTYPES - Abstract
Objective Recently, de novo mutations in GRIN1 have been identified in patients with nonsyndromic intellectual disability and epileptic encephalopathy. Whole exome sequencing ( WES) analysis of patients with genetically unsolved epileptic encephalopathies identified four patients with GRIN1 mutations, allowing us to investigate the phenotypic spectrum of GRIN1 mutations. Methods Eighty-eight patients with unclassified early onset epileptic encephalopathies (EOEEs) with an age of onset <1 year were analyzed by WES. The effect of mutations on N-methyl- d-aspartate (NMDA) receptors was examined by mapping altered amino acids onto three-dimensional models. Results We identified four de novo missense GRIN1 mutations in 4 of 88 patients with unclassified EOEEs. In these four patients, initial symptoms appeared within 3 months of birth, including hyperkinetic movements in two patients (2/4, 50%), and seizures in two patients (2/4, 50%). Involuntary movements, severe developmental delay, and intellectual disability were recognized in all four patients. In addition, abnormal eye movements resembling oculogyric crises and stereotypic hand movements were observed in two and three patients, respectively. All the four patients exhibited only nonspecific focal and diffuse epileptiform abnormality, and never showed suppression-burst or hypsarrhythmia during infancy. A de novo mosaic mutation (c.1923G>A) with a mutant allele frequency of 16% (in DNA of blood leukocytes) was detected in one patient. Three mutations were located in the transmembrane domain (3/4, 75%), and one in the extracellular loop near transmembrane helix 1. All the mutations were predicted to impair the function of the NMDA receptor. Significance Clinical features of de novo GRIN1 mutations include infantile involuntary movements, seizures, and hand stereotypies, suggesting that GRIN1 mutations cause encephalopathy resulting in seizures and movement disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
50. NMDA receptor-deficient mice display sexual dimorphism in the onset and severity of behavioural abnormalities.
- Author
-
Milenkovic, M., Mielnik, C. A., and Ramsey, A. J.
- Subjects
- *
METHYL aspartate receptors , *BEHAVIOR disorders , *SEXUAL dimorphism , *PATHOLOGICAL physiology , *SCHIZOPHRENIA , *LABORATORY mice - Abstract
N-methyl- d-aspartate ( NMDA) receptor-deficient mice can be used to understand the role that NMDA receptors ( NMDARs) play in the pathophysiology of neurodevelopmental disorders such as schizophrenia. Genetically modified mice with low levels of NR1 subunit ( NR1 knockdown mice) have reduced receptor levels throughout development, and have robust abnormalities in behaviours that are relevant to schizophrenia. We traced the onset and severity of these behaviours at three developmental stages to understand when in development the underlying circuits depend on intact NMDAR function. We examined social behaviour, working memory, executive function, locomotor activity and stereotypy at 3, 6 and 12 weeks of age in NR1 knockdown mice and their wild-type littermates. We discovered that each of these behaviours had a unique developmental trajectory in mutant mice, and males showed an earlier onset and severity than females in several behaviours. Hyperlocomotion was most substantial in juvenile mice and plateaued in adult mice, whereas stereotypy progressively worsened with age. Impairments in working memory and sociability were sexually dimorphic, with deficits first detected in peri-adolescent males but only detected in adult females. Interestingly, executive function was most impaired in peri-adolescent mice of either sex. Furthermore, while juvenile mutant mice had some ability to problem solve in the puzzle box test, the same mice lost this ability when tested 4 weeks later. Our studies highlight key developmental periods for males and females in the expression of behaviours that are relevant to psychiatric disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.