Similar Datasets
Project description:Epilepsy is considered to result from an imbalance between excitation and inhibition of the central nervous system. Pathogenic mutations in the methyl-CpG binding domain protein 5 gene (MBD5) are known to cause epilepsy. However, the function and mechanism of MBD5 in epilepsy remain elusive. Here, we found that MBD5 was mainly localized in the pyramidal cells and granular cells of mouse hippocampus, and its expression was increased in the brain tissues of mouse models of epilepsy. Exogenous overexpression of MBD5 inhibited the transcription of the signal transducer and activator of transcription 1 gene (Stat1), resulting in increased expression of N-methyl-D-aspartate receptor (NMDAR) subunit 1 (GluN1), 2A (GluN2A) and 2B (GluN2B), leading to aggravation of the epileptic behaviour phenotype in mice. In contrast, overexpression of STAT1 reduced the expression of NMDARs and alleviated the epileptic behavioural phenotype of mice. Furthermore, the epileptic behavioural phenotype was relieved by the NMDAR antagonist memantine. These results indicate that MBD5 accumulation affects seizures through STAT1-mediated inhibition of NMDAR expression in mice. Collectively, our findings suggest that the MBD5-STAT1- NMDAR pathway may be a new pathway that regulates the epileptic behavioural phenotype and may represent a new treatment target.
2023-02-16 | GSE225101 | GEO
Project description:Epilepsy is considered to result from an imbalance between excitation and inhibition of the central nervous system. Pathogenic mutations in the methyl-CpG binding domain protein 5 gene (MBD5) are known to cause epilepsy. However, the function and mechanism of MBD5 in epilepsy remain elusive. Here, we found that MBD5 was mainly localized in the pyramidal cells and granular cells of mouse hippocampus, and its expression was increased in the brain tissues of mouse models of epilepsy. Exogenous overexpression of MBD5 inhibited the transcription of the signal transducer and activator of transcription 1 gene (Stat1), resulting in increased expression of N-methyl-D-aspartate receptor (NMDAR) subunit 1 (GluN1), 2A (GluN2A) and 2B (GluN2B), leading to aggravation of the epileptic behaviour phenotype in mice. In contrast, overexpression of STAT1 reduced the expression of NMDARs and alleviated the epileptic behavioural phenotype of mice. Furthermore, the epileptic behavioural phenotype was relieved by the NMDAR antagonist memantine. These results indicate that MBD5 accumulation affects seizures through STAT1-mediated inhibition of NMDAR expression in mice. Collectively, our findings suggest that the MBD5-STAT1- NMDAR pathway may be a new pathway that regulates the epileptic behavioural phenotype and may represent a new treatment target.
2023-02-16 | GSE225100 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-05-14 | GSE245728 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-07-21 | GSE98362 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-09-08 | GSE131145 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-05-03 | GSE193680 | GEO
Project description:Intracellular tau accumulation forming neurofibrillary tangles is hallmark pathology of Alzheimer's disease (AD), but how tau accumulation induces synapse impairment is elusive. By overexpressing human full-length wild-type tau (termed hTau) to mimic tau abnormality as seen in the brain of sporadic AD patients, we find that hTau accumulation activates JAK2 to phosphorylate STAT1 (signal transducer and activator of transcription 1) at Tyr701 leading to STAT1 dimerization, nuclear translocation, and its activation. STAT1 activation suppresses expression of N-methyl-D-aspartate receptors (NMDARs) through direct binding to the specific GAS element of GluN1, GluN2A, and GluN2B promoters, while knockdown of STAT1 by AAV-Cre in STAT1flox/flox mice or expressing dominant negative Y701F-STAT1 efficiently rescues hTau-induced suppression of NMDAR expression with amelioration of synaptic functions and memory performance. These findings indicate that hTau accumulation impairs synaptic plasticity through JAK2/STAT1-induced suppression of NMDAR expression, revealing a novel mechanism for hTau-associated synapse and memory deficits.
| S-EPMC6549025 | biostudies-literature
Project description:Intracellular tau accumulation forming neurofibrillary tangles is one hallmark of Alzheimer's disease (AD), but how tau accumulation induces synaptic impairment remains elusive. Here, by overexpressing human full-length wildtype tau (hTau) to mimic tau abnormalities as seen in the brain of sporadic AD patients, we find that hTau accumulation activates JAK2-dependent STAT1 phosphorylation at Tyr701, triggering STAT1 dimerization, activation and nuclear translocation. STAT1 activation subsequently suppresses the expression of N-methyl-D-aspartate receptors (NMDARs) through direct binding to specific GAS elements in the GluN1, GluN2A and GluN2B promoters. Knockdown of STAT1, or the expression of dominant negative Y701F-STAT1 in mice, efficiently rescues hTau-induced suppression of NMDAR expression, ameliorating synaptic functions and memory performance. These findings indicate that hTau accumulation impairs synaptic plasticity through JAK2/STAT1-induced suppression of NMDAR expression, revealing a novel mechanism explaining hTau-associated synapse and memory deficits.
| S-SCDT-EMBOR-2018-47202V1 | biostudies-other
Project description:N-Methyl-d-aspartate (NMDA) receptors are major glutamatergic receptors involved in most excitatory neurotransmission in the brain. The transcriptional regulation of NMDA receptors is not fully understood. Previously, we found that the GluN1 and GluN2B subunits of the NMDA receptor are regulated by nuclear respiratory factors 1 and 2 (NRF-1 and NRF-2). NRF-1 and NRF-2 also regulate all 13 subunits of cytochrome c oxidase (COX), a critical energy-generating enzyme, thereby coupling neuronal activity and energy metabolism at the transcriptional level. Specificity protein (Sp) is a family of transcription factors that bind to GC-rich regions, with Sp1, Sp3, and Sp4 all binding to the same cis- motifs. Sp1 and Sp3 are ubiquitously expressed, whereas Sp4 expression is restricted to neurons and testicular cells. Recently, we found that the Sp1 factor regulates all subunits of COX. The goal of the present study was to test our hypothesis that the Sp factors also regulate specific subunits of NMDA receptors, and that they function with NRF-1 and NRF-2 via one of three mechanisms: complementary, concurrent and parallel, or a combination of complementary and concurrent/parallel. By means of multiple approaches we found that Sp4 functionally regulated GluN1, GluN2A, and GluN2B, but not GluN2C. On the other hand, Sp1 and Sp3 did not regulate these subunits as previously thought. Our data suggest that Sp4 operates in a complementary and concurrent/parallel manner with NRF-1 and NRF-2 to mediate the tight coupling between energy metabolism and neuronal activity at the molecular level.
| S-EPMC3834217 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-11-05 | E-GEOD-48379 | biostudies-arrayexpress