MBD5 regulates NMDA receptor expression and seizures by inhibiting Stat1 transcription

Feng lin Tang, Xiao gang Zhang, Ping yang Ke, Jie Liu, Zhi juan Zhang, Dan mei Hu, Juan Gu, Hui Zhang, Hao kun Guo, Qian wen Zang, Rui Huang, Yuan lin Ma, Patrick Kwan

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

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. The epileptic behavioural phenotype was alleviated by overexpression of STAT1 which reduced the expression of NMDARs, and 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.

Original languageEnglish
Article number106103
Number of pages18
JournalNeurobiology of Disease
Volume181
DOIs
Publication statusPublished - 1 Jun 2023

Keywords

  • Epilepsy
  • MBD5
  • Neuroscience

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