2. Academic Validation
  3. MBD5 regulates NMDA receptor expression and seizures by inhibiting Stat1 transcription

MBD5 regulates NMDA receptor expression and seizures by inhibiting Stat1 transcription

  • Neurobiol Dis. 2023 Mar 28;106103. doi: 10.1016/j.nbd.2023.106103.
Feng-Lin Tang 1,  Xiao-Gang Zhang 2,  Ping-Yang Ke 1,  Jie Liu 1,  Zhi-Juan Zhang 1,  Dan-Mei Hu 3,  Juan Gu 1,  Hui Zhang 1,  Hao-Kun Guo 1,  Qian-Wen Zang 4,  Rui Huang 1,  Yuan-Lin Ma 1,  Patrick Kwan 5
Affiliations

Affiliations

  • 1 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing 400016, China.
  • 2 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing 400016, China; Department of Neurology, Chongqing General Hospital, Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing 401147, China.
  • 3 Department of Neurology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 030032, China; Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, Taiyuan, China.
  • 4 Department of Rehabilitation Medicine and Physical Therapy, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China.
  • 5 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing 400016, China; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia. Electronic address: patrick.kwan@monash.edu.
PMID: 36997128 DOI: 10.1016/j.nbd.2023.106103
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.

Keywords

Epilepsy; MBD5; Neuroscience.

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