MBD5 regulates NMDA receptor expression and seizures by inhibiting Stat1 transcription [ChIP-Seq]

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. Overall design: One month after injecting Mbd5 lentivirus (LV-MBD5) and its control virus (LV Control) into the hippocampus of mice, the model was made with kainic acid (KA). One month later, the mouse hippocampus was used for RNA sequencing (6, LV Control models; 6, LV-MBD5 models) and ChIP sequencing (LV-MBD5 model).