MBD5 regulates NMDA receptor expression and seizures by inhibiting Stat1 transcription.

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.

Pre- and postoperative heart rate variability and vagus nerve stimulation in patients with drug-resistant epilepsy - A meta-analysis.

OBJECTIVE: The effect of vagus nerve stimulation (VNS), an important auxiliary therapy for treating drug-resistant epilepsy (DRE), on autonomic nerve function is still controversial. Heart rate variability is a widely used indicator of autonomic nerve function. To clarify the relationship between VNS and heart rate variability (HRV), we performed a meta-analysis to systematically evaluate the effect of VNS on HRV in patients with epilepsy. METHODS: We performed a systematic review by searching the following online databases: PubMed, Web of Science, EMBASE and the Cochrane Library. The key search terms were "vagal nerve stimulation," "epilepsy" and "heart rate variability". Other features of VNS in patients with epilepsy include postoperative changes in low-frequency (LF), high-frequency (HF) and low-frequency/high-frequency (LF/HF) heart rate variability, which were used as evaluation indices, and the Newcastle-Ottawa Quality Assessment Scale and Stata 14.0 statistical software were used for literature quality evaluation and meta-analysis. RESULTS: Twelve studies published in English were obtained, and 229 patients with epilepsy who underwent VNS were ultimately included after elimination of duplicate articles and those that did not meet the inclusion criteria. Regarding LF heart rate variability, in the response subgroup, patients with DRE with VNS presented a lower value (-0.58) before surgery than after surgery, with a 95% confidence interval (CI) ranging from -1.00 to -0.15. For HF heart rate variability, patients with DRE with VNS had a lower value (-0.45) before surgery than after surgery in the response subgroup, with a 95% CI ranging from -0.74 to -0.17. No differences were found for LF/HF values or the LF and HF values of other subgroups. CONCLUSION: VNS has little effect on the balance of sympathetic and parasympathetic nerve activity and would not be expected to cause cardiovascular autonomic dysfunction in patients with DRE. For patients with DRE, VNS can control seizures and has little effect on autonomic nervous function.