Guo Haokun, Zhang Hui, Zhang Chenlu, Shen Yuanyuan, Jiang Liumi, Yang Min, Zhang Yuansong, Zhang Ningning, Zhang Ruirui, Yu Ran, Yang Yong, Tian Xin
Department of Geriatrics.
Department of Neurology, and.
JCI Insight. 2025 Aug 22;10(16). doi: 10.1172/jci.insight.191347.
Epilepsy is a common neurological disorder resulting from an imbalance between neuronal excitation and inhibition. Synapses play a pivotal role in the pathogenesis of epilepsy. Src-homology 2 (SH2) domain-containing protein 5 (SH2D5) is highly expressed in the brain and is implicated in the regulation of synaptic function. However, its role and mechanism in epilepsy remain unclear. In this study, we found that SH2D5 was predominantly localized to pyramidal neurons in the mouse hippocampus and was upregulated in the hippocampus of epileptic brains. KO of Sh2d5 in the hippocampus alleviated both the susceptibility to and severity of epileptic activity. Mechanistically, SH2D5 regulated N-methyl-D-aspartate receptor-mediated (NMDAR-mediated) excitatory synaptic transmission by altering the protein expression levels of NMDAR subunits. We further demonstrated that SH2D5 modulated the transcription of NMDARs by promoting the autophagic degradation of STAT1. These findings suggest that targeting the SH2D5/STAT1/NMDAR pathway may offer a potential therapeutic strategy for epilepsy.
癫痫是一种常见的神经系统疾病，由神经元兴奋与抑制之间的失衡引起。突触在癫痫的发病机制中起关键作用。含Src同源2（SH2）结构域蛋白5（SH2D5）在大脑中高度表达，并参与突触功能的调节。然而，其在癫痫中的作用和机制仍不清楚。在本研究中，我们发现SH2D5主要定位于小鼠海马体中的锥体神经元，并且在癫痫脑的海马体中上调。海马体中Sh2d5基因敲除减轻了癫痫活动的易感性和严重程度。从机制上讲，SH2D5通过改变N-甲基-D-天冬氨酸受体（NMDAR）亚基的蛋白表达水平来调节NMDAR介导的兴奋性突触传递。我们进一步证明，SH2D5通过促进STAT1的自噬降解来调节NMDAR的转录。这些发现表明，靶向SH2D5/STAT1/NMDAR途径可能为癫痫提供一种潜在的治疗策略。
