睡眠相关的运动过度性癫痫（SHE）与睡眠关系密切，主要发生于非快速眼动期（NREM），这一特征为癫痫发生机制研究提供了新的切入点。近期我课题组首次发现SHE患者携带GABRG2基因功能增强型突变（错义突变：c.1070C>A，p.T357N）。结合NREM期特征性生理变化，丘脑网状核GABA能神经元抑制丘脑额叶皮质环路，导致局部回路锥体神经元超极化后出现同步化放电（对癫痫发作有易化作用）。提示：丘脑皮质环路GABA能活动过度增强可能是导致SHE发生的关键机制。本项目拟首先应用CRISPR/Cas9技术构建突变敲入鼠，观察突变鼠的行为学和脑功能变化；其次观察基因突变对丘脑及额叶皮质神经元GABAAR的生物钟昼夜节律性表达、膜转运以及电生理特性的影响；进而探索基因突变对丘脑额叶皮质环路电活动的影响；最后调控丘脑GABAAR的功能，观察对SHE发生的影响。本项目的完成为癫痫发生机制提供新的思路。

Sleep-related hypermotor epilepsy (SHE) is an epilepsy syndrome that is closely related with sleep, typically arising during non-rapid eye movement (NREM) sleep. The exploration of pathogenic mechanism of SHE may bring about a breakthrough in the understanding of the origin, propagation and termination of epilepsy. Recently, we discovered a likely pathogenic mutation in GABRG2 (c.1070C>A, p.T357 N) in SHE patients for the first time. In in-vitro experiment, we found that GABAA receptors containing a mutant γ2 subunit had increased GABA-evoked whole-cell current amplitudes compared with wild-type α1β2γ2 receptors. Previous studies demonstrated that the GABAergic neurons of thalamic reticular nucleus can inhibit the thalamocortical circuit during NREM sleep, which leads to synchronized activity of cortical pyramidal neurons and further facilitates epileptic activity. These findings indicated that increased activity of GABAAR of thalamocortical circuit might be the key cause of SHE. Based on our previous preliminary work, we aim to clarify the role of GABRG2 mutations in the pathogenic mechanism of SHE. Firstly, we will evaluate the behavioral and EEG feature of our established Gabrg2T357N/WT knock-in mice using CRISP/Cas9 technology. Then, we will examine the circadian expression profile and membrane transportation of GABAAR in the model. We will further explore the effects of GABRG2 mutation on the electrophysiological properties of neuron and the activity of thalamocortical circuit. Finally, we will assess the effects of regulating the function of GABAAR of thalamus on the attack of SHE. Our study will provide new understanding of pathogenic mechanism in epilepsy.