SH2D5通过活化Rac1调控兴奋性突触传递参与癫痫发作的作用及机制

癫痫严重威胁人类健康。神经兴奋抑制功能失衡是癫痫发病的核心元素，研究调控兴奋性/抑制性突触传递的关键分子有助于癫痫防治。课题组基于长期建立的癫痫家系遗传库及癫痫患者术后脑库，分别利用全外显子测序及基因芯片扫描两种方式同时筛选出病理生理功能知之甚少的SH2D5，其与癫痫的关系目前未见报道。本项目预实验发现SH2D5在癫痫脑组织中表达上调，干预海马SH2D5表达可以影响戊四氮动物模型的癫痫点燃进程并选择性调节无镁癫痫脑片中的微小兴奋性突触后电流，此外亦发现干预SH2D5可以相应改变Rac1活性，这些结果初步提示SH2D5可能通过活化Rac1调控兴奋性突触传递参与癫痫发作，但还需进一步论证和研究具体功能机制。本项目拟在分子、细胞、动物和癫痫患者脑组织层面，借助分子生物学、动物行为学、在体场电位、膜片钳等技术，多维度验证SH2D5参与癫痫发生发展的角色并探讨潜在机制，为癫痫治疗提供新的靶点和依据。

Epilepsy is a serious threat to human health. The imbalance between neuronal excitation and inhibition is the core element of epilepsy. Further analysis of the key molecules regulating excitatory/inhibitory synaptic transmission is helpful for the prevention and treatment of epilepsy. Based on the long-established genetic database of epileptic pedigrees and brain tissue bank of patients with epilepsy, SH2D5 was simultaneously screened at different levels by whole exon sequencing and gene chip technology. Little is known about the pathophysiological function of SH2D5, and its relationship with epilepsy has not been reported. In the pre-experiment of this project, we found that the expression of SH2D5 is upregulated in epileptic brain tissue, and intervention of hippocampal SH2D5 expression can affect the kindling process of a pentylenetetrazol mouse model and selectively regulate the miniature excitatory postsynaptic currents in a magnesium-free-induced brain slice model of epileptiform activity. In addition, interference with SH2D5 altered the Rac1 activity in vivo. These results suggest that SH2D5 may participate in epilepsy by activating Rac1 to regulate excitatory synaptic transmission, but the specific functional mechanism needs to be further verified and studied. The purpose of this project is to verify the role of SH2D5 in the development of epilepsy and explore the possible mechanism at the levels of molecules, cells, animals and tissues from epileptic patients by using molecular biology assays, animal behavior analysis, local field potentials, patch clamp analysis and other techniques to provide a new target and basis for the treatment of epilepsy.