EphrinB2关联GluN2调节稳态突触可塑性在NMDAR抗体相关自身免疫性癫痫发作中的作用

NMDAR抗体相关性癫痫发作临床特征独特，其异常网络发生和崩解机制不明。既往研究显示GluN2功能障碍可能是此类癫痫发作主要原因，而EphrinB2是GluN2通路核心调控因子。课题组前期研究证实患者急性期耐药，恢复期预后良好的阶段性特征，发现fMRI异常信号主要累及GluN2分布区域，与抗原同源的畸胎瘤中异形神经元高表达GluN2且与IgG共定位，脑脊液中炎性因子高表达，因此提出EphrinB2关联GluN2通路障碍对稳态突触可塑性破坏很可能是导致癫痫发作的主要原因，同时炎性因子促进癫痫发作。课题组结合临床、动物和体外实验，纵向研究不同时期异常神经网络衍变特征和差异蛋白表达，同时在动物模型中采用单细胞转录组测序筛选并提取关键因子，并在体外实验给予干预，评估对癫痫发作异常网络的影响，明确EphrinB2-GluN2-稳态突触可塑性具体作用途径，力图在自免性癫痫发作机制研究方面取得突破。

NMDAR antibody-related seizures are the most common type of autoimmune seizures, and the mechanism of abnormal neural network occurrence and disintegration is unknown. Previous studies have shown that GluN2 dysfunction leading to synaptic homeostasis may be the main cause of such seizures, and EphrinB2 is the core regulator of the GluN2 pathway. The previous study of us confirmed the stage characteristics of patients with acute drug resistance and good prognosis during the recovery period. It was found that the abnormal signal of fMRI mainly involved the distribution area of GluN2. In the teratoma homologous to the antigen, heteromorphic neurons highly expressed the GluN2 receptor and were associated with the co-localization of IgG, and the high expression of inflammatory factors was found in the cerebrospinal fluid. It suggests that the disruption of Ephrin2B-associated GluN2 pathway disorders to homeostatic synaptic plasticity is likely to be the main cause of seizures. At the same time, the activation of inflammation factors promotes seizures. The research team plan to combine clinical, animal and in vitro experiments to longitudinally study the abnormal neural network, evaluate characters and differential protein expression of patients at different periods, and used single-cell transcriptome sequencing to screen and extract key factors in animal models, and evaluate seizure and abnormal network after intervention in vitro experiments. We plan to make clear the details of pathway of EphrinB2-GluN2-homeostatic synaptic plasticity, and its impact on the abnormal network causing seizure. This project group try to make a breakthrough in the study of the mechanism of autoimmune seizures.