CD200调控神经炎性反应在皮质发育畸形癫痫发生中的作用及机制

皮质发育畸形（MCD）是难治性癫痫的重要病因，神经炎性反应在MCD所致癫痫发生中起重要作用，CD200/R下调可导致神经炎性反应。申请者前期研究发现，CD200低表达于MCD的致痫细胞-“异构神经元”上，并在预实验中观察到CD200基因敲除MCD小鼠的癫痫发作频率较野生型小鼠明显增加。提示CD200通过调控神经炎性反应参与MCD所致癫痫的发生，但其分子机制尚不清楚。本项目拟以MCD动物模型为研究对象，综合运用形态学、分子生物学、神经电生理等技术，从在体和离体水平研究：（1）CD200/R对MCD动物模型及离体脑片中小胶质细胞活化程度、相关炎性因子的表达及对癫痫发作的影响；（2）MCD中是否存在CD200/R-Dok2-RasGAP-Ras-ERK-炎性因子的调控机制。初步阐明CD200调控神经炎性反应在MCD癫痫发生中的作用及分子机制，为难治性癫痫的防治提供新的理论依据和药物靶点。

Malformations of cortical development (MCD) are major causes of intractable paediatric epilepsy. Accumulating evidence suggests that activation of the microglia and concomitant inflammatory response in MCD may contribute to the initiation and recurrence of seizures. The membrane glycoproteins CD200, highly expressed on neurons, is a mediators of microglia inhibition via its receptor CD200Ron microglia. Down-regulation of CD200-CD200R results in microglia activation and concomitant inflammatory response. We have reported that CD200 expression is decreased in MCD patients and our preliminary experiment revealed lower seizure frequencies in CD200-/- MCD mouse models compare with control group. Therefore, we speculate that decreased expression of CD200 result in the activation of microglia and thus participate in the epileptogenesis of MCD by regulating the inflammation, but the specific molecular mechanisms is uncovered. In the present project, we will employ molecular biological, electrophysiological and some other methods to investigate the effect of CD200 on the electroencephalograph and behaviour of seizure, and elaborate a mechanism of CD200/R-Dok2-RasGAP-Ras-ERK-inflammtion in MCD. This project will raise new strategies for both mechanism underlying epileptogenesis and antiepileptic therapies of intractable epilepsy.