肌动蛋白－Cofilin异常在癫痫后记忆损伤中的作用及机制研究

项目名称： 肌动蛋白－Cofilin异常在癫痫后记忆损伤中的作用及机制研究

项目编号： No.31271188

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 医药、卫生

项目作者： 汪昕

作者单位： 复旦大学

项目金额： 88万元

中文摘要： 癫痫反复发作后记忆功能缺损的神经机制至今还缺乏研究。近年的研究表明肌动蛋白及其调控蛋白cofilin在异常刺激下会形成栓状结构（rod），阻碍神经元胞浆运输，与老年或疾病相关的记忆功能衰退的早期发病相关。我们在前期癫痫机制的研究以及初步预实验的基础上提出如下假说：癫痫发作中神经元的异常活动引发cofilin rod生成后阻碍神经元胞浆运输、诱导神经元突触丢失和突触传递功能下降而引起的神经元退行病变是癫痫记忆缺损的重要机制之一。本项目拟在整体动物和离体培养海马神经元癫痫模型上，运用电生理、免疫荧光组化、分子生物学以及行为学方法阐明：1)癫痫诱导cofilin rod形成在突触功能的损伤与丢失、海马学习记忆功能缺损中的作用及机制；2）癫痫改变cofilin、LIMK和SSH的平衡关系在调控cofilin rod形成中的作用机制。本项目的完成将为癫痫记忆损伤研究与药物研发提供新理论与新靶点。

中文关键词： 癫痫；肌动蛋白调控蛋白；认知功能；树突棘；突触

英文摘要： Memory deficits in epilepsy are common in patients but its cause are still unknown. Cofilin is a major actin-depolymerizing factor in the CNS for regulation of actin dynamics. Certain stress stimulation can induce the formation of cofilin rod, a pathological structure composed of cofilin and actin, which disrupts cytoplasm transport, and it has been implied to neurodegenerative diseases. Based on our previous studies, we hypotyhesis that seizure related neuronal epileptiform activities will trigger the cofilin rod formation, in turn disrupt synapse function and cause neurite lost, which is the mechanism underline epilepsy related memory deficits. In this study, by applying electrophysiological, molecular biological and immunohistochmistry methods, we tended to answer 1) whether epilepsy will cause cofilin rod formation in hippocampal neurons and its relation to synapse dysfunction and nurite loss, and its association with memory deficit, 2) whether epileptiform activity imbalanced cofilin and its regulatory proteins LIM Kainase and Slingshot, which causes cofilin over active to form rod structure. From this study, we will reveal a noval mechanism underlying epilepsy related memory deficits , and will provide evidence and potential drug development target.

英文关键词： Seizure；cofilin；cognition；spine；synapse