microRNAs对PTZ致痫大鼠记忆损害调控机制的研究

Epilepsy patients with memory disorders seriously affect the quality of patients' life and attract much attention at all times, but the exact mechanisms as how microRNA mediates their actions are still to be elucidated. Studies had shown that there is a close relationship between an abnormalities regulation of microRNA and memory disorders of some diseases of nervous system disease, such as epilepsy, Alzheimer's Disease and ischemic cerebrovascular disease. However, it is not clear whether microRNA is also implicated in memory impairment of epilepsy. PTZ will be injected into abdomen to induce chronic epilepsy rat mode in this research, behavioral features and memory impairment of the chronic epilepsy rats are detected; the microRNA expression in the brain tissue and blood will be compared with each other, to investigate the change of microRNA expression in chronic epilepsy rat with memory impairment,the target genes will be predicted and possibly enriched biological signaling pathways by biology will be analyzed; and then, the changes of memory impairment and microRNA expression will be studied after intervened by microRNA agonists; finally,the molecular biology changes of miroRNA and the electrophysiological of brain slices in vitro will be studied through the whole cell patch clamp technology and various molecular biology techniques. The study on microRNA can provide new drug target for clinical prevention and treatment for memory disorders in epilepsy.

癫痫患者的记忆障碍因严重影响患者的生活质量而备受关注，但至今仍无明确的机制或靶点。研究表明，microRNA表达和功能的异常与癫痫、AD及缺血性脑血管病的学习、记忆障碍等有密切的关系，但microRNA是否参与癫痫记忆障碍的调控尚不明确。本研究拟采用PTZ慢性癫痫大鼠模型，行为学实验检测大鼠记忆损害情况，通过比较各组大鼠脑组织及血液中的microRNA表达谱变化，筛选差异表达的microRNA；然后进行生物学分析，预测靶基因及可能富集的生物学信号通路；随后用microRNA激动剂干预癫痫大鼠后，观察其记忆障碍变化情况及microRNA的表达情况；最后应用全细胞膜片钳技术和分子生物学技术，研究大鼠模型离体脑片电生理学指标和脑内miRNA差异表达的分子生物学指标的改变，旨在通过探讨microRNA在癫痫大鼠的记忆障碍中的作用及意义，为癫痫记忆障碍的研究和诊治提供新的依据和靶点。

认知功能障碍是常见的癫痫共患病，因其严重影响患者的生活质量而备受关注。研究表明，microRNA表达及功能的异常与癫痫和认知功能障碍关系密切，但microRNA是否参与癫痫后认知障碍的调控仍不明确。本研究以戊四氮构建慢性癫痫大鼠模型，建立了Morris水迷宫认知功能评价体系；通过芯片扫描，获得了伴及不伴认知功能障碍致痫大鼠海马组织中存在差异性表达的microRNA，其中包括4种上调表达因子及7种下调表达因子；通过生物学分析，预测了靶基因及可能富集的生物学信号通路，并利用MAPK通路抑制剂SB203580，证实p38-MAPK通路可通过介导凋亡途径导致癫痫后认知功能障碍；同时，经microRNA激动剂/抑制剂干预，进一步明确了miR-let-7c-1、miR-344a、miR-328a、miR-181a、miR-34c可通过介导细胞凋亡及调节BACE、NMDA受体表达，参与癫痫共患认知功能障碍的形成。本课题通过探讨microRNA在癫痫大鼠的记忆障碍中的作用及意义，为大鼠认知功能提供了新的评估体系，为癫痫共患认知功能障碍的研究和诊治提供新的依据和靶点。