Kir2.1钾通道调节miR-9/FOXP2通路参与癫痫后学习记忆障碍的机制研究

学习记忆功能障碍是颞叶癫痫（TLE）最常见的伴随症状，与海马神经元活性改变以及突触重塑有关，但具体机制一直未能阐明，缺乏有效治疗。申请人在前期工作中发现：内向整流钾离子通道Kir2.1亚基(Kir2.1)是介导癫痫后学习记忆障碍的关键分子。过表达Kir2.1降低海马齿状回颗粒细胞兴奋性，上调非编码小分子RNA miR-9水平，miR-9靶向结合核转录因子叉头框P2基因（FOXP2）。因此申请人推测：癫痫发作上调Kir2.1，激活活性依赖性miR-9/FOXP2信号通路，损伤突触可塑性，导致学习记忆功能减退。本项目拟在此基础上，构建过表达Kir2.1转基因小鼠，建立TLE慢性期小鼠模型，结合分子生物学、免疫组化、膜片钳电生理以及动物行为学技术进一步探讨癫痫发作后Kir2.1介导学习记忆障碍的作用与机制，为临床治疗TLE诱发的认知功能损伤提供新策略。

The learning and memory dysfunction is the most common symptom caused by temporal lobe epilepsy (TLE). So far, there is no effective treatment for learning and memory impairment. It has been suggested that the pathogenesis of learning and memory impairment is associated with neuronal activity and synapse reorganization after TLE, but its underlying mechanisms is still not fully elucidated. Our previous work demonstrate that the Kir2.1 inward rectifying potassium channel (kir2.1) is a key molecular mediates deficit of learning and memory in TLE mice. Overexpression of Kir2.1 channel decreased the excitability of hippocampal dentate granule cells, meanwhile, the level of activity-regulated miR-9 is increased in TLE mice. miR-9 can target to bind Forkhead box protein P2(FOXP2). We hypothesize that seizures may increases the function expression of Kir2.1 channel, which activate miR-9/FOXP2 signaling pathway and cause synaptic plasticity damage and learning and memory disorders. Based on the previous work, the proposed study will use the Kir2.1 mutant mice to construct cognitive dysfunction mice model induced by TLE, combined with applying molecular biology, immunohistochemistry, electrophysiological recording and animal behaviour detection methods, we will further explore the effects and mechanisms of Kir2.1 in earning and memory deficts induced by TLE . Our study will provide a new idea and strategy for the clinical treatment of cognitive dysfunction.