KCNQ2相关发育性癫痫性脑病中KCNQ3基因的补偿失衡机制研究

发育性癫痫性脑病是婴幼儿早期起病的神经发育障碍性疾病，两大核心表型为难治性癫痫与发育障碍。KCNQ2基因是发育性癫痫性脑病最常见的遗传学病因之一，随访中我们发现癫痫的早期控制并未逆转患儿远期严重的发育障碍，而如何改善大脑发育障碍，是诊治中面临的巨大挑战。申请人基于前期预实验结果提出KCNQ3基因对Kv7通道功能的补偿失衡可能是KCNQ2相关发育性癫痫性脑病遗留严重发育障碍的重要原因。本项目中，我们拟比较KCNQ2不同表型及野生鼠大脑发育过程中KCNQ3的动态表达谱，Kv7通道功能及海马突触可塑性等差异，并通过遗传药理学等技术干预KCNQ3的表达或通道功能，评估小鼠认知改善，进一步验证上述猜想。项目的实施将从新的角度阐明KCNQ2相关发育性癫痫性脑病中认知障碍的形成机制，为后续改善大脑发育提供新的理论依据和切实可行的干预靶点。

Developmental epileptic encephalopathy (DEE) is a neurodevelopmental disorder with early onset in infants and young children. The two core phenotypes are refractory epilepsy and developmental impariment. KCNQ2 gene is one of the most common genetic causes of DEE. In the follow-up, we found that the early control of epilepsy did not reverse the long-term severe developmental impariment of the children, and how to improve the brain development disorder is a challenge in the diagnosis and treatment. Based on the preliminary experimental results, the applicant proposed that the imbalance of KCNQ3 gene's compensation for the function of Kv7 channel might be an important reason for the developmental retardation of KCNQ2-related DEE. In this project, we planned to compare the dynamic expression profile of KCNQ3, Kv7 channel function and hippocampal synaptic plasticity during different phenotypes of KCNQ2 and the brain development of wild mice, and to evaluate the cognitive improvement of mice by intervening the expression or channel function of KCNQ3 through genetic and pharmacological techniques, so as to further verify the above conjecture. The implementation of the project will clarify the formation mechanism of cognitive impairment in KCNQ2-related DEE from a new perspective, and provide a new theoretical basis and a feasible intervention target for the subsequent improvement of brain development.