近年遗传学研究发现多种家族性遗传癫痫病患者携带Slo家族钾通道基因的突变。我们最近的研究表明这些突变通过提高通道开放可能性 (Po)导致通道过度激活。然而这些突变如何改变通道开放可能性以及怎样诱发癫痫仍未得到阐明。本课题将以此为切入点，运用爪蟾卵母细胞表达系统，采用双电极、内向外膜片钳记录方法，结合结晶学、计算机模拟揭示这些突变产生过度激活的分子机制。同时本项目将采用基因敲除(Loss-of-function)小鼠、过度激活致痫突变(Gain-of-function)小鼠，通过行为学、免疫双标、离子选择性电极、分子荧光探针和电生理膜片钳相结合的方法，以分子-细胞-脑区-行为整合研究阐明突变过度激活导致癫痫的细胞生物学机制。本课题将为深入理解Slo家族钾通道过度激活致痫机制提供理论基础，也为临床医生对携带这些突变的癫痫病人寻求相应的治疗方案和药物选择提供依据。

Recently, genetic research has revealed that several types of genetic family Epilepsy patients carry Slo family channel mutations. Our recent work revealed that these mutants lead to channel over-activity by increasing open probabilities （Po） of Slo channels. However, how the Po of Slo channels is altered and how these mutants cause seizures remains elusive. In this project, we will address molecular mechanisms that how these mutants increase channel open probabilities by using the methods of patch-clamp recordings in the Xenopus expression system, crystallography, computer modeling and simulations. In the meantime, we will take advantage of both channel knockout (Loss-of-function) and mutant (Gain-of-function) mice to investigate cellular mechanism of the mutants lead to seizure by combing the methods of brain-slice recordings, immunostaining, ion selective electrode and fluorescence probes. The overall goal of this project is going to provide a theoretical basis for understanding the mechanism of seizures induced by Slo-family mutants. Also, the results of this project can help clinicians select effective methods and drugs for treatment of epilepsy patients who carry these mutants.