Interneuron-based mechanisms of temporal lobe epilepsy

项目总结/摘要 癫痫在一生中影响26个美国人中的1个。颞叶癫痫是最常见的 常见类型三分之一的病人治疗失败。有效疗法的开发受到以下因素的限制： 关于自发性癫痫开始的知识缺口。确定自发性癫痫发作是如何开始的 颞叶癫痫是我们的长期目标该项目的主要目标是测试假设 癫痫发作的开始，至少部分是因为抑制性中间神经元降低了它们的动作电位放电频率， （失活），其减少兴奋性神经元的抑制控制。目的1是检测中间神经元是否 失活是针对特定的癫痫发作。癫痫患者多个脑区的局部场电位记录 治疗的大鼠将用于鉴定癫痫发作起始的部位。海马神经元的同步单位记录 将评估中间神经元以测试中间神经元失活是否在神经元中更频繁和更严重。 癫痫大鼠与对照大鼠以及癫痫发作部位与非发作部位。目标2是测试是否 防止中间神经元失活可防止癫痫发作。来自许多大脑区域的局部场电位记录 将被用于识别腹侧海马是癫痫发作焦点的大鼠。闭环激活 中间神经元可以防止癫痫发作部位的失活。光遗传学和依赖Cr 在谷氨酸脱羧酶-Cre和小清蛋白-Cre转基因中表达通道视紫红质的病毒载体 大鼠将被用于选择性地激活特定的中间神经元亚型。光遗传刺激 由快速眼动睡眠的实时检测触发，这是大鼠模型中许多癫痫发作的前兆。 颞叶癫痫目的3是测试是否灭活中间神经元导致癫痫发作。实验 方法将类似于目标2，除了新的Cl-传导视蛋白SwiChR++将用于 使中间神经元失活我们的失活假说与其他人的观点相反，其他人认为， interneurons是癫痫发作起始的机制。拟议的项目将严格测试多个 颞叶癫痫发生假说和对自发性癫痫发作如何开始的进一步理解。

Project Summary / Abstract Epilepsy affects 1 in 26 Americans over the course of a lifetime. Temporal lobe epilepsy is one of the most common types. Medical treatment fails in one-third of patients. Development of effective therapies is limited by gaps in knowledge about how spontaneous seizures begin. Determining how spontaneous seizures initiate in temporal lobe epilepsy is our long-term goal. The primary goal of the proposed project is to test the hypothesis that seizures start, at least in part, because inhibitory interneurons reduce their action potential firing frequency (deactivate), which reduces inhibitory control of excitatory neurons. Aim 1 is to test whether interneuron deactivation is seizure specific. Local field potential recordings from many brain regions in epileptic pilocarpine- treated rats would be used to identify sites of seizure initiation. Simultaneous unit recordings of hippocampal interneurons would be evaluated to test whether interneuron deactivation is more frequent and severe in epileptic versus control rats and at seizure onset sites versus non-onset sites. Aim 2 is to test whether preventing interneuron deactivation prevents seizures. Local field potential recordings from many brain regions would be used to identify rats in which the ventral hippocampus is the seizure focus. Closed-loop activation of interneurons would prevent deactivation at sites of seizure onset. Optogenetics and Cre-dependent channelrhodopsin-expressing viral vectors in glutamic acid decarboxylase-Cre and parvalbumin-Cre transgenic rats would be used to selectively activate specific interneuron subtypes. Optogenetic stimulation would be triggered by real-time detection of rapid eye movement sleep, which precedes many seizures in rat models of temporal lobe epilepsy. Aim 3 is to test whether deactivating interneurons causes seizures. The experimental approach would be similar to that of Aim 2, except the novel Cl--conducting opsin SwiChR++ would be used to deactivate interneurons. Our deactivation hypothesis is opposite of others that contend that hyperactivity of interneurons is a mechanism of seizure initiation. The proposed project would rigorously test multiple hypotheses of temporal lobe ictogenesis and advance understanding of how spontaneous seizures start.