POTASSIUM CHANNELS AND EPILEPTOGENESIS

本申请适用于指导临床科学家开发 奖项（K 08）。该候选人获得了儿童临床培训 在加州大学洛杉矶分校的神经病学，然后完成了为期两年的奖学金， 美国国立卫生研究院神经药理学（癫痫 研究分支，NINDS）之前，他目前的教师 1994年在华盛顿大学任职。 很长的- 候选人的长期职业目标是研究关系 离子通道和癫痫发生之间的联系， 发展性癫痫的新疗法， 分子基础，并探讨遗传关系 易感性和环境影响在发病机制中的作用 发展性癫痫 大学医学中心和 儿童医院在基础设施方面优势互补， 神经科学和临床儿科癫痫学。 实验室空间、设备和专业顾问 在合作的基础上提供给候选人， 几个学术部门。 这种环境非常适合 支持和培养候选人的长期专业 目标. 我们选择mKv1.1作为实验模型 钾通道单基因小鼠突变体， 在发育早期自发性癫痫发作 首先我们假设 CA 3中一个特定的钾通道亚基的缺失 海马区的功能改变， 锥体神经元的生理特性， 变得过度兴奋，并倾向于过度同步， 放电 其次，我们假设药物治疗 可以改变癫痫的自然过程，并可能保护 动物神经元损伤的结果，反复 癫痫发作 最后，我们将探讨部分表达是否 mKv1.1基因在正/负小鼠中，导致增强的 癫痫发作的易感性，可以通过二次暴露来改变 海人酸（一种强效的惊厥剂和神经毒素） 发展 最初的努力将涉及电生理学 海马切片中CA 3锥体神经元的记录 取自不同年龄的无效突变体;内在和突触 这些细胞的特性，以及全细胞钾电流， 将采用细胞外、细胞内和膜片钳技术进行测量 记录技术。视频EEG监测（带深度 电极）将用于记录癫痫样或癫痫发作 海马区的活性，以及 神经元损伤和/或可塑性将用常规方法进行， 特殊的（例如，Timm）污渍。 这些研究的结果可能会导致 更好地理解离子通道在 癫痫发生，可能揭示了有争议的问题， 慢性癫痫发作是否会导致脑损伤， 进一步研究遗传和 大脑发育中的环境交互作用。

This application is for a Mentored Clinical Scientist Development Award (K08). The candidate obtained clinical training in Child Neurology at UCLA, and then completed a two-year fellowship in neuropharmacology at the National Institutes of Health (Epilepsy Research Branch, NINDS) prior to taking his current faculty appointment in 1994 at the University of Washington. The long- term career goal of the candidate is to study the relationship between ion channels and epileptogenesis, to identify potentially novel treatments for developmental epilepsies that have a rational molecular basis, and to explore the relationship between genetic susceptibility and environmental influence in the pathogenesis of the developmental epilepsies. The university medical center and Children's Hospital possess complementary strengths in the basic neurosciences and clinical pediatric epileptology, respectively. Laboratory space, equipment, and specialized consultants are available to the candidate on a collaborative basis provided by several academic departments. This environment is ideally suited for supporting and fostering the candidate's long-term professional goals. We have chosen as our experimental model the mKv1.1 potassiumchannel single gene mouse mutant which exhibits spontaneous seizures early in development. First, we hypothesize that loss of a specific potassium channel subunit in the CA 3 region of the hippocampus results in a functional alteration in physiological properties of pyramidal neurons such that they became hyperexcitable and prone to excessive synchronization of discharge. Second, we postulate that pharmacological treatment can alter the natural course of the epilepsy and may protect the animal from neuronal injury as a consequence of repeated seizures. Finally, we will explore whether partial expression of the mKv1.1 gene in plus/minus mice, resulting in an enhanced susceptibility to seizures, can be modified by secondary exposure to kainic acid (a potent convulsant and neurotoxin) early in development. Initial efforts will involve electrophysiological recordings from CA3 pyramidal neurons in hippocampal slices taken from null mutants at different ages; intrinsic and synaptic properties of these cells, as well as whole-cell potassium currents, will be measured with extracellular, intracellular and patch-clamp recording techniques. Video-EEG monitoring (with depth electrodes) will be employed to document epileptiform or seizure activity in the hippocampus, and histochemical analysis of neuronal damage and/or plasticity will be made with routine and special (e.g., Timm) stains. The results of these studies may lead to an improved understanding of the role ion channels play in epileptogenesis, may shed light on the controversial issue of whether chronic seizures can cause brain damage, and will provide a framework for further studies examining genetic and environmental interactions in the developing brain.