Mechanisms of Limbic Epileptogenesis

描述（由申请人提供）：了解边缘癫痫发生的机制可能会导致新的疾病修饰疗法。我们已经发现癫痫发生与海马苔藓纤维通路中TrkB的增强激活有关。我们还发现神经营养因子受体TrkB是点燃模型中癫痫发生所需的。本申请的目的是解决两个关键问题：增强的TrkB激活存在于苔藓纤维通路内的哪些神经元群体中？TrkB在点燃模型中的强大抗癫痫作用是否可推广到其他临床相关模型？新品系转基因小鼠的形态学和电生理学研究将用于解决这些问题。我们提出三个目标。确定与边缘癫痫发生相关的TrkB激活增加的替代指标在苔藓纤维通路内的细胞定位。确定在匹鲁卡品癫痫持续状态模型中抑制TrkB信号传导是否可预防癫痫发生。确定抑制TrkB信号传导是否可预防Kv1.1 -/-小鼠的癫痫发生。这些目标的成功完成将为阐明TrkB缺失限制癫痫发生的细胞机制提供有价值的信息。这些实验也可以确定一个新的分子靶点，用于开发特异性和有效的抗癫痫治疗。公共卫生相关性：了解边缘癫痫发生的机制可能会导致新的疾病修饰疗法。我们已经发现癫痫发生与海马苔藓纤维通路中TrkB的增强激活有关。我们还发现神经营养因子受体TrkB是点燃模型中癫痫发生所需的。我们试图确定抑制TrkB信号传导是否可以防止动物模型中其他类型的癫痫发生。这些信息将指导旨在利用TrkB作为抗癫痫治疗的分子靶点的努力。

DESCRIPTION (provided by applicant): Understanding the mechanisms of limbic epileptogenesis may lead to novel disease modifying therapies. We have discovered that epileptogenesis is associated with enhanced activation of TrkB in the mossy fiber pathway of hippocampus. We have also discovered that the neurotrophin receptor, TrkB, is required for epileptogenesis in the kindling model. The objective of this application is to address two key questions: In what population of neurons within the mossy fiber pathway does the enhanced TrkB activation reside? Is the powerful antiepileptogenic effect of TrkB in the kindling model generalizable to other clinically relevant models? Morphological and electrophysiological studies of novel lines of genetically modified mice will be used to address these questions. We propose three Aims. To determine the cellular localization within the mossy fiber pathway of a surrogate measure of increased TrkB activation associated with limbic epileptogenesis. To determine whether inhibiting TrkB signaling prevents epileptogenesis in the pilocarpine status epilepticus model. To determine whether inhibiting TrkB signaling prevents epileptogenesis in the Kv1.1 -/- mouse. Successful completion of these Aims will provide valuable information for elucidating a cellular mechanism by which deletion of TrkB limits epileptogenesis. These experiments may also identify a novel molecular target for development of specific and effective anti-epileptogenic therapies. PUBLIC HEALTH RELEVANCE: Understanding the mechanisms of limbic epileptogenesis may lead to novel disease modifying therapies. We have discovered that epileptogenesis is associated with enhanced activation of TrkB in the mossy fiber pathway of hippocampus. We have also discovered that the neurotrophin receptor, TrkB, is required for epileptogenesis in the kindling model. We seek to determine whether inhibiting TrkB signaling prevents other types of epileptogenesis in animal models. This information will guide efforts aimed at exploiting TrkB as a molecular target for anti-epileptogenic therapies.