TrkB in status epilepticus-induced LTP of the mossy fiber-CA3 synapse

描述(申请人提供)：一次持续的癫痫发作活动，癫痫持续状态，足以引起颞叶癫痫。最近的工作已经确认TrkB激酶的激活是癫痫持续状态导致终生颞叶癫痫的分子机制；然而，这种TrkB激活将大脑从正常转变为癫痫的细胞后果尚未确定。长期以来，边缘系统主神经元之间兴奋性突触传递(长时程增强[LTP])的增强效应一直被认为是颞叶癫痫的一个机制。此外，海马体中苔藓状纤维-CA3突触在癫痫持续状态后经历长期增强，这是一种突触可塑性，可能有助于癫痫大脑。间接证据使我假设癫痫持续状态诱导的突触LTP需要激活TrkB。我的建议的目的是用化学遗传学方法与从动物模型分离的海马片的细胞电生理学和光遗传学研究相结合来检验这一假说。这项拟议工作的成功完成有望阐明TrkB激活可能导致颞叶癫痫发生的细胞学后果。

DESCRIPTION (provided by applicant): An episode of continuous seizure activity, status epilepticus, is sufficient to induce temporal lobe epilepsy. Recent work has identified activation of TrkB kinase as a molecular mechanism by which an episode of status epilepticus induces lifelong temporal lobe epilepsy; however, the cellular consequences of this TrkB activation that transform the brain from normal to epileptic have not been identified. Enhanced efficacy of excitatory synaptic transmission (long-term potentiation [LTP]) between principal neurons of the limbic system has long been advanced as one mechanism underlying temporal lobe epilepsy. Moreover, the mossy fiber-CA3 synapse in the hippocampus undergoes long-term potentiation after status epilepticus, a synaptic plasticity that could contribute to the epileptic brain. Circumstantial evidence leads me to hypothesize that status epilepticus-induced LTP of this synapse requires activation of TrkB. The objective of my proposal is to test this hypothesis using a combination of a chemical-genetic method with cellular electrophysiological and optogenetic studies of hippocampal slices isolated from an animal model. Successful completion of the proposed work promises to shed light on putative cellular consequences of TrkB activation that underlie development of temporal lobe epilepsy.