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

描述（由申请人提供）：持续发作活动的发作，癫痫持续状态，足以诱发颞叶癫痫。最近的工作已经确定TrkB激酶的激活是癫痫持续状态发作诱发终身颞叶癫痫的分子机制；然而，TrkB激活将大脑从正常转变为癫痫的细胞后果尚未确定。边缘系统主要神经元间兴奋性突触传递（LTP）的效力增强一直被认为是颞叶癫痫的一种机制。此外，海马体中的苔藓纤维- ca3突触在癫痫持续状态后经历了长期增强，这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状态诱导的该突触LTP需要TrkB的激活。我的建议的目的是通过结合化学遗传学方法和光遗传学研究从动物模型中分离的海马切片来验证这一假设。这项工作的成功完成有望揭示TrkB激活的假定细胞后果，这是颞叶癫痫发展的基础。

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.