癫痫发生发展不同时期BDNF在脑内的作用存在很大的争议。我们前期研究发现慢性发作期癫痫鼠海马内BDNF和TrkB的表达减少，而突触外GABAA受体介导的紧张性抑制与癫痫的发生发展有密切的关系。BDNF可调节GABAA受体亚单位的运输，我们推测在癫痫慢性期持续性注射BDNF恢复海马内BDNF水平可通过调节突触外GABAA受体表达与功能抑制癫痫发作。本项目将在CTZ/KA癫痫动物模型上应用行为学、电生理、Western blot以及免疫组织化学等方法研究阐明在癫痫慢性发作期：1）BDNF-TrkB以及突触外GABAA受体表达分布变化；2）增加海马内BDNF含量对癫痫发作的影响作用；3）BDNF-TrkB-PLCγ调控突触外GABAA受体δ和α5亚单位表达与功能的机制。本项目的完成将阐明癫痫慢性期BDNF-TrkB-PLCγ通路调控突触外GABAA受体中的作用机制及其抑制自发癫痫发作的作用

It is controversial about role of BDNF in epileptogenesis and development of seizure. Our previous work discovered that BDNF and its receptor TrkB are decreased in the chronic recurrent phase of the epileptic rats; and the tonic inhibition mediated by the extrasynaptic GABAA receptors is closely related to the epileptogenesis. BDNF has been reported to regulate the transportation of GABAA receptors to the synapse. We hypothesis that increasing BDNF levels by continuous intrahippocampal infusion will up regulate the extrasynaptic GABAA receptor expression and function, and in turn to inhibit the epileptogenesis in the chronic phase of the epilepsy. We plan, by using behavioral, electrophysiological, Western blot and immunohistochemistry techniques in the chronic CTZ and KA seizure animal model，to study: 1) whether any change of the BDNF, TrkB and the extrasynaptic GABAA receptor expression occurred in the chronic phase of the epilepsy, 2) what the effect on the recurrent seizure by artificial increasing of the BDNF level in the hippocampus, and 3) how the BDNF-TrkB-PLCγ and its down stream signaling pathway regulate the expression and the function of the δ and α5 subunit of the extrasynatic GABAA receptors. The completion of this project will demonstrate that the mechanism of BDNF-TrkB-PLCγ and its down stream signaling pathway regulating extrasynaptic GABAA receptor in chronic recurrent phase of epilepsy and the role of BDNF-TrkB-PLCγ signaling pathway inhibit recurrent seizure.