丘脑前核GABA能神经元在全导多棘波串的产生及特发性全面性癫痫耐药机制中的作用研究

特发性全面性癫痫的耐药机制是目前癫痫领域的热点和难点问题。申请人研究首次发现全导多棘波串是耐药性特发性全面性癫痫的脑电图标志物（Neurology, 2018），提示深入分析全导多棘波串可能会揭示其耐药机制。丘脑前核是临床上深部脑刺激治疗耐药性癫痫的靶点之一，申请人预实验发现耐药性患者丘脑区域的γ-氨基丁酸(GABA)功能异常，且基础研究发现光遗传学激活丘脑前核GABA能神经元能够有效抑制耐药性癫痫发作。因此申请人推断丘脑前核GABA能异常可能与全导多棘波串的产生及耐药性机制有关。申请人拟在前期研究基础上，通过EEG-fMRI、EEG-MRS、钙信号记录、离体电生理、光/化学遗传学和药理学等手段，在临床研究和基础整体动物模型两个层面明确在耐药性特发性全面性癫痫中，丘脑前核GABA能突触抑制作用在全导多棘波串的产生及耐药机制中的作用，为临床药物治疗提供理论依据，同时也为新药研发提供新的靶点。

It is still a hot and difficult point for the mechanisms of drug resistance in idiopathic generalized epilepsy. We found that generalized polyspike train is a biomarker of drug resistant idiopathic generalized epilepsy for the first time in the world. By deeply studying of generalized polyspike train we may find the mechanism of drug resistance. Anterior nucleus of thalamus is one of the treatment target of deep brain stimulation. The applicant found that γ-aminobutyric acid (GABA) function in thalamic area of drug-resistant patients was abnormal in the preliminary experiment, and the basic research found that the activation of GABA neurons in the light of genetics can effectively inhibit drug-resistant epilepsy. Therefore, the applicant infers that the abnormal GABAergic activity in the anterior thalamic nucleus may be related to the production of generalized polyspike train and the mechanism of drug resistance. On the basis of previous studies, the applicant intends to clarify the role of GABA synaptic inhibition in the production of generalized polyspike train and the mechanism of drug resistance by means of EEG-fMRI, EEG-MRS, calcium signal recording, in vitro electrophysiology, photochemical genetics and pharmacology in clinical research and basic whole animal model, so as to provide theoretical foundation for clinical drug treatment and potential target for new drug development.