兴奋性自体突触在癫痫发生中的作用及其InsP6介导机制

Epilepsy is a common chronic neurological condition that is characterized by recurrent unprovoked epileptic seizures. These seizures are transient signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. It affects approximately 50 million people worldwide, and pediatric patients accounted for 2/3. Although the development of diagnostic and therapeutic strategy and epilepsy is usually controlled, but not cured, with medication, its biological process still cannot be corrected. It suggests that its pace-maker remains unclear. In the immature brain, the excitatory autapses (EA) are common, can increase the excitability of the neuron itself. However, its roles in epileptogenesis are not clear. We have demonstrated that the numbers of EA within epileptic foci increased significantly, and the structural cutting of EA by 2-photon axotomy could block the discharge of epileptic forms. Therefore, in the present study, using transgenic and optogenetic animals to establish a epilepsy model combining focal cortical dysplasia with status epilepsy, further applying tools to knockdown or over-express certain genes in hot brain regions, and combining with the application of molecular biology, optogenetics, electrophysiology, pharmacology, morphology, and behavioral tests, we try to answer the following questions: the pattern of EA distribution and EA numbers within epileptic foci during epileptogenesis; the exact role of EA in epileptogenesis; InsP6 signaling pathway-mediated EA transmission and its roles in epileptogenesis. Aims to elucidate the role of EA in epileptogenesis and the mechanisms underlying EA transmission, and to reveal that EA and its transmission may be an important mechanism for pediatric epilepsy. The results will help us to better understand the role of EA in the pathophysiology of associated neurological and mental illness in children, and provides us a novel biological strategy for controlling of these diseases.

癫痫是一种常见疑难病症，儿童患者占到2/3。虽治疗策略发展迅速，但仍然不能纠正其生物学进程，提示其根本机制仍未阐明。未成熟脑内兴奋性自身突触（EA）较为常见，能提高神经元自身的兴奋性，但在癫痫发生中的作用并不明确。我们前期研究发现癫痫灶内EA数量显著增加，结构性切断EA能阻断癫痫波的发放。在此基础上，本项目拟应用转基因、光遗传学等动物，制备“双重打击”癫痫模型，并综合应用分子生物学、光遗传学、电生理学、药理学、形态学及行为学等手段，研究癫痫灶内神经元EA数量和分布的时空变化规律及神经生物学特性；EA在癫痫发生中的确切作用；肌醇六磷酸信号通路介导EA传递及其在癫痫发生中的作用。旨在阐明EA调控癫痫发生的作用和EA传递的介导机制，揭示EA及其相关机制可能是儿童癫痫发病的重要机制。本研究将有助于人们更好地了解EA在儿童相关神经精神疾病病理生理机制中的作用，并为这些疾病的生物学防治提供新的策略。

癫痫是一种常见疑难病症，儿童患者占到2/3。虽然治疗策略发展迅速，但仍然不能纠正其生物学进程，提示其根本机制仍未完全阐明。未成熟脑内兴奋性自身突触（EA）较为常见，能提高神经元自身的兴奋性，但在癫痫发生中的作用并不明确。本项目应用基因敲除等动物，制备“双重打击”癫痫模型，并综合应用分子生物学、电生理学、药理学、形态学及行为学等手段，获取了癫痫灶内神经元EA 数量和分布的时空变化规律及神经生物学特性；初步明确了EA在癫痫发生中的确切作用；并发现InsP6信号通路介导EA传递及其在癫痫发生中的作用。本研究将有助于人们更好地了解EA在儿童相关神经精神疾病病理生理机制中的作用，并为这些疾病的生物学防治提供新的策略。目前已发表SCI论文6篇(第一标注4篇，第二标注1篇，第三标注1篇)，国内一级刊物论文2篇(第一标注)，培养博士研究生3人(毕业)、在读博士生1人、硕士生1人。已完成英文手稿(2篇，投稿中)。完成国内外学术交流13人次，国外教授来实验室交流4次。项目主持在在国内兼任多个学术兼职，比如2016-2019年任中华医学会儿科学分会脑科学委员会副主任、浙江省数理医学学会新型生物标记物专委会常委(2019年起)、浙江省医学会儿科分会小儿神经学组委员(2016年起)，对推动学科发展起到了积极作用。