Caspase-1介导的突触剥离在小儿热惊厥发生中的作用及其特异性拮抗剂的研究

小儿热惊厥（FS）是由高热引起的痫性发作，易出现神经发育迟缓、智力低下、精神情感类障碍等。目前治疗FS主要采用地西泮或传统抗癫痫药物，但这些药物副作用大，且只能控制发作而不能预防FS的发生。我们最新研究发现，高热诱导小胶质细胞对神经元胞体上的突触进行剥离的行为并可能参与了FS发生，发现Caspase-1调控小胶质细胞突触剥离行为，进而介导了FS发生，提示Caspase-1可能是潜在的防治FS药物靶点。本课题将在前期预实验的基础上，利用Caspase-1基因敲除以及条件性基因敲除等多种转基因小鼠，采用胚胎电转、电生理、化学遗传学并结合在体钙成像和双光子技术，深入研究Caspase-1调控小胶质细胞介导的突触剥离行为作用及其在FS发生中的作用机制，在此基础上评价以Caspase-1为靶点的小分子化合物。本项目将有助于阐明FS的发病机制、发掘防治FS发生的新靶点并获得高效低毒的先导化合物。

Febrile seizures are convulsive events induced by fever, affecting 3-14% infants aged 6 months to 5 years old. These seizures are lack of therapeutic options as they are generated from abnormal, sudden and excessive electrical discharges. Consequently, one-third of the simple febrile seizure patients will have recurrence or prolong, which are always followed by high risks of developing into temporal lobe epilepsy, cognitive impairment or psychiatric disorder in their later life. Our preliminary data suggest that the microglia-mediated synaptic stripping may be involved in febrile seizure generation; and hyperthermia-induced Caspase-1 may promote microglia-mediated synaptic stripping and contribute to the generation of febrile seizure. In this project, we set out to study the role of Caspase-1 in microglia-mediated synaptic stripping and febrile seizure, by using various techniques including in vivo field potential recording, electron microscope, two photon calcium imaging combined with real-time visualization and in vitro electrophysiological methods. We will also dock the candidate molecules targeting Caspase-1 to prevent febrile seizure. Our study will shed light on the understanding of the pathogenesis of febrile seizure as well as help to find the effective preventive and curative leading compounds.