癫痫后齿状回新生神经元异位迁移是导致难治性癫痫的病理生理基础之一。我们的前期研究发现敲除DISC1可使体外培养的神经干细胞过度迁移，而癫痫导致DISC1在海马区表达下调。但DISC1对癫痫后新生神经元迁移的作用及调控机制尚不明确。国外研究提示 AKT-mTOR和Reelin通路可调控新生神经元迁移，而DISC1可能在两条通路中发挥作用。故我们提出假说：DISC1通过AKT-mTOR、Reelin通路调控癫痫后新生神经元迁移。为验证假说，本项目拟建立匹罗卡品自发性痫性发作小鼠模型，采用逆转录病毒或慢病毒载体进行单基因干预，结合分子生物学、电生理学、行为学等研究技术，以“DISC1-新生神经元迁移-癫痫”为新视点，从“功能-机制-干预”三个层次研究DISC1对癫痫后新生神经元迁移的调控机制，为揭示海马局部异常神经环路形成的分子病理生理机制奠定基础，以期为难治性癫痫药物治疗提供新的干预靶点。

Ectopic migration of newborn neurons in the dentate gyrus (DG) after seizures in adults often contributes to the pathophysiology of intact epilepsy. Our previous study revealed that DISC1 reduced in hippocampus after seizures, and its knockdown led to over-migration of neural stem cells in vitro. However, the mechanism for DISC1 regulation of these newborn neurons’ migration after epileptic seizures is still unknown. Other studies demonstrate that AKT-mTOR and Reelin signal pathways are related not only to DISC1, but also to the migration of new neurons. Therefore, we hypothesize that DISC1 regulates migration of newborn neurons in the DG after epileptic seizures via AKT-mTOR or/and Reelin signal pathways. To confirm our hypothesis, we designed a study based on retrovirus or lentivirus-based gene intervention in a pilocarpine-induced chronic spontaneous seizures C57BL/6 mouse model, combined with related techniques in molecular biology, electrophysiology, and ethology. This project will provide novel insight on the relationship between DISC1, new neuron migration, and epileptogenesis by examining the mechanism and potential interventions for DISC1 regulation of newborn neuron migration in the DG in epilepsy. Additionally, our study could supply evidence for the theory that abnormal neural circuits form in the hippocampus after epileptic seizures, potentially providing therapeutic targets for intact epilepsy.