MSCs通过调控抑制性网络参与癫痫发病机制的研究

Imbalance between excitatory and inhibitory function is one of the most important mechanisms in epilepsy and epileptogenesis, which not only including the malformation of excitatory neuron network but also the malformation of inhibitory neuron network.Our previous study discovered that by regulating the GABAA receptors-related proteins could enhance the inhibitory function in epileptic-seizure. However, There a lot of neuronal loss could be seen in epilepsy and the severity of epilepsy might be associated with a reduction in the efficiency of inhibitory function of some GABAA receptors.In a long run, Both gene and neural cell transplantation therapies have great promise for reducing neuronal loss and might rehabilitate inhibitory function thus could restrain the development of SE and epileptogenesis.This project is to investigate the mechanism of MSCs participating in epilepsy by regulating inhitory function by using cytological, histological, proteomics, electrophysiology,genetic method.The study will provide theoretical foundation for cell transplantation in curing epilepsy and improving inhibitory function in epilepsy either in experimental research or in clinical.

兴奋性抑制性功能失调是癫痫形成的重要机制，其中不仅包括异常兴奋性神经网络形成也包括异常抑制性神经网络形成，而后者目前研究范围极其有限。我们前期研究发现通过调控抑制性GABA受体相关蛋白可以一定程度上促进抑制功能恢复从而控制癫痫。但癫痫形成过程中伴随大量神经元死亡故仅内源性提高抑制功能程度也很有限。最新研究也表明主导脑内抑制功能的GABA受体变异是导致其抑制功能降低的主要原因。故通过外源性移植细胞替代死亡细胞恢复抑制功能将是未来研究发展方向。本项目通过细胞学、组织学、蛋白组学、电生理学、基因学多层次，直接间接相结合的方式探索MSCs移植对癫痫形成中抑制功能的影响及相关机制。为以后外源性细胞移植恢复抑制功能及治疗癫痫提供理论基础，以期为临床治疗癫痫拓展新思路。

GABA受体结合位点显著减少是癫痫持续状态演变为难治性癫痫持续状态的主要原因，同时也与苯二氮唑类药物失效有关。因此，我们需要对苯二氮类药物耐药的癫痫持续状态患者寻找其他治疗方法。证据表明细胞外分泌外泌体可与其母细胞发挥相似功能，我们假设将中间神经元前体细胞胞外囊泡移植到癫痫持续状态模型脑内可能起到重要抑制作用甚至可能对苯二氮类药物耐药的癫痫持续状态起作用。本实验结果发现移植后外泌体可延长匹罗卡品癫痫持续状态模型小鼠的癫痫发作潜伏期及缩短苯二氮卓类药物终止癫痫持续状态的时间，提高其稳定治疗效果。实验同时发现移植外泌体模型中抑制性受体增加。本实验为临床治疗难治性癫痫提供了新的治疗方法，同时也为各种gaba能神经元异常引起相关疾病带来全新研究思路。