Notch信号途径对惊厥不同时期发育期海马神经发生动态改变的调控机制

Seizure is one of the most common critical diseases of the nervous system in children with higher incidence of seizure-induced brain damage than adult. Recent research found that interference of hippocampal neurogenesis is one of the important characteristics of brain damage induced by seizure, but the changes of hippocampal neurogenesis in developmental brain is lack of system research and the mechanism is poorly understood. Notch signaling pathway plays an important role in regulating of neurogenesis in the brain, and is an important regulation of the neural stem cell in hippocampal subgranular zone. Our research group has found that the expression of Notch1 protein is consistent with the extent of neural stem cell proliferation in hippocampal subgranular zone at acute and chronic phase after status convulsion on the basis of preliminary study. Therefore, this study will deeply study the characteristics of hippocampus neurogenesis in developing brain at different period of seizure (acute phase, latency phase and chronic phase), and research the possible mechanism of Notch signaling pathway regulating hippocampal neurogenesis at different period after seizure. Meanwhile we will observe the effect of targeted regulating Notch signaling pathway on hippocampal neurogenesis at acute and chronic period of seizure. This study will provide a new theoretical basis for sustaining normal hippocampal neurogenesis and reducing seizure-induced brain damage in developing brain.

惊厥是儿童期神经系统常见的危急症之一，惊厥性脑损伤的发生率远较成人高，减轻惊厥性脑损伤是当前小儿神经科学急需解决的热点问题。最新研究发现海马神经发生进程的显著干扰也是惊厥性脑损伤的重要特征，但目前尚缺乏在发育脑内的系统研究，机理更是知之甚少。Notch信号途径在神经发生调控中发挥重要作用，是海马齿状回下区干细胞群行为的重要调节点。本课题组在前期基础上进一步发现惊厥急、慢性期Notch1表达同海马神经干细胞增殖呈现一致的动态改变，因此本项目拟对惊厥不同时期（急性期、潜伏期及慢性期）发育期海马神经发生的动态演变特征进行系统研究，并从Notch信号途径关键环节入手，探索Notch信号途径在惊厥后海马神经发生中的可能调控作用，同时在惊厥急、慢性期针对性调控Notch信号途径，观察能否有效干预惊厥后异常的海马神经发生进程。本项目将为维持惊厥后发育期海马神经发生正常稳态，减轻惊厥性脑损伤提供新的途径。

惊厥是儿童期神经系统常见的危急症之一，惊厥性脑损伤的发生率远较成人高，减轻惊厥性脑损伤是当前小儿神经科学急需解决的热点问题。海马神经发生进程的显著干扰是惊厥性脑损伤的一个重要特征。本研究证实惊厥不同时期（急性期、潜伏期及慢性期）发育期海马神经发生呈现先过度增加后显著抑制的动态过程，并通过对Notch信号途径的关键蛋白和靶基因进行分析，发现Notch信号途径的激活或抑制与惊厥后海马神经发生的动态改变具有一致相关性，证实Notch信号途径在惊厥后神经发生调控中发挥重要作用：即在急性惊厥期Notch信号途径过度激活，导致海马神经发生异常增加，新增殖的细胞分化紊乱；慢性惊厥期Notch信号途径受到抑制，进而可能解除了其侧面抑制效应，导致海马齿状回未分化的神经干细胞不受抑制而大量分化，从而使神经干细胞池中未分化神经细胞的数目降低，最终使神经干细胞耗竭，进而破坏海马神经细胞稳态的维持。本实验还在此基础上对惊厥急、慢性期探索性的调控Notch信号途径，发现可改善惊厥后异常的海马神经发生进程。本项目为维持惊厥后发育期海马神经发生正常稳态、减轻惊厥性脑损伤提供新的实验室依据。