电活动依赖的NLGN3释放参与AKT/mTOR通路调控OPCs增殖、分化和髓鞘化的机制研究

少突胶质前体细胞(OPCs)的增殖和发育是损伤轴突再髓鞘化的关键，亦是脊髓损伤(SCI)的潜在干预靶点。前期研究获悉轴突的髓鞘化程度受神经电活动水平调控，结合神经电活动依赖的NLGN3促进细胞增殖且和AKT/mTOR激活有关的新近研究成果，我们推测刺激神经电活动可能通过NLGN3-AKT/mTOR通路发挥促进OPCs增殖及再髓鞘修复SCI的作用。项目拟构建大鼠颈5脊髓半侧打击模型，通过靶向调节（激活/抑制）残存皮质脊髓束锥体神经元电活动，条件性抑制NLGN3释放或AKT/mTOR活性，解析模型动物OPCs增殖、分化、轴突髓鞘化以及前肢运动功能恢复的机制；进一步采用Cre-Loxp系统条件性敲除OPCs的Myrf基因阻断再髓鞘，勾勒髓鞘修复与运动功能恢复两者间的联系，项目能为治疗SCI提供新的康复思路和切入点。

Axon remyelination relies on the proliferation and development of oligodendrocyte progenitor cells (OPCs), which is a potential target in spinal cord injury (SCI) repair. Our previous studies showed that the degree of axon remyelination is regulated by the level of neuronal activity. Recently, researchers reported that the release of NLGN3, which is triggered by neuronal activity, plays a role in promoting cell proliferation and is related to AKT / mTOR activation. Hence, we speculate that the stimulation of neuronal activity may plays a role in promoting OPCs proliferation and remyelination to repair SCI through the NLGN3-AKT / mTOR pathway. We plan to establish a cervical 5 spinal cord hemi-contusion injury rat model, regulate（activation or inhibition）the activity of spared corticospinal tract pyramidal neurons and then observe the remyelination and forelimb motor recoveries under different circumstances, such as inhibition release of NLGN3 or AKT/mTOR pathway. Further, the Cre-Loxp system would be used to conditionally knock out the Myrf gene to block the remyelination, which could outline the relationship between myelin repair and motor function recovery. The project could provide new ideas and breakthrough points for the rehabilitation of SCI.