颅脑创伤后星状胶质细胞的p75NTR影响突触可塑性参与形成认知功能障碍的机制探究

Traumatic brain injury (TBI) results in significant cognitive deficits particularly in attention, learning and memory, and higher-order executive functions. However, despite significant effort very few therapeutic options exist to prevent or reverse cognitive impairment following TBI. Synaptic plasticity plays an important role on the cognition function. The 75 neurotrophin receptor (p75NTR, encoded by NGFR) is a transmembrane glycoprotein member of the TNF receptor (TNFR) superfamily and binds to all neurotrophins to mediate various functions. The expression of p75NTR on the astrocyte in the brain are upregulated after TBI. Whether does p75NTR expressed on the astrocyte participate cognition dysfunction via modulating synaptic plasticity after TBI? These questions remain unclear so far. Therefore, this project will explore the mechanism of p75NTR expressed on the astrocyte participating in the cognition deficient after TBI by use of molecular biology technology, cellular biology technology and transgenic animal model. The contents about this project will include three parts: (1) The determination of cognition function, synaptic plasticity, cell survival and the expression of p75NTR in the cortex and hippocampus after TBI in mice. (2) The effect of p75NTR expressed on the astrocyte on synaptic plasticity, cognition function and astrocyte reactive and related protein after TBI in mice. (3) The possible mechanism of p75NTR expressed on the astrocyte affect the cognition function and synaptic plasticity after TBI in mice. This study will help to clarify the role of p75NTR expressed on the astrocyte affecting in synaptic plasticity after TBI and highlight the contribution of p75NTR expressed on the astrocyte to the cognition dysfunction after TBI in mice. The p75NTR will provide a novel site for modifying synaptic plasticity and improving cognition after TBI, and become to be potential target for drug development in treatment TBI.

颅脑创伤后认知功能障碍是临床常见的行为障碍，与突触可塑性失调密切相关。p75NTR是神经营养因子的受体。颅脑创伤后星状胶质细胞表达增加的p75NTR是否介导突触可塑性改变而参与认知功能障碍的形成？国内外无相关报道。所以，本课题利用分子生物学、细胞生物学技术和转基因动物，从分子、细胞、脑片和整体动物等多层面，探讨颅脑创伤后星状胶质细胞的p75NTR影响突触可塑性参与认知功能障碍的机制，内容包括（1）颅脑创伤后小鼠认知功能和突触可塑性的改变、细胞存活和p75NTR的表达。（2）颅脑创伤后星状胶质细胞的p75NTR对认知功能、突触可塑性和星状胶质细胞激活和相关蛋白的影响。（3）星状胶质细胞的p75NTR影响突触可塑性的机制。本课题的完成将阐明颅脑创伤后星状胶质细胞的p75NTR影响突触可塑性参与认知功能障碍的机制，为将来针对以p75NTR为靶点的药物开发和临床改善颅脑创伤后认知功能提供新的思路。

颅脑创伤后的认知功能障碍是临床常见的严重功能障碍，与突触可塑性失调密切相关。本项目从分子、细胞、脑片和整体动物等多层面，探讨颅脑创伤后星状胶质细胞的p75NTR影响突触可塑性参与认知功能障碍的机制，具体研究结果：（1）小鼠闭合性颅脑创伤后的认知功能显著降低，同时还引起皮层与海马的突触结构与功能受损以及星状胶质细胞p75NTR的表达上调；（2）降低海马星形胶质细胞p75NTR的表达，能够显著降低星形胶质细胞的肥大样形态、抑制A1表型相关基因的表达、降低海马透析液中谷氨酸与D-serine 的浓度、改善海马内的突触功能以及小鼠的认知功能；（3）在过表达p75NTR的脑片，同时降低TRAF2以及TRAF6能够抑制星形胶质细胞的肥大样活化并增强海马神经元的sEPSC以及sIPSC的幅值及频率。释放谷氨酸与D-serine，影响突触可塑性。（4）星状胶质细胞p75NTR表达上调，通过募集TRAF2或TRAF6激活PI3K/Akt/IP3R2信号通路诱使细胞内钙库释放使胞内钙离子浓度增加，活化星形胶质细胞促进谷氨酸与D-serine的合成及释放。总之，颅脑创伤造模后海马星状胶质细胞的p75NTR的表达上调，募集胞内的TRAF2与TRAF6活化星形胶质细胞，使细胞内钙库释放使胞内钙离子浓度增加，促使海马内谷氨酸及D-serine的浓度升高，突触可塑性改变，最终引起认知功能障碍。本项目的完成阐明颅脑创伤后星状胶质细胞的p75NTR影响突触可塑性参与认知功能障碍的机制，为将来针对以p75NTR为靶点的药物开发和临床改善颅脑创伤后认知功能提供新的思路。本项目共发表15篇文章，其中SCI有8篇，影响因子46.61，核心期刊5篇，参加2次国际会议，5次国内会议，会议论文2篇，会议poster展示获二等奖。在此期间培养博士生2名，硕士研究生6名，3名学生分别获得国家奖学金及企业奖学金。