Neuroligin-1介导的海马突触传递兴奋/抑制失衡在术后认知功能障碍中的作用及机制

Our previous study has shown that hippocampal microglia activation-mediated neuroinflammation leads to PV interneuron phenotype loss accompanied by reduction of excitatory synaptic transmission to PV interneurons in the mice with postoperative cognitive dysfunction (POCD), suggesting that dysfunction of PV interneurons might be involved in the development of POCD, but the mechanisms remain to be elusive. Based on the following findings: 1) PV interneurons output inhibitory signals and the dysfunction of PV interneurons are deeply involved in the pathogenesis of many neuropsychiatric disorders; 2) neuroligin-1 (NL1) is a postsynaptic protein found in excitatory synapses and dynamically shapes excitatory synaptic efficacy and plasticity; and 3) neuroinflammation modulates the expression of NL1 via activating HDAC2. Therefore, we hypothesize that anesthesia and surgery activate hippocampal microglia and subsequent enhance neuroinflammation, which down-regulates NL1 expression by activating HDAC2 and consequently suppresses excitatory synaptic inputs to PV interneurons, contributing to reduced inhibitory synaptic outputs of PV interneurons. Finally, the imbalance of the excitatory and inhibitory synaptic transmission in the hippocampus may result in the development of POCD. We will apply molecular biology, electrophysiological techniques and behavioral tests to reveal the new mechanisms underlying POCD in terms of molecules-synapses-cells-overall behaviors. Our work will provide potential interventional targets for the prevention and treatment of POCD.

我们前期研究发现：POCD小鼠海马小胶质细胞活化介导的神经炎症反应可引起PV中间神经元“表型缺失”伴兴奋性传入减少，提示海马PV中间神经元功能受损参与POCD的发生，但机制不清。鉴于：1）PV中间神经元输出抑制性信号，其功能异常可致多种神经精神疾病；2）神经连接蛋白-1（Neuroligin-1，NL1）位于兴奋性突触后膜，动态调节兴奋性突触的效能及可塑性；3）HDAC2参与神经炎症反应对NL1表达的调控，我们推测麻醉手术活化海马小胶质细胞，引起神经炎症反应，激活HDAC2，下调NL1表达，导致PV中间神经元接受的兴奋性传入减少，引起其抑制性输出亦减少，表现为海马突触传递兴奋/抑制失衡，最终导致POCD。本课题拟采用POCD动物模型，通过分子生物学、电生理、行为学等技术，从分子信号—突触形成—细胞功能—整体行为多层次揭示POCD发生的新机制，为POCD防治的干预提供潜在新靶点。

术后认知功能障碍（postoperative cognitive dysfunction，POCD）是麻醉手术后出现的一种常见中枢神经系统并发症，尤其好发于老年患者，其临床主要表现为学习、记忆、注意力等认知功能受损。一项多中心研究表明，在60岁以上的老年人经历非心脏大手术中，POCD的发生率在术后一周为25.8%，术后3个月为9.9%。POCD的发生延长患者住院时间，使患者生活质量下降，增加患者死亡率。尽管关于POCD机制的研究多种多样，但神经炎症反应在POCD中的重要作用已得到公认。本项目从神经炎症入手，探讨其引起POCD的相关机制。. 通过本项目研究，我们初步得出一些结果：. （1）POCD模型小鼠海马小胶质细胞和星形胶质细胞活化，神经炎症反应增加；（2）POCD模型小鼠NMDAR和钙蛋白酶过度活化，TrkB 受体（full-length receptor，TrkB-FL）截断增加，脑源性神经营养因子（Brain-derived neurotrophic factor，BDNF）表达下降，BDNF/TrkB信号失调；（3）高尔基染色表明POCD模型小鼠海马树突棘数量减少；（4）给予NMDAR拮抗剂美金刚和钙蛋白酶抑制剂MDL28170均可改善上述变化及认知功能。本课题揭示了NMDAR/Ca2+/calpain信号通路介导的BDNF/TrkB信号失调是POCD发生的重要机制，有望为POCD的防治提供新视角和实验依据。