探讨GABA(A)R对小胶质细胞的调控在POCD中的作用机制

Postoperative cognitive dysfunction (POCD) is a severe complication frequently seen in aged patients after surgery. Neuroinflammaiton, which is induced by significant peripheral inflammation, is important in provoking the occurrence and development of POCD after peripheral surgery. Microglia activation and microgliosis induced by the recruitment of bone marrow-derived mononuclear macrophages (BM-DP) after TLR4 activation play an important role between peripheral inflammation and neuroinflammation. GABA(A)R participates in the regulation of macrophages activation by TLR4 signal. But the relationship between the GABA(A)R and POCD has not been elucidated. Our previous study showed that GABA(A)R submits in hippocampus were downregulated in mice of POCD. We also found that pretreatment of GABA(A)R agonist decreased hippocampal TNF-α and MCP-1 expression, and finally protected the cognitive function of LPS-treated mice. Accordingly, we hypothesized that GABA(A)R contribute to the occurrence of POCD by promoting TLR4 related BM-DP migration and activation. So we will investigate the effect of GABA(A)R on POCD and further understand the relevant mechanism from the animal and cell models. It will provide us a new insight of POCD.

术后认知功能障碍（POCD）是老年患者术后常见的严重神经系统并发症。目前认为引发POCD的中枢炎症与外周炎症息息相关。TLR4介导的骨髓来源的单核巨噬细胞（BM-DP）迁移进入中枢参与小胶质细胞的增生和活化，是联系外周炎症和中枢炎症的重要枢纽。已知GABA(A)R参与调控TLR4介导的单核细胞活化。GABA(A)R和POCD之间有何关联？我们的预实验发现POCD小鼠海马中GABA(A)R表达下调，而GABA(A)R兴奋剂可明显减轻腹腔注射LPS的小鼠海马中小胶质细胞的增生和活化，减轻中枢炎症，改善认知功能。据此我们推测GABA(A)R通过调控TLR4介导的BM-DP活化和迁移，放大中枢炎症，参与POCD的进程。为验证此假说，我们拟从整体和细胞两个层面采用嵌合体小鼠等基因分子技术探讨GABA(A)R在POCD中的作用及机制。该项目将揭示POCD发病的新机制，为防治POCD提供新思路。