小胶质细胞外泌体miR-146a-5p通过KLF4/CDK5途径调控抑郁症大鼠海马神经发生

近年临床证据表明，神经炎症是抑郁症发病的潜在危险因素，但机制不清。小胶质细胞是中枢神经系统炎症反应的主要参与者。申请人前期研究表明，抑郁症大鼠脑内小胶质细胞激活，高通量测序显示其分泌的外泌体中miR-146a-5p显著增加。进一步研究发现抑郁大鼠海马齿状回(DG)新生的神经元减少，并伴随miR-146a-5p靶向调控蛋白KLF4的表达降低；而敲减DG区miR-146a-5p则显著增加新生的神经元，并发挥抗抑郁效应。外泌体是最近发现的一种新的细胞间通讯方式，由此我们推测激活的小胶质细胞可能通过分泌富含miR-146a-5p的外泌体，调控海马神经发生，继而参与抑郁症的发病。因此本项目拟研究：1）小胶质细胞通过外泌体调控海马神经发生的分子机制；2）外泌体携带的miR-146a-5p调控神经发生在抑郁症发病中的作用。从而阐明神经炎症介导抑郁症发病的机理，为临床抗抑郁治疗提供新的药物靶点。

Recently, neuroinflammation is considered as an important risk factor involved in the pathogenisis of depression. Microglia is the primary candidate for the inflammatory response in the central nervous system. We have previously found that microglia were significantly activated within the brain of depression animal model. High-throughput sequencing showed that the exosomes derived from microglia including high level of miR-146a-5p in depressed rats compared with the normal rats. Moreover, we found that the neurogenesis in hippocampal DG regions is reduced and the target protein of miR-146a-5p such as KLF4 is decreased in stressed rats, while knockdown miR-146a-5p in DG could improve neurogenesis in depressed rats, and thus ameliorated the depression-like behaviors. These results suggested that microglia-derived exosomes may suppressed neurogenesis via miR-146a-5p/KLF4 signaling pathway, and finally contribute to the induction of depression. Exosome is a new cell-cell communication type that founded in recent years. Therefore, based on the previous findings, we will use Cre-loxp conditional gene knockout methods to further investigate the following aspects: (1) Investigate the role of microglia-derived exosomes signaling pathway on the function of neuronal circuit and the mechanism of exosome on regulating the neurogenesis; (2) Illustrate the mechanisms by which miR-146a-5p/KLF4 signaling pathway could contribute to the neurogenesis in vivo and as well as depression-like disorders in chronic stress induced depressive rats. Controlling the expression of this pathway could improve mental disorders therapy and provide the new target for drug discovery and development.