Ito Hikaru, Nozaki Kanako, Sakimura Kenji, Abe Manabu, Yamawaki Shigeto, Aizawa Hidenori
Department of Neurobiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
Center for Experimental Animals, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Neuropsychopharmacology. 2021 Jan;46(2):442-454. doi: 10.1038/s41386-020-00843-0. Epub 2020 Sep 17.
The lateral habenula (LHb) attracts a growing interest as a regulator of monoaminergic activity which were frequently reported to be defective in depression. Here we found that chronic social defeat stress (CSDS) increased production of pro-inflammatory cytokines in LHb associated with mobilization of monocytes and remodeling of extracellular matrix by increased matrix metalloproteinase (MMP) activity. RNA-seq analysis identified proprotein convertase Pcsk5 as an upstream regulator of MMP activation, with upregulation in LHb neurons of mice with susceptibility to CSDS. PCSK5 facilitated motility of microglia in vitro by converting inactive pro-MMP14 and pro-MMP2 to their active forms, highlighting its role in mobilization of microglia and monocytes in neuroinflammation. Suppression of Pcsk5 expression via small interfering RNA (siRNA) ameliorated depressive-like behaviors and pathological mobilization of monocytes in mice with susceptibility to CSDS. PCSK5-MMPs signaling pathway could be a target for development of the antidepressants targeting the inflammatory response in specific brain regions implicated in depression.
外侧缰核（LHb）作为单胺能活性的调节因子，正吸引着越来越多的关注，单胺能活性在抑郁症中常被报道存在缺陷。在此，我们发现慢性社会挫败应激（CSDS）增加了LHb中促炎细胞因子的产生，这与单核细胞的动员以及细胞外基质通过基质金属蛋白酶（MMP）活性增加而重塑有关。RNA测序分析确定前蛋白转化酶Pcsk5是MMP激活的上游调节因子，在对CSDS敏感的小鼠的LHb神经元中上调。PCSK5通过将无活性的前MMP14和前MMP2转化为其活性形式，促进了体外小胶质细胞的运动，突出了其在神经炎症中动员小胶质细胞和单核细胞的作用。通过小干扰RNA（siRNA）抑制Pcsk5表达可改善对CSDS敏感的小鼠的抑郁样行为和单核细胞的病理性动员。PCSK5-MMPs信号通路可能成为开发针对抑郁症相关特定脑区炎症反应的抗抑郁药物的靶点。
