Activation of proprotein convertase in the mouse habenula causes depressive-like behaviors through remodeling of extracellular matrix
Activation of proprotein convertase in the mouse habenula causes depressive-like behaviors through remodeling of extracellular matrix
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DOI：
10.1038/s41386-020-00843-0
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发表时间：
2020-09-17
影响因子：
7.6
通讯作者：
Aizawa, Hidenori
中科院分区：
文献类型：
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作者：
Ito, Hikaru;Nozaki, Kanako;Aizawa, Hidenori
外侧缰核（LHb）作为单胺能活性的调节剂引起了越来越多的兴趣，单胺能活性经常被报道为在抑郁症中存在缺陷。在这里，我们发现慢性社交失败压力（CSDS）增加了LHb中促炎细胞因子的产生，这些细胞因子与单核细胞的动员和基质金属蛋白酶（MMP）活性增加而重塑细胞外基质相关。 RNA-seq 分析发现前蛋白转化酶 Pcsk5 是 MMP 激活的上游调节因子，在对 CSDS 敏感的小鼠的 LHb 神经元中表达上调。 PCSK5 通过将非活性的 pro-MMP14 和 pro-MMP2 转化为其活性形式，在体外促进小胶质细胞的运动，突出了其在神经炎症中小胶质细胞和单核细胞动员中的作用。通过小干扰 RNA (siRNA) 抑制 Pcsk5 表达可改善 CSDS 易感性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抗抑郁药的目标，该药物针对与抑郁症相关的特定大脑区域的炎症反应。
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 convertasePcsk5as 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 ofPcsk5expression 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.