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.
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We thank Dr. Deepa Kamath Kasaragod for critical reading of the manuscript and Ms. Yuka Ishimaru, Ms. Sawako Ogata, Ms. Fumie Nishimura, Ms. Saori Okamura, and Natural Science Center for Basic Research and Development of Hiroshima University for the technical assistance. This research was supported by the Program of the Network-type Joint Usage/Research Center for Radiation Disaster Medical Science.
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Ito, H., Nozaki, K., Sakimura, K. et al. Activation of proprotein convertase in the mouse habenula causes depressive-like behaviors through remodeling of extracellular matrix. Neuropsychopharmacol. (2020). https://doi.org/10.1038/s41386-020-00843-0