MiR-129-5p prevents depressive-like behaviors by targeting MAPK1 to suppress inflammation

Depression is a complex etiological disease with limited effective treatments. Previous studies have indicated the involvement of miRNAs in the pathophysiology of mood disorders. In this study, we focused on the role and mechanisms of miR-129-5p in depression by successfully constructing mice models of depressive-like behavior via chronic unpredictable mild stress (CUMS) exposure. Herein, miR-129-5p expression was decreased in the hippocampus of CUMS mice model. Upregulation of miR-129-5p reduced depressive-like behaviors of CUMS mice, as revealed in sucrose preference test, novelty suppressed feeding test, forced swim test, tail suspension test, social interaction test. MiR-129-5p upregulation decreased the concentrations and protein levels of proinflammatory cytokines (IL-6, IL-1β and TNF-α), indicating the inhibitory role of miR-129-5p in inflammation. Furthermore, miR-129-5p was identified to target MAPK1. MAPK1 was negatively regulated by miR-129-5p, and silencing of MAPK1 attenuated depressive-like behaviors in CUMS mice. Moreover, MAPK1 downregulation decreased inflammation in the hippocampus of CUMS mice. Upregulation of MAPK1 reversed the suppressive effects of miR-129-5p upregulation on depressive-like behaviors and inflammation in CUMS mice. In conclusion, the current study identified that miR-129-5p reduces depressive-like behaviors and suppresses inflammation by targeting MAPK1 in CUMS mice, offering a novel molecular interpretation for depression prevention.