miR-146a reduces depressive behavior by inhibiting microglial activation

Depression is one of the major psychiatric diseases affecting the quality of life for individuals worldwide. Numerous reports have investigated depression, although its etiology remains to be elucidated. microRNA (miR)-146a is suggested to regulate innate immune and inflammatory responses. However, it is unclear whether miR-146a is involved in depression. Depression model mice were established using lipopolysaccharide-induced depression and chronic unpredictable mild stress, separately. miR-146a mimic and short interfering RNA were used to treat depressed mice. Depression-like behaviors and levels of pro-inflammatory cytokines were measured, while ionized calcium binding adapter molecule 1 (Iba-1) expression in hippocampus was quantified by immunohistochemistry. Neuroinflammatory factor levels in hippocampus were measured by western blotting. BV-2 cells were used to confirm that miR-146a suppressed microglia activation. Compared with control mice, the two depressed mouse models showed clearly decreased sucrose preference and significantly increased immobility time in the forced swimming test and tail suspension test (P<0.05). miR-146a overexpression significantly increased sucrose preference and reduced immobility time in depressed mice (P<0.05). However, total distance traveled in the locomotor activity test did not differ among groups. Compared with controls, expression levels of Iba-1, inducible nitric oxide, IL-1β, TNF-α, interleukin 1 receptor associated kinase 1 (IRAK1), TNF receptor-associated factor 6 (TRAF6) and phosphorylated NF-κB p65 were significantly increased in depressed mice (P<0.05). miR-146a overexpression effectively inhibited expression of these neuroinflammatory proteins, while miR-146a silencing significantly upregulated their expression (P<0.05). Consistent with these in vivo results, miR-146a mimic treatment inhibited TNF-α, IL-1β, IRAK1 and TRAF6 expression in BV-2 cells. miR-146a improved depressive behaviors in depressed model mice by inhibiting microglial activation and neuroinflammatory factor expression.