Microglial forkhead box O3a deficiency attenuates LPS‐induced neuro‐inflammation and depressive‐like behaviour through regulating the expression of peroxisome proliferator‐activated receptor‐γ

Background and Purpose Depression is closely linked with microglial activation and neuro‐inflammation. Peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) plays an important role in M2 activation of microglia. Forkhead box (FOX) O3a has been implicated in the regulation of mood‐relevant behaviour. However, little is known about the inflammatory mechanisms of in the microglia of the brain. Here, we have investigated the role of microglial FOXO3a/PPAR‐γ in the development of depression. Experimental Approach The effect of FOXO3a on microglia inflammation was analysed in vitro and in lipopolysaccharide (LPS)‐induced depression‐like behaviours in vivo . ChIP‐seq and Dual‐luciferase reporter assays were used to confirm the interaction between FOXO3a and PPAR‐γ. Behavioural changes were measured, while inflammatory cytokines, microglial phenotype and morphological properties were determined by ELISA, qRT‐PCR, western blotting and immunostaining. Key Results Overexpression of FOXO3a significantly attenuated expression of PPAR‐γ and enhanced the microglial polarization towards the M1 phenotype, while knockdown of FOXO3a had the opposite effect. FOXO3a binds to the promoters of PPAR‐γ and decreases its transcription activity. Importantly, deacetylation and activation of FOXO3a regulate LPS‐induced neuro‐inflammation by inhibiting the expression of PPAR‐γ in microglia cells, supporting the antidepressant potential of histone deacetylase inhibitors. Microglial FOXO3a deficiency in mice alleviated LPS‐induced neuro‐inflammation and depression‐like behaviours but failed to reduce anxiety behaviour, whereas pharmacological inhibition of PPAR‐γ by GW9662 restored LPS‐induced microglial activation and depressive‐like behaviours in microglial FOXO3a‐deficient mice. Conclusion and Implications FOXO3a/PPAR‐γ axis plays an important role in microglial activation and depression, identifying a new therapeutic avenue for the treatment of major depression.