Medial prefrontal cortical PPM1F alters depression‐related behaviors by modifying p300 activity via the AMPK signaling pathway

AIMS: Protein phosphatase Mg2+/Mn2+‐dependent 1F (PPM1F) is a serine/threonine phosphatase, and its dysfunction in depression in the hippocampal dentate gyrus has been previously identified. Nevertheless, its role in depression of another critical emotion‐controlling brain region, the medial prefrontal cortex (mPFC), remains unclear. We explored the functional relevance of PPM1F in the pathogenesis of depression. METHODS: The gene expression levels and colocalization of PPM1F in the mPFC of depressed mice were measured by real‐time PCR, western blot and immunohistochemistry. An adeno‐associated virus strategy was applied to determine the impact of knockdown or overexpression of PPM1F in the excitatory neurons on depression‐related behaviors under basal and stress conditions in both male and female mice. The neuronal excitability, expression of p300 and AMPK phosphorylation levels in the mPFC after knockdown of PPM1F were measured by electrophysiological recordings, real‐time PCR and western blot. The depression‐related behavior induced by PPM1F knockdown after AMPKα2 knockout or the antidepressant activity of PPM1F overexpression after inhibiting acetylation activity of p300 was evaluated. RESULTS: Our results indicate that the expression levels of PPM1F were largely decreased in the mPFC of mice exposed to chronic unpredictable stress (CUS). Behavioral alterations relevant to depression emerged with short hairpin RNA (shRNA)‐mediated genetic knockdown of PPM1F in the mPFC, while overexpression of PPM1F produced antidepressant activity and ameliorated behavioral responses to stress in CUS‐exposed mice. Molecularly, PPM1F knockdown decreased the excitability of pyramidal neurons in the mPFC, and restoring this low excitability decreased the depression‐related behaviors induced by PPM1F knockdown. PPM1F knockdown reduced the expression of CREB‐binding protein (CBP)/E1A‐associated protein (p300), a histone acetyltransferase (HAT), and induced hyperphosphorylation of AMPK, resulting in microglial activation and upregulation of proinflammatory cytokines. Conditional knockout of AMPK revealed an antidepressant phenotype, which can also block depression‐related behaviors induced by PPM1F knockdown. Furthermore, inhibiting the acetylase activity of p300 abolished the beneficial effects of PPM1F elevation on CUS‐induced depressive behaviors. CONCLUSION: Our findings demonstrate that PPM1F in the mPFC modulates depression‐related behavioral responses by regulating the function of p300 via the AMPK signaling pathway.