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Major depressive disorder (MDD) is a common, serious, debilitating mental illness. Protein phosphatase Mg2+/Mn2+-dependent 1F (PPM1F), a serine/threonine phosphatase, has been reported to have multiple biological and cellular functions. However, the effects of PPM1F and its neuronal substrates on depressive behaviors remain largely unknown. Here, we showed that PPM1F is widely distributed in the hippocampus, and chronic unpredictable stress (CUS) can induce increased expression of PPM1F in the hippocampus, which was correlated with depression-associated behaviors. Overexpression of PPM1F mediated by adeno-associated virus (AAV) in the dentate gyrus (DG) produced depression-related behaviors and enhanced susceptibility to subthreshold CUS (SCUS) in both male and female mice, while, knockout of PPM1F in DG produced antidepressant phonotypes under stress conditions. Whole-cell patch-clamp recordings demonstrated that overexpression of PPM1F increased the neuronal excitability of the granule cells in the DG. Consistent with neuronal hyperexcitability, overexpression of PPM1F regulated the expression of certain ion channel genes and induced decreased phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CAMKII) and Adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) in hippocampus. These results suggest that PPM1F in the DG regulates depression-related behaviors by modulating neuronal excitability, which might be an important pathological gene for depression or other mental diseases. • CUS induces depression-related behaviors and increases the expression of PPM1F in hippocampus. • Overexpression of PPM1F in hippocampal DG produces depression-related behaviors. • Knockout of PPM1F in hippocampal DG produces antidepressant phonotypes. • Manipulation of PPM1F affects the excitability of DG granule cells, the expression of ion channel genes, and phosphorylation levels of CAMKII and AMPK. [ABSTRACT FROM AUTHOR]