PPM1F in Dentate Gyrus Modulates Anxiety-Related Behaviors by Regulating BDNF Expression via AKT/JNK/p-H3S10 Pathway

Anxiety is a serious psychiatric disorder, with a higher incidence rate in women than in men. Protein phosphatase Mg 2+ /Mn 2+ -dependent 1F (PPM1F), a serine/threonine phosphatase, has been shown to have multiple biological and cellular functions. However, the effects of PPM1F and its neuronal substrates on anxiety remain largely unclear. In this study, we showed that chronic restraint stress (CRS) induced anxiety-related behaviors only in female mice, while acute restraint stress (ARS) produced anxiety-related behaviors in both male and female mice in light–dark and elevated plus maze tests and induced upregulation of PPM1F and downregulation of brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Adeno-associated virus–mediated overexpression of PPM1F or conditional knockout of BDNF in dentate gyrus (DG) led to a more pronounced anxiety-related behavior in female than in male mice as indicated by the behavioral evaluations. Meanwhile, overexpression of PPM1F in the DG decreased total Bdnf exon–specific messenger RNA expression in the hippocampus with the decreased binding activity of phosphorylated H3S10 to its individual promoters in female mice. Furthermore, we identified that overexpression of PPM1F decreased the phosphorylation levels of AKT and JNK in the hippocampus of female mice. These results may suggest that PPM1F regulates anxiety-related behaviors by modulating BDNF expression and H3S10 phosphorylation–mediated epigenetic modification, which may be served as potentially pathological genes associated with anxiety or other mental diseases.