In summary, this study's results indicate that PPM1F‐AMPK‐p300 activity in the mPFC neurons is a key regulator of depression‐related behaviors, and our data suggest that abnormal PPM1F activity, impaired neuronal excitability in the pyramidal neurons and enhanced neuroinflammation state may contribute to the development of depression. The gene discussed is PPM1F; the disease is major depressive disorder.