PDE4D Regulates Mitochondrial Homeostasis and Adult Hippocampal Neurogenesis via the cAMP/CREB Signaling Pathway in Chronic Stress‐Induced Depressive‐Like Behavior

ABSTRACT Phosphodiesterase 4D (PDE4D), a major enzyme responsible for cAMP degradation in the hippocampus, has been implicated in mood regulation. Although PDE4D inhibition exerts antidepressant effects, the underlying mechanisms remain poorly understood. Here, we explored the role of PDE4D in chronic stress‐induced depressive‐like behaviors, mitochondrial dysfunction, and impaired adult hippocampal neurogenesis (AHN). Using a chronic restraint stress (CRS) model, we found that PDE4D expression was significantly upregulated in the hippocampal dentate gyrus (DG) of CRS mice, leading to suppressed CREB signaling, mitochondrial dysfunction, and impaired AHN. PDE4D knockout (PDE4D‐KO) restored mitochondrial quality by enhancing mitochondrial biogenesis, normalizing mitophagy, and improving oxidative phosphorylation (OXPHOS) via the nucleus and mitochondria cAMP/CREB signaling, ultimately promoting AHN and alleviating depression‐like symptoms. These findings define PDE4D as a key regulator of mitochondrial homeostasis and AHN, suggesting that targeting PDE4D in the hippocampal DG may represent a novel treatment mechanism for depression.