Pigment epithelium-derived factor alleviates depressive-like behaviors in mice by modulating adult hippocampal synaptic growth and Wnt pathway

Abstract Pigment epithelium-derived factor (PEDF, also known as SERPINF1) is a secreted glycoprotein with neuroprotective effects. However, the potential role of PEDF in major depressive disorder (MDD) remains largely unknown. Here, applying two-dimensional gel electrophoresis (2-DE) proteomics, we found that PEDF levels were significantly decreased in the plasma of 12 first-episode treatment-naive MDD patients (FETND) compared to the levels in 12 healthy controls (HCs). PEDF levels were especially lower in MDD patients than in HCs and patients with bipolar disorder (BD) and schizophrenia (SCZ), and elevated PEDF were consistent with decreased HAM-D scores in patients given antidepressant therapy (ADT). Animal research indicated that PEDF was decreased in the periphery and hippocampus of two well-known depression rodent models (the chronic unpredictable mild stress (CUMS) rat model and chronic social defeat stress (CSDS) mouse model). Decreased PEDF levels in the hippocampus led to depressive-like behaviors, synaptic impairments and aberrant Wnt signaling in C57BL mice, while increased PEDF resulted in the opposite results. Mechanistic studies indicated that PEDF contributes to dendritic growth and Wnt signaling activation in the hippocampus of adult mice. Taken together, the results of our study demonstrate the involvement of PEDF and its related mechanism in depression, thus providing translational evidence suggesting that PEDF may be a novel therapeutic target for depression.