VPS25 alleviates depression-like behavior in rats by inhibiting apoptosis in the hippocampus.

Abstract

BACKGROUND: Depression is a psychiatric disorder manifested by significant and persistent depressive symptoms. In recent years, autophagy has been identified with a key role in neuronal survival, synaptic plasticity, and depression. We previously observed that vacuolar protein sorting 25 (VPS25) was up-regulated in the hippocampus of depressive rats, but the mechanisms were unclear. METHODS: In chronic unpredictable mild stress (CUMS)-stimulated rats, lateral ventricles were injected with adeno-associated virus (AAV) to silence VPS25. Depression status in rats was evaluated using behavioral tests. In the corticosterone (CORT)-induced PC12 cell apoptosis model, Cell Counting Kit-8 (CCK-8) assays were used to determine cell viability. We next investigated the effects of CORT and VPS25 on PC12 apoptosis and proliferation using flow cytometry and cell proliferation assays. VPS25 mRNA expression was determined using qRT-PCR, while VPS25, Bax, Bcl-2, cleaved-caspase3, P62, Beclin-1, LC3, JAK1, p-JAK1, STAT1, and p-STAT1 levels of expression were assessed using western blotting. RESULTS: Our data demonstrate that in CORT-induced PC12 cells or a CUMS-induced rat depression model, VPS25 silencing not only alleviated CUMS-induced neuronal apoptosis in rats but also reduced CORT-induced apoptosis in PC12 cells. Notably, VPS25 silencing alleviated CUMS-provoked depression-like behaviors, reduced neuronal apoptosis (as evidenced by TUNEL staining), and promoted autophagy flux by increasing the LC3-II/LC3-I ratio. These effects were associated with the blockade of JAK/STAT signaling. CONCLUSION: These results indicate that silencing VPS25 alleviates depression symptoms by promoting autophagy and inhibiting neuronal apoptosis, partly through the JAK/STAT signaling pathway.