Agomelatine alleviates depressive-like behaviors in mice by promoting mitophagy in parvalbumin-expressing neurons of the hippocampal ventral dentate gyrus.

Abstract

BACKGROUND: Major depressive disorder (MDD) is highly prevalent, but some patients are refractory to conventional treatments. Mitochondrial dysfunction, impaired mitophagy, and parvalbumin (PV)-expressing hippocampal neuron deficits are linked to MDD pathogenesis, while agomelatine's antidepressant mechanism involving these elements remains unclear. AIM: This study aimed to clarify whether agomelatine alleviates depressive-like behaviors in mice by promoting mitophagy in PV neurons of the hippocampal ventral dentate gyrus (vDG). METHODS: Male C57BL/6J and Pvalb-creAi14 mice underwent chronic unpredictable mild stress (CUMS) for depression modeling. Groups included Control, CUMS, CUMS + Fluoxetine (FLX), CUMS + Agomelatine (AGO), CUMS + AGO+3-Methyladenine (autophagy inhibitor), CUMS + AGO + Rapamycin (an mTORC1 inhibitor that indirectly promotes autophagy in a cell-type-dependent manner), and CUMS with vDG-targeted AAV-Beclin1 overexpression (oeBeclin1) ± AGO. Behavioral tests (TST, FST, SPT, OFT, SIT) and molecular/morphological analyses (Western blotting, IF, RT-qPCR, DHE staining, TEM, Golgi staining) were conducted. RESULTS: CUMS induced depressive-like behaviors and reduced PV neuron density. AGO's performance is no less effective than FLX. Mechanistically, it upregulated autophagy-related proteins (Beclin1, ATG5, LC3II/I) and downregulated p62. oeBeclin1 synergized with agomelatine to improve mitochondrial morphology, reduce ROS, and inhibit neuroinflammation. CONCLUSION: In conclusion, agomelatine alleviates CUMS-induced depressive-like behaviors in mice, which is associated with the promotion of mitophagy in vDG PV neurons of the hippocampus, mitigating mitochondrial damage and neuroinflammation. This uncovers a novel mechanism for its efficacy and highlights targeted mitophagy activation as a promising MDD therapeutic strategy.