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

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.