Drp1-Dependent Mitochondrial Fission in the Hippocampus Drives Chronic Stress-Induced Depressive-like Behaviors in Mice

The mechanism of action of mice in chronic stress-induced depressive like behavior remains unclear. In this study, we found that chronic social defeat stress (CSDS) upregulates Drp1 expression in mouse hippocampal tissue, leading to excessive mitochondrial fission, which further impairs bioenergetics, induces oxidative stress, disrupts mitochondrial autophagy, and reduces excitatory synaptic transmission. Stereotactic injection of Drp1 inhibitor Mdivi-1 into the hippocampus reversed the aforementioned neuronal defects and alleviated CSDS-induced depressive-like behaviors, including social avoidance, anhedonia, and behavioral despair. Our findings indicate that elevated Drp1 triggers mitochondrial fission, representing a key pathophysiological mechanism underlying stress-induced depression. Therefore, targeting the regulation of mitochondrial dynamics may represent a viable therapeutic strategy.