SARM1 deficiency induced depressive-like behavior via AMPKα/p-eEF2 axis to synapse dysfunction

Sterile Alpha and TIR Motif Containing 1 (SARM1) are proteins implicated in various neurological processes; however, their role in depression remains unexplored. This study investigated the contribution of SARM1 to depressive-like behaviors in a chronic stress-induced depression model and SARM1 knockout (KO) mice. Depressive-like behaviors were assessed using a battery of behavioral tests, including the Open Field Test (OFT), the Forced Swim Test (FST), the Sucrose Preference Test (SPT), and the Tail Suspension Test (TST). Mitochondrial energy metabolism alteration, cytokine level changes, and other related molecular signaling protein expression were evaluated using ELISA and western blotting techniques to investigate the underlying mechanisms. Behavioral assessments (OFT, FST, SPT, TST) revealed depressive-like phenotypes in SARM1 KO mice, accompanied by altered mitochondrial energy metabolism (NAD+, ATP) in the cortex. Intriguingly, SARM1 depletion led to peripheral inflammation, as evidenced by elevated cytokine levels in plasma but not in brain regions (cortex). In addition, we found dysregulated energy metabolism, AMPK signaling, and synaptic plasticity in the cortex of SARM1 KO mice. Notably, AICAR (Acadesine), an AMPK activator, ameliorated depressive-like behaviors and synaptic dysfunction, while Compound C, an AMPK inhibitor, reversed these effects. Additionally, NH125, an eEF2 kinase inhibitor, improved depressive-like behaviors in SARM1 KO mice. These findings demonstrate that SARM1 is critical in regulating depressive-like behaviours through the AMPKα/p-eEF2 signaling pathway. Targeting AMPK signaling and synaptic function may offer novel therapeutic avenues for depression.