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

Area of Science:

• Neuroscience
• Molecular Biology
• Psychiatry

Background:

• Sterile Alpha and TIR Motif Containing 1 (SARM1) proteins are involved in neurological processes, but their role in depression is unknown.
• Depression is a complex disorder with poorly understood underlying molecular mechanisms.

Purpose of the Study:

• To investigate the role of SARM1 in depressive-like behaviors using a chronic stress model and SARM1 knockout (KO) mice.
• To elucidate the molecular mechanisms, including mitochondrial function, inflammation, and signaling pathways, involved in SARM1-mediated depression.

Main Methods:

• Behavioral tests (Open Field Test, Forced Swim Test, Sucrose Preference Test, Tail Suspension Test) to assess depressive-like phenotypes.
• ELISA and western blotting to analyze mitochondrial energy metabolism (NAD+, ATP), cytokine levels, and signaling proteins (AMPK, eEF2).
• Pharmacological interventions using AICAR (AMPK activator), Compound C (AMPK inhibitor), and NH125 (eEF2 kinase inhibitor).

Main Results:

• SARM1 KO mice exhibited depressive-like behaviors and altered cortical mitochondrial energy metabolism (NAD+, ATP).
• SARM1 depletion induced peripheral inflammation (elevated plasma cytokines) but not central inflammation.
• Dysregulated cortical energy metabolism, AMPK signaling, and synaptic plasticity were observed in SARM1 KO mice.
• AICAR and NH125 treatment ameliorated depressive-like behaviors and synaptic dysfunction in SARM1 KO mice, while Compound C reversed these effects.

Conclusions:

• SARM1 plays a critical role in regulating depressive-like behaviors.
• The SARM1-mediated regulation of depression involves the AMPKα/p-eEF2 signaling pathway and impacts synaptic function.
• Targeting AMPK signaling and synaptic plasticity presents potential therapeutic strategies for depression.