Regulation of oligodendrocyte metabolism and myelination by acetyl-L-carnitine in a mouse model of post-weaning social isolation.

Adolescent social stress can impair myelination and increase vulnerability to psychiatric symptoms. We investigated whether acetyl-L-carnitine (ALC), a metabolite linking energy and lipid metabolism, regulates oligodendrocyte (OL) myelination and rescues behavioral deficits in a post-weaning social isolation (PWSI) mouse model. In vitro, ALC uptake and conversion through the OCTN2/CrAT axis promoted myelin sheath expansion without affecting OL precursor proliferation or early differentiation. ALC activated ERK signaling, increased histone acetylation, promoted PPARγ nuclear translocation, and selectively enhanced mitochondrial respiration in mature OLs. In vivo, oral ALC supplementation restored social preference and medial prefrontal cortex MBP expression in PWSI mice, whereas cuprizone co-administration abolished these effects, suggesting that the therapeutic effects of ALC are closely associated with its impact on myelination. Lipidomic analysis of the corpus callosum showed that ALC restored PWSI-induced changes in fatty acid chain length and unsaturation. These findings identify ALC as a metabolic regulator that restores social isolation-induced myelin deficits by coordinating myelin protein synthesis, mitochondrial function, and myelin lipid remodeling. ALC may therefore provide a metabolic strategy for targeting myelin-related neurodevelopmental and psychiatric disorders.