The role of ucOCN in aerobic exercise induced amelioration of autism spectrum disorder phenotypes.

Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder closely associated with synaptic dysfunction that contributes to core behavioral deficits. Aerobic exercise (AE) serves as a promising adjuvant intervention for diverse neuropsychiatric conditions, and accumulating evidence suggests favorable effects of AE on ASD-related behaviors and physiological traits. The bone-derived hormone undercarboxylated osteocalcin (ucOCN) induced by AE can cross the blood-brain barrier to regulate synaptic plasticity. Mendelian randomization analysis suggests an association between genetically predicted higher physical activity levels and lower ASD risk, as well as between physical inactivity and higher ASD risk. In BTBR mice (a classic ASD animal model), AE intervention was associated with improvements in ASD-like phenotypes, increased cortical ucOCN, GPR158, BDNF, and synaptic proteins, and altered MAPK/ERK/Akt2 signaling. This work provides potential mechanistic clues for AE-associated changes in synaptic plasticity, supporting non-pharmacological intervention strategies for ASD.