Copper-deficiency is associated with impairments in social behavior and oligodendrocyte development via mTOR signaling pathway

Autism spectrum disorder (ASD) is a heterogeneous disorder characterized by impaired social communication and restricted repetitive behaviors, however the biological mechanisms remain unclear. Although trace elements play essential roles in the living body, it is unclear how alterations of trace elements in ASD are involved in pathogenesis. Here we analyzed the plasma metallome and identified the alterations of 11 elements in individuals with ASD. The copper decrease was negatively correlated with ASD symptom scores. A copper-deficient mouse model reflecting the condition showed ASD-like behaviors and impaired oligodendrocyte development. In copper-deficient mice, mechanistic target of rapamycin (mTOR) signaling was reduced, and its activation by agonist improved social impairment and oligodendrocyte developmental defects. Supporting these results, white matter volumes were negatively correlated with social symptoms in individuals with ASD. Our results demonstrate that copper-deficiency contributes to ASD by causing oligodendrocytes impairment via mTOR signaling. Our findings indicate that the effects of copper-deficiency and mTOR imbalance are relevant to the pathogenesis of ASD and are potential therapeutic targets.