Elevation of H₂S Underlies Social Deficits in Environmental Factor Double-Hit Autism Model

The underlying mechanism for the environmental factor-induced autism spectrum disorder (ASD) remains largely unclear. Considering the recent reports that mitochondria-associated amino acid metabolism contributes to ASD development, we explored the roles of hydrogen sulfide (H₂S), a gaseous product of sulfur-containing amino acid metabolism, in the social deficits of ASD mice induced by the environmental factor double-hit (DH). We detected synaptic and mitochondrial dysfunction, elevation of H₂S, dysregulation of sulfur-containing metabolites, and upregulation of cystathionine-β-synthase (CBS) in the anterior cingulate cortex of DH mice. Inhibiting mitochondrial function induced H₂S accumulation in wild-type neurons, whereas introducing healthy mitochondria suppressed H₂S levels in DH neurons. Knocking down CBS or restricting sulfur intake significantly ameliorated synaptic dysfunction, social impairments, and anxiety-like behaviors in DH mice. Similar H₂S accumulation was detected in human DH neurons and ASD patients. Our data demonstrated a role of H₂S overload in the social dysfunction of environmental factor-induced ASD.