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

Area of Science:

• Neuroscience
• Biochemistry
• Genetics

Background:

• The mechanisms behind environmental factor-induced autism spectrum disorder (ASD) are not fully understood.
• Mitochondria-associated amino acid metabolism is increasingly implicated in ASD development.

Purpose of the Study:

• To investigate the role of hydrogen sulfide (H2S) in social deficits of mice exposed to an environmental "double-hit" (DH) model of ASD.
• To explore the link between sulfur-containing amino acid metabolism and H2S in ASD.

Main Methods:

• Assessed synaptic and mitochondrial function in the anterior cingulate cortex of DH mice.
• Measured H2S levels, sulfur-containing metabolites, and cystathionine-β-synthase (CBS) expression.
• Utilized mitochondrial inhibition and transplantation in neurons.
• Genetically modified CBS expression and dietary sulfur restriction in DH mice.
• Analyzed H2S levels in human DH neurons and ASD patients.

Main Results:

• DH mice exhibited synaptic and mitochondrial dysfunction, elevated H2S, altered sulfur metabolites, and increased CBS in the anterior cingulate cortex.
• Mitochondrial dysfunction led to H2S accumulation in neurons; healthy mitochondria reduced H2S in DH neurons.
• Reducing CBS or sulfur intake improved synaptic function and social behaviors in DH mice.
• Elevated H2S was observed in human DH neurons and ASD patients.

Conclusions:

• H2S overload plays a significant role in the social dysfunction associated with environmentally induced ASD.
• Targeting H2S metabolism presents a potential therapeutic avenue for ASD.