Sex-specific gene-environment interactions underlying ASD-like behaviors

Area of Science:

• Neurodevelopmental Disorders
• Genetics
• Environmental Science

Background:

• Autism spectrum disorders (ASDs) exhibit a notable male bias in incidence.
• The underlying causes of this sex bias in ASD etiology remain largely unknown.
• Understanding the sex bias is crucial for a comprehensive understanding of ASD.

Purpose of the Study:

• To investigate the "three-hit" theory (genetic load × environmental factor × sex) as a potential explanation for the male predominance in ASD.
• To examine sex-specific effects of interacting genetic and environmental factors in an ASD mouse model.

Main Methods:

• Utilized the contactin-associated protein-like 2 (Cntnap2) mouse model for ASD.
• Induced maternal immune activation using lipopolysaccharide (LPS).
• Assessed social behaviors, ultrasonic vocalizations, and corticotropin-releasing hormone receptor-1 (Crhr1) gene expression with epigenetic analysis (H3K4me3).

Main Results:

• Maternal immune activation led to male-specific deficits in social responses.
• Cumulative effects of genetic load, immune activation, and sex influenced ultrasonic vocalizations.
• Synergistic interaction of all three factors impaired social recognition in adulthood.
• A three-way interaction on Crhr1 gene expression in the hippocampus, linked to epigenetic alterations, was observed.

Conclusions:

• The study provides proof-of-principle that genetic and environmental factors interact to produce sex-specific effects in ASD.
• These sex-specific effects may contribute to the observed male bias in ASD incidence.
• Changes in stress system gene expression, like Crhr1, are implicated in these interactions.