Chd8 Deficiency in Zebrafish Causes Autism-Like Behavioral Deficits

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with strong genetic and environmental components. Despite progress made over the past decades, no effective therapies targeting the core symptoms of ASD are currently available. More research is required to explore the underlying mechanisms of ASD and discover potential therapeutic targets. Chromodomain helicase DNA-binding protein 8 (CHD8) is one of the most significant high-confidence ASD risk genes identified to date. However, the precise roles and mechanisms of CHD8 in neurodevelopment and behaviors remain incompletely understood. Zebrafish represent an emerging model organism for ASD research. While several zebrafish models with Chd8 disruption have been established, behavioral consequences have not been thoroughly characterized.

Leveraging the high survival rate of homozygous Chd8 mutant males, we comprehensively assessed their behaviors.

The mutants exhibited social deficits across multiple assays, including shoaling, social interaction and three-chamber social preference test. Additionally, anxiety-like behavior, locomotor coordination deficits, and macrocephaly were observed. These phenotypes closely resemble the symptoms in patients carrying disruptive CHD8 mutations.

Our findings establish this Chd8 mutant zebrafish line as a robust model for investigating ASD pathological mechanisms and screening for potential therapies.