Modeling autism spectrum disorders in zebrafish: social deficits, visual lateralization and cerebral asymmetry

Cerebral asymmetry is critical for typical brain function and development; at the same time, altered brain lateralization seems to be associated with neuropsychiatric disorders. In autism spectrum disorders (ASD), studies have suggested reduced functional and structural cerebral asymmetry, reporting changes in asymmetric activation of brain structures involved in language and social processing and increased prevalence of left-handedness. Zebrafish are increasingly emerging as model species to study brain lateralization, using asymmetric development of the habenula, a phylogenetically old brain structure associated with social and emotional processing, to investigate the relationship between brain asymmetry and social behavior. We exposed 5-h post-fertilization zebrafish embryos to valproic acid (VPA), a compound used to model the core signs of ASD in many vertebrate species, and assessed social interaction, visual lateralization, and gene expression in the thalamus and the telencephalon. VPA-exposed zebrafish exhibit social deficits and a “symmetrization” of social visual laterality. We also observe changes in the asymmetric expression of the epithalamic marker leftover and the size of the dorsolateral part of the habenula in adult zebrafish. Our data indicate that VPA exposure neutralizes the animals’ visual field bias, with a complete loss of the left-eye use bias in front of their mirror image, and alters brain asymmetric gene expression and morphology, opening new perspectives to investigate brain lateralization and its link to atypical social cognitive development.