Valproic acid exposure alters social visual lateralization and asymmetric gene expression in zebrafish larvae

Cerebral asymmetry is a fundamental aspect of brain organization. Abnormal language hemispheric activation and differences in the prevalence of handedness have been observed in individuals with ASD, suggesting reduced functional and structural cerebral asymmetry. Zebrafish are increasingly emerging among the key model species to study brain lateralization, with asymmetric development of the epithalamus as a model to investigate the relationship between brain asymmetry and behavior. We exposed zebrafish embryos at 5 hour post-fertilization to one micromolar dosage of valproic acid for 24 and 48 hours, assessed social interaction and visual lateralization in a social task, the mirror test, and measured gene expression changes in the thalamus and the telencephalon. We show that after exposure to valproic acid, a compound used to model the core signs of ASD in many vertebrate species, zebrafish exhibit social deficits and alterations in lateralized social responses to their own reflected image. Valproic acid exposure also induced changes in the asymmetric gene expression of the thalamic marker kctd12.1/leftover and had a significant effect on telencephalic genes known to be asymmetrically expressed in adult fish. Our data indicate that one micromolar doses of VPA are sufficient to neutralize both the visual field bias and the asymmetric epithalamic gene expression, opening new perspectives to investigate altered brain lateralization and its link to ASD in a zebrafish model.