Disruption of Brain Lateralization in Zebrafish exposed to valproic acid: implications for Autism Spectrum Disorders

Cerebral lateralization is a fundamental organizational principle of the nervous system and plays a critical role in cognitive and social processes. Accumulating evidence suggest that altered structural and functional asymmetry may contribute to the pathophysiology of neurodevelopmental disorders, including autism spectrum disorders (ASD). Individuals with ASD often display reduced brain lateralization accompanied by impairments in language and social behavior. 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. To explore the link between brain asymmetry and neurodevelopmental disorders, we exposed 5-h post-fertilization zebrafish embryos to valproic acid (VPA), an anticonvulsant associated with increased ASD risk used to model the core signs of ASD in many vertebrate species. We then assessed social behavior, visual lateralization and gene expression in the thalamus and the telencephalon. VPA-treated zebrafish exhibited deficits in social behavior and a “symmetrization” of social visual laterality, reflected in the loss of the typical left-eye preference during mirror-induced social responses. Moreover, VPA disrupted the asymmetric expression of the epithalamic marker leftover and altered the morphology of the dorsolateral habenula in adult zebrafish. Overall, these results support the idea that disrupted brain asymmetry may contribute to atypical social development. In conclusion, our findings highlight the value of the zebrafish model in unraveling the molecular and behavioral mechanisms linking brain lateralization to neurodevelopmental disorders, offering new insights into ASD etiology and paving the way for targeted therapeutic approaches.