Disrupted Brain Lateralization in Neurodevelopmental Disorders: Insights from Zebrafish and Valproic Acid Exposure

Cerebral lateralization is fundamental for brain function and development and plays a key role in social and cognitive processes. Accumulating evidence suggests that altered cerebral asymmetry could be at the basis of neurodevelopmental disorders, including autism spectrum disorders (ASD). A reduced structural and functional lateralization, including deficits in language and social behaviors, has been found in ASD patients. Zebrafish represent a robust animal model for studying brain lateralization for the presence of highly conserved asymmetric brain structures, i.e the habenula, linked to social and emotional processing. A previous study aimed to investigate the asymmetric expression of pallial genes in zebrafish has revealed conserved patterns with mammalian brains, including the asymmetric distribution of several genes linked to ASD (e.g., auts2, baiap2, robo1, arrb2, fez1, gap43). These findings suggest that lateralization of brain gene expression could be a fundamental feature of vertebrate neurobiology, underlying typical and atypical cognitive development. To explore the relationship between brain lateralization and neurodevelopmental disorders, we exposed zebrafish embryos to valproic acid (VPA), an anticonvulsant associated with increased ASD risk. VPA-exposed zebrafish displayed social interaction deficits and “symmetrization” of social visual laterality, characterized by the loss of a left-eye use bias during interactions with their mirror image. Additionally, VPA disrupted the asymmetric expression of the epithalamic marker leftover and altered the morphology of the dorsolateral habenula in adult zebrafish. These findings support the notion of a functional role of disrupted brain asymmetry in atypical social and cognitive development. In conclusion, our findings emphasize the use of zebrafish as animal model to unravel the molecular and behavioral mechanisms of brain lateralization in neurodevelopmental disorders offering novel insights into the etiology of ASD and paving the way for targeted interventions to address other complex neurodevelopmental disorders.