Pleiotropic contribution of to psychiatric and neurodevelopmental phenotypes in a zebrafish model.

is a highly pleiotropic gene that contributes to several psychiatric and neurodevelopmental disorders. Both rare and common variants in have been associated with several psychiatric conditions, but the mechanisms underlying the pleiotropic effects of are not yet understood. Here we found that, in zebrafish, is expressed in spinal cord, mid- and hindbrain during developmental stages. In adults, expression is restricted to specific areas of the brain, including telencephalic and diencephalic regions with an important role in receiving and processing sensory information and in directing behaviour. To investigate the effect of deficiency on behaviour, we used , a loss-of-function line. We found that mutants present hyperactivity, thigmotaxis, decreased freezing behaviour and altered social behaviour. We repeated these behavioural tests in a second loss-of-function line with a different genetic background, , and found that deficiency affects behaviour similarly in this line, although there were some differences. mutants present similar thigmotaxis, but stronger alterations in social behaviour and lower levels of hyperactivity than fish. Taken together, these results suggest that deficiency leads to multiple behavioural changes in zebrafish that might be modulated by environmental, epigenetic and genetic background effects, and that resemble phenotypic alterations present in -deficient mice and in patients with different psychiatric conditions. Our study thus highlights the evolutionary conservation of function in behaviour and paves the way to further investigate the mechanisms underlying pleiotropy on the onset of neurodevelopmental and psychiatric disorders.