Paroxetine-induced transient apoptosis with delayed neurogenesis triggers brain-preferential regeneration in developing zebrafish

Autism spectrum disorder (ASD) is a neurodevelopmental condition caused by a combination of genetic and environmental factors. Its cardinal symptoms include impaired social behavior involving the amygdala. Maternal use of antidepressants such as paroxetine during early pregnancy increases the risk of ASD in offspring. However, the underlying pathogenic mechanisms remain poorly understood. Herein, we demonstrate that early exposure of zebrafish embryos to paroxetine delays neurogenesis in the optic tectum and telencephalon, including a region corresponding to the mammalian amygdala. Paroxetine-treated embryos exhibit growth restriction characterized by small heads and short-body lengths resulting from transient apoptosis. This phenotype resembles the early-onset fetal growth restriction (FGR) associated with ASD. Interestingly, we observed regeneration of delayed neurogenesis in the reduced brain following paroxetine withdrawal. This regenerative process was accompanied by extended retinotectal projections, suggesting brain-preferential regeneration. Finally, we examined the social behavior of paroxetine-treated fish. Taken together, our findings suggest a biological mechanism linking early paroxetine exposure, a risk factor for ASD, to its pathogenesis.