Valproic acid induces p19Arf-mediated cellular senescence to cause neurodevelopmental defects

Valproic acid (VPA) is widely prescribed to treat epilepsy, bipolar disorder and migraine. However, if taken during pregnancy, exposure to the developing embryo can cause birth defects, cognitive impairment and Autism-Spectrum Disorder. How VPA causes these developmental defects remains unclear. Here, we used embryonic mice and human organoids to model key features of drug exposure, including exencephaly, microcephaly and spinal defects. In the malformed tissues, in which neurogenesis is defective, we find that induction of cellular senescence in neuroepithelial cells is a core feature. Through genetic and functional studies, we identified p19Arf as the instrumental mediator of senescence and microcephaly, but not exencephaly and spinal defects. These findings identify VPA-induced ectopic senescence as a causative mechanism disrupting normal neurodevelopment, illuminating how VPA-exposure during embryonic development can lead to cognitive defects and Autism-Spectrum Disorder.