Chronic haloperidol exposure impairs neurodevelopment via Notch1 signaling in human stem cell-derived brain organoids

Haloperidol is a typical antipsychotic used to treat schizophrenia and induces dopamine D2 receptor antagonism. Long-term use of haloperidol can reduce brain size in animals and humans; however, the underlying mechanism of this effect remains unclear. Notch1 signaling regulates the development and function of the nervous system by balancing stem cell proliferation and differentiation. Therefore, we investigated the effects of long-term exposure to haloperidol on human-derived brain organoids, which served as sophisticated in vitro models of human brain development. Long-term exposure to haloperidol reduced the size of brain organoids and decreased the ventricular zone and Notch1 signaling. When propionate, which protects against haloperidol-induced toxicity, was combined with haloperidol, it rescued both the overall size of brain organoids and Notch1 expression levels. Additionally, treatment with valproic acid, a Notch1 activator, partially restored the size of brain organoids and the thickness of the ventricular layer. Taken together, these data suggest that long-term exposure to haloperidol impairs neurodevelopment via Notch1 signaling in brain organoids. These findings contribute to our understanding of antipsychotic drug safety and provide information for new neurodevelopmental toxicity assessments.