Ethanol exposure impaired mitotic division in apical radial glial cells and disrupted early cortical development in human forebrain organoids: Implications for ethanol-induced microcephaly

Maternal alcohol exposure can severely disrupt the differentiation of neural stem/progenitor cells, leading to a reduced number of neurons and decreased volume and thickness of the cortical layers, a hallmark feature commonly associated with microcephaly. Recent studies from our laboratory have demonstrated that ethanol exposure interfered with the formation of radial glial processes and impaired the generation and migration of outer radial glial cells in human forebrain organoids. However, the precise mechanisms by which ethanol affects the production of outer radial glial cells remain unclear. In this study, human forebrain organoids were used to investigate the effects of ethanol exposure on the mitotic divisions of radial glial cells and cortical development. Our findings revealed that ethanol exposure significantly reduced mitotic cell division in apical radial glial cells. Exposure to ethanol also significantly decreased symmetric cell division while increasing asymmetrical cell division in these cells. Additionally, ethanol exposure reduced the number of outer radial glial cells in forebrain organoids, suggesting that ethanol exposure impaired the production of outer radial glial cells by disrupting the mitotic division of apical radial glial cells. Our findings also revealed that ethanol-induced disruptions in mitotic cell division in apical radial cells and the subsequent reduction in outer radial glial cells contributed to the reduced thickness of the developing cortical wall and resulted in smaller forebrain organoids. This study significantly advances our understanding of the cellular mechanisms underlying ethanol-induced microcephaly and provides potential avenues for developing novel interventions to prevent or mitigate the neurodevelopmental deficits associated with prenatal alcohol exposure, including ethanol-induced microcephaly.