Mechanisms and consequences of CNS aneuploidies altered by fetal ethanol exposure

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DESCRIPTION (provided by applicant): In utero exposure to alcohol can have major deleterious effects as documented for "fetal alcohol syndrome (FAS)" and more recently and broadly as "fetal alcohol spectrum disorders (FASD)." These disorders are associated with a range of debilitating neurodevelopmental and psychiatric problems after birth. Myriad molecular and cellular defects have been associated with fetal brain exposure to ethanol, which generally lack common, underlying mechanisms. This proposal will examine a newly identified, somatic change in the genomes of central nervous system (CNS) cells produced by fetal ethanol exposure that could help to provide a common mechanistic foundation: mosaic aneuploidies. These cells show somatically produced chromosomal gains and/or losses, constituting an inherent, if surprising element of normal brain organization. Constitutive aneuploidies (where all cells have the same form of aneuploidy) have clear consequences for cellular dysfunction in cancers, and deleterious behavioral consequences as observed in Down Syndrome, suggesting that deviations from the normal mosaic aneuploidy states could contribute to the range of neural deficits seen in FASD. Here, we will test the hypothesis that identifiable changes in neural mosaic aneuploidies represent a common endpoint of prenatal exposure to alcohol. Three aims will be pursued over the next 5 years. Aim 1 will identify effects of fetal alcohol exposure that alter neural progenitor cell (NPC) aneuploidies after embryonic exposure ex vivo. Aim 2 will determine cell fate and functional consequences of alcohol exposure to aneuploid & aneusomic NPC populations during development, and neurons in adult cortical cell populations. Aim 3 will determine neuronal and non-neuronal identities and distributions of specific aneusomies produced by fetal alcohol exposure using a novel in vivo reporter system. Completion of these Aims could provide a new framework for understanding and therapeutically approaching FASD.