Acute Oligodendrocyte Loss with Persistent White Matter Injury in a Third Trimester Equivalent Mouse Model of Fetal Alcohol Spectrum Disorder

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Newville J, Valenzuela CF, Li L, Jantzie L, Cunningham LA

University of New Mexico Health Sciences Center, Department of Neurosciences, Albuquerque, New Mexico, USA

Human imaging studies have revealed significant white matter abnormalities linked to cognitive impairment in children with FASD, but the underlying mechanisms have not been elucidated. Here, we evaluated the acute and long-term impact of alcohol exposure on oligodendrocyte number and white matter integrity within the corpus callosum in a third trimester equivalent mouse model of FASD, in which mouse pups were exposed to alcohol during the first two weeks of postnatal development. During this developmental epoch the corpus callosum is undergoing rapid myelination and considerable cellular transformation, marked by infiltration of oligodendrocyte progenitors that are derived from distinct telencephalic germinal domains. To distinguish oligodendrocyte lineage cells derived from the postnatal subventricular zone (SVZ) from those that originated during embryonic development, we utilized a genetic Cre-loxP fate mapping approach to selectively label cells derived from nestin+ progenitors of the postnatal SVZ, coupled with immunofluorescence detection of all mature oligodendrocytes (OLs) and proliferating oligodendrocyte progenitor cells (OPCs). Our findings demonstrate a marked 50% decrease in the number of OLs and a 75% decrease in the number of proliferating oligodendrocyte progenitor cells (OPCs) within the corpus callosum in alcohol-exposed mice at postnatal day 16 (P16). Interestingly, neither OLs nor OPCs derived from the postnatal SVZ were numerically affected by alcohol exposure, indicating heterogeneity in susceptibility based on ontogenetic origin. Although the number of OL lineage cells recovered by P50, early postnatal alcohol exposure resulted in enduring alterations in biochemical and microstructural indices of white matter integrity, including upregulation of myelin basic protein (MBP) expression and decreased fractional anisotropy as assessed by MRI diffusion tensor imaging (DTI). These observations indicate a heterogeneity in alcohol susceptibility among oligodendrocyte populations based on ontogenetic origin and demonstrate persistent alterations in white matter integrity.
Grant Support: National Institutes of Health NIAAA P50-AA022534 and R37-AA015614