Developmental Deficiency of Oligodendrocytes and Myelination in the Central Nervous System of the Fetal Alcohol Syndrome Mouse Model

Abstract

ABSTRACT Background Fetal alcohol spectrum disorder (FASD) is a severe condition characterized by physical and neurodevelopmental abnormalities in the fetus resulting from prenatal alcohol exposure (PAE) or prenatal and lactation alcohol exposure (PLAE). Behavioral abnormalities associated with white matter damage have been extensively investigated in FASD patients and animal models, which suggested the involvement of myelination in FASD pathology. However, the impact of FASD on oligodendrocytes (OLs) and myelination within the central nervous system (CNS) and the underlying mechanisms are little discovered. This study aimed to reveal the effect and role of PLAE on CNS myelination in a FASD mouse model. Methods We set up a PLAE approach to generate the FASD mouse model to explore the effects of FASD on CNS myelination. Open‐field test, elevated plus maze, and tail suspension test were used to evaluate possible behavior deficiency of the FASD mice. Myelination in the cortex and hippocampus of the FASD mice was detected at postnatal days 14, 21, and 90 (P14, P21, and P 90). Then we counted the number of oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes (mOLs) to reveal the cell fates of oligodendrocyte lineage cells in the FASD mice. Next, we set up BLBP+/GFAP+ double‐staining to monitor the possible dysfunction of radial glial cells, which may contribute to the myelination deficiency in FASD mice. Finally, an FDA‐approved pro‐myelination drug, clemastine fumarate (CF), was used to validate the possible advantages of myelin restoration and behavior defects in the FASD mice. Results Impaired myelination was observed in the cortex and hippocampus of the male FASD offspring, associated with hyperactivity‐like behaviors, whereas the female FASD mice exhibited delayed myelin formation and normal behaviors, indicating a gender‐specific manner of FASD pathology. Furthermore, the different myelination deficiency between male and female FASD mice is due to the fact that only the male FASD mice exhibited a failure of oligodendrocyte differentiation. Additionally, FASD exerts an impact on the quantity and differentiation of radial glia cells, which may contribute to the myelination defect. Finally, CF‐treated male FASD mice showed myelin regeneration, leading to partial alleviation of behavioral abnormality in the male FASD mice. Conclusion Our data reveal a gender‐related deficiency of CNS myelination in the FASD mouse model, suggesting a potential therapy target for FASD.