Neuronal miR-17-5p contributes to interhemispheric cortical connectivity defects induced by prenatal alcohol exposure

Abstract

Prenatal alcohol exposure (PAE) is the leading cause of non-genetic intellectual disabilities in the Western world and is responsible of a wide spectrum of neurodevelopmental disorders referred to as Fetal Alcohol Spectrum Disorders (FASD). Structural and functional deficits in brain connectivity have been reported in FASD patients; still, whether and how PAE affects the axonal development of neurons and disrupts the wiring between brain regions is not known. Here, we developed a mouse model of moderate alcohol exposure during prenatal brain wiring to study the impact of PAE on corpus callosum (CC) development, a major white matter tract reported to be affected in FASD patients. Our results show that PAE induces aberrant navigation of interhemispheric CC axons that persist even after the end of the exposure, causing their ectopic termination in the contralateral cortex. Furthermore, these defects in interhemispheric connectivity persist into adulthood and are associated with defective bilateral sensorimotor coordination in behavioral tasks requiring cortical control and interhemispheric communication. Finally, we identified neuronal miR-17-5p and its target Ephrin type A receptor 4 (EphA4) as mediators of the effect of alcohol on the contralateral targeting of CC axons. Taken together, our results suggest that alteration of miRNA-mediated regulation of axon guidance signaling by prenatal alcohol exposure affects interhemispheric cortical connectivity and associated behavior in FASD.