Deciphering how prenatal alcohol exposure impairs somatosensory cortex development at single cell level

Background: Prenatal alcohol exposure (PAE) is known to damage the fetal brain and lead to life-long cognitive and behavioral dysfunctions. PAE is a major public health problem and a better understanding of PAE pathophysiology is crucially needed. Studies have shown that alcohol interferes with the cerebral cortex development in a variety of ways, including defects in neurogenesis, neuron survival and neurotransmission. However, the cellular and molecular mechanisms underlying alcohol’s actions on cerebral cortex development are still poorly understood.
Methods: In this study, we use a mouse model of FASD, in which mice voluntarily drink high amounts of alcohol throughout pregnancy and reach blood alcohol concentration level comparable to those reported in binge-drinking human. In order to investigate the alcohol-induced defects in corticogenesis, we analyzed the different steps of embryonic cortex development and focused on glutamatergic projection neurons.
Results: We observed a moderate microcephaly phenotype in PAE pups as compared to water littermates and reported a significant delay in upper layer neuron migration following PAE. By using time-lapse imaging in organotypic slices, we demonstrated an alcohol-induced defect in the multipolar-bipolar transition as well as in the locomotion step of neuronal migration. We observed further postnatal defects such as abnormal morphology of upper-layer neurons, reduced callosal projections, and impaired tactile sensitivity. Furthermore, single-cell RNA-seq analysis identified several mRNA differentially expressed in migrating neurons populating the sensory cortex of PAE and water control embryos. We are currently working on identifying the specific signaling pathways responsible for the alcohol-induced migration defects and behavioral impairments.