Prenatal alcohol exposure impairs mouse somatosensory cortex development by delaying projection neurons migration

Background: Prenatal alcohol exposure (PAE) is known to damage the fetal brain and lead to life-long cognitive and behavioral dysfunctions. Despite prevention campaigns discouraging alcohol drinking during pregnancy, the prevalence of FASD has not decreased over the past years. PAE is a major public health problem and understanding the precise pathophysiology of FASD is crucially needed in order to develop new pharmacological strategies. 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 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. Importantly, this model avoids potential bias resulting from stressful alcohol administration procedures (gavage or injection). We showed that in this model mice 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 that PAE leads to a delay in upper layers neuron migration. By using time-lapse imaging in organotypic slices, we demonstrated that PAE induces a 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 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.