Thesis, COLLÉGIALITÉ

Abstract

Fetal alcohol spectrum disorder (FASD) is a major public health issue worldwide and the most preventable cause of intellectual disability. The most severe form of FASD is fetal alcohol syndrome (FAS), which is characterized by growth deficiencies (mild microcephaly), specific facial malformations and severe central nervous system (CNS) impairments. The lack of awareness on the devastating effects of alcohol in utero and the insufficient expertise in diagnosing FASD have led to an increase in the prevalence of this pathology over the past years. FASD has been reported to impact diverse neural cell types and activity across the developing cerebral cortex, but the precise pathophysiological effects on developing projection neurons (PNs) are unclear. Studies in rodents reported that in utero alcohol exposure alters PN development at several stages like proliferation, migration, differentiation and maturation. Previous experiments in the host laboratory focusing on PNs revealed impairments in migration dynamics upon PAE coupled with COUP-TF1 upregulation. In the present research study, we used the drinking in the dark paradigm (DID) model of alcohol administration to assess the role of COUP-TF1 in the migratory defects observed upon PAE. This mode of ethanol administration was chosen compared to other models such as gavage and injection because it was shown to mimic the human pattern of binge-drinking, induce a slow increase in blood alcohol (BAC) and less maternal stress. We showed that alcohol-induced migratory defects in PNs were rescued by the downregulation of COUP-TF1 in migrating PNs by in utero electroporation of a plasmid expressing miRNA against COUP-TF1 under the promoter DCX in PAE dams. Altogether, these findings suggest that COUP TF1 is the main target gene responsible for migratory defects upon PAE. This reinforces the interest to further investigate the molecular mechanisms by which COUP-TF1 affects migration of PNs upon PAE which might contribute to better understanding the pathophysiology of FASD.