Unveiling the neurogenesis defects induced by prenatal alcohol exposure

Prenatal alcohol exposure (PAE) is known to damage the fetal brain and leads to life-long cognitive and behavioral dysfunctions. Fetal Alcohol Spectrum Disorders (FASD), which collectively describes the constellation of effects resulting from alcohol consumption during pregnancy, is a complex syndrome that affects up to 5% of children and is the leading cause of preventable intellectual disability. Despite prevention campaigns discouraging alcohol drinking during pregnancy, the number of children suffering from FASD has not decreased over the past years. The consequences of PAE have become a global public health problem and understanding the alcohol-related mechanisms is crucially needed to develop new pharmacological strategies and treatments. Studies have shown that alcohol interferes with the cerebral cortex development in a variety of ways, including defects in neurogenesis, impaired cell proliferation and cell migration, reduced survival and disrupted neurotransmission. However, the precise pathophysiological mechanisms underlying alco-hol’s actions on cortical development are yet poorly understood. In this study, we set up a mouse model of FASD, using an alcohol consumption paradigm in which mice voluntarily drink high amounts of alcohol throughout pregnancy. Importantly, this model avoids any bias resulting from maternal stress that could be introduced by stressful alcohol consump-tion procedures such as gavage or injection. We first showed that this model accurately reflects alcohol consumption in human, as mice reach blood alcohol concentration levels comparable to those reported in binge-drinking humans. In order to investigate alcohol-dependent corticogenesis defects, we are analyzing the number, proliferation and specifi-cation of glutamatergic projection neurons during embryonic development and at postnatal stages. By using in utero electroporation, we are investigating the migration pattern of pro-jection neurons during neurogenesis. Our preliminary results reveal an abnormal accumu-lation of neurons in deep layers of the cortex of alcohol-exposed embryos, suggesting im-paired neuronal migration or dysregulated layer specification. Analysis of radial migration at postnatal stage showed that projection neurons have finally reached the upper layer, similar to control. However, the morphology of neurons seems to be affected by prenatal alcohol exposure, especially at the level of apical dendrites. We thus plan to investigate more specifically the terminal differentiation and dendritogenesis of projection neurons of alcohol-exposed pups. We will also evaluate adult mice behavior and alcohol consumption in order to determine whether PAE has a long-term impact on adult behavior and drinking pattern.