Ethanol exposure in utero: effects on radial migration, form, and function of pyramidal neurons in the somatosensory cortex.

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Project Summary Fetal Alcohol Spectrum Disorder (FASD) is a leading cause of non-genetic intellectual disability, including behavioral, sensory, and cognitive deficits. Even though gestational ethanol consumption is a significant threat to the unborn child, it has been reported that 1 pregnant woman in 10 in the United States drinks alcohol, and 1 in 33 binge drinks in the past 30 days. Binge-type drinking during pregnancy is particularly dangerous due to abrupt and exceedingly high blood alcohol levels. While FASD necessitates a postnatal diagnosis, the underlying embryonic etiology, specifically corticogenesis, is understudied. The tangential migration of GABAergic interneurons and the radial migration of glutamatergic primordial pyramidal neurons are intricately regulated processes that are key to corticogenesis. While is it known that in utero binge-type exposure to ethanol results in aberrances in tangential migration, its effects on radial migration are not known. The long- term goal of this project is to contribute to our understanding of how cortical development is affected in FASD. The short-term objectives are to investigate the effects of in utero binge-type exposure to ethanol on the radial migration of primordial pyramidal neurons, and the enduring effects on pyramidal neuron form and function in the somatosensory cortex. These objectives will be embodied in two specific aims: Aim 1. Test the hypothesis that prenatal exposure to ethanol disrupts the radial migration of primordial pyramidal neurons during embryonic corticogenesis. Immunohistochemistry and organotypic slice culture paired with real-time videomicroscopy will investigate changes in radial migration during embryonic development. Aim 2. Test the hypothesis that the effects of prenatal exposure to ethanol on migration persist postnatally as altered neuroanatomical/functional disposition and excitatory/inhibitory synaptic balance on pyramidal neurons. A combination of immunohistochemical, morphological, electrophysiological, and optogenetic approaches will be used in early postnatal and young adult mice to investigate the persistent effects of binge- type exposure to ethanol on the disposition and functional properties of pyramidal neurons. This will include the balance between the excitatory and inhibitory cortical circuits during the time of synaptogenesis and adulthood. The findings from this project will fill a critical void in our knowledge regarding the cellular and molecular mechanisms underlying FASD. This will inform future research focused on further elucidating the neurodevelopmental consequences of in utero exposure to ethanol on the unborn child and their management.