Consumption of ethanol during pregnancy can be detrimental to the offspring, the most severe detriment being the developmental defects collectively referred to as fetal alcohol syndrome (FAS). In brain, FAS is hallmarked by defects in gross morphology (e.g., microcephaly, hydrocephaly, porencephaly, hydroanencephaly) that have been attributed to insult during corticogenesis. Prenatal chronic ethanol exposure compromises the GABAergic system in the immature brain and, thus, inhibitory regulation, contributing to increased susceptibility to seizures and deficits in sensory information processing associated with FAS. In this proposal, we ask whether chronic ethanol consumption (1-6% EtOH) during pregnancy leads to abnormal development of the GABAergic system in the offspring. The overriding hypothesis is that the abnormal disposition of the postnatal and mature cortex seen in FAS manifests itself early on in corticogenesis by affecting the migration of primordial GABAergic interneurons to their usual laminar positions within the neocortex. In rodent, these GABAergic interneurons arise extracortically primarily from the medial ganglionic eminence (MGE) and migrate tangentially into the developing neocortex.
In Specific Aim 1, we will quantitatively assess the patterns and kinetics of the tangential migration of MGE-derived cells with the specific hypothesis that the disruption of tangential migration is dependent on the dose and time of ethanol insult in utero.
Specific Aim 2 will employ real-time videomicroscopy in heterotypic and heterochronic telencephalic slice cocultures to test the specific hypothesis that both cell intrinsic and extrinsic mechanisms contribute to alter the pattern of tangentil migration with in utero ethanol.
Specific Aim 3 will incorporate electrophysiological, gene profiling, and immunohistochemical approaches to test the hypothesis that in utero ethanol exposure interacts with the GABAergic system to exert its effect on tangential migration of MGE-derived cells. Overall, this project will for the first time define the effect of ethanol consumption during early stages of pregnancy on the embryonic development of a specific and important population of cells in the neocortex, notably the GABAergic cortical interneurons. In the long run, the proposed studies will lay the groundwork for assessing how disruptions of the cortical neuronal circuitry underlie many of the behavioral abnormalities seen in FAS. ? ? ?
