University of Rochester Medical Center

Verginia Carmella Cuzon

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Abuse of ethanol during pregnancy can be detrimental to the offspring, the most severe being the constellation of developmental defects and abnormalities commonly referred to as fetal alcohol syndrome (FAS). In the central nervous system FAS is hallmarked by a wide range of defects in brain morphology, including microcephalus, the formation of neuronal heterotopias, and disorders in cortical lamination, all of which are associated with insult to the brain during corticogenesis. These deficits can result in behavioral disorders such as motor dysfunction, hyperactivity, increased susceptibility to seizures, and deficits in learning and memory.

There is now abundant evidence of an interaction between ethanol and the GABAA receptor. Prenatal chronic ethanol exposure has been shown to increase the number of GABAA receptors, alter the expression of certain GABAA receptor subunits and decrease the number of GAD-positive cells. These changes suggest compromised GABAergic transmission. Loss of inhibitory regulation in the cortex with chronic prenatal ethanol exposure could contribute to the abnormalities in seizure susceptibility and deficits in sensory information processing associated with FAS.

In my thesis work I ask whether chronic ethanol consumption during pregnancy leads to abnormal development of the GABAergic system in the offspring. I will test the hypothesis that the abnormalities of the cortex seen in FAS manifest itself early in corticogenesis by affecting the migration of primordial GABAergic interneurons to their usual laminar position within the cortex. Since in the rodent, the medial ganglionic eminence (MGE) is the principle source of cortical GABAergic interneurons I will focus on the interaction between ethanol exposure and the tangential migration of MGE-derived cells into the cortex. In testing the central hypothesis, I propose three specific aims to answer the following questions: (1) Does prenatal ethanol exposure in utero disrupt the tangential migration of MGE-derived cells in a dose and time dependent manner? (2) Are the observed changes in tangential migration of MGE-derived cells the result of a direct interaction between ethanol and the GABAergic system? (3) If so, does chronic ethanol exposure in utero cause changes in GABAA receptors of MGE-derived cells or in GABA release mechanisms? Answers to these questions will contribute to the understanding of the deleterious effects of maternal ethanol consumption on corticogenesis in the offspring.

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