GABA and GABAergic Interneurons During Corticogenesis: MigrationFunctional Maturation, and Consequences of Gestational Ethanol Exposure,

Abstract

Thesis (Ph.D.)--University of Rochester. School of Medicine and Dentistry. Dept. of Interdepartmental Graduate Program in Neuroscience, 2008.Migration during corticogenesis plays an important role in orchestrating the assembly of cortical neurons within the laminated layout of the neocortex. Pyramidal cells migrate radially from the ventricular zone of the cortex while the majority of GABAergic neurons migrate tangentially from the medial ganglionic eminence (MGE). One of the factors that has been postulated to regulate the migration of cortical cells is the neurotransmitter GABA due to the early expression of GABA and its receptor, before the formation of synapses. The results of experiments present in this thesis uncover a role for GABA in regulating the migration of primordial GABAergic cells, mainly those arising from the MGE, as well as a developmentally dynamic expression of GABAA receptor subunits in this population of cells. Transgenic mice lines in which the expression of GFP is driven by either the expression of the GABA-producing enzyme, glutamic acid decarboxylase (GAD), or the gene Lhx6, whose CNS expression is limited to cells derived from the MGE, were used to examine the in vivo disposition of putative GABAergic cells or MGE-derived cells, respectively. A combination of experimental approaches including slice cultures, whole-cell patch clamp recording, immunohistochemistry and single-cell RT-PCR, were used to demonstrate the presence of ambient GABA along the tangential migratory path of MGE-derived cells. We demonstrate further that ambient GABA, through activation of GABAA receptors modulates the cortical entry of tangentially migrating MGE-derived cells. Increases or decreases in ambient levels of GABA or GABAA receptor function can increase or decrease the number of MGE-derived cells that enter into the neocortex, respectively. MGE-derived cells acquire increased sensitivity to GABA as they migrate, and this observation led to revealing the dynamic expression of GABAA receptor number and isoforms in tangentially migrating MGE-derived cells. Errors in the migration process and subsequent development of cortical cells, specifically GABAergic cortical interneurons, have been implicated in disorders with developmentally etiology such as schizophrenia, epilepsy, and autism, as well in consequences of prenatal exposure to teratogens, notably ethanol. Previous studies have suggested that prenatal exposure to ethanol compromises GABAergic transmission. In this light, this thesis tested the hypothesis that prenatal exprosure to ethanol affects the tangential migration and development of primordial cortical GABAergic interneurons through ethanol’s interaction with the developing GABAergic system. Our results demonstrate an increase in tangential migration, resulting in a net increase in the number of MGEderived cells with in utero ethanol exposure. This ethanol-induced increase in migration occurs concurrently with an increase in ambient GABA along the migratory path and alterations in the subunit composition of GABAA receptors expressed by MGE-derived cells. Our data implicate GABA as an important regulation of corticogenesis and establish the basic framework for investigating how cortical development might be affected by maternal ethanol consumption