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The Journal of Neuroscience, February 20, 2008, 28(8):1854-1864; doi:10.1523/JNEUROSCI.5110-07.2008

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Development/Plasticity/Repair
Ethanol Consumption during Early Pregnancy Alters the Disposition of Tangentially Migrating GABAergic Interneurons in the Fetal Cortex

Verginia C. Cuzon,¹ Pamela W. L. Yeh,¹ Yuchio Yanagawa,² Kunihiko Obata,³ and Hermes H. Yeh¹

¹Department of Physiology, Dartmouth Medical School, Lebanon, New Hampshire 03756, ²Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi 371-0198, Japan, and ³RIKEN Brain Science Institute, Saitama, 351-0198, Japan

Correspondence should be addressed to Dr. Hermes H. Yeh, Department of Physiology, Dartmouth Medical School, Lebanon, NH 03756. Email: Hermes.Yeh{at}dartmouth.edu

Consumption of alcohol (ethanol) during pregnancy can lead to developmental defects in the offspring, the most devastating being the constellation of symptoms collectively referred to as fetal alcohol syndrome (FAS). In the brain, a hallmark of FAS is abnormal cerebral cortical morphology consistent with insult during corticogenesis. Here, we report that exposure to a relatively low level of ethanol in utero (average maternal and fetal blood alcohol level of 25 mg/dl) promotes premature tangential migration into the cortical anlage of primordial GABAergic interneurons, including those originating in the medial ganglionic eminence (MGE). This ethanol-induced effect was evident in vivo at embryonic day 14.5 (E14.5) in GAD67 knock-in and BAC-Lhx6 embryos, as well as in vitro in isotypic telencephalic slice cocultures obtained from E14.5 embryos exposed to ethanol in utero. Analysis of heterotypic cocultures indicated that both cell-intrinsic and -extrinsic factors contribute to the aberrant migratory profile of MGE-derived cells. In this light, we provide evidence for an interaction between ethanol exposure in utero and the embryonic GABAergic system. Exposure to ethanol in utero elevated the ambient level of GABA and increased the sensitivity to GABA of MGE-derived cells. Our results uncovered for the first time an effect of ethanol consumption during pregnancy on the embryonic development of GABAergic cortical interneurons. We propose that ethanol exerts its effect on the tangential migration of GABAergic interneurons extrinsically by modulating extracellular levels of GABA and intrinsically by altering GABA_A receptor function.

Key words: medial ganglionic eminence; fetal alcohol syndrome; ambient GABA; GABA_A receptor; GFP+/MGE; telencephalic slice culture

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Received Nov. 16, 2007; revised Jan. 7, 2008; accepted Jan. 8, 2008.

Correspondence should be addressed to Dr. Hermes H. Yeh, Department of Physiology, Dartmouth Medical School, Lebanon, NH 03756. Email: Hermes.Yeh{at}dartmouth.edu

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