NEURONAL MIGRATION, CIRCUIT FORMATION AND FASD: TOWARD A UNIFIED VIEW OF NEURODEVELOPMENTAL DISORDERS

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Yeh HH1, Skorput AGJ2, Delatour LC1

1 The Geisel School of Medicine at Dartmouth, Hanover, NH, USA
2 University of Minnesota Medical School Twin Cities, Minneapolis, MN, USA

An alarming percentage of women drink during pregnancy; some even binge drink to risky levels. Since ethanol readily crosses the placental and embryonic blood-brain barriers, binge drinking during pregnancy places the fetus at high risk for Fetal Alcohol Spectrum Disorder (FASD) due to exposure to sudden and repeated surges of high maternal blood ethanol levels when the embryonic brain is particularly vulnerable to the teratogenic effects of ethanol.

During embryonic development of the cerebral cortex, neuronal migration is dynamically regulated, as tangential migration of primordial GABAergic interneurons and radial migration of pyramidal neurons are intricately interwoven to shape cortical form and function. Anomalies in the migration of cortical neurons have been implicated in long-term aberrances in cortical disposition. In particular, “interneuronopathy”, broadly defined as neurodevelopmental disorder of interneuronal migration, has been attributed in part to neuropathies such as epilepsy, schizophrenia and autism. Indeed, FASD presents with behavioral and cognitive deficits reminiscent of these neurodevelopmental conditions, and its diagnosis is often either missed, misdiagnosed or considered comorbid or a risk factor for one or more of these disorders.

Here at ISBRA/ESBRA-2016, we present evidence that exposure to ethanol in utero affects both tangential and radial migration in the embryonic cortex. For this presentation, we focus on tangential migration, and summarize results indicating that ethanol exposure in utero results in a form of interneuronopathy that exerts short-term effects on the migration of GABAergic cortical interneurons and longer-term effects of cortical form, circuit function, and behavior. In addition, we present preliminary evidence for potential pharmacology-based therapeutic intervention of this in utero ethanol exposure-induced interneuronopathy. Overall, our studies on cortical neuronal migration will contribute to our understanding of how the development of the cerebral cortex is affected in FASD in order to enhance its treatment or management.

Support: NIH R01 AA024036 and R21 AA023410

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