The NKCC1 antagonist bumetanide mitigates interneuronopathy associated with ethanol exposure in utero
- Geisel School of Medicine at Dartmouth, United States
Abstract
Prenatal exposure to ethanol induces aberrant tangential migration of corticopetal GABAergic interneurons, and long-term alterations in the form and function of the prefrontal cortex. We have hypothesized that interneuronopathy contributes significantly to the pathoetiology of fetal alcohol spectrum disorders (FASD). Activity-dependent tangential migration of GABAergic cortical neurons is driven by depolarizing responses to ambient GABA present in the cortical enclave. We found that ethanol exposure potentiates the depolarizing action of GABA in GABAergic cortical interneurons of the embryonic mouse brain. Pharmacological antagonism of the cotransporter NKCC1 mitigated ethanol-induced potentiation of GABA depolarization and prevented aberrant patterns of tangential migration induced by ethanol in vitro. In a model of FASD, maternal bumetanide treatment prevented interneuronopathy in the prefrontal cortex of ethanol exposed offspring, including deficits in behavioral flexibility. These findings position interneuronopathy as a mechanism of FASD symptomatology, and posit NKCC1 as a pharmacological target for the management of FASD.
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All data generated or analyzed during this study are included in the manuscript.
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Funding
National Institutes of Health (PHS NIH R01 AA-023410)
- Hermes H Yeh
National Institutes of Health (PHS NIH R21 A-024036)
- Hermes H Yeh
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experimental procedures were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and approved by the Dartmouth Institutional Animal Care and Use Committee (IACUC Protocol# 00002109(m18a)).
Copyright
© 2019, Skorput et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The NKCC1 antagonist bumetanide mitigates interneuronopathy associated with ethanol exposure in utero
eLife 8:e48648.
https://doi.org/10.7554/eLife.48648
