The NKCC1 antagonist bumetanide mitigates interneuronopathy associated with ethanol exposure in utero

  1. Alexander G J Skorput
  2. Stephanie M Lee
  3. Pamela W L Yeh
  4. Hermes H Yeh  Is a corresponding author
  1. 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.

Data availability

All data generated or analyzed during this study are included in the manuscript.

Article and author information

Author details

  1. Alexander G J Skorput

    Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Stephanie M Lee

    Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Pamela W L Yeh

    Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Hermes H Yeh

    Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, United States
    For correspondence
    hermes.yeh@dartmouth.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6733-3692

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)).

Reviewing Editor

  1. Joseph G Gleeson, Howard Hughes Medical Institute, The Rockefeller University, United States

Publication history

  1. Received: May 21, 2019
  2. Accepted: September 22, 2019
  3. Accepted Manuscript published: September 23, 2019 (version 1)
  4. Version of Record published: September 30, 2019 (version 2)

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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  1. Alexander G J Skorput
  2. Stephanie M Lee
  3. Pamela W L Yeh
  4. Hermes H Yeh
(2019)
The NKCC1 antagonist bumetanide mitigates interneuronopathy associated with ethanol exposure in utero
eLife 8:e48648.
https://doi.org/10.7554/eLife.48648

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