Work

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

Year: 2019

Type: article

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.

Source: eLife

DOI: 10.7554/elife.48648

Authors: Alexander G. J. Skorput, Stephanie M. Lee, Pamela W. L. Yeh, Hermes H. Yeh

Institutions: Dartmouth College, University of Minnesota

Language: English

Topic: Prenatal Substance Exposure Effects

Subfield: Pediatrics, Perinatology and Child Health

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,500