The NKCC1 antagonist bumetanide mitigates interneuronopathy associated with ethanol exposure in utero.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 31545168.
- Also identified by DOI 10.7554/eLife.48648 and PMC identifier 6768659.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Alcohol Drinking
- Bumetanide
- Fetal Alcohol Spectrum Disorders
- Pregnancy Complications
- Sodium Potassium Chloride Symporter Inhibitors
- Solute Carrier Family 12, Member 2