The NKCC1 antagonist bumetanide mitigates interneuronopathy associated with ethanol exposure in utero.
Elife
; 82019 09 23.
Article
em En
| MEDLINE
| ID: mdl-31545168
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Complicações na Gravidez
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Bumetanida
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Consumo de Bebidas Alcoólicas
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Inibidores de Simportadores de Cloreto de Sódio e Potássio
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Transtornos do Espectro Alcoólico Fetal
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Membro 2 da Família 12 de Carreador de Soluto
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Animals
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Pregnancy
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article