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.
Highlights
Binge-type exposure of the embryonic mouse brain to a moderate level of ethanol leads to interneuronopathy, hallmarked by aberrant tangential migration of corticopetal GABAergic interneurons derived from the medial ganglionic eminence (MGE) (Skorput et al, 2015)
Ethanol induces a depolarizing shift in the GABA reversal potential of embryonic MGE-derived GABAergic cortical interneurons that is normalized by the NKCC1 inhibitor bumetanide
Taken together with our earlier finding that GABA-activated current responses in embryonic MGE-derived GABAergic interneurons are mediated by GABAA receptors (Cuzon Carlson and Yeh, 2011; Cuzon et al, 2008), these results indicate that NKCC1 antagonism attenuates ethanol-induced potentiation of depolarizing GABAAR-activated responses in migrating GABAergic cortical interneurons
Summary
Binge-type exposure of the embryonic mouse brain to a moderate level of ethanol leads to interneuronopathy, hallmarked by aberrant tangential migration of corticopetal GABAergic interneurons derived from the medial ganglionic eminence (MGE) (Skorput et al, 2015). The loop diuretic bumetanide is an NKCC1 antagonist that shifts the EGABA of embryonic neuroblasts to a more negative membrane potential when administered maternally (Wang and Kriegstein, 2011) Given these considerations, we tested the hypothesis that in utero treatment with bumetanide during the period of prenatal ethanol exposure will mitigate manifestation of prenatal ethanol-induced aberrant tangential migration, and prevent deficits in behavioral flexibility. We established a mouse model that simulates an early gestational, mid-first trimester human equivalent, exposure to binge-type maternal ethanol consumption from embryonic day (E) 13.5 - E16.5 (Clancy et al, 2001; Skorput et al, 2015) Using this model, we demonstrated enhanced entry of MGE-derived GABAergic interneurons into the prefrontal cortex (PFC), a persistent increase in the number of PV+ interneurons in the young adult PFC, and impairment in the PFC-dependent behavioral flexibility of offspring (Skorput et al, 2015). Our findings support the feasibility of a pharmacological strategy to target NKCC1 for the management of FASD
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