TY - JOUR T1 - L-Type Calcium Channels Contribute to Ethanol-Induced Aberrant Tangential Migration of Primordial Cortical GABAergic Interneurons in the Embryonic Medial Prefrontal Cortex JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0359-21.2021 SP - ENEURO.0359-21.2021 AU - Stephanie M. Lee AU - Pamela W.L. Yeh AU - Hermes H. Yeh Y1 - 2021/12/16 UR - http://www.eneuro.org/content/early/2021/12/15/ENEURO.0359-21.2021.abstract N2 - Exposure of the fetus to alcohol (ethanol) via maternal consumption during pregnancy can result in fetal alcohol spectrum disorders (FASD), hallmarked by long-term physical, behavioral, and intellectual abnormalities. In our preclinical mouse model of FASD, prenatal ethanol exposure disrupts tangential migration of corticopetal GABAergic interneurons in the embryonic medial prefrontal cortex (mPFC). We postulated that ethanol perturbed the normal pattern of tangential migration via enhancing GABAA receptor-mediated membrane depolarization that prevails during embryonic development in GABAergic cortical interneurons. However, beyond this, our understanding of the underlying mechanisms is incomplete. Here, we tested the hypothesis that the ethanol-enhanced depolarization triggers downstream an increase in high-voltage activated nifedipine-sensitive L-type calcium channel (LTCC) activity, and provide evidence implicating calcium dynamics in the signaling scheme underlying the migration of embryonic GABAergic interneurons and its aberrance. Tangentially migrating Nkx2.1+ GABAergic interneurons expressed immunoreactivity to Cav1.2, the canonical neuronal isoform of the L-type calcium channel. Prenatal ethanol exposure did not alter its protein expression profile in the embryonic mPFC. However, exposing ethanol concomitantly with the LTCC blocker nifedipine prevented the ethanol-induced aberrant migration both in vitro and in vivo. In addition, whole-cell patch clamp recording of LTCCs in GABAergic interneurons migrating in embryonic medial prefrontal cortical slices revealed that acutely applied ethanol potentiated LTCC activity in migrating GABAergic interneurons. Based on evidence reported in the present study, we conclude that calcium is an important intracellular intermediary downstream of GABAA receptor-mediated depolarization in the mechanistic scheme of an ethanol-induced aberrant tangential migration of embryonic GABAergic cortical interneurons.Significance StatementThe etiology of fetal alcohol spectrum disorders (FASD) takes place in utero when the fetus is exposed to alcohol. While the outcome of FASD has been well characterized, the mechanism underlying its embryonic etiology is incompletely understood. Here, we investigated the role of L-type voltage-gated calcium channels (LTCCs) in the ethanol-induced aberrant tangential migration of cortical GABAergic interneurons. The findings from our study highlight LTCCs as important regulators underlying the aberrant tangential migration resulting from prenatal ethanol exposure and suggest that they bear therapeutic potential in managing and treating FASD. The results also propose an interplay between chloride and calcium in the migrating embryonic interneurons, and exposure to ethanol may enhance this interaction, contributing to the etiology of FASD. ER -