Neonatal ethanol exposure triggers apoptosis in the murine retrosplenial cortex: Role of inhibition of NMDA receptor-driven action potential firing. (1st January 2020)

• Record Type: Journal Article
• Authors: Bird, Clark W.; Barber, Megan J.; Post, Hilary R.; Jacquez, Belkis; Chavez, Glenna J.; Faturos, Nicholas G.; Valenzuela, C. Fernando
• Is Part Of: Neuropharmacology. Volume 162(2020)
• Publication Date: 2020-01-01
• Subjects: Fetal -- Alcohol -- Ethanol -- Development -- Cortex -- Retrosplenial -- Apoptosis -- Glutamate -- Electrophysiology -- Neonatal; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2019.107837
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Exposure to ethanol during the last trimester equivalent of human pregnancy causes apoptotic neurodegeneration in the developing brain, an effect that is thought to be mediated, in part, by inhibition of NMDA receptors. However, NMDA receptors can rapidly adapt to the acute effects of ethanol and are ethanol resistant in some populations of developing neurons. Here, we characterized the effect of ethanol on NMDA and non-NMDA receptor-mediated synaptic transmission in the retrosplenial cortex (RSC), a brain region involved in the integration of different modalities of spatial information that is among the most sensitive regions to ethanol-induced neurodegeneration. A single 4-h exposure to ethanol vapor of 7-day-old transgenic mice that express the Venus fluorescent protein in interneurons triggered extensive apoptosis in the RSC. Slice electrophysiological recordings showed that bath-applied ethanol inhibits NMDA and non-NMDA receptor excitatory postsynaptic currents (EPSCs) in pyramidal neurons and interneurons; however, we found no evidence of acute tolerance development to this effect after the 4-h in-vivo ethanol vapor exposure. Acute bath application of ethanol reduced action potential firing evoked by synaptic stimulation to a greater extent in pyramidal neurons than interneurons. Submaximal inhibition of NMDA EPSCs, but not non-NMDA EPSCs, mimicked the acute effect of ethanol on synaptically-evoked action potential firing. These findings indicate that partial inhibition of NMDA receptors by ethanol has sizable effects on the excitability of glutamatergic and GABAergic neurons in the developing RSC, and suggest that positive allosteric modulators of these receptors could ameliorate ethanol intoxication-induced neurodegeneration during late stages of fetal development. Highlights: Postnatal day 7 Venus-VGAT mice were exposed to vaporized ethanol for 4 h. This triggered apoptotic neurodegeneration in the P7 mouse retrosplenial cortex. Inhibition of firing evoked by synaptic input could contribute to this effect. This effect is mediated, at least in part, by NMDA receptor inhibition. There were differences in ethanol's effect in pyramidal neurons vs interneurons.