Neonatal ethanol exposure triggers apoptosis in the murine retrosplenial cortex: Role of inhibition of NMDA receptor-driven action potential firing

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 ethanolinduced neurodegeneration. A single four-hour 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 four-hour 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.

Enhancement of parvalbumin interneuron-mediated neurotransmission in the retrosplenial cortex of adolescent mice following third trimester-equivalent ethanol exposure

“…Studies with mice have demonstrated that heavy binge-like exposure to ethanol at P7 triggers apoptosis of pyramidal neurons and PV-INs in the RSC, an effect that could, in part, underlie the deficits in contextual fear conditioning and navigation in the Morris water maze caused by this ethanol exposure paradigm 22 – 27 . Consistent with these studies, we recently reported that P7 ethanol vapor administration (peak BEC = 400 mg/dl) triggers apoptotic neurodegeneration of INs in the murine RSC 28 . In the same study, we also found that acute bath application of ethanol to brain slices from P6–8 mice decreased the amplitude of both NMDA and non-NMDA glutamatergic excitatory postsynaptic currents; however, only inhibition of NMDA receptors affected synaptic excitability in RSC neurons.…”

“…Slice electrophysiology experiments were performed as described previously 28 . Briefly, P6–P8 pups were anaesthetized with isoflurane (Piramal Critical Care, Bethelhem, PA) and rapidly decapitated.…”

“…Ethanol vapor concentrations were determined using a breathalyzer (Intoximeters, St. Louis, MO) and were between 8 and 9 g/dl. This exposure paradigm produces peak BECs in pups near 80 mM and triggers apoptotic neurodegeneration in several brain regions, including the RSC 13 , 28 .…”

Enhancement of Parvalbumin Interneuron-Mediated Neurotransmission in the Retrosplenial Cortex of Adolescent Mice Following Third Trimester-Equivalent Ethanol Exposure

“…Studies with mice have demonstrated that heavy binge-like exposure to ethanol at P7 triggers apoptosis of pyramidal neurons and PV-INs in the RSC, an effect that could, in part, underlie the deficits in contextual fear conditioning and navigation in the Morris water maze caused by this ethanol exposure paradigm [22][23][24][25][26][27] . Consistent with these studies, we recently reported that P7 ethanol vapor administration (peak BEC = 400 mg/dl) triggers apoptotic neurodegeneration of INs in the murine RSC 28 . In the same study, we also found that acute bath application of ethanol to brain slices from P6-8 mice decreased the amplitude of both NMDA and non-NMDA glutamatergic excitatory postsynaptic currents; however, only inhibition of NMDA receptors affected synaptic excitability in RSC neurons.…”

“…Ethanol vapor concentrations were determined using a breathalyzer (Intoximeters, St. Louis, MO) and were between 8-9 g/dl. This exposure paradigm produces peak BECs in pups near 80 mM and triggers apoptotic neurodegeneration in several brain regions, including the RSC 13,28 .…”