Neonatal ethanol exposure triggers apoptosis in the murine retrosplenial cortex: Role of inhibition of NMDA receptor-driven action potential firing
Neonatal ethanol exposure triggers apoptosis in the murine retrosplenial cortex: Role of inhibition of NMDA receptor-driven action potential firing
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DOI：
10.1016/j.neuropharm.2019.107837
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发表时间：
2020-01-01
影响因子：
4.7
通讯作者：
Valenzuela, C. Fernando
中科院分区：
文献类型：
--
作者：
Bird, Clark W.;Barber, Megan J.;Valenzuela, C. Fernando
在人类妊娠的最后三个月暴露于乙醇会导致发育中的大脑发生凋亡性神经变性，这种作用被认为部分是通过抑制NMDA受体介导的。然而，NMDA受体可以迅速适应乙醇的急性效应，并且在一些发育中的神经元群体中具有乙醇抗性。在这里，我们的特点是影响乙醇对NMDA和非NMDA受体介导的突触传递的压后皮质（RSC），参与整合不同形式的空间信息，是最敏感的区域之一，乙醇诱导的神经变性的脑区。一个单一的4小时暴露于乙醇蒸汽的7天大的转基因小鼠，表达金星荧光蛋白在中间神经元引发广泛的细胞凋亡的RSC。切片电生理记录表明，浴应用乙醇抑制NMDA和非NMDA受体兴奋性突触后电流（EPSC）在锥体神经元和中间神经元，但是，我们没有发现急性耐受性发展的证据后，4小时在体内乙醇蒸汽暴露的影响。急性浴应用乙醇减少动作电位放电诱发的突触刺激在更大程度上在锥体神经元比中间神经元。次最大抑制的NMDA EPSCs，但不是非NMDA EPSCs，模仿急性乙醇对突触诱发的动作电位放电的影响。这些研究结果表明，部分抑制NMDA受体的乙醇有相当大的影响发育中的RSC中的谷氨酸能和GABA能神经元的兴奋性，并建议这些受体的正变构调节剂可以改善乙醇中毒诱导的神经变性在胎儿发育的后期阶段。
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.