The positive allosteric modulator of NMDA receptors, GNE-9278, blocks the ethanol-induced decrease of excitability in developing retrosplenial cortex neurons from mice.
The positive allosteric modulator of NMDA receptors, GNE-9278, blocks the ethanol-induced decrease of excitability in developing retrosplenial cortex neurons from mice.
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DOI：
10.1002/npr2.12306
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发表时间：
2023-03
影响因子：
2.5
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在大脑生长突增期间，酒精的过度暴露会引发多个大脑区域的凋亡性神经变性，包括压后皮质，这是海马-间脑-扣带记忆网络的一部分。这在一定程度上是由N-甲基-d-天冬氨酸（NMDA）受体的Ca 2+内流减少以及促生存基因激活的减少介导的。在这里，我们测试是否积极的别构调节剂的NMDA受体可以抵消乙醇对发展压后皮质锥体神经元的抑制作用。我们在出生后第6-8天小鼠的急性切片中使用膜片钳电生理技术来测试正变构调节剂GNE-9278对乙醇诱导的NMDA受体功能抑制的影响。GNE-9278剂量依赖性增加NMDA兴奋性突触后电流的振幅、衰减时间和总电荷。在5 μmol L−1浓度下，GNE-9278显著降低90 mmol L−1乙醇诱导的NMDA兴奋性突触后电流振幅、衰减时间和总电荷的抑制。电流钳实验表明，5 μmol L-1 GNE-9278改善了90 mmol L-1乙醇诱导的突触诱发动作电位放电和复合兴奋性突触后电位振幅的抑制。这些发现表明，正变构调节剂减轻了发育中的大脑皮层神经元中乙醇诱导的NMDA受体功能低下，这种作用可以改善其在胎儿发育后期的促凋亡作用。在大脑生长突增期间，酒精的过度暴露会引发压后皮质的凋亡性神经变性，压后皮质是海马-间脑-扣带记忆网络的一部分。这在一定程度上是通过NMDA受体的钙内流减少，随后促生存基因的激活减少来介导的。我们在这里报告，一种正变构调节剂减轻了乙醇诱导的发育中的压后皮质神经元NMDA受体功能低下。
Binge‐like exposure to ethanol during the brain growth spurt triggers apoptotic neurodegeneration in multiple brain regions, including the retrosplenial cortex, a brain region that is part of the hippocampal‐diencephalic‐cingulate memory network. This is mediated, in part, by reduced Ca2+ influx through N‐methyl‐d‐aspartate (NMDA) receptors followed by a decrease in the activation of pro‐survival genes. Here, we tested whether a positive allosteric modulator of NMDA receptors could counteract the inhibitory effect of ethanol on developing retrosplenial cortex pyramidal neurons. We used patch‐clamp electrophysiological techniques in acute slices from postnatal day 6–8 mice to test the effect of the positive allosteric modulator GNE‐9278 on ethanol‐induced inhibition of NMDA receptor function. GNE‐9278 dose‐dependently increased the amplitude, decay time, and total charge of NMDA excitatory postsynaptic currents. At a concentration of 5 μmol L−1, GNE‐9278 significantly reduced the 90 mmol L−1 ethanol‐induced inhibition of NMDA excitatory postsynaptic current amplitude, decay time, and total charge. Current‐clamp experiments showed that 5 μmol L−1 GNE‐9278 ameliorated the 90 mmol L−1 ethanol‐induced inhibition of synaptically‐evoked action potential firing and compound excitatory postsynaptic potential amplitude. These findings indicate that positive allosteric modulators mitigate ethanol‐induced hypofunction of NMDA receptors in developing cerebral cortex neurons, an effect that could ameliorate its pro‐apoptotic effects during the late stages of fetal development. Binge‐like exposure to ethanol during the brain growth spurt triggers apoptotic neurodegeneration in the retrosplenial cortex, a brain region that is part of the hippocampal‐diencephalic‐cingulate memory network. This is mediated, in part, by reduced calcium influx through NMDA receptors followed by a decrease in the activation of pro‐survival genes. We report here that a positive allosteric modulator mitigates the ethanol‐induced hypofunction of NMDA receptors in developing retrosplenial cortex neurons.