The positive allosteric modulator of NMDA receptors, GNE-9278, blocks the ethanol-induced decrease of excitability in...

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.