Receptor-linked ionic channels mediate N-methyl-D-aspartate neurotoxicity in rat cerebellar slices

In young rat cerebellar slices, histological methods showed that the neurotoxic potency of N-methyl-D-aspartate (NMDA) towards granule cells and intracerebellar nucleus neurons was increased 2- to 3-fold on removal of Mg ions, which have a blocking effect on NMDA-activated ion channels. The depolarizing potency of NMDA on granule cells, recorded using a gap method, was similarly enhanced whereas that of kainate, a non-NMDA receptor agonist, was unchanged. The neurotoxic potency of kainate (towards Golgi cells) was also unaltered by removal of Mg2+. In Mg2+-containing medium, neuronal depolarization induced either by kainate or by high K+ potentiated NMDA toxicity, apparently by reducing the channel block by Mg2+. The results strongly support the hypothesis that excessive Ca2+ influx through NMDA/Mg2+-gated ion channels mediates NMDA toxicity. They also have clear implications regarding the likely mechanism of toxicity of agonists, such as glutamate, able to activate both NMDA and non-NMDA receptors.