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.
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D002118:Calcium / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects*; D007473:Ion Channels / Q000502:physiology*; D008274:Magnesium / Q000378:metabolism; D016202:N-Methylaspartate; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D011188:Potassium / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000502:physiology*
D007473:Ion Channels; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D001224:Aspartic Acid; D016202:N-Methylaspartate; D008274:Magnesium; D011188:Potassium; D002118:Calcium