Excitatory amino acid neurotoxicity in the hippocampal slice preparation.
The effect of sustained activation of excitatory amino acid receptors on neuronal survival was studied using slices of adult rat hippocampus and light and electron microscopy. Kainate, N-methyl-D-aspartate, quisqualate, and ibotenate all produce signs of severe neurotoxicity within 90 min. Neuronal damage occurs in the form of perikaryal and dendritic swelling, cytoplasmic and nucleoplasmic disintegration, and plasma and nuclear membrane ruffling and collapse. The toxicity is restricted to intrinsic neuronal somata, dendrites and spines, while afferent axons, boutons and glia are spared. Although damage is generally distributed throughout all areas of hippocampus, kainate has little effect on pyramidal neurons in the CA2 region. Quantitative analysis of neuronal survival indicates that agonists induce dose-dependent damage over concentration ranges known to be excitatory. Based on selective antagonism by DL-aminophosphonoheptanoate and the patterns of damage produced by each, N-methyl-D-aspartate, kainate, and quisqualate trigger neurotoxicity by acting on distinct receptor classes. It is concluded that, in hippocampal slices, excitatory amino acids induce neurotoxicity in a similar manner to their actions in vivo. The results support the hypothesis that hippocampal neurotoxicity is initiated by excessive excitation, and provide another example of the capacity of adult hippocampal neurons for rapid structural modification.
D000596:Amino Acids / Q000633:toxicity*; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000648:ultrastructure*; D007051:Ibotenic Acid / Q000633:toxicity; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D008854:Microscopy, Electron; D016202:N-Methylaspartate; D009498:Neurotoxins / Q000494:pharmacology*; D010069:Oxadiazoles / Q000633:toxicity; D016318:Quisqualic Acid; D051381:Rats; D011919:Rats, Inbred Strains
D000596:Amino Acids; D009498:Neurotoxins; D010069:Oxadiazoles; D007051:Ibotenic Acid; D001224:Aspartic Acid; D016202:N-Methylaspartate; D016318:Quisqualic Acid; D007608:Kainic Acid