title: Mechanisms of AMPA Neurotoxicity in Rat Brain Slices.
abstract: The mechanisms underlying the neurodegenerative effects of the glutamate receptor agonist, AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate), were studied using brain slice preparations of young rat (8 - 9 days old) cerebellum and hippocampus. Rapid AMPA toxicity (exerted on some cerebellar interneurons) was inhibited by including the appropriate receptor blocker, CNQX (6-cyano-7-nitroquinoxaline-2,3-dione, 10 microM), in the exposing solution. The degeneration of other neurons, including Purkinje cells and hippocampal pyramidal neurons, persisted. It could, however, be largely prevented if CNQX was included for 1.5 h during the post-incubation period, suggesting that an enduring 'rebound' AMPA receptor activation was responsible for this delayed type of degeneration, not the exposure itself. In cerebellar slices, independent evidence for the occurrence, postexposure, of persisting AMPA receptor stimulation was obtained electrophysiologically. Omission of Ca2+ during the exposure period (and for 10 min beforehand) markedly reduced rapid AMPA toxicity but was ineffective in protecting most of the Purkinje cells. However, if the slices were previously starved of Ca2+ for 1 h, then most of these neurons survived, even if the ion was reinstated during the recovery period. Slow AMPA toxicity, which takes place during long (2 h) exposures, could be inhibited either by CNQX or by omission of Ca2+ (30 min preincubation). The results indicate that the rapid oedematous necrosis induced by AMPA, like that caused by N-methyl-d-aspartate and kainate, is likely to involve excessive influx of Ca2+. In contrast, the induction of the delayed mechanisms, as well as its 'expression' during the postincubation period, probably depends on intracellular Ca2+, rather than Ca2+ influx.
authors.affiliation: Department of Physiology, University of Liverpool, Brownlow Hill, PO Box 147, Liverpool L69 3BX, UK.
authors.forename: Giti
authors.initials: G
authors.lastname: Garthwaite
authors.forename: John
authors.initials: J
authors.lastname: Garthwaite