AMPA Neurotoxicity in Rat Cerebellar and Hippocampal Slices: Histological Evidence for Three Mechanisms

Abstract

Excitatory amino acid-induced death of central neurons may be mediated by at least two receptor types, the so-called NMDA (N-methyl-d-aspartate) and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate) receptors. We have studied the neurodegenerative mechanisms set in motion by AMPA receptor activation using incubated slices of 8-day-old rat cerebellum and hippocampus. In both preparations, AMPA induced a pattern of degeneration that differed markedly from the one previously shown to be elicited by NMDA. In cerebellar slices, AMPA induced the degeneration of most Purkinje cells together with a population of Golgi cells; in hippocampal slices the neurons were affected in the order CA3 > CA1 > dentate granule cells. Three mechanisms could be discerned: an acute one in which neurons (e.g. cerebellar Golgi cells) underwent a rapid degeneration; a delayed one in which the neurons (Purkinje cells and hippocampal neurons) appeared to be only mildly affected immediately after a 30 min exposure but then underwent a protracted degeneration during the postincubation period (1.5–3 h); and finally a slow toxicity, which took place during long (2 h) exposures to AMPA (3–30 μM). Although Purkinje cells were vulnerable in both cases, the efficacy of AMPA was higher for the delayed mechanism than for the slow one. The pathology displayed by the acutely destroyed Golgi neurons was a classical oedematous necrosis, whereas most neurons vulnerable to the delayed and slow mechanisms displayed a ‘dark cell degeneration’, whose cytological features bore a close resemblance to those of neurons irreversibly damaged by ischaemia, hypoglycaemia or status epilepticus in vivo.