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Articles

Ca2+ entry via AMPA/KA receptors and excitotoxicity in cultured cerebellar Purkinje cells

JR Brorson, PA Manzolillo and RJ Miller
Journal of Neuroscience 1 January 1994, 14 (1) 187-197; https://doi.org/10.1523/JNEUROSCI.14-01-00187.1994
JR Brorson
Department of Neurology, University of Chicago, Illinois 60637.
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PA Manzolillo
Department of Neurology, University of Chicago, Illinois 60637.
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RJ Miller
Department of Neurology, University of Chicago, Illinois 60637.
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Abstract

Initial studies of glutamate receptors activated by kainate (KA) found them to be Ca2+ impermeable. Activation of these receptors was thought to produce Ca2+ influx into neurons only indirectly by Na(+)-dependent depolarization. However, Ca2+ entry via AMPA/KA receptors has now been demonstrated in several neuronal types, including cerebellar Purkinje cells. We have investigated whether such Ca2+ influx is sufficient to induce excitotoxicity in cultures of cerebellar neurons enriched for Purkinje cells. Agonists at non-NMDA receptors induced Ca2+ influx in the majority of these cells, as measured by whole-cell voltage clamp and by fura-2 [Ca2+]i microfluorimetry. To assess excitotoxicity, neurons were exposed to agonists for 20 min and cell survival was evaluated by a fluorescence assay 24 hr later. KA (100 microM) reduced neuronal survival relative to controls to 43 +/- 3% when applied in Na(+)-containing solution and to 45 +/- 3% in Na(+)-free solution. This toxicity was blocked completely by CNQX but only slightly by 100 microM Cd2+ and 50 microM D-(-)-2-amino-5-phosphonovaleric acid. Both Purkinje neurons and non-Purkinje cell types present in the cultures were similarly vulnerable to toxic KA exposure, but the population marked by KA-induced Co2+ uptake was selectively diminished by the excitotoxicity. Na(+)-independent excitotoxicity could also be induced by domoate, AMPA, or glutamate. Compared to KA, NMDA was relatively ineffective in inducing cell death. Most of the KA-induced excitotoxicity could be blocked by removal of extracellular Ca2+ during the KA exposure and for a 5 min period thereafter. Furthermore, antagonists of the Ca(2+)-activated enzymes nitric oxide synthase and calpain significantly reduced the KA-induced cell death. These results show that non-NMDA receptor activation can cause excitotoxicity in cerebellar Purkinje neurons by mechanisms not involving Na+ influx, but rather depending on direct Ca2+ permeation and activation of Ca(2+)- dependent enzymatic processes.

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The Journal of Neuroscience: 14 (1)
Journal of Neuroscience
Vol. 14, Issue 1
1 Jan 1994
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Ca2+ entry via AMPA/KA receptors and excitotoxicity in cultured cerebellar Purkinje cells
JR Brorson, PA Manzolillo, RJ Miller
Journal of Neuroscience 1 January 1994, 14 (1) 187-197; DOI: 10.1523/JNEUROSCI.14-01-00187.1994

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Ca2+ entry via AMPA/KA receptors and excitotoxicity in cultured cerebellar Purkinje cells
JR Brorson, PA Manzolillo, RJ Miller
Journal of Neuroscience 1 January 1994, 14 (1) 187-197; DOI: 10.1523/JNEUROSCI.14-01-00187.1994
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