Role of GluR2 expression in AMPA-induced toxicity in cultured murine cerebral cortical neurons

Abstract

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R)-mediated neurotoxicity was studied in relation to subunit expression and the presence of Ca2+-permeable receptor channels. AMPA-mediated toxicity had two components: 1) a direct AMPA-R-mediated component, which was not due to Ca2+ influx through voltage-gated Ca2+ channels, reversal of the Na+/Ca2+ exchanger or release of calcium from dantrolene-sensitive intracellular Ca2+ stores, and 2) a minor, indirect component involving activation of NMDA receptor channels, because of glutamate release and removal of the Mg2+ block of the NMDA receptor on AMPA-R stimulation. The involvement of Ca2+ influx through AMPA-R was also examined. The number of neurons possessing Ca2+-permeable AMPA-R increased during culture development, concurrently with an increasing susceptibility for AMPA-induced toxicity during development. GluR2(R) levels also increased during development, and channel blockers of Ca2+-permeable AMPA-R lacking the GluR2(R) subunit (spermine and philanthotoxin) failed to prevent neurotoxicity or increases in [Ca2+]i. Thus, the direct AMPA-R-mediated toxicity may be explained by initiation of cell death by Ca2+ fluxing through AMPA-R containing GluR2(R). The components of direct AMPA-R-mediated toxicity are proposed to be 1) toxicity mediated by GluR2(R)-lacking AMPA-R and 2) toxicity mediated by low-Ca2+-permeability AMPA-R containing GluR2(R). © 2001 Wiley-Liss, Inc.