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

alpha -Amino-3-hydroxy-5-methyl-4-isoxazoleproplonic acid receptor (AMPA-R) -mediated neurotoxicity was studied in relation to subunit expression and t he presence of Ca2+-permeable receptor channels. AMPA-mediated toxicity had two components: 1) a direct AMPA-R-mediated component, which was not due t o Ca2+ influx through voltage-gated Ca2+ channels, reversal of the Na+/Ca2 exchanger or release of calcium from dantrolene-sensitive intracellular Ca 2+ stores, and 2) a minor, indirect component involving activation of NMDA receptor channels, because of glutamate release and removal of the Mg2+ blo ck of the NMDA receptor on AMPA-R stimulation. The involvement of Ca2+ infl ux 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. Gl uR2(R) levels also increased during development, and channel blockers of Ca 2+-permeable AMPA-R lacking the GluR2(R) subunit (spermine and philanthotox in) failed to prevent neurotoxicity or increases in [Ca2+](i). Thus, the di rect AMPA-R-mediated toxicity may be explained by initiation of cell death by Ca2+ fluxing through AMPA-R containing GluR2(R). The components of direc t 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). J. Neurosci. Res. 65:267-277, 2001. (C) 2001 Wiley-Li ss, Inc.