Developmental expression and self-regulation of Ca2+ entry via AMPA/KA receptors in the embryonic chick retina

Excessive activation of glutamate receptors in the late embryonic and adult retina leads to excitotoxic cell death through an increase in intracellular calcium concentration. Here we use the cobalt-staining technique of Pruss et al. to investigate the developmental expression of Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid/kainate (AMPA/KA) receptors in the embryonic chick retina, and the effects of AMPA/KA receptor activation on cell survival and AMPA/KA receptor expression. Ca(2+)-permeable AMPA/KA receptors are present in the retina as early as embryonic day 6 (E6). While sustained activation of these receptors with KA led to massive cell death in explant and dissociated cultures of the chick retina late in development, continuous application of high doses of KA from early times was not excitotoxic. Cell survival in KA is correlated with both a reduction in cobalt staining and the KA-evoked membrane current, and thus with a reduction in the Ca2+ entry into cells via AMPA/KA receptors. The effects of KA could be blocked by the non-N-methyl-D-aspartic acid (NMDA) receptor antagonist 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), but not by the NMDA receptor antagonist D-2-amino-5-phosphonovalerate (AP5) nor the L-type Ca2+ channel blockers diltiazem and nifedipine. The action of AP5 was mimicked by exposure to glutamate but not by the metabotropic receptor agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid. Thus exposure of retinal neurons to glutamate early in development may protect them from its excitotoxic actions later on.