Biochemical and morphological analysis of non-NMDA receptor mediated excitotoxicity in chick embryo retina

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate glutamatergic neurotransmission, and when pathologically overstimul ated induce excitotoxic neuronal death. Of the two families of iGluRs, the non-NMDA receptors have received less experimental attention than the NMDA receptors as mediators of neuronal death in in vitro systems. We have demon strated that non-NMDA receptor activation is highly lethal for neurons of t he chick embryo retina, and further characterize this phenomenon here. Trea tment of isolated retinas with any of the non-NMDA receptor agonists glutam ate, AMPA, or KA, in the presence of the NMDA receptor antagonist MK-801, l ed to pathomorphology and cell death. KA was the most effective toxin. All of KA-induced toxicity could be blocked by selective AMPA receptor blockers . The toxicity of both AMPA and glutamate could be greatly increased using cyclothiazide, which blocks AMPA receptor desensitization. These results in dicate that KA is the most powerful toxin because it is a non-desensitizing agonist at the AMPA receptors. Glutamate exhibited a paradoxical ability t o prevent KA-induced toxicity as measured by a biochemical assay of cell de ath. Also, histological studies indicated that glutamate selectively blocke d KA-induced pathomorphological changes in bipolar cells. This protective e ffect of glutamate was not mimicked by AMPA, NMDA, or any of several metabo tropic receptor agonists, indicating that it may be mediated by a receptor of undescribed pharmacology.