Ca2+-independent excitotoxic neurodegeneration in isolated retina, an intact neural net:: A role for Cl- and inhibitory transmitters

Rapidly triggered excitotoxic cell death is widely thought to be due to excessive influx of extracellular Ca2+, primarily through the N-methyl-D-aspartate subtype of glutamate receptor. By devising conditions that permit the maintenance of isolated retina in the absence of Ca2+, it has become technically feasible to test the dependence of excitotoxic neurodegeneration in this intact neural system on extracellular Ca2+. Using biochemical, Ca2+ imaging, and electrophysiological techniques, we found that (1) rapidly triggered excitotoxic cell death in this system occurs independently of both extracellular Ca2+ and increases in intracellular Ca2+; (2) this cell death is highly dependent on extracellular Cl-; and (3) lethal Cl- entry occurs by multiple paths, but a significant fraction occurs through pathologically activated gamma-aminobutyric acid and glycine receptors. These results emphasize the importance of Ca2+-independent mechanisms and the role that local transmitter circuitry plays in excitotoxic cell death.