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 Γ-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.