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.
Chen
Q
Q
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Olney
J W
JW
Lukasiewicz
P D
PD
Almli
T
T
Romano
C
C
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D002712:Chlorides / Q000502:physiology*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000633:toxicity*; D018377:Neurotransmitter Agents / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D012160:Retina / Q000187:drug effects*; D012964:Sodium / Q000502:physiology
D002712:Chlorides; D018690:Excitatory Amino Acid Agonists; D018377:Neurotransmitter Agents; D016194:Receptors, N-Methyl-D-Aspartate; D012964:Sodium; D007608:Kainic Acid; D002118:Calcium