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Volume 16, Number 18, Issue of September 15, 1996 pp. 5688-5697
Copyright ©1996 Society for Neuroscience

Mitochondrial Depolarization in Glutamate-Stimulated Neurons: An Early Signal Specific to Excitotoxin Exposure

Received April 26, 1996; revised June 26, 1996; accepted June 28, 1996.

R. James White and Ian J. Reynolds

Center for Neuroscience and Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

A brief exposure to high concentrations of glutamate kills cultured forebrain neurons by an excitotoxic process that is dependent on Ca²⁺ influx through the NMDA receptor. In this study, we have measured striking changes in mitochondrial function during and immediately after intense glutamate receptor activation. Using indo-1 microfluorometry and a specific inhibitor of the mitochondrial Na⁺/Ca²⁺ exchanger, CGP-37157, we have demonstrated that mitochondria accumulate large quantities of Ca²⁺ during a toxic glutamate stimulus and further that Ca²⁺ efflux from mitochondria contributes to the prolonged [Ca²⁺]_i elevation after glutamate removal. We then used JC-1 (5,5,6,6-tetrachloro-1,1,3,3-tetraethylbenzimidazolocarbocyanine iodide), a ratiometric indicator of mitochondrial membrane potential (), to show that Ca²⁺ accumulation within the organelle dissipates . The abrupt loss of after glutamate stimulation did not occur in the presence of MK801 or in the absence of extracellular Ca²⁺. The mitochondrial depolarization was also cyclosporin A-sensitive, indicating a probable role for the permeability transition pore. Hence mitochondrial Ca²⁺ accumulation and the subsequent permeability transition may be a critical early event specific to the NMDA receptor-mediated excitotoxic cascade.

Key words: intracellular calcium; permeability transition pore; NMDA; excitotoxicity; forebrain neurons; CGP-37157

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