The hypothesis that a destabilization of mitochondrial function during neuronal exposure to excitatory amino acids may be involved in the mechanism of neuronal death was examined. The mitochondrial membrane potential (Delta(psi)m) and the cytoplasmic Ca2+ concentration ([Ca2+]c) were monitored simultaneously in single cultured rat cerebellar granule cells (CGCs) loaded with tetramethylrhodamine methyl ester (TMR) and fura-2; CGCs were depolarized with K+, or exposed to excitotoxic doses of glutamate or kainate, and viability of the same neurons was studied for 24-30 h. This approach made it possible to single out the neurons that died, and to describe the changes in Delta(psi)m and [Ca2+]c that were characteristic for these neurons. Exposure to glutamate caused an increase in [Ca2+]c that was associated with a decrease in the mitochondrial TMR fluorescence, which indicates a decrease in Delta(psi)m. The neurons that failed to restore Delta(psi)m following glutamate withdrawal, also failed to restore low [Ca2+]c, and later died. Although a similar number of neurons died following kainate exposure as did after glutamate exposure, the kainate-elicited neuronal death resulted not from the collapse of Delta(psi)m but from an excessive neuronal swelling, which led to rupture of the plasma membrane. Depolarization with K+ was not neurotoxic and caused only a minor decrease in TMR fluorescence. These results indicate that in vitro glutamate and kainate destroy neurons by different mechanisms: glutamate by a failure to restore Delta(psi)m following the exposure, and kainate by an osmotic lesion of the plasma membrane.
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Lech Kiedrowski (1998) studied this question.