The quantity of calcium that appears to induce neuronal death

Excessive entry of Ca2+ through the NMDA receptor is thought to be the major cause of glutamate toxicity in brain neurons. However, actual quantitation of the calcium overload has not been achieved. Here we show that the absolute amount of 45Ca2+ taken up via the NMDA receptor correlates quantitatively with the amount of acute cell death in cultured cerebellar granule cells of the rat. Analysis of 9- and 16-day cultures reveals that the NMDA-induced Ca2+ uptake is about the same at these ages, whereas the Ca-dependent lethal process is more developed in the older neurons. The calculated lethal concentration of 45Ca taken up exceeds by approximately 10,000 times the maximal concentration of [Ca2+]i that can be measured by fluorescence imaging. It is suggested that the Ca2+ taken up induces the lethal process in a subcellular structure in which it has been segregated.