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BRIEF exposures of cortical cultures to kainate (100μM) plus Zn2+ (300μM) cause fluorescence of the Zn2+sensitive dye, TS-Q, to appear in virtually all neurons, probably reflecting depolarization and secondary Zn2+permeation through voltage-sensitive Ca2+ channels. However, if Na+ ions are removed from the media (to prevent depolarization), prominent TS-Q fluorescence is still observed in the small subset of neurons labeled by kainate stimulated Co2+ uptake (Co2+(+) neurons), a histochemical technique that identifies neurons expressing Ca2+ permeable AMPA/kainate receptor-gated channels. Kainate/Zn2+ exposures in Na+ containing media with lower (50–100 μM) Zn2+ concentrations resulted 24 h later in selective loss of the Co2+(+) neurons, suggesting that these channels may permit particularly high rates of Zn2+ passage. Thus, direct permeation of synaptically released Zn + through Ca2+permeable AMPA/kainate channels could contribute to selective degeneration of neurons in disease as well as subserving physiological signaling functions.