Intrinsic redox properties of N-methyl-D-aspartate receptor can determine the developmental expression of excitotoxicity in rat cortical neurons in vitro.

The sensitivity of central neurons in culture to N-methyl-D-aspartate (NMDA) receptor-mediated cell death increases with development. In this study, we show that this phenomenon in vitro may be due, at least in part, to changes in the redox properties of the NMDA receptor itself. With increasing days in culture, NMDA-induced electrical responses in rat cortical neurons are less sensitive to dithiothreitol-induced potentiation and spontaneously oxidize less readily than in younger cells. These results imply that at earlier developmental ages NMDA receptors prefer a more oxidized state. Hence, in the presence of a reducing agent, NMDA-induced neurotoxicity was produced in normally resistant younger neurons. The observed changes in NMDA receptor properties with development could not be attributed to long-range diffusible redox endogenous factors. An oxidized NMDA receptor thus confers maturing neurons a protective mechanism against glutamate toxicity during development.