Removal of extracellular Mg2+ triggered the onset of repetitive excitatory discharges in cultured murine cortical neurons, detected by recording with patch electrodes in the whole cell configuration. The discharges were suppressed by 100 microM D-2-amino-5-phosphonovalerate. Over the next 24-72 h substantial numbers of neurons, but not glia, degenerated, releasing lactate dehydrogenase to the bathing medium. The neuronal death induced by removal of extracellular Mg2+ could be attenuated by either 3 microM tetrodotoxin or 50 microM dextrorphan, and thus likely reflects excessive activation of N-methyl-D-aspartate receptors triggered by excitatory discharges. This Mg2+ removal model may be a useful model in which to study certain aspects of epileptic neocortical injury.