Spreading depression-like neuron depolarization was induced in CA1 of hippocampal tissue slices by irrigation with artificial cerebrospinal fluid containing 133.5 mM K⁺ for 8–40 min. Evoked responses disappeared during irrigation with high-K⁺ solution. Following 8–20 min irrigation orthodromic responses showed a triphasic recovery cycle: early partial return with evidence of neuron hyperexcitability, then secondary depression and finally slow partial recovery. After 30 min or more of high-K⁺ exposure, ortho- and antidromic responses remained severely depressed for at least 5.5 to 6.5 h. When, however, the tissue was deprived of calcium, or N-methyl-d-aspartate (NMDA) receptors were blocked by 10 μM3-((±)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), then evoked responses recovered partially after a 30- or 40-min high-K⁺ exposure. Post-exposure hyperexcitability was not prevented by CPP. We conclude that prolonged depolarization by elevated K⁺ causes irreversible neuron damage, which is triggered or accelerated by influx of calcium ions into neurons, mediated in part by NMDA receptor activation.