Microglial activation occurs during excitotoxin-induced neurodegeneration. We have reported that microglia can exhibit neurotoxic behaviors after injection of excitotoxins into the hippocampus. It is not known, however, whether microglial proliferation, which is part of the activation response, is required for neurodegeneration to be observed, or whether activation of the pre-existing resident microglia suffices. Using osteopetrotic (op/op) mice, in which injury-induced microglial proliferation does not take place, we demonstrate that only the microglia initially residing in the CNS are adequate to promote neurodegeneration. Our data suggest that there is a threshold at which a maximal microglial contribution to neurotoxicity is observed. This threshold appears to be sufficiently low, such that activation of just 40% of the microglia present in wild-type mice serves to trigger neurodegeneration. Furthermore, since the decrease in microglial numbers coincides with a decrease in tissue plasminogen activator's activity, we suggest that tissue plasminogen activator can be used as a marker for microglial proliferation.