Neuronal Death: Now You See It, Now You Don't

Fatally injured neurons may necrose and rupture immediately, or they may initiate a programmed cell death pathway and then wait for microglial phagocytosis. Biochemical and histopathologic assays of neuronal death assess the numbers of neurons awaiting phagocytosis at a particular time point after injury. This number varies with the fraction of neurons that have necrosed vs initiated programmed cell death, the time elapsed since injury, the rate of phagocytosis, and the assay's ability to detect neurons at different stages of programmed cell death. Many of these variables can be altered by putatively neurotoxic and neuroprotective interventions independent of the effects on neuronal death. This complicates analyses of neurotoxicity and neuroprotection and has likely contributed to difficulties with clinical translation of neuroprotective strategies after brain injury. Time-resolved assays of neuronal health, such as ongoing expression of transgenic fluorescent proteins, are a useful means of avoiding these problems.