Neuronal cell death is an irreversible, end-stage cellular response. Programmed cell death of neurons is integral to nervous system development. However, terminally differentiated neurons represent an essentially non-regenerative cell population; therefore, toxicant-induced neuronal death has significant implications for safety assessment, and histologic examination is a critical endpoint for detection of this signal. The most recognized appearance of neuronal necrosis is a shrunken hypereosinophilic cell body, or “red dead” neuron, but other histomorphologies of neuronal cell death occur. Artifactual “dark” neurons must be distinguished from true neuron necrosis. Fluorescence microscopy and special histochemical stains can aid detection of dying neurons. Remnants of dead neurons are removed by glial cells, after which neuron death may be indicated only by secondary glial foci or neuronal loss. The transient window of neuronal necrosis and removal is an important consideration in designing timepoints and selecting ancillary diagnostics for neurotoxicity studies.
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