Non-NMDA and NMDA receptor-mediated excitotoxic neuronal deaths in adult brain are morphologically distinct: further evidence for an apoptosis-necrosis continuum.

Apoptosis and necrosis are generally recognized as two distinct pathways of cell death, based on biochemical and morphological characteristics. Despite rapid advances in elucidating molecular mechanisms of cell death, little is known about the morphological progression of death in neurons and the relationship between different mechanisms of neuronal death and the resulting subcellular alterations. With excitotoxicity, a clinically relevant model of neuronal death, apoptotic DNA laddering and morphologic evidence of necrosis can occur simultaneously in the same region of adult brain. Here, we tested the hypothesis that activation of N-methyl-D-aspartic acid (NMDA) and non-NMDA glutamate receptors (GluR) results in a spectrum of morphologically distinct phenotypes of neuronal death, with apoptosis and necrosis as its endpoints. The ultrastructural morphologies of newborn and adult neurons at different times following intrastriatal injections of non-NMDA and NMDA GluR agonists were compared to apoptosis, as established during naturally occurring neuronal death in the developing rat brain. Excitotoxic neuronal death in newborn striatum was morphologically indistinguishable from developmental apoptosis. In the adult, non-NMDA receptor agonist-induced neuronal death was characterized by extensive chromatin condensation that was reminiscent of, but not identical to, apoptosis during normal development. In contrast, quinolinate, an NMDA receptor agonist, produced only minor chromatin clumping and rapid cytoplasmic disintegration, which is suggestive of necrosis. These findings support the concept that degenerative phenotypes of excitotoxically injured neurons are influenced by the degree of brain maturity and GluR subtype stimulation, independent of the severity of excitotoxic insult, along a morphological continuum or gradient ranging from apoptosis to necrosis.