Apoptosis in the in vivo mammalian forebrain

Apoptosis is a word originally introduced by Kerr, Wyllie, and colleagues f or a cell death process they defined in terms of its ultrastructural appear ance in nonneuronal cells from various tissues. There are very few studies providing detailed ultrastructural criteria for recognizing neuronal apopto sis in the in vivo mammalian brain. In the absence of such criteria, the Ke rr/Wyllie description pertaining to nonneuronal cells has served as a refer ence standard. However, contemporary neurobiologists typically rely on cell culture models for studying neuronal apoptosis, and these models are rarel y validated ultrastructurally; rather they are assumed to be appropriate mo dels based on unvalidated biochemical tests for apoptosis. Relying on evide nce generated in such cell culture models or on nonspecific cytochemical te sts applied to brain tissue, many authors have recently suggested that an a poptotic mechanism may mediate neuronal death in a wide variety of human ne urodegenerative diseases. Whether the cell death process in neurodegenerati ve diseases meets ultrastructural criteria for apoptosis has been given ver y little consideration. Recently, several methods have been described for t riggering extensive apoptotic neurodegeneration in the developing in vivo m ammalian brain. These methods include head trauma or treatment with several types of drugs (NMDA antagonists, GABA, agonists, or ethanol). We have per formed an ultrastructural analysis of the neuronal cell death process trigg ered in the cerebral cortex and thalamus by these several methods and compa red it with physiological cell death (PCD), a prototypic example of neurona l apoptosis that occurs naturally in the developing brain. Our findings, wh ich are reviewed herein, demonstrate that the types and sequence of changes induced by each of the above methods are identical to those that character ize PCD. This confirms that each of these methods produces bona fide in viv o apoptotic neurodegeneration, and it signifies that our description of thi s neuronal apoptotic process, which differs in some respects from the Kerr/ Wyllie description of nonneuronal apoptosis, can serve as a useful referenc e standard for recognizing the characteristic changes that in vivo neurons undergo when they are dying by an apoptotic mechanism. (C) 2001 Academic Pr ess.