Novel non-apoptotic morphological changes in neurons of the mouse hippocampus following transient hypoxic-ischemia

Apoptosis has been recently implicated in the dying process of neurons under several pathological conditions including ischemia. However, although apoptosis was originally defined on the basis of its unique ultrastructural features (Kerr et al., 1972. Br. J. Cancer 26, 239-257; Wyllie et al., 1980. Int. Rev. Cytol. 68, 251-306), unambiguous ultrastructural evidence of apoptosis has been rarely demonstrated in the adult brain. In this study, we examined ultrastructural changes in mouse hippocampal neurons after transient hypoxic-ischemia. A small population of dentate granule cells showed typical apoptotic ultrastructures that could be used as internal morphological standards of apoptosis, whereas most other hippocampal neurons consistently showed a distinct form of cellular disintegration. Nuclei of the latter cells shrank and became TUNEL-positive but were distinguishable from apoptotic nuclei by both the presence of characteristic reticular-formed chromatin condensation and the absence of nuclear fragmentation. Perikarya of degenerating neurons also shrank as in apoptosis, but apoptotic bodies were not observed. Although organelles other than mitochondria disappeared almost completely from the perikarya, neither plasma nor mitochondrial membranes were disrupted, indicating that these changes were also different from typical necrosis. The presence of a novel form of cell death suggests the necessity of morphological re-examination of neuronal death, particularly in mature neurons in vivo.