Transneuronal degeneration in substantia nigra pars reticulata following striatal excitotoxic injury in adult rat: time-course, distribution, and morphology of cell death.

Previous studies have demonstrated neuronal loss in the substantia nigra pars reticulata following excitotoxic injury to the striatum of adult rats, and have considered this to be an anterograde transneuronal effect. However, the mode and temporal pattern of cell death in this model are unknown. We injected ibotenate into the striatum of adult rats and performed Nissl and silver staining of the substantial nigra, the globus pallidus and the entopeduncular nucleus at multiple times up to postlesion day 28. Silver-stained degenerating cells were identified in the substantia nigra pars reticulata at days 3-14 after the lesion, with maximal occurrence at day 3. Degenerating cells and fibers were preferentially distributed in the central region of the substantia nigra pars reticulata. At the cellular level, degenerating cells, frequently demonstrating morphological characteristics of neurons, showed intense silver staining of the nucleus and punctate staining of the cytoplasm. Apoptosis was not observed. In situ end-labeling confirmed the non-apoptotic nature of the cell death. There was no secondary cellular degeneration in other striatal targets, including the globus pallidus, substantia nigra pars compacta or entopeduncular nucleus. Double staining with silver and tyrosine hydroxylase immunohistochemistry disclosed degenerating cells within the tyrosine hydroxylase-positive ventral tier in the substantia nigra pars reticulata, but in no instance was there double staining within a single cell. Our results demonstrate that secondary neuronal degeneration occurs within the substantia nigra pars reticulata within a few days following excitotoxic injury to the striatum of adult rats. The cell death is non-apoptotic, unlike that occurring in the substantia nigra of neonatal rats following similar striatal lesion. This mode of transneuronal cell death may be relevant to human diseases, such as Huntington's disease and the multiple system atrophies, in which, in addition to the major striatal neuronal loss, there is considerable loss of neurons in the substantia nigra pars reticulata.