Retinal degeneration in the nervous mutant mouse. II. Electron microscopic analysis.

Nervous mutant mice (nr/nr) show a rapid loss of most of cerebellar Purkinje cells between the ages of 3 and 7 weeks, as well as a progressive photoreceptor cell degeneration that occurs most rapidly between postnatal days (P) 13 and 19, but with a much slower attrition during the subsequent months. We have carried out an electron microscopic analysis of nr/nr and littermate control mice at representative ages to characterize the subcellular cytopathological changes in this form of retinal degeneration, to gain insight into photoreceptor cell degeneration mechanisms by comparing these changes to those in other rodent forms of retinal degeneration, and to compare the photoreceptor changes with those of cerebellar Purkinje cells. Ultrastructural observations were limited to rod photoreceptors, since the number of cones was limited in our micrographs. The retinas of nr/nr mutant mice can be distinguished from those of normal littermates as early as postnatal day (P) 6. At this time, some of the mitochondria in rod inner segments are larger and more rounded than normal. This represents the earliest cytopathological change thus far observed in this mutant. As early as P9 and thereafter, the volume and integrity of rod outer segment membranes are reduced from normal. In the inner segments of some rod photoreceptor cells, there is a reduction in the volume or number of polyribosomes as early as P11, a reduction in rough endoplasmic reticulum as early as P13, and reduced incidence and less organized Golgi membranes as early as P16. Qualitative evaluation and quantitative stereological analysis show that the enlarged mitochondria in rod inner segments never become normal in shape or size. No changes are seen in the inner retinal layers at any age. Despite similarities with inherited retinal dystrophy in the Royal College of Surgeons rat, as noted in the original description of retinal degeneration in nr/nr mice, ultrastructural features clearly distinguish these mutants. Moreover, nr/nr mice can be distinguished from all other murine forms of retinal degeneration by electron microscopy.