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We have recently noted that the inner nuclear layer (INL) and the inner plexiform layer (IPL) were significantly thinner in mice homozygous for the nervousdefect (nr/ nr) than in control (nr/+ or +/+) littermates. Here, we have carried out a series of anatomical studies to further understand these inner retinal changes. At postnatal day (P) 13, there was no difference in the inner retina between nervousand control mice, while a significant difference was observed at P30. Similar changes were not seen in other mouse models of photoreceptor degeneration. There was a significant reduction in the density of cells in the INL that were stained by antibodies against the inhibitory neurotransmitters GABA and glycine. These results indicate that the nervousdefect causes a degeneration of one or more sub-types of amacrine cells, in addition to the loss of cerebellar Purkinje cells and retinal photoreceptors that is known to occur in these mutant animals. Finally, evidence is provided that photoreceptors die by an apoptotic pathway in nervousmice.

The nervous(nr) mutation induces a progressive and severe degeneration of cerebellar Purkinje cells and retinal photoreceptors that is virtually complete within the first few months of life. Previous studies of the retina in nervous(nr) mice have focused primarily on the structural abnormalities seen at the level of the photoreceptor cell bodies and outer segments. Here, we have carried out a series of functional studies of the visual pathway innervousmice and have quantified the status of the inner retinal cell and plexiform layers. Affected animals were obtained by mating nr/+ heterozygotes and screening the offspring for the ataxia characteristic of nervousanimals; phenotypically normal littermates (i.e. nr/+ or +/+) were used as controls. As described previously, there is a substantial loss of photoreceptors cells in the nervousretina and a marked shortening of the inner and outer segments. These changes are accompanied by a more modest decline in the thickness of the inner plexiform and inner nuclear layers. These anatomic abnormalities were accompanied by reproducible changes in visual function, as measured with the electroretinogram (ERG) and visual evoked potential (VEP). The dark-adapted ERGs of nervousand control mice had similar waveforms, although thenervousresponses were substantially smaller in amplitude. The reductions in the amplitude of the ERG a-wave corresponded to the loss of photoreceptor cells and shortened outer segments seen histologically. Nevertheless, the kinetics of the leading edge of the a-wave did not differ between nervousand control mice, indicating that the rod outer segments of nervousmice continue to respond to light in a normal fashion. The amplitudes of cone ERGs were also reduced in nervousmice, although the extent of this reduction in any given animal was always less than that for rod-mediated ERG components. Overall, this result is consistent with cone involvement occurring only as a secondary effect of rod photoreceptor degeneration. The peak latencies of VEPs of nervousmice were slower than those of control littermates. These functional abnormalities correspond well to the structural changes induced by the nervousmutation, which does not appear to prevent visual signals from being transmitted centrally, beyond the limitations imposed by the degenerative process.