It is important to assess the level of cone function with objective methods, because the degree of preservation greatly influences the quality of life. Although previous studies have indicated abnormal cone function in RP, the high incidence (more than four fifths of the patients) of abnormally low cone
S values in all genetic forms of RP found in the present study seems surprising. There are numerous reports of cytological and biochemical abnormalities in cone photoreceptors of patients with RP. It has been shown, for example, that the disease process affects cone maturation in an animal model of a rhodopsin mutation.
36 A common morphologic finding is that axons of peripheral cones are abnormally elongated and branched in RP
27 38 and/or make ectopic synapses with rod bipolar cells.
39 In addition, it has been shown that γ-aminobutyric acid (GABA)–reactive and glycine-reactive processes from amacrine cells extend through the outer plexiform and outer nuclear layers as far as the external limiting membrane.
40 It has been demonstrated recently that horizontal cells contain vesicles that accumulate GABA and glycine, possibly for vesicular release.
41 42 Thus, it may be possible that even minimal sustained release of both neurotransmitters from the processes of the amacrine cells changes the neurotransmitter balance in the outer retina, which can affect cone function through the feedback (gating of chloride conductance) from the horizontal cells to the cones.
43 44 Moreover, studies have shown that calbindin and other cytoplasmic proteins (7G6, X-arrestin, and recoverin) are markedly decreased in the cone cytoplasm of some patients with RP, although otherwise the cones were unremarkable cytologically.
40 45 Although the relationship between the proteins calbindin and 7G6 with phototransduction is unclear at this time, both X-arrestin
46 and recoverin
47 have an established role in the phototransduction process. Müller cells also respond to photoreceptor degeneration by upregulated expression of glial fibrillary acidic protein in areas where cones show loss of cytoplasmic proteins and ectopic nuclei.
28 45 An important mitochondria-specific enzyme, cytochrome
c oxidase, was also decreased in the inner segments of RP cones.
45 Taken together, all these findings suggest that several pathologic changes in the outer retina (abnormal synaptogenesis, downregulation of several cone protein expressions, decrease in mitochondrial cone activity, and changes in the neighboring Müller cells) could alter the cone function and exert a measurable effect on the high-energy a-wave parameters.