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Comparative Study
.2009 Apr 8;29(14):4616-21.
doi: 10.1523/JNEUROSCI.0063-09.2009.

Normal cone function requires the interphotoreceptor retinoid binding protein

Affiliations
Comparative Study

Normal cone function requires the interphotoreceptor retinoid binding protein

Ryan O Parker et al. J Neurosci..

Abstract

11-cis-retinal is the light-sensitive component in rod and cone photoreceptors, and its isomerization to all-trans retinal in the presence of light initiates the visual response. For photoreceptors to function normally, all-trans retinal must be converted back into 11-cis-retinal through a series of enzymatic steps known as the visual cycle. The interphotoreceptor retinoid-binding protein (IRBP) is a proposed retinoid transporter in the visual cycle, but rods in Irbp(-/-) mice have a normal visual cycle. While rods are primarily responsible for dim light vision, the ability of cones to function in constant light is essential to human vision and may be facilitated by cone-specific visual cycle pathways. We analyzed the cones in Irbp(-/-) mice to determine whether IRBP has a cone-specific visual cycle function. Cone electroretinogram (ERG) responses were reduced in Irbp(-/-) mice, but similar responses from Irbp(-/-) mice at all ages suggest that degeneration does not underlie cone dysfunction. Furthermore, cone densities and opsin levels in Irbp(-/-) mice were similar to C57BL/6 (wild-type) mice, and both cone opsins were properly localized to the cone outer segments. To test for retinoid deficiency in Irbp(-/-) mice, ERGs were analyzed before and after intraperitoneal injections of 9-cis-retinal. Treatment with 9-cis-retinal produced a significant recovery of the cone response in Irbp(-/-) mice and shows that retinoid deficiency underlies cone dysfunction. These data indicate that IRBP is essential to normal cone function and demonstrate that differences exist in the visual cycle of rods and cones.

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Figures

Figure 1.
Figure 1.
Cone function is stable in agingIrbp−/− mice.A, Single-flash photopic ERG responses from individual WT andIrbp−/− mice to a 0.4 log cd*s/m2 flash.B, Single-flash photopic ERGs (0.4 log cd*s/m2 stimulus) ofIrbp−/− mice at 1 (n = 9), 2 (n = 12), 3 (n = 13), and 8 (n = 12) months showed no significant change with age (p = 0.28, 1-way ANOVA).C, Thirty hertz Flicker ERG responses from individual WT andIrbp−/− mice.D, Flicker responses inIrbp−/− mice (n = 3) were reduced relative to WT (n = 3), but remained stable from 1 to 9 months (n = 3). Data points represent mean amplitudes ± SD.
Figure 2.
Figure 2.
Cone densities inIrbp−/− and WT mice.A, Images (400×) of cones from PNA-stained (green) retina flat-mounts in WT andIrbp−/− mice at 1 month and 8 months of age.B, Cone densities were similar inIrbp−/− and WT mice at 1 (Irbp−/−,n = 4; WT,n = 4;p = 0.47, Mann–Whitney test) and 8 (Irbp−/−,n = 3; WT,n = 3;p = 1.00, Mann–Whitney test) months.C, Cone densities counted from PNA-stained retina flat-mounts ofIrbp−/− mice at 1 (n = 4), 2 (n = 3), 6 (n = 4), and 9 (n = 4) months showed a drop between 1 and 2 months (p = 0.03, Mann–Whitney test) but were stable between 2 and 9 months (p = 0.14, Kruskal–Wallis test). Densities were similar between the dorsal and ventral retina at all ages. All bars represent means ± SD.
Figure 3.
Figure 3.
Cone opsin expression inIrbp−/− and WT mice. Western blots were used to identify MWS and SWS cone opsin levels from 20 μg of total retina protein. At 4 months of age, levels of the MWS and SWS cone opsins were similar inIrbp−/− and WT mice. After staining for either the MWS or SWS cone opsins, membranes were stripped and reprobed for β-actin as a loading control.
Figure 4.
Figure 4.
Cone opsin expression inIrbp−/− and WT mice at 3 and 10 weeks of age. Confocal images of MWS and SWS opsins inIrbp−/− and WT mice at 3 and 10 weeks show normal opsin localization. Sections (630×) were stained with either anti-MWS or anti-SWS opsin antibodies (red). Nuclei were stained with DRAQ5 (blue). Images of MWS cone opsin were captured from the mid-dorsal retina, and images of SWS cone opsin were from the mid-ventral retina.
Figure 5.
Figure 5.
Recovery of cone ERGs inIrbp−/− mice with exogenous 9-cis-retinal.A, Representative ERG traces from 2-month-old animals are shown. Control responses from theIrbp−/− mouse were reduced relative to WT at all intensities. After the intraperitoneal injection of 9-cis-retinal (0.375 mg), responses from the same mouse recovered to WT levels.B, Intensity–response plots from ERG recordings of 2-month-oldIrbp−/− mice (n = 8) treated with 9-cis-retinal (0.375 mg, i.p.) showed a significant recovery of cone responses at all intensities above −0.8 log cd*s/m2 (p = 0.005, paired 2-way ANOVA).C, 9-cis-Retinal injections resulted in cone responses between 80 and 100% of the WT response values.D, Responses of WT (n = 4) andIrbp−/− mice after 9-cis-retinal injections were not significantly different (p = 0.25, 2-way ANOVA).E, Scotopic ERGs ofIrbp−/− mice (n = 5) were no different after 9-cis-retinal injections. Error bars have been removed for clarity. All data points represent means ± SD.
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