Abstract
Early studies on Rpe65 knockout mice reported that remaining visual function was attributable to cone function. However, this finding has been challenged more and more as time has passed. Electroretinograms (ERGs) showed that rd12 mice, a spontaneous animal model of RPE65 Leber’s congenital amaurosis, had sizeable photopic responses. Unfortunately, the recorded ERG waveform was difficult to interpret because of a remarkably delayed peak-time, which resembles a rod response more than a cone response. Here, we compare flicker ERGs in animals with normal rod and cone function (C57BL/6J mice), pure rod function (cpfl5 mice), and pure cone function (Rho-/- mice) under different adaptation levels and stimulus intensities. These responses were then compared with those obtained from rd12 mice. Our results showed that normal rods respond to low frequency flicker (5 and 15 Hz) and that normal cones respond to both low and high frequency flicker (5–35 Hz). As was seen in cpfl5 mice, rd12 mice had recordable responses to low frequency flicker (5 and 15Hz), but not to high frequency flicker (25 and 35 Hz). We hypothesize that abnormal rods may be the source of residual vision in rd12 mice, which is proved correct here with double mutant rd12mice. In this study, we show, for the first time, that frequency-response ERGs can effectively distinguish cone- and rod-driven responses in the rd12 mouse. It is another simple and valid method for evaluating the respective contributions of retinal rods and cones.
Highlights
Leber’s congenital amaurosis type 2 (LCA2) is caused by retinal pigment epithelium-specific 65 kDa protein (RPE65) mutations, which lead to early onset of blindness [1,2,3,4]
Under light-adapted conditions and with bright stimuli, sizeable ERG signals were recorded from rd12 eyes, but had obvious peak-time delays compared to cone responses in C57BL/6J and Rho-/- mice (Fig. 1)
Significant differences were found in b-wave peak times among rd12, C57BL/6J, and Rho-/- mice (114.0 ± 15.5, 57.4 ± 5.9, and 58.2 ± 3.8 ms, respectively, P < 0.001)
Summary
Leber’s congenital amaurosis type 2 (LCA2) is caused by retinal pigment epithelium-specific 65 kDa protein (RPE65) mutations, which lead to early onset of blindness [1,2,3,4]. Expressed inside of RPE cells, RPE65 is necessary for regeneration of 11-cis-retinal, the ligand of rod and cone opsins [5]. As an isomerohydrolase of the visual cycle, RPE65 allows the phototransduction cascade to begin by providing the chromophore that captures photon energy. Rhodopsin in rods is composed of opsin, an apoprotein opsin, and 11-cis retinal, a chromophore. Cone pigment is composed of cone opsin and 11-cis retinal [7]. Loss of RPE65 function may result in loss of both rod and cone photoreceptor function [6, 8, 9]
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