Light-Evoked Responses of the Retinal Pigment Epithelium: Changes Accompanying Photoreceptor Loss in the Mouse

Abstract

. Mutations in genes expressed in the retinal pigment epithelium (RPE) underlie a number of human inherited retinal disorders that manifest with photoreceptor degeneration. Because light-evoked responses of the RPE are generated secondary to rod photoreceptor activity, RPE response reductions observed in human patients or animal models may simply reflect decreased photoreceptor input. The purpose of this study was to define how the electrophysiological characteristics of the RPE change when the complement of rod photoreceptors is decreased. To measure RPE function, we used an electroretinogram (dc-ERG)-based technique. We studied a slowly progressive mouse model of photoreceptor degeneration (Prph Rd2/ϩ ), which was crossed onto a Nyx nob background to eliminate the b-wave and most other postreceptoral ERG components. On this background, Prph Rd2/ϩ mice display characteristic reductions in a-wave amplitude, which parallel those in slow PIII amplitude and the loss of rod photoreceptors. At 2 and 4 mo of age, the amplitude of each dc-ERG component (c-wave, fast oscillation, light peak, and off response) was larger in Prph Rd2/ϩ mice than predicted by rod photoreceptor activity (Rm P3 ) or anatomical analysis. At 4 mo of age, the RPE in Prph Rd2/ϩ mice showed several structural abnormalities including vacuoles and swollen, hypertrophic cells. These data demonstrate that insights into RPE function can be gained despite a loss of photoreceptors and structural changes in RPE cells and, moreover, that RPE function can be evaluated in a broader range of mouse models of human retinal disease.

Early retinal pigment epithelium dysfunction is concomitant with hyperglycemia in mouse models of type 1 and type 2 diabetes

“…1, D-F) beginning at 2 wk after onset of hyperglycemia. We have previously shown in the Prph Rd2/ϩ mouse model of photoreceptor degeneration (Samuels et al 2010) that RPE function was preserved despite a significant loss in rod outer segment and outer nuclear layer thickness and the development of vacuoles and hypertrophy. This result indicates that the RPE function measured by the dc-ERG, although dependent on rod photoreceptor activity for its initiation, is not simply a surrogate measure of photoreceptor function.…”

“…2H), the data also fell close to the diagonal line, indicating that these amplitude reductions were equivalent to the reduced photoreceptor response underlying the a-wave. Given that RPE components are generated secondary to photoreceptor activity (Berman 1991;Samuels et al 2010;Wu et al 2004b), it is possible that the reduction in the dc-ERG components reflects photoreceptor dysfunction, with the exception of the 2-wk c-wave.…”

“…None of the dc-ERG components are a direct response to light, but instead reflect the summed RPE/Müller cell responses generated subsequent to the response of rod photoreceptors. These components thus provide noninvasive measures of RPE function, although their interpretation must take into account the status of rod photoreceptor function (Samuels et al 2010). …”

The progress in understanding and treatment of diabetic retinopathy

“…In other diabetic animal models, the RPE has been shown to suffer a degree of nitrosative stress (Rosales et al, 2014a). Components of the ERG in animal models, particularly the negative-polarity fast oscillations in the cat retina, indicate the recovery of [K + ] and a [Cl − ]-dependent hyperpolarization of the basal RPE membrane (Linsenmeier and Steinberg, 1982) and this may represent a useful, non-invasive measure of RPE and interlinked photoreceptor function (Samuels et al, 2010). Recently this parameter has been used to study the influence of diabetes on the function of the RPE in murine T1D…”

Selective Impairment of a Subset of Ran-GTP-binding Domains of Ran-binding Protein 2 (Ranbp2) Suffices to Recapitulate the Degeneration of the Retinal Pigment Epithelium (RPE) Triggered by Ranbp2 Ablation

“…The exacerbating effect of Tg RBD2/3*-HA ::RPE-cre::Ranbp2 Ϫ/Ϫ on dc-ERG amplitudes was not due to the transgene itself or a dominant effect of the transgene because the expression of Tg RBD2/3*-HA in a wildtype RPE background had normal dc-ERG responses (data not shown). Because the dc-ERG is generated secondary to activities of rod photoreceptor neurons (66), the amplitude reduction could reflect a change in RPE function or in the response of the outer retina (86). To examine these possibilities, we recorded strobe flash ERGs at the same ages.…”