Light Evoked Responses of the Retinal Pigment Epithelium : Changes Accompanying 1 Photoreceptor Loss in the Mouse 2 3

18 19 Mutations in genes expressed in the retinal pigment epithelium (RPE) underlie a number of 20 human inherited retinal disorders that manifest with photoreceptor degeneration. Because light 21 evoked responses of the RPE are generated secondary to rod photoreceptor activity, RPE 22 response reductions observed in human patients or animal models may simply reflect decreased 23 photoreceptor input. The purpose of this study was to define how the electrophysiological 24 characteristics of the RPE change when the complement of rod photoreceptors is decreased. To 25 measure RPE function, we used an electroretinogram (dc-ERG)-based technique. We studied a 26 slowly progressive mouse model of photoreceptor degeneration (Prph) which was crossed 27 onto a Nyx background to eliminate the b-wave and most other post-receptoral ERG 28 components. On this background, Prph mice display characteristic reductions in a-wave 29 amplitude, which parallel those in slow PIII amplitude and the loss of rod photoreceptors. At 30 two and four months of age, the amplitude of each dc-ERG component (c-wave, fast oscillation, 31 light peak and off response) was larger in Prph mice than predicted by rod photoreceptor 32 activity (RmP3) or anatomical analysis. At four months of age, the RPE in Prph mice 33 showed several structural abnormalities including vacuoles and swollen, hypertrophic cells. 34 These data demonstrate that insights into RPE function can be gained despite a loss of 35 photoreceptors and structural changes in RPE cells, and moreover, that RPE function can be 36 evaluated in a broader range of mouse models of human retinal disease. 37 38