Abstract
Vision loss in age-related macular degeneration (AMD) stems from disruption of photoreceptor cells in the macula, the central retinal area required for high-acuity vision. Mice and rats have no macula, but surgical insertion of a subretinal implant can induce localized photoreceptor degeneration due to chronic separation from retinal pigment epithelium, simulating a key aspect of AMD. We find that the implant-induced loss of photoreceptors in rat retina leads to local changes in the physiology of downstream retinal ganglion cells (RGCs), similar to changes in RGCs of rodent models of retinitis pigmentosa (RP), an inherited disease causing retina-wide photoreceptor degeneration. The local implant-induced changes in RGCs include enhanced intrinsic excitability leading to accelerated spontaneous firing, increased membrane permeability to fluorescent dyes, and enhanced photosensitization by azobenzene photoswitches. The local physiological changes are correlated with an increase in retinoic acid receptor-induced (RAR-induced) gene transcription, the key process underlying retinal remodeling in mouse models of RP. Hence the loss of photoreceptors, whether by local physical perturbation or by inherited mutation, leads to a stereotypical set of pathophysiological consequences in RGCs. These findings implicate RAR as a possible common therapeutic target for reversing the signal-corrupting effects of retinal remodeling in both RP and AMD.
Highlights
Age-related macular degeneration (AMD) is the leading cause of vision loss in people above 60 years of age [1]
In retinas from mouse and rat models of retinitis pigmentosa (RP), elevated retinoic acid (RA) signaling can be detected in the ganglion cell layer (GCL) with an retinoic acid receptor (RAR)-induced fluorescent protein reporter [11]
The reporter construct has 2 tandem cassettes: red fluorescent protein (RFP), with expression controlled by a constitutive CMV promoter, and green fluorescent protein (GFP), with expression controlled by the RA response element (RARE), a DNA sequence that binds activated RAR
Summary
Age-related macular degeneration (AMD) is the leading cause of vision loss in people above 60 years of age [1]. In AMD, the deposition of extracellular material, called drusen, locally disrupts retinal pigment epithelium (RPE) cells and destroys rod and cone photoreceptor cells in the central part of the retina, known as the macula. This leads to the occurrence of blind spots that impair high-acuity vision, including most notably the ability to read and recognize faces. Because mice and rats have a rod-dominant retina without a macula or a fovea, they cannot develop AMD. Larger mammals, including nonhuman primates, have cone-dominant retinas with a macula and fovea similar to humans, but spontaneous photoreceptor loss characteristic of AMD has not yet been found in species other than humans
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