Blue light-induced retinal lesions, intraretinal vascular leakage and edema formation in the all-cone mouse retina

P Geiger,C Grimm,M Samardzija,M Barben

doi:10.1038/cddis.2015.333

Abstract

Little is known about the mechanisms underlying macular degenerations, mainly for the scarcity of adequate experimental models to investigate cone cell death. Recently, we generated R91W;Nrl−/− double-mutant mice, which display a well-ordered all-cone retina with normal retinal vasculature and a strong photopic function that generates useful vision. Here we exposed R91W;Nrl−/− and wild-type (wt) mice to toxic levels of blue light and analyzed their retinas at different time points post illumination (up to 10 days). While exposure of wt mice resulted in massive pyknosis in a focal region of the outer nuclear layer (ONL), the exposure of R91W;Nrl−/− mice led to additional cell death detected within the inner nuclear layer. Microglia/macrophage infiltration at the site of injury was more pronounced in the all-cone retina of R91W;Nrl−/− than in wt mice. Similarly, vascular leakage was abundant in the inner and outer retina in R91W;Nrl−/− mice, whereas it was mild and restricted to the subretinal space in wt mice. This was accompanied by retinal swelling and the appearance of cystoid spaces in both inner and ONLs of R91W;Nrl−/− mice indicating edema in affected areas. In addition, basal expression levels of tight junction protein-1 encoding ZO1 were lower in R91W;Nrl−/− than in wt retinas. Collectively, our data suggest that exposure of R91W;Nrl−/− mice to blue light not only induces cone cell death but also disrupts the inner blood–retinal barrier. Macular edema in humans is a result of diffuse capillary leakage and microaneurysms in the macular region. Blue light exposure of the R91W;Nrl−/− mouse could therefore be used to study molecular events preceding edema formation in a cone-rich environment, and thus potentially help to develop treatment strategies for edema-based complications in macular degenerations.

Highlights

Wild-type mice to toxic levels of blue light and analyzed their retinas at different time points post illumination
While exposure of wt mice resulted in massive pyknosis in a focal region of the outer nuclear layer (ONL), the exposure of R91W;Nrl−/− mice led to additional cell death detected within the inner nuclear layer
As the R91W mutation leads to a hypomorphic RPE65 protein substantially reducing levels of 11-cis-retinal in the retina,[2,5] the disturbed cone layering with rosette formation typically found in the Nrl−/− mouse retinas is corrected in double-mutant R91W;Nrl−/− mice

Summary

Introduction

Wild-type (wt) mice to toxic levels of blue light and analyzed their retinas at different time points post illumination Vascular leakage was abundant in the inner and outer retina in R91W;Nrl−/− mice, whereas it was mild and restricted to the subretinal space in wt mice This was accompanied by retinal swelling and the appearance of cystoid spaces in both inner and ONLs of R91W;Nrl−/− mice indicating edema in affected areas. As the R91W mutation leads to a hypomorphic RPE65 protein substantially reducing levels of 11-cis-retinal in the retina,[2,5] the disturbed cone layering with rosette formation typically found in the Nrl−/− mouse retinas is corrected in double-mutant R91W;Nrl−/− mice. The acute model of light-induced retinal degeneration uses short exposure to bright white light to study photoreceptor cell death leading to loss of vision.[6,7] High photon flux, oxygen tension and the high levels of polyunsaturated fatty acids present in rod outer segment membranes make rod photoreceptor cells especially vulnerable to photochemical damage. Endotoxins released by degenerating rods,[9] the lack of trophic and mechanical support[10,11] after loss of rod cells or sudden exposure to increased oxygen levels in the absence of rods[12] have been implicated in the secondary cone cell death

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