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Phagocytosis is essential for the removal of photoreceptor debris following retinal injury. We used two mouse models, mice injected with green fluorescent protein-labeled bone marrow cells or green fluorescent protein-labeled microglia, to study the origin and activation patterns of phagocytic cells after acute blue light-induced retinal lesions. We show that following injury, blood-borne macrophages enter the eye via the optic nerve and ciliary body and soon migrate into the injured retinal area. Resident microglia are also activated rapidly throughout the entire retina and adopt macrophage characteristics only in the injured region. Both blood-borne-and microgliaderived macrophages were involved in the phagocytosis of dead photoreceptors. No obvious breakdown of the blood-retinal barrier was observed. Ccl4, Ccl12, Tgfb1, Csf1, and Tnf were differentially expressed in both the isolated retina and the eyecup of wild-type mice. Debris-laden macrophages appeared to leave the retina into the general circulation, suggesting their potential to become antigen-presenting cells. These experiments provide evidence that both local and immigrant macrophages remove apoptotic photoreceptors and cell debris in the injured retina.

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The Rho (-/-) mouse is the first animal model that depicts all major pathological changes, even in the late stages of RP. Using the rho (-/-) mouse model we were able to analyze the complete dynamic process of BSP formation. Therefore we conclude that: (1) In rho (-/-) retinas, BSPs only form in areas devoid of photoreceptors; (2) Direct contact between inner retinal vessels and RPE appears to be a major trigger for migration of RPE cells; (3) The distribution of the RPE cells in BSPs reflects the vascular network at the time of formation. The similarity of the disease process between mouse and human and the possibility to study all consecutive steps of the course of the disease makes the rho (-/-) mouse valuable for further insights in the dynamics of BSP formation in human RP.

Cone dystrophies are genetic diseases characterized by loss of cone photoreceptor function and severe impairment of daylight vision. Loss of function is accompanied by a progressive degeneration of cones limiting potential therapeutic interventions. In this study we combined microarray-based gene-expression analysis with electroretinography and immunohistochemistry to characterize the pathological processes in the cone photoreceptor function loss 1 (cpfl1) mouse model. The cpfl1-mouse is a naturally arising mouse mutant with a loss-of-function mutation in the cone-specific Pde6c gene. Cpfl1-mice displayed normal rod-specific light responses while cone-specific responses were strongly diminished. Despite the lack of a general retinal degeneration, the cone-specific functional defect resulted in a marked activation of GFAP, a hallmark of Müller-cell gliosis. Microarray-based network-analysis confirmed activation of Müller-glia-specific transcripts. Unexpectedly, we found up-regulation of the cytokine LIF and the anti-apoptotic transcription factor STAT3 in cpfl1 cone photoreceptors. We postulate that STAT3-related pathways are induced in cpfl1 cone photoreceptors to counteract degeneration.

The mammalian retina contains three classes of photoreceptor. In addition to the rods and cones, a subset of retinal ganglion cells that express the putative sensory photopigment melanopsin are intrinsically photosensitive. Functional and anatomical studies suggest that these inner retinal photoreceptors provide light information for a number of non-image-forming light responses including photoentrainment of the circadian clock and the pupil light reflex. Here, we employ a newly developed mouse model bearing lesions of both rod and cone phototransduction cascades (Rho(-/-) Cnga3(-/-)) to further examine the function of these non-rod non-cone photoreceptors. Calcium imaging confirms the presence of inner retinal photoreceptors in Rho(-/-) Cnga3(-/-) mice. Moreover, these animals retain a pupil light reflex, photoentrainment, and light induction of the immediate early gene c-fos in the suprachiasmatic nuclei, consistent with previous findings that pupillary and circadian responses can employ inner retinal photoreceptors. Rho(-/-) Cnga3(-/-) mice also show a light-dependent increase in the number of FOS-positive cells in both the ganglion cell and (particularly) inner nuclear layers of the retina. The average number of cells affected is several times greater than the number of melanopsin-positive cells in the mouse retina, suggesting functional intercellular connections from these inner retinal photoreceptors within the retina. Finally, however, while we show that wild types exhibit an increase in heart rate upon light exposure, this response is absent in Rho(-/-) Cnga3(-/-) mice. Thus, it seems that non-rod non-cone photoreceptors can drive many, but not all, non-image-forming light responses.

Purpose Accumulation of lipids, and especially of cholesteryl esters, under the retinal pigment epithelium and within Bruch’s membrane is a normal feature of aging and has also been observed in human eyes with age‐related maculopathy. Our objective was to evaluate the retinal phenotype of apoB100,LDLR‐/‐ mice, a model for lipid metabolism dysfunction and potentially of aging of the retina. Methods ApoB100,LDLR‐/‐ mice were studied at 7 and 14 months of age by standard scotopic and photopic electroretinography by comparison to control animals. Fundus images were obtained with a confocal SLO (Heidelberg Retina Angiograph). The integrity of the vascular system was investigated by means of fluoresceine and indocyanine green angiography. Sections of eye cups were stained by filipin to detect cholesterol deposits. Results Both scotopic and photopic b‐wave amplitudes were reduced in apoB100,LDLR‐/‐ mice compared to control mice (Rmax=125 µV vs 208 µV for the scotopic b‐wave amplitude at 7 months, and 83 µV vs 162 µV at 14 months). Similarly rods and cones sensitivity was 0.5log unit lower in apoB100,LDLR‐/‐ mice at 14 months, compared to control mice. Although the retinal and the choroidal vascular systems were normal, apoB100,LDLR‐/‐ mice displayed white auto‐fluorescent dots in the retinal pigment epithelium layer which likely corresponded to cholesterol deposits. Conclusion The present apoB100,LDLR‐/‐ mouse, is one of the only models with neutral lipid deposits at the basement of RPE that can potentially be very useful to study the mechanisms of lipid deposition that occurs universally in human retina while aging.