Retinal Ganglion Cell Death as a Late Remodeling Effect of Photoreceptor Degeneration

Abstract

Inherited or acquired photoreceptor degenerations, one of the leading causes of irreversible blindness in the world, are a group of retinal disorders that initially affect rods and cones, situated in the outer retina. For many years it was assumed that these diseases did not spread to the inner retina. However, it is now known that photoreceptor loss leads to an unavoidable chain of events that cause neurovascular changes in the retina including migration of retinal pigment epithelium cells, formation of “subretinal vascular complexes”, vessel displacement, retinal ganglion cell (RGC) axonal strangulation by retinal vessels, axonal transport alteration and, ultimately, RGC death. These events are common to all photoreceptor degenerations regardless of the initial trigger and thus threaten the outcome of photoreceptor substitution as a therapeutic approach, because with a degenerating inner retina, the photoreceptor signal will not reach the brain. In conclusion, therapies should be applied early in the course of photoreceptor degeneration, before the remodeling process reaches the inner retina.

Coordinated Intervention of Microglial and Müller Cells in Light-Induced Retinal Degeneration

“…Two-month-old albino Sprague-Dawley female rats (150-180 g body weight) were obtained from the University of Murcia breeding colony (n = 24) and exposed to 3000 lux of cold fluorescent white light continuously for 48 hours following previously described methods. 2,3,13,15 Another group of animals (n = 8) was used as control group. Experimental animals were processed 1, 2, or 3 months after light exposure (ALE).…”

“…Tissue fixation was performed by transcardial perfusion of the rats, first with saline and then with 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.4), following standard protocols of our laboratory. 3,56,57,63 The retinas were then dissected as whole-mounts and double immunodetection was performed following previously described methods. 13,23,56,57,64 Primary antibodies were used to immunodetect different retinal cell populations: 1 Secondary detection was performed using four different antibodies: donkey anti-goat Alexa 488 (AB_2534102), donkey anti-goat Alexa 594 (AB_142540), donkey anti-rabbit Alexa 594 (AB_141637), and goat anti-Guinea-Pig Alexa 647 (AB_2535867), all from Molecular Probes (Invitrogen, Ther-moFisher, Madrid, Spain) and diluted at 1:500.…”

“…L ight is necessary for vision but, paradoxically, can also damage in the retina, an effect known as phototoxicity. [1][2][3][4] Light exposure causes well-documented apoptotic cellular death, mostly to the outer retinal layers. 2,5,6 Furthermore, light is also a known risk factor for some retinal degenerations 7,8 and exacerbates photoreceptor degeneration in some inherited [9][10][11][12] or induced 13,14 retinal degenerations.…”

“…Light-induced retinal degeneration has been widely used to study the mechanisms of cell death in retinal degenerations. [1][2][3][4]11,13,[15][16][17] This model has several advantages compared with inherited retinal degenerations because it is independent of the genetic defect and the age of the animals. Furthermore, because the degeneration is induced, the degree and duration of the insult can be manipulated, allowing the researcher to control the rate and the onset of retinal damage.…”

“…29,59 There is also evidence that there is an interaction between microglial and Müller cells that affects trophic factor release by Müller cells 60 and therefore this interplay may also be important to regulate the responses of Müller cells in different scenarios, such as the regenerating zebrafish retina, 61 in animal models of retinal degenerations 62 and also in cocultures of activated microglia and Müller cells. 60 In this study, we have used our previously described model of light-induced retinal degeneration 2,3,13,15 and immunodetection of cones, Müller and microglial cells to investigate the role of the macro-and microglial cells in the rings of photoreceptor degeneration. To our knowledge, this is the first time that the relationship between cone degeneration, and microglial and macroglial cell reactivity has been analyzed in this model.…”