Figure 9. A, In the light-adapted animal, a ribbon synapse with two postsynaptic elements, either ganglion or amacrine cell processes x. Note the pentalaminate structure of the synaptic ribbon s. B, In the dark-adapted fish, a bipolar terminal flanked by five synaptic processes x. It does not contain any ribbons. Os-EPTA; magnification x 48, From Wagner, So the question of plasticity in the adult normal mammalian retina had not been established until recently. However in , Peichl and Bolz 43 exposed retinas to kainic acid to induce structural remodeling Figure 10 which they described as dose-dependent morphological changes in horizontal cells of adult mammalian retinas cats and rabbits.
Of course they found that high concentrations of kainic acid killed the cells, but when exposed to sublethal doses, horizontal cells contracted their dendritic fields and sent sprouting processes into the inner retina. So under certain experimental conditions it appeared that some retinal neurons could remodel and plasticity was suggested for the first time in species other than fish.
We now know from studies of retinal degenerations that adult mammalian retinas can undergo substantial plastic and aberrant reorganization in response to damage. The rest of this chapter illustrates plasticity in the retina under traumatic and degenerative retinal disease. Figure Sprouting A-type horizontal cells. The open arrow points to a ganglion cell. All horizontal cells in this field showed sprouting. Each horizontal cell shows two inward sprouts in addition to its normal OPL dendrites. The relative thickness of the layers in cat d and rabbit e retina differs.
The ganglion cell layer and optic nerve fiber ONF layer are thin and disorganized due to KA- induced degeneration. The OPL dendrites are incomplete where they leave the section. IS, photoreceptor inner segments. From Peichl and Bolz, The plasticity and remodeling that occurs in retinitis pigmentosa like diseases in mammalian retinas. It has been already mentioned that classical histological examination of human retinas with retinitis pigmentosa RP or rodent models with this type of degeneration were being done in the s, and gave the impression that apart from photoreceptors degenerating Figure 6 the remaining neural retina was normal.
It took electron microscopy to show that there were changes other that photoreceptor degeneration also occurring in the neuropil of the inner retina. In and later in , there were ultrastructural studies in the literature on RP that documented an autosomal dominant form of the disease 44, Papers by Szamier, Berson et al 46, 47 followed later.
These papers all concentrated on the pigment epithelium and state of the rods and cones in the diseased retinas simply because that is all that seemed to be recognizable as retinal elements by electron microscopy at the time. The rod photoreceptors in all these examples were degenerating or totally absent. The cones of the fovea were best preserved Figure 11a but outside the fovea cones were reduced to inner segment stubs Figure 11b.
The foveal inner retina was not examined in this RP retina and inner retina in the parafoveal area was an indistinguishable tissue of vacuoles and debris Figure 11b. Light a, b and Electron micrographs c, d of cone photoreceptors in the foveal region of retina of a patient with autosomal dominant retinitis pigmentosa.
The inner segments are normal in length but wider than normal for the fovea. The outer segments have broken disorganized discs often at unusual angles to each other. Fi g ure Electron micro g raph of a portion of bone corpuscular pi g mentation. The cells comprisin g the pi g ment clump appear to be of the same type as the cells of the peripheral pi g ment epithelium. The surface is folded due to the pro j ectin g cells, each of which has basement membrane material b, thick arrows.
Can Retinal Degenerative Diseases Cause Headaches?
Each cell contains melanin g ranules and rou g h endoplasmic reticulum r. From Kolb and Gouras, Kolb and Gouras 44 were also able to look at the bone spicules in this human RP retina Figure This electron micrograph shows that cells comprising the pigment clump are of the same type as the cells of the peripheral pigment epithelium.
This observation pointed out that RPE cells had migrated into the neural retina, thus forming the characteristic bone spicules of advanced retinitis pigmentosa seen in fundus photography Figure 4. This early finding could now be interpreted as plasticity and remodeling of retina in response to degenerating retinal integrity.
Sprouting of horizontal cell dendrites in RCS rat retinas. Arrows indicate the pigment epithelium. In the RCS rat retinas the CaBP labelled horizontal cell processes extended throughout the outer nuclear layer and debris zone and were tortuous and swollen. Some of the somas were displaced from the INL, as is evident in the cell on the far left in this micrograph. From Chu, Humphrey and Constable, It was not until almost two decades later that another paper came out that examined aberrant plasticity in retinal tissues. The paper from Chu, Humphrey and Constable 48 showed that the RCS rat demonstrated retinal remodeling though they called it disorganization of horizontal cell processes in the degenerate retina Figure Normal and RP human retinas after immunofluorescence labeling.
The yellow band corresponds to autofluorescent lipofuscin in the retinal pigment epithelium. The anti-SV2 labels the outer and inner ZPL plexiform layers, plus bulb-shaped varicosities arrows on the rhodopsin-positive rod neurites.
C, Cones in the peripheral region of an RP retina labeled for cone transducing alpha, which fills the cone cytoplasm. Some cone axons arrow, are abnormally long and branched, extending into the inner plexiform layer see D. The cones are labeled with both antibodies, and the cone axon arrow extends into the inner plexiform layer. The rhodopsin-positive rod neurites pass through the band of calbindin-positive horizontal cell processes arrows. Five amacrine cells are also labeled with anti-calbindin. The rhodopsin-positive rod neurites course between and past the labeled rod bipolar cells arrows and reach the inner limiting membrane.
Magnification, X. From Li, et. In , Li, Kljavin and Milam 1 reported that rhodopsin positive neurites extended from the photoreceptor layer down into the inner retina and ganglion cell layer in 15 human RP samples Figure This was the very first paper that showed neurites sprouting from photoreceptor cells and demonstrated conclusively that rhodopsin delocalized into the membrane of the photoreceptor cell, apparently after mis-trafficking.
A Normal retina. Labeling occurs only in the rod bipolar cells, including the fine dendritic processes in the outer plexiform layer OPL , the cell bodies in the inner nuclear layer INL , the axon, and the axon terminal. B 1-day retinal detachment. Labeling is present in bipolar cell processes extending into the outer nuclear layer ONL. Faint labeling also begins to appear in other cell types in the ganglion cell layer GCL. C 1-day retinal detachment. Higher magnification of the bipolar cell labeling in the ONL in a different area than shown in C.
D day retinal detachment. Low magnification showing labeled bipolar cell processes extending into the ONL. The fainter signal in the inner retina is from other cell types, including Muller cell and astrocyte processes, and does not extend past the inner plexiform layer IPL. A, C, and D are projections of nine images; B, is a projection of 13 images. From Lewis, Linberg and Fisher, They conclusively demonstrated aberrant sprouting of fine dendritic processes from rod bipolar cells projecting into the outer nuclear layer ONL in response to retinal detachment in the feline retina.
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The important thing with respect to interventions for blinding diseases is that these authors also invoked the implications of sprouting inner retinal neurons for therapies like retinal photoreceptor transplant. Immunolabeling of rod photoreceptors with anti-opsin green in normal and retinitis pigmentosa retinas. Left image Normal retina UW Opsin immunolabeling green is strongest in the outer segments OS and weak in the plasma membranes of rod somata in the outer nuclear layer and synapses in the outer plexiform layer.
Two years later in , Fariss, Li and Milam 4 examined rod photoreceptors, amacrine cells and horizontal cells in human RP retinas and demonstrated aberrant sprouting in those cell classes, particularly in GABA positive amacrine cells and calbindin positive horizontal cells Figure They also noted that rod neurites that projected into the inner retina, and at least contacted the somas of GABA positive amacrine cells, though no mention of synaptic connectivity was noted.
This study continued the previous work, and included GABAergic amacrine cells into those neurons in the retina that contribute to the rewiring phenomenon that was starting to emerge. Whole-mount staining with neurofilament antibodies. Compare the tight network made by horizontal cell axonal endings in the OPL of wt retinas A to the loose arrangements of hypertrophic process in the rd B.
The authors concluded that these modifications were dependent upon photoreceptor loss and again raised the specter of potential impact on retinal rescue models. Human retina with taurine, glycine and glutathione assigned to red, green and blue color channels respectively, revealing varied cell classes. The year was also the year our research lab came into the retinal degenerative community with some reticence.
Robert Marc had published 5 years previously, the first paper using Computational Molecular Phenotyping CMP 49 and we were busy using these technologies to explore mammalian and non-mammalian retinas. CMP is a fusion of 3 techniques including anti-hapten IgG libraries, tissue array fabrication and computational pattern recognition.
CMP allows for simultaneous quantitative probing of multiple immunolabels or more with hapten -specific IgG probes with subcellular resolution in all cells.
The technique profiles the metabolic state of every cell in a tissue. Figure 18 is a typical 3-space reconstruction of molecular data in human retinal tissue that uses red r , green g and blue b color space to visually present differential labeling of small-molecule concentrations in tissues.
In Figure 18, we can see taurine, glycine and glutathione represented, revealing the vascular choroid in blue at top, the RPE in pink, photoreceptor cell classes in orange, ON-cone bipolar cells with low concentrations of glycine in light green, due to coupling with AII and other glycinergic amacrine cells, and their fine processes extending down into the IPL in bright green.
We were interested and intensely focused on the normal circuitry of the retina and decidedly uninterested in pathology, but two events conspired to bring us into the field. The first event was a generous gift by Ann Milam of some human RP tissues to examine. At this point, we knew relatively little about retinal remodeling and were largely unaware of these few studies mentioned above.
That said, upon processing the tissues that Dr. Milam had sent us, the following image is the first thing we saw. This first image that came out of that initial analysis is shown in Figure We were unprepared for what it revealed to us. In fact, it is fair to say that since we had no context to understand what we were seeing, we were completely flummoxed as the topology looked nothing like retina. In this image with the small molecular mapping as in Figure 18, you can see that the entire topology of the retina is altered. Glycinergic amacrine cells in bright green are jumbled and altered in their lamination and appearance.
Isolated RPE cells are seen with punctate light green labeling throughout the retina and unknown glutathione rich cells are colored blue. Despite some curiosity, we did not know what to do with these tissues and set them aside returning to what we knew, the normal vertebrate retina.
An image of a GHL mouse retina with taurine, glutamine and glutamate mapped to red, green and blue color channels respectively. The tissues Dr. Frederick was offering were osmicated and in blocks ready to be sectioned for transmission electron microscopy TEM and examined. CMP is compatible with TEM analysis, so we decided to see what aged mouse retina from a degenerate model looked like and we were stunned to see that these GHL mouse retinas looked precisely like the tissues from the human RP retinas that Ann Milam had sent and exhibited the same progressive degeneration as human RP retinas Figure The problem with this was that there were more than a few papers that stated definitively that the neural retina was refractory to photoreceptor loss.
We also examined induced models like the light damage models and oxidative stress models.
Colleagues from all over the planet were more than gracious in assisting us and some like Matt LaVail went above and beyond by contributing dozens of samples collected over the previous 30 years of work. The fundamental truth that came out of this work was that everywhere we looked in retinal degeneration, despite what was in much of the retinal transplant and vision rescue literature, we saw retinal remodeling from the molecular to the histologic scales.
The really stunning thing was how little work was in the literature at this time. For example, when we reviewed the literature in , there were fewer than 30 papers in retinal degeneration that mentioned anything about inner retina neurons. Human retina from a patient with advanced autosomal dominant RP. The remarkable thing about the community being misinformed about the state of the retina is that the histology in advanced forms of the disease, is dramatically altered from the normal appearance of the retina.
One of the explanations might be that rodent models rarely get older than a year of age and for many investigators, once the photoreceptors were degenerated, they did not bother waiting longer for the more dramatic changes to ensue. That said, while aged rodent models of retinal disease are uncommon, there have been plenty of opportunities to study advanced human disease. Our explorations of advanced human RP have revealed dramatic alterations in the glial substrate as well as shown new structures termed microneuromas that form from neuritic sprouting from all neuronal cell classes in the retina Figure These processes are the beginnings of microneuroma formation.
It is also important to note that retinal remodeling and plasticity is not exclusive to RP and RP like disorders. Figure 22 is from a patient with an early geographic atrophy diagnosis. Neural emigration in a rat light damage model of retinal degeneration. Again, overall anatomical structure of the neural retina, particularly the inner nuclear layer, inner plexiform layer and ganglion cell layer seems normal or close to normal.
However early in LIRD, key synaptic markers in inner retina demonstrate rapid inner retina responses to photoreceptor stress that lead to functional reprogramming of neuronal responses. This reprogramming is a result of AMPA GluR2 subunits largely associated with inner retinal processing, exhibiting rapid changes in protein level.
Early stage porcine P23H model of retinal degeneration. The American Academy of Ophthalmology notes that findings regarding AMD and risk factors have been contradictory, depending on the study. The only risk factors consistently found in studies to be associated with the eye disease are aging and smoking. There is as yet no outright cure for age-related macular degeneration, but some treatments may delay its progression or even improve vision.
Treatments for macular degeneration depend on whether the disease is in its early-stage, dry form or in the more advanced, wet form that can lead to serious vision loss. No FDA-approved treatments exist yet for dry macular degeneration, although nutritional intervention may help prevent its progression to the wet form.
Lucentis has been shown to improve vision in a significant number of people with macular degeneration. Many organizations and independent researchers are conducting studies to determine if dietary modifications can reduce a person's risk of macular degeneration and vision loss associated with the condition. And some of these studies are revealing positive associations between good nutrition and reduced risk of AMD.
For example, some studies have suggested a diet that includes plenty of salmon and other coldwater fish, which contain high amounts of omega-3 fatty acids , may help prevent AMD or reduce the risk of its progression. Other studies have shown that supplements containing lutein and zeaxanthin increase the density of pigments in the macula that are associated with protecting the eyes from AMD. Visit and bookmark our Eye Nutrition News page for the latest developments in nutritional research that may prevent or limit vision problems from AMD, cataracts and other eye conditions. Although much progress has been made recently in macular degeneration treatment research, complete recovery of vision lost to AMD is unlikely.
Your eye doctor may ask you to check your vision regularly with the Amsler grid described above. Viewing the Amsler grid separately with each eye helps you monitor your vision loss. The Amsler grid is a very sensitive test and it may reveal central vision problems before your eye doctor sees AMD-related damage to the macula in a routine eye exam.
Grant awarded - anti oxidant therapy for retinal degenerative disease
For those who have vision loss from macular degeneration, many low vision devices are available to help with mobility and specific visual tasks. Published online May Healthy diets and the subsequent prevalence of nuclear cataract in women. Archives of Ophthalmology. June Omega-3 long-chain polyunsaturated fatty acid intake and year incidence of neovascular age-related macular degeneration and central geographic atrophy: AREDS report 30, a prospective cohort from the Age-Related Eye Disease Study.
American Journal of Clinical Nutrition.
December Oily fish consumption, dietary docosahexaenoic acid and eicosapentaenoic acid intakes, and associations with neovascular age-related macular degeneration. August March Dietary carotenoids, vitamins C and E, and risk of cataract in women. January Complement C3 variant and the risk of age-related macular degeneration. New England Journal of Medicine. Macular pigment response to a supplement containing meso-zeaxanthin, lutein and zeaxanthin.
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