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Physiology of the Retina

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Physiology of the Retina PHYSIOLOGY OF THE RETINA András M. Komáromy Michigan State University [email protected] 12th Biannual William Magrane Basic Science Course in Veterinary and Comparative Ophthalmology PHYSIOLOGY OF THE RETINA • INTRODUCTION • PHOTORECEPTORS • OTHER RETINAL NEURONS • NON-NEURONAL RETINAL CELLS • RETINAL BLOOD FLOW Retina ©Webvision Retina Retinal pigment epithelium (RPE) Photoreceptor segments Outer limiting membrane (OLM) Outer nuclear layer (ONL) Outer plexiform layer (OPL) Inner nuclear layer (INL) Inner plexiform layer (IPL) Ganglion cell layer Nerve fiber layer Inner limiting membrane (ILM) ©Webvision Inherited Retinal Degenerations • Retinitis pigmentosa (RP) – Approx. 1 in 3,500 people affected • Age-related macular degeneration (AMD) – 15 Mio people affected in U.S. www.nei.nih.gov Mutations Causing Retinal Disease http://www.sph.uth.tmc.edu/Retnet/ Retina Optical Coherence Tomography (OCT) Histology Monkey (Macaca fascicularis) fovea Ultrahigh-resolution OCT Drexler & Fujimoto 2008 9 Adaptive Optics Roorda & Williams 1999 6 Types of Retinal Neurons • Photoreceptor cells (rods, cones) • Horizontal cells • Bipolar cells • Amacrine cells • Interplexiform cells • Ganglion cells Signal Transmission 1st order SPECIES DIFFERENCES!! Photoreceptors Horizontal cells 2nd order Bipolar cells Amacrine cells 3rd order Retinal ganglion cells Visual Pathway lgn, lateral geniculate nucleus Changes in Membrane Potential Net positive charge out Net positive charge in PHYSIOLOGY OF THE RETINA • INTRODUCTION • PHOTORECEPTORS • OTHER RETINAL NEURONS • NON-NEURONAL RETINAL CELLS • RETINAL BLOOD FLOW Photoreceptors Retinal pigment epithelium (RPE) Photoreceptor segments Outer limiting membrane (OLM) Outer nuclear layer (ONL) Outer plexiform layer (OPL) Inner nuclear layer (INL) Inner plexiform layer (IPL) Ganglion cell layer Nerve fiber layer Inner limiting membrane (ILM) ©Webvision Photoreceptor Cells • Rods – Vision in dim light • Cones – Vision in bright light – Color vision – Central visual acuity ©webvision Photoreceptor Cells Dowling 1998 cones discs are open to extracellular space (rapid flux of substances) cell body OS = outer segment IS = inner segment Photoreceptors • Topographic variations in numbers and rod/cone ratios in different species • Spatial distribution of cones correlated to visual acuity • Domestic animals do not have a fovea, but an area centralis, area of high cone density • Visual streak is region with greatest concentration of RGC Densities of rods and cones in the human retina Sternberg 1935 Gradient central peripheral Peak cone densities: 64,000-212,000 cells/m2 •22 Rod density: 200,000-540,000/mm2 Peak density matched spatially with thickest part of tapetum Dorsal to visual streak. 23 PHYSIOLOGY OF THE RETINA • PHOTORECEPTOR CELLS – PHOTOTRANSDUCTION Phototransduction Yau & Hardie 2009 Rod Phototransduction • Light: 11-cis-retinal all-trans-retinal • Dissociation of rhodopsin opsin and all-trans-retinal • Activation of alpha transducin (Gtα) • Gtα activates cGMP-PDE • cGMP-PDE hydrolyzes cGMP, which closes the OS plasma membrane channel Rod Phototransduction • Rod stimuli by light leads to hyperpolarization, which means an increase in intrinsic negative charge • Darkness is the actual stimulus that gives rise to a depolarization and transmitter release. Upon stimuli this continuous signal is interrupted. Phototransduction Darkness: channel open Light: channel closed Arshavsky et al. 2002 PHYSIOLOGY OF THE RETINA • PHOTORECEPTOR CELLS – PHOTOTRANSDUCTION • VISUAL PIGMENT Phototransduction Yau & Hardie 2009 Visual Pigments • Holopigment – Opsin = protein moiety – 11-cis retinal = chromophore • Covalently linked by Schiff base ©Webvision Retinoid Structures Picaud 2003 ©Webvision Light Rhodopsin Mutations • Over 100 different mutations identified P = proline • Most common mutation: P23H H = histidine • Majority are gain-of-function mutations • Autosomal dominant Arshavsky et al. 2002 Autosomal Dominant PRA Kijas, James W. et al. (2002) Proc. Natl. Acad. Sci. USA 99, 6328-6333 Fig. 1. Consequences of clinical human retinal photography in Modest light levels, as used the RHO mutant dog in routine clinical practice, dramatically accelerate the neurodegeneration!!! Cideciyan, Artur V. et al. (2005) Proc. Natl. Acad. Sci. USA 102, 5233-5238 A-D: standard microscope E-F: night-vision system • Severe light-induced retinal damage • Visual performance preserved • Islands of surviving photoreceptors 37 PHYSIOLOGY OF THE RETINA • PHOTORECEPTOR CELLS – PHOTOTRANSDUCTION • VISUAL PIGMENT • COLOR VISION Different types of cone photoreceptor ©Webvision Some Specificities of Color Vision • Human color vision depends on 3 types of cones which differ from each other in their absorption spectra • In highly diurnal animals (turtles and goldfish) there are 4 classes of cones • In less diurnal animals (dogs, cats, squirrels) there are only 2 classes of cones Canine Retina Different types of cone photoreceptor Goldsmith 2013 ©Webvision Photopigments in the Retina Rod photoreceptors: Rhodopsin ~506-510nm (dog) Rhodopsin ©webvision Photopigments in the Retina Rod photoreceptors: Rhodopsin ~506-510nm (dog) Red/Green cone photoreceptors: L/M-opsin ~555nm (dog) -opsin L/M ©webvision Photopigments in the Retina Rod photoreceptors: Rhodopsin ~506-510nm (dog) Red/Green cone photoreceptors: L/M-opsin ~555nm (dog) Blue cone photoreceptors: S-opsin ~429-435nm (dog) S-opsin ©webvision Cone Photopigments – Spectral Tuning Jacobs 2008 Cone Photopigments – Spectral Tuning X chromosome Neitz & Neitz 2011 Dichromatic vs. Trichromatic Jacobs & Nathans 2009 How Primate Trichromacy Evolved Jacobs & Nathans 2009 Jacobs & Nathans 2009 2 Designs forPrimate Vision Color Old World Primates Jacobs & Nathans 2009 New World Primates Jacobs & Nathans 2009 https://www.youtube.com/watch?v=Ya8c6VdPwng http://www.neitzvision.com/ PHYSIOLOGY OF THE RETINA • PHOTORECEPTOR CELLS – PHOTOTRANSDUCTION • VISUAL PIGMENT • COLOR VISION • RETINOIDS AND THE VISUAL CYCLE Phototransduction Yau & Hardie 2009 Retinoids and the Visual Cycle Light 11-cis-retinal all-trans-retinal Dissociation of all-trans-retinal and opsin All-trans-retinal all-trans-retinol exits cell Binding to interphotoreceptor retinoid- binding protein (IRBP) Transport to RPE Yau & Hardie 2009 R-ester, retinyl ester RDH, retinol dehydrogenase REH, retinyl ester hydrolase LRAT, lecithin:retinol acyl tranferase CRBP, cellular retinol-binding protein CRALBP, cellular retinaldehyde-binding protein IRBP, interphotoreceptor retinoid binding protein hv, photon RAL, retinal ROL, retinol R-ester, retinyl ester Photopigment Regeneration • All-trans-retinal is reduced to all-trans-retinol • All-trans-retinol leaves photoreceptor, traverses IPM, finds IRBP, and enters RPE • Esterified by LRAT (lecithin:retinol acyl tranferase) • Ester is converted to 11-cis-retinol by retinyl isomerohydrolase = RPE65 • 11-cis-retinol ester is stored or oxidized by 11-RDH, and 11-cis-retinal passes into the receptor and binds with opsin to regenerate rhodopsin IPM, interphotoreceptor matrix Visual Pigments Because chromophore is highly hydrophobic Intracellular carrier proteins: CRBP and CRALBP involved in shuttling Extracellular carrier protein: IRBP involved in shuttling CRBP, cellular retinol-binding protein CRALBP, cellular retinaldehyde-binding protein IRBP, interphotoreceptor retinoid binding protein Substrate for Retinoids • Bleached pigment is one of the substrates for 11-cis-retinaldehyde synthesis in RPE • Dietary uptake is main source – Vitamin A (retinol) is formed in intestine from carotenoid compounds in food – Esterified and transported to liver, bound to retinol binding protein (RBP), further transported to the eye – Specific receptors cause retinol to be taken up by the RPE cell, where it is bound to CRBP R-ester, retinyl ester RDH, retinol dehydrogenase REH, retinyl ester hydrolase LRAT, lecithin:retinol acyl tranferase CRBP, cellular retinol-binding protein CRALBP, cellular retinaldehyde-binding protein IRBP, interphotoreceptor retinoid binding protein hv, photon RAL, retinal ROL, retinol R-ester, retinyl ester Wang & Kefalov 2011 61 Pigment Cycle • Pigment regeneration in RPE – Both rods and cones • Dedicated regeneration pathway for cones – Necessary because rod opsin outcompetes cone opsin in acquiring chromophore; acts as huge sink for for 11-cis-retinal – Müller cells • All-trans-retinol 11-cis-retinol returned to cones – Cones • 11-cis-retinol 11-cis-retinal Yau & Hardie 2009 R-ester, retinyl ester RDH, retinol dehydrogenase REH, retinyl ester hydrolase ARAT, acyl-CoA:retinol acyl tranferase CRBP, cellular retinol-binding protein CRALBP, cellular retinaldehyde-binding protein IRBP, interphotoreceptor retinoid binding protein hv, photon RAL, retinal ROL, retinol R-ester, retinyl ester R-ester, retinyl ester RDH, retinol dehydrogenase REH, retinyl ester hydrolase LRAT, lecithin:retinol acyl tranferase CRBP, cellular retinol-binding protein CRALBP, cellular retinaldehyde-binding protein IRBP, interphotoreceptor retinoid binding protein hv, photon RAL, retinal ROL, retinol R-ester, retinyl ester Wang & Kefalov 2011 64 Palczewski 2012 65 Leber Congenital Amaurosis (LCA) • Theodor Leber (1869) • Syndrome in children characterized by severe visual deficiency, with total or nearly total blindness, present at birth or shortly thereafter; pendular or searching nystagmus, with slowly progressive retinal atrophy. Inheritance is autosomal recessive and disease is heterogeneous • Mutations in at least 20 different
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