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Retina (Philadelphia, Pa.) Oct 2020To evaluate dark adaptation (DA) in patients with macular telangiectasia Type 2 (MacTel).
PURPOSE
To evaluate dark adaptation (DA) in patients with macular telangiectasia Type 2 (MacTel).
METHODS
After a local photobleach (4 × 4° size, 83% bleach), DA was measured using a test stimulus (2° diameter) projected at 5° eccentricity horizontal from the foveal center within the temporal parafovea. Cone plateau, rod intercept time, and rod recovery rate (S2) were calculated from the resulting DA curves. Findings were correlated with disease stages (according to Gass and Blodi), the area of ellipsoid zone loss in optical coherence tomography, and macular pigment loss ("MP-Classes 1-3").
RESULTS
Fifty-nine eyes of 59 patients were compared with 18 eyes of 18 healthy controls. Dark adaptation was significantly impaired in patients with MacTel. Although differences were most pronounced for parameters indicating rod-mediated recovery, cone-mediated recovery was also decreased, yet to a lesser extent. Dark adaptation parameters were only weakly associated with disease stages and ellipsoid zone loss. A better association was found between rod-mediated recovery (S2 and rod intercept time) and macular pigment loss (Kendall's tau for rod intercept time: 0.69 and S2: -0.51; both P < 0.0001).
CONCLUSION
Dark adaptation is significantly impaired in patients with MacTel. Our results indicate an association of reduced macular pigment and rod dysfunction in MacTel.
Topics: Aged; Cross-Sectional Studies; Dark Adaptation; Female; Humans; Macular Pigment; Male; Middle Aged; Prospective Studies; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Telangiectasia, Hereditary Hemorrhagic; Tomography, Optical Coherence; Visual Acuity
PubMed: 31800456
DOI: 10.1097/IAE.0000000000002694 -
Vision Research Nov 2019The white noise electroretinogram (wnERG) provides a measure of the impulse response function under conditions of retinal equilibrium; it is yet to be determined how the...
The white noise electroretinogram (wnERG) provides a measure of the impulse response function under conditions of retinal equilibrium; it is yet to be determined how the electrical response generated by melanopsin ganglion cell photoreception is expressed in the impulse response. To this end, we recorded the human wnERG to continuous temporal white noise (TWN) stimuli that were melanopsin-directed (rod and cone silent) or cone-directed (rod and melanopsin silent). The impulse response of the electroretinogram was derived by cross-correlating the TWN stimulus with the wnERG response. We observed that the LMS-cone directed wnERG contained the expected N1 wave (24.1 ± 2.4 ms; mean ± SEM) and P1 wave (49.7 ± 1.8 ms). Melanopsin-directed stimuli produced a unique wnERG with a slower negative deflection (N) at 62.9 ± 3.3 ms followed by a positive deflection (P) at 126.3 ± 5.1 ms. Additional experiments indicated this melanopsin-directed wnERG response was not due to cone intrusion. The N and NP amplitudes increased with illuminance (32,000-80,000 Td; no rod intrusion) and melanopsin contrast (10-36% Michelson contrast). As there are known pathways connecting melanopsin cells to the outer retina, we then measured the wnERG to combined melanopsin and cone-directed stimuli to quantify melanopsin interactions with cone signalling. With the combined stimuli, the N1P1 amplitudes were suppressed by ~59%, which may be a result of a destructive interference between the positive (P1) and negative (N) waves generated by the cone and melanopsin pathways. We conclude that the human wnERG to melanopsin-directed stimuli may reflect the combined response of intra-retinal melanopsin pathways, independent of rod and cone photoreception.
Topics: Adult; Dark Adaptation; Electroretinography; Female; Humans; Male; Photic Stimulation; Pupil; Reflex, Pupillary; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Rod Opsins; Young Adult
PubMed: 31542209
DOI: 10.1016/j.visres.2019.08.007 -
Life Science Alliance May 2020Retinal degeneration is the leading cause of incurable blindness worldwide and is characterised by progressive loss of light-sensing photoreceptors in the neural retina....
Retinal degeneration is the leading cause of incurable blindness worldwide and is characterised by progressive loss of light-sensing photoreceptors in the neural retina. SARM1 is known for its role in axonal degeneration, but a role for SARM1 in photoreceptor cell degeneration has not been reported. SARM1 is known to mediate neuronal cell degeneration through depletion of essential metabolite NAD and induction of energy crisis. Here, we demonstrate that SARM1 is expressed in photoreceptors, and using retinal tissue explant, we confirm that activation of SARM1 causes destruction of NAD pools in the photoreceptor layer. Through generation of double knockout mice, we demonstrate that genetic deletion of SARM1 promotes both rod and cone photoreceptor cell survival in the rhodopsin knockout ( ) mouse model of photoreceptor degeneration. Finally, we demonstrate that SARM1 deficiency preserves cone visual function in the surviving photoreceptors when assayed by electroretinography. Overall, our data indicate that endogenous SARM1 has the capacity to consume NAD in photoreceptor cells and identifies a previously unappreciated role for SARM1-dependent cell death in photoreceptor cell degeneration.
Topics: Animals; Armadillo Domain Proteins; Cytoskeletal Proteins; Disease Models, Animal; Electroretinography; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NAD; Photoreceptor Cells; Retina; Retinal Cone Photoreceptor Cells; Retinal Degeneration; Retinal Rod Photoreceptor Cells; Retinitis Pigmentosa; Rhodopsin; Vision, Ocular
PubMed: 32312889
DOI: 10.26508/lsa.201900618 -
BMC Veterinary Research Dec 2022The On-Off, or long flash, full field electroretinogram (ERG) separates retinal responses to flash onset and offset. Depending on degree of dark-adaptation and stimulus...
BACKGROUND
The On-Off, or long flash, full field electroretinogram (ERG) separates retinal responses to flash onset and offset. Depending on degree of dark-adaptation and stimulus strength the On and Off ERG can be shaped by rod and cone photoreceptors and postreceptoral cells, including ON and OFF bipolar cells. Interspecies differences have been shown, with predominantly positive Off-response in humans and other primates and a negative Off-response in rodents and dogs. However, the rod signaling pathways that contribute to these differential responses have not been characterized. In this study, we designed a long flash protocol in the dog that varied in background luminance and stimulus strength allowing for some rod components to be present to better characterize how rod pathways vary from scotopic to mesopic conditions.
RESULTS
With low background light the rod a-wave remains while the b-wave is significantly reduced resulting in a predominantly negative waveform in mesopic conditions. Through modeling and subtraction of the rod-driven response, we show that rod bipolar cells saturate with dimmer backgrounds than rod photoreceptors, resulting in rod hyperpolarization contributing to a large underlying negativity with mesopic backgrounds.
CONCLUSIONS
Reduction in rod bipolar cell responses in mesopic conditions prior to suppression of rod photoreceptor responses may reflect the changes in signaling pathway of rod-driven responses needed to extend the range of lighting conditions over which the retina functions.
Topics: Humans; Dogs; Animals; Signal Transduction; Retina
PubMed: 36463174
DOI: 10.1186/s12917-022-03505-z -
JCI Insight Jan 2022BACKGROUNDOutcome measures sensitive to disease progression are needed for ATP-binding cassette, sub-family A, member 4-associated (ABCA4-associated) retinopathy. We... (Observational Study)
Observational Study
BACKGROUNDOutcome measures sensitive to disease progression are needed for ATP-binding cassette, sub-family A, member 4-associated (ABCA4-associated) retinopathy. We aimed to quantify ellipsoid zone (EZ) loss and photoreceptor degeneration beyond EZ-loss in ABCA4-associated retinopathy and investigate associations between photoreceptor degeneration, genotype, and age.METHODSWe analyzed 132 eyes from 66 patients (of 67 enrolled) with molecularly confirmed ABCA4-associated retinopathy from a prospective natural history study with a median [IQR] follow-up of 4.2 years [3.1, 5.1]. Longitudinal spectral-domain optical coherence tomography volume scans (37 B-scans, 30° × 15°) were segmented using a deep learning (DL) approach. For genotype-phenotype analysis, a model of ABCA4 variants was applied with the age of criterion EZ-loss (6.25 mm2) as the dependent variable.RESULTSPatients exhibited an average (square-root-transformed) EZ-loss progression rate of [95% CI] 0.09 mm/y [0.06, 0.11]. Outer nuclear layer (ONL) thinning extended beyond the area of EZ-loss. The average distance from the EZ-loss boundary to normalization of ONL thickness (to ±2 z score units) was 3.20° [2.53, 3.87]. Inner segment (IS) and outer segment (OS) thinning was less pronounced, with an average distance from the EZ-loss boundary to layer thickness normalization of 1.20° [0.91, 1.48] for the IS and 0.60° [0.49, 0.72] for the OS. An additive model of allele severity explained 52.7% of variability in the age of criterion EZ-loss.CONCLUSIONPatients with ABCA4-associated retinopathy exhibited significant alterations of photoreceptors outside of EZ-loss. DL-based analysis of photoreceptor laminae may help monitor disease progression and estimate the severity of ABCA4 variants.TRIAL REGISTRATIONClinicalTrials.gov identifier: NCT01736293.FUNDINGNational Eye Institute Intramural Research Program and German Research Foundation grant PF950/1-1.
Topics: ATP-Binding Cassette Transporters; Age Factors; Deep Learning; Disease Progression; Electroretinography; Female; Follow-Up Studies; Genetic Association Studies; Humans; Male; Middle Aged; Photoreceptor Cells, Vertebrate; Retina; Retinal Degeneration; Rod Cell Outer Segment; Severity of Illness Index; Tomography, Optical Coherence
PubMed: 35076026
DOI: 10.1172/jci.insight.155373 -
Scientific Reports Feb 2021Establishing correct neuronal cell identity is essential to build intricate neural tissue architecture and acquire precise neural function during vertebrate development....
Establishing correct neuronal cell identity is essential to build intricate neural tissue architecture and acquire precise neural function during vertebrate development. While it is known that transcription factors play important roles in retinal cell differentiation, the contribution of epigenetic factors to establishing cell identity during retinal development remains unclear. We previously reported that Samd7, a rod photoreceptor cell-specific sterile alpha motif (SAM) domain protein, functions as a Polycomb repressive complex 1 component (PRC1) that is essential for establishing rod identity. In the current study, we analyzed a functional role of Samd11, another photoreceptor-enriched SAM-domain protein, in photoreceptor differentiation and maturation. We observed that Samd11 interacts with Phc2 and Samd7, suggesting that Samd11 is a component of PRC1 in photoreceptor cells. We generated Samd11-null allele and established Samd7/11 double knock-out (DKO) mouse. The Samd7/11 DKO retina exhibits shortened photoreceptor outer segments by electron microscopy analysis. Microarray analysis revealed that Samd7/11 DKO up-regulated more retinal genes than Samd7 alone, partial functional redundancy of Samd7 and Samd11. Taken together, the current results suggest that Samd7 and Samd11 are PRC1 components and that Samd7 is the major regulator while Samd11 is an accessory factor used for the establishment of precise rod photoreceptor identity.
Topics: Animals; Cell Differentiation; Cell Line; Cell Nucleus; Eye Proteins; Homeodomain Proteins; Mice; Photoreceptor Cells, Vertebrate; Polycomb Repressive Complex 1; Polycomb Repressive Complex 2; Retina; Retinal Rod Photoreceptor Cells; Trans-Activators
PubMed: 33603070
DOI: 10.1038/s41598-021-83781-1 -
Proceedings of the National Academy of... Aug 2020We have used recent measurements of mammalian cone light responses and voltage-gated currents to calculate cone ATP utilization and compare it to that of rods. The...
We have used recent measurements of mammalian cone light responses and voltage-gated currents to calculate cone ATP utilization and compare it to that of rods. The largest expenditure of ATP results from ion transport, particularly from removal of Na entering outer segment light-dependent channels and inner segment hyperpolarization-activated cyclic nucleotide-gated channels, and from ATP-dependent pumping of Ca entering voltage-gated channels at the synaptic terminal. Single cones expend nearly twice as much energy as single rods in darkness, largely because they make more synapses with second-order retinal cells and thus must extrude more Ca In daylight, cone ATP utilization per cell remains high because cones never remain saturated and must continue to export Na and synaptic Ca even in bright illumination. In mouse and human retina, rods greatly outnumber cones and consume more energy overall even in background light. In primates, however, the high density of cones in the fovea produces a pronounced peak of ATP utilization, which becomes particularly prominent in daylight and may make this part of the retina especially sensitive to changes in energy availability.
Topics: Adenosine Triphosphate; Animals; Calcium; Cyclic GMP; Cyclic Nucleotide-Gated Cation Channels; Fovea Centralis; Humans; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Ion Channel Gating; Light; Mice; Presynaptic Terminals; Retina; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Sodium
PubMed: 32719136
DOI: 10.1073/pnas.2001776117 -
Investigative Ophthalmology & Visual... Dec 2022To test the hypothesis that rod energy biomarkers in light and dark are similar in mice without functional rod transducin (Gnat1rd17).
PURPOSE
To test the hypothesis that rod energy biomarkers in light and dark are similar in mice without functional rod transducin (Gnat1rd17).
METHODS
Gnat1rd17 and wildtype (WT) mice were studied in canonically low energy demand (light) and high energy demand (dark) conditions. We measured rod inner segment ellipsoid zone (ISez) profile shape, external limiting membrane-retinal pigment epithelium (ELM-RPE) thickness, and magnitude of a hyporeflective band (HB) intensity dip located between photoreceptor tips and apical RPE; antioxidants were given in a subset of mice. Oxygen consumption rate (OCR) and visual performance indexes were also measured.
RESULTS
The lower energy demand expected in light-adapted wildtype retinas was associated with an elongated ISez, thicker ELM-RPE, and higher HB magnitude, and lower OCR compared to high energy demand conditions in the dark. Gnat1rd17 mice showed a wildtype-like ISez profile shape at 20 minutes of light that became rounder at 60 minutes; at both times, ELM-RPE was smaller than wildtype values, and the HB magnitude was unmeasurable. OCR was higher than in the dark. Light-adapted Gnat1rd17 mice biomarkers were unaffected by anti-oxidants. Gnat1rd17 mice showed modest outer nuclear layer thinning and no reduction in visual performance indexes.
CONCLUSIONS
Light-stimulated changes in all biomarkers in WT mice are consistent with the established light-induced decrease in net energy demand. In contrast, biomarker changes in Gnat1rd17 mice raise the possibility that light increases net energy demand in the absence of rod phototransduction.
Topics: Animals; Mice; Transducin; Tomography, Optical Coherence; Retina; Retinal Rod Photoreceptor Cells; Biomarkers
PubMed: 36576748
DOI: 10.1167/iovs.63.13.22 -
Free Radical Biology & Medicine Mar 2022Retinitis pigmentosa occurs due to mutations that cause rod photoreceptor degeneration. Once most rods are lost, gradual degeneration of cone photoreceptors occurs....
Retinitis pigmentosa occurs due to mutations that cause rod photoreceptor degeneration. Once most rods are lost, gradual degeneration of cone photoreceptors occurs. Oxidative damage and abnormal glucose metabolism have been implicated as contributors to cone photoreceptor death. Herein, we show increased phosphorylation of key enzymes of glucose metabolism in the retinas of rd10 mice, a model of RP, and retinas of wild type mice with paraquat-induced oxidative stress, thereby inhibiting these key enzymes. Dietary supplementation with glucose and pyruvate failed to overcome the inhibition, but increased reducing equivalents in the retina and improved cone function and survival. Dichloroacetate reversed the increased phosphorylation of pyruvate dehydrogenase in rd10 retina and increased histone acetylation and levels of TP53-induced glycolysis and apoptosis regulator (TIGAR), which redirected glucose metabolism toward the pentose phosphate pathway. These data indicate that oxidative stress induced damage can be reversed by shifting glycolytic intermediates toward the pentose phosphate pathway which increases reducing equivalents and provides photoreceptor protection.
Topics: Animals; Disease Models, Animal; Glucose; Mice; Mice, Inbred C57BL; Oxidative Stress; Retina; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Retinitis Pigmentosa
PubMed: 35134532
DOI: 10.1016/j.freeradbiomed.2022.01.032 -
BMJ Open Diabetes Research & Care Aug 2020Diabetic retinopathy is a major complication of diabetes recently associated with compromised photoreceptor function. Multiple stressors in diabetes, such as...
INTRODUCTION
Diabetic retinopathy is a major complication of diabetes recently associated with compromised photoreceptor function. Multiple stressors in diabetes, such as hyperglycemia, oxidative stress and inflammatory factors, have been identified, but systemic effects of diabetes on outer retina function are incompletely understood. We assessed photoreceptor physiology in vivo and in isolated retinas to better understand how alterations in the cellular environment compared with intrinsic cellular/molecular properties of the photoreceptors, affect light signal transduction and transmission in the retina in chronic type 2 diabetes.
RESEARCH DESIGN AND METHODS
Photoreceptor function was assessed in BKS.Cs-Dock7+/+Lepr /J mice, using homozygotes for Lepr as a model of type 2 diabetes and heterozygotes as non-diabetic controls. In vivo electroretinogram (ERG) was recorded in dark-adapted mice at both 3 and 6 months of age. For ex vivo ERG, isolated retinas were superfused with oxygenated Ames' media supplemented with 30 mM glucose or mannitol as iso-osmotic control and electrical responses to light stimuli were recorded.
RESULTS
We found that both transduction and transmission of light signals by rod photoreceptors were compromised in 6-month-old (n=9-10 eyes from 5 animals, ***p<0.001) but not in 3-month-old diabetic mice in vivo (n=4-8 eyes from 2 to 4 animals). In contrast, rod signaling was similar in isolated retinas from 6-month-old control and diabetic mice under normoglycemic conditions (n=11). Acutely elevated glucose ex vivo increased light-evoked rod photoreceptor responses in control mice (n=11, ***p<0.001), but did not affect light responses in diabetic mice (n=11).
CONCLUSIONS
Our data suggest that long-term diabetes does not irreversibly change the ability of rod photoreceptors to transduce and mediate light signals. However, type 2 diabetes appears to induce adaptational changes in the rods that render them less sensitive to increased availability of glucose.
Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Light Signal Transduction; Mice; Mice, Inbred C57BL; Retinal Rod Photoreceptor Cells
PubMed: 32784250
DOI: 10.1136/bmjdrc-2020-001571