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Angiogenesis Mar 2024Pathological retinal angiogenesis profoundly impacts visual function in vascular eye diseases, such as retinopathy of prematurity (ROP) in preterm infants and...
Pathological retinal angiogenesis profoundly impacts visual function in vascular eye diseases, such as retinopathy of prematurity (ROP) in preterm infants and age-related macular degeneration in the elderly. While the involvement of photoreceptors in these diseases is recognized, the underlying mechanisms remain unclear. This study delved into the pivotal role of photoreceptors in regulating abnormal retinal blood vessel growth using an oxygen-induced retinopathy (OIR) mouse model through the c-Fos/A disintegrin and metalloprotease 17 (Adam17) axis. Our findings revealed a significant induction of c-Fos expression in rod photoreceptors, and c-Fos depletion in these cells inhibited pathological neovascularization and reduced blood vessel leakage in the OIR mouse model. Mechanistically, c-Fos directly regulated the transcription of Adam17 a shedding protease responsible for the production of bioactive molecules involved in inflammation, angiogenesis, and cell adhesion and migration. Furthermore, we demonstrated the therapeutic potential by using an adeno-associated virus carrying a rod photoreceptor-specific short hairpin RNA against c-fos which effectively mitigated abnormal retinal blood vessel overgrowth, restored retinal thickness, and improved electroretinographic (ERG) responses. In conclusion, this study highlights the significance of photoreceptor c-Fos in ROP pathology, offering a novel perspective for the treatment of this disease.
PubMed: 38483712
DOI: 10.1007/s10456-024-09912-0 -
Frontiers in Molecular Neuroscience 2024Adaptation of photoreceptor sensitivity to varying light intensities is a fundamental requirement for retinal function and vision. Adaptive mechanisms in signal...
Adaptation of photoreceptor sensitivity to varying light intensities is a fundamental requirement for retinal function and vision. Adaptive mechanisms in signal transduction are well described, but little is known about the mechanisms that adapt the photoreceptor synapse to changing light intensities. The SNARE complex regulators Complexin 3 and Complexin 4 have been proposed to be involved in synaptic light adaptation by limiting synaptic vesicle recruitment and fusion. How this Complexin effect is exerted is unknown. Focusing on rod photoreceptors, we established Complexin 4 as the predominant Complexin in the light-dependent regulation of neurotransmitter release. The number of readily releasable synaptic vesicles is significantly smaller in light than in dark at wildtype compared to Complexin 4 deficient rod photoreceptor ribbon synapses. Electrophysiology indicates that Complexin 4 reduces or clamps Ca-dependent sustained synaptic vesicle release, thereby enhancing light signaling at the synapse. Complexin 4 deficiency increased synaptic vesicle release and desensitized light signaling. In a quantitative proteomic screen, we identified Transducin as an interactor of the Complexin 4-SNARE complex. Our results provide evidence for a presynaptic interplay of both Complexin 4 and Transducin with the SNARE complex, an interplay that may facilitate the adaptation of synaptic transmission to light at rod photoreceptor ribbon synapses.
PubMed: 38481472
DOI: 10.3389/fnmol.2024.1308466 -
Investigative Ophthalmology & Visual... Mar 2024The purpose of this study was to investigate rod photopigment bleaching-driven intrinsic optical signals (IOS) in the human outer retina and its measurement...
PURPOSE
The purpose of this study was to investigate rod photopigment bleaching-driven intrinsic optical signals (IOS) in the human outer retina and its measurement repeatability based on a commercial optical coherence tomography (OCT) platform.
METHODS
The optical path length of the rod photoreceptor subretinal space (SRS), that is, the distance between signal bands of rod outer segment tips and retinal pigment epithelium, was measured in 15 healthy subjects in ambient light and during a long-duration bleaching white-light exposure.
RESULTS
On 2 identical study days (day 1 and day 2 [D1 and D2]), light stimulation resulted in a significant decrease in rod SRS by 21.3 ± 7.6% and 19.8 ± 8.5% (both P < 0.001), respectively. The test-retest reliability of the SRS maximum change of an individual subject was moderate for single measures (intraclass correlation coefficient [ICC] = 0.730, 95% confidence interval [CI] = 0.376, 0.900, P < 0.001) and good for average measures (ICC = 0.844, 95% CI = 0.546, 0.947, P < 0.001). The mean area under the stimulus response curve with values of 14.8 ± 9.4 and 15.5 ± 7.5 µm × minutes (P = 0.782) showed excellent agreement between the stimulus response on D1 and D2. Intermittent dark adaptation of the retina led to an initial increase of the SRS by 6.1% (P = 0.018) and thereafter showed a decrease toward baseline, despite continued dark adaptation.
CONCLUSIONS
The data indicate the potential of commercial OCT in measuring slow IOS in the outer retina suggesting that the rod SRS could serve as a biomarker for photoreceptor function. The presented approach could provide an easily implementable clinical tool for the early detection of diseases affecting photoreceptor health.
Topics: Humans; Reproducibility of Results; Tomography, Optical Coherence; Retina; Dark Adaptation; Rod Cell Outer Segment
PubMed: 38470325
DOI: 10.1167/iovs.65.3.20 -
Investigative Ophthalmology & Visual... Mar 2024A progression sequence for age-related macular degeneration onset may be determinable with consensus neuroanatomical nomenclature augmented by drusen biology and... (Review)
Review
A progression sequence for age-related macular degeneration onset may be determinable with consensus neuroanatomical nomenclature augmented by drusen biology and eye-tracked clinical imaging. This narrative review proposes to supplement the Early Treatment of Diabetic Retinopathy Study (sETDRS) grid with a ring to capture high rod densities. Published photoreceptor and retinal pigment epithelium (RPE) densities in flat mounted aged-normal donor eyes were recomputed for sETDRS rings including near-periphery rich in rods and cumulatively for circular fovea-centered regions. Literature was reviewed for tissue-level studies of aging outer retina, population-level epidemiology studies regionally assessing risk, vision studies regionally assessing rod-mediated dark adaptation (RMDA), and impact of atrophy on photopic visual acuity. The 3 mm-diameter xanthophyll-rich macula lutea is rod-dominant and loses rods in aging whereas cone and RPE numbers are relatively stable. Across layers, the largest aging effects are accumulation of lipids prominent in drusen, loss of choriocapillary coverage of Bruch's membrane, and loss of rods. Epidemiology shows maximal risk for drusen-related progression in the central subfield with only one third of this risk level in the inner ring. RMDA studies report greatest slowing at the perimeter of this high-risk area. Vision declines precipitously when the cone-rich central subfield is invaded by geographic atrophy. Lifelong sustenance of foveal cone vision within the macula lutea leads to vulnerability in late adulthood that especially impacts rods at its perimeter. Adherence to an sETDRS grid and outer retinal cell populations within it will help dissect mechanisms, prioritize research, and assist in selecting patients for emerging treatments.
Topics: Humans; Adult; Aged; Macular Degeneration; Retina; Macula Lutea; Geographic Atrophy; Retinal Cone Photoreceptor Cells
PubMed: 38466281
DOI: 10.1167/iovs.65.3.4 -
BioRxiv : the Preprint Server For... Mar 2024Mutations in cause Usher syndrome type IIIA (USH3A), an autosomal recessive disorder characterized by hearing and vision loss, and often accompanied by vestibular...
Mutations in cause Usher syndrome type IIIA (USH3A), an autosomal recessive disorder characterized by hearing and vision loss, and often accompanied by vestibular balance issues. The identity of the cell types responsible for the pathology and mechanisms leading to vision loss in USH3A remains elusive. To address this, we employed CRISPR/Cas9 technology to delete a large region in the coding and untranslated (UTR) region of zebrafish . Retina of mutant larvae exhibited sensitivity to cell stress, along with age-dependent loss of function and degeneration in the photoreceptor layer. Investigation revealed disorganization in the outer retina in mutants, including actin-based structures of the Müller glia and photoreceptor cells. To assess cell-specific contributions to USH3A pathology, we specifically re-expressed in either Müller glia or photoreceptor cells. Müller glia re-expression of prevented the elevated cell death observed in larval mutant zebrafish exposed to high-intensity light. Notably, the degree of phenotypic rescue correlated with the level of Clrn1 re-expression. Surprisingly, high levels of Clrn1 expression enhanced cell death in both wild-type and mutant animals. However, rod- or cone-specific Clrn1 re-expression did not rescue the extent of cell death. Taken together, our findings underscore three crucial insights. First, mutant zebrafish exhibit key pathological features of USH3A; second, Clrn1 within Müller glia plays a pivotal role in photoreceptor maintenance, with its expression requiring controlled regulation; third, the reliance of photoreceptors on Müller glia suggests a structural support mechanism, possibly through direct interactions between Müller glia and photoreceptors mediated in part by Clrn1 protein.
PubMed: 38464015
DOI: 10.1101/2024.02.29.582878 -
Experimental Biology and Medicine... 2024This research aims to investigate the potential of using intrinsic optical signal (IOS) optoretinography (ORG) to objectively detect dark adaptation (DA) abnormalities...
This research aims to investigate the potential of using intrinsic optical signal (IOS) optoretinography (ORG) to objectively detect dark adaptation (DA) abnormalities related to rod photoreceptor degeneration. Functional optical coherence tomography (OCT) was employed in both wild-type (WT) and retinal degeneration 10 (rd10) mice to conduct this assessment. Dynamic OCT measurements captured the changes in retinal thickness and reflectance from light-to-dark transition. Comparative analysis revealed significant IOS alterations within the outer retina. Specifically, a reduction in thickness from external limiting membrane (ELM) peak to retinal pigment epithelium (RPE) peak was observed (WT: 1.13 ± 0.69 µm, 30 min DA; rd10: 2.64 ± 0.86 µm, 30 min DA), as well as a decrease in the intensity of the inner segment ellipsoid zone (EZ) in 30 min DA compared to light adaptation (LA). The reduction of relative EZ intensity was notable in rd10 after 5 min DA and in WT after 15 min DA, with a distinguishable difference between rd10 and WT after 10 min DA. Furthermore, our findings indicated a significant decrease in the relative intensity of the hypo-reflective band between EZ and RPE in rd10 retinas during DA, which primarily corresponds to the outer segment (OS) region. In conclusion, the observed DA-IOS abnormalities, including changes in ELM-RPE thickness, EZ, and OS intensity, hold promise as differentiators between WT and rd10 mice before noticeable morphological abnormalities occur. These findings suggest the potential of this non-invasive imaging technique for the early detection of dysfunction in retinal photoreceptors.
Topics: Mice; Animals; Retinal Degeneration; Dark Adaptation; Retina; Retinal Pigment Epithelium; Retinal Rod Photoreceptor Cells
PubMed: 38463390
DOI: 10.3389/ebm.2024.10024 -
Vision Research May 2024Mutations in BEST1 cause an autosomal recessive disease in dogs where the earliest changes localize to the photoreceptor-RPE interface and show a retina-wide...
Mutations in BEST1 cause an autosomal recessive disease in dogs where the earliest changes localize to the photoreceptor-RPE interface and show a retina-wide micro-detachment that is modulated by light exposure. The purpose of this study was to define the spatial and temporal details of the outer retina and its response to light with ultra-high resolution OCT across a range of ages and with different BEST1 mutations. Three retinal regions were selected in each eye: near the fovea-like area, near the optic nerve, both in the tapetal area, and inferior to the optic nerve in the non-tapetal area. The OS+ slab thickness was defined between the peak near the junction of inner and outer segments (IS/OS) and the transition between basal RPE, Bruch membrane, choriocapillaris and proximal tapetum (RPE/T). In wildtype (WT) dogs, two tapetal regions showed additional hyperscattering OCT peaks within the OS+ slab likely representing cone and rod outer segment tips (COST and ROST). The inferior non-tapetal region of WT dogs had only one of these peaks, likely ROST. In dogs with BEST1 mutations, all three locations showed a single peak, likely suggesting optical silence of COST. Light-dependent expansion of the micro-detachment by about 10 um was detectable in both tapetal and non-tapetal retina across all ages and BEST1 mutations.
Topics: Dogs; Animals; Tomography, Optical Coherence; Retina; Retinal Cone Photoreceptor Cells; Vision, Ocular
PubMed: 38460402
DOI: 10.1016/j.visres.2024.108379 -
Vision Research Apr 2024Human photoreceptors consist of cones, rods, and melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs). First studied in circadian...
Human photoreceptors consist of cones, rods, and melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs). First studied in circadian regulation and pupillary control, ipRGCs project to a variety of brain centers suggesting a broader involvement beyond non-visual functions. IpRGC responses are stable, long-lasting, and with a particular codification of photoreceptor signals. In comparison with the transient and adaptive nature of cone and rod signals, ipRGCs' signaling might provide an ecological advantage to different attributes of color vision. Previous studies have indicated melanopsin's influence on visual responses yet its contribution to color perception in humans remains debated. We summarized evidence and hypotheses (from physiology, psychophysics, and natural image statistics) about direct and indirect involvement of ipRGCs in human color vision, by first briefly assessing the current knowledge about the role of melanopsin and ipRGCs in vision and codification of spectral signals. We then approached the question about melanopsin activation eliciting a color percept, discussing studies using the silent substitution method. Finally, we explore various avenues through which ipRGCs might impact color perception indirectly, such as through involvement in peripheral color matching, post-receptoral pathways, color constancy, long-term chromatic adaptation, and chromatic induction. While there is consensus about the role of ipRGCs in brightness perception, confirming its direct contribution to human color perception requires further investigation. We proposed potential approaches for future research, emphasizing the need for empirical validation and methodological thoroughness to elucidate the exact role of ipRGCs in human color vision.
Topics: Humans; Retinal Ganglion Cells; Color Vision; Retinal Cone Photoreceptor Cells; Visual Perception; Rod Opsins; Psychophysics; Light
PubMed: 38458004
DOI: 10.1016/j.visres.2024.108378 -
Ophthalmic Genetics Mar 2024Disease-causing variants in the gene are associated with "cone dystrophy with supernormal rod responses," a rare autosomal recessive retinal dystrophy. There is no...
BACKGROUND
Disease-causing variants in the gene are associated with "cone dystrophy with supernormal rod responses," a rare autosomal recessive retinal dystrophy. There is no previous report of hypomorphic variants in the disease.
MATERIAL AND METHODS
Medical history, genetic testing, ocular examination, high-resolution retinal imaging including adaptive optics scanning light ophthalmoscopy (AOSLO), and functional assessments.
RESULTS
A 16-year-old male with mild cone-rod dystrophy presented with reduced central vision and photophobia. Genetic testing showed two variants in , c.614_617dupAGCG (p.207AlafsTer166) and c.854T>G (p.Met285Arg), the latter which was previously considered benign. Electrophysiological assessment revealed the pathognomic electroretinogram waveforms associated with -retinopathy. Optical coherence tomography showed discrete focal ellipsoid zone disruption, while fundus autofluorescence was normal. Non-waveguiding cones corresponding to areas of loss of photoreceptor integrity were visible on adaptive optics scanning light ophthalmoscopy. Retinal sensitivity and fixation were relatively preserved, with a demonstrable deterioration after 14 months of follow-up.
CONCLUSIONS
We provide functional and structural evidence that the variant M285R is disease-causing if associated with a loss-of-function variant. To the best of our knowledge, this is the first hypomorphic allele reported in .
PubMed: 38454848
DOI: 10.1080/13816810.2024.2324046 -
FASEB Journal : Official Publication of... Mar 2024Lipid processing by the retinal pigment epithelium (RPE) is necessary to maintain retinal health and function. Dysregulation of retinal lipid homeostasis due to normal...
Lipid processing by the retinal pigment epithelium (RPE) is necessary to maintain retinal health and function. Dysregulation of retinal lipid homeostasis due to normal aging or age-related disease triggers lipid accumulation within the RPE, on Bruch's membrane (BrM), and in the subretinal space. In its role as a hub for lipid trafficking into and out of the neural retina, the RPE packages a significant amount of lipid into lipid droplets for storage and into apolipoprotein B (APOB)-containing lipoproteins (Blps) for export. Microsomal triglyceride transfer protein (MTP), encoded by the MTTP gene, is essential for Blp assembly. Herein we test the hypothesis that MTP expression in the RPE is essential to maintain lipid balance and retinal function using the newly generated RPEΔMttp mouse model. Using non-invasive ocular imaging, electroretinography, and histochemical and biochemical analyses we show that genetic depletion of Mttp from the RPE results in intracellular lipid accumulation, increased photoreceptor-associated cholesterol deposits, and photoreceptor cell death, and loss of rod but not cone function. RPE-specific reduction in Mttp had no significant effect on plasma lipids and lipoproteins. While APOB was decreased in the RPE, most ocular retinoids remained unchanged, with the exception of the storage form of retinoid, retinyl ester. Thus suggesting that RPE MTP is critical for Blp synthesis and assembly but is not directly involved in plasma lipoprotein metabolism. These studies demonstrate that RPE-specific MTP expression is necessary to establish and maintain retinal lipid homeostasis and visual function.
Topics: Animals; Mice; Retina; Retinal Pigment Epithelium; Retinoids; Apolipoproteins B; Homeostasis; Carrier Proteins
PubMed: 38445789
DOI: 10.1096/fj.202302491R