Search Results (183)

Adaptive optics scanning laser ophthalmoscopy optoretinography quantifies cellular function in the living retina by measuring the en face intensity change in cone photoreceptors due to visual stimulation. To fulfill the potential of optoretinography as a biomarker for assessing function in disease, we require normative optoretinographic measurements across the retina. Here we provide such measurements. We use a custom adaptive optics scanning laser ophthalmoscope to investigate cone optoretinogram (ORG) amplitudes across retinal eccentricity in five normal-sighted participants. For this purpose, we aggregated signals across cones in each measurement (~1° by 1° patch) to provide a measurement we call the population ORG. Average population ORG amplitudes decreased with increasing eccentricity for all participants, although there were individual differences in the detailed pattern of the decrease. ORG amplitudes were correlated with the thickness of the outer retina as measured using clinical OCT, which also decreases with eccentricity. Characterizing the population cone ORG as a function of eccentricity in normal-sighted participants is an important step towards establishing norms that will allow it to be used as a biomarker for assessing photoreceptor function in retinal disease. Full article

Pollinating fig wasps (Agaonidae) engage in an obligate mutualism with Ficus species, which is mediated by host-specific chemical cues. However, the role of visual perception in host recognition remains poorly understood, particularly because of a lack of structural studies of their compound eyes. We investigated the ocular morphology of female Ceratosolen gravelyi (exclusive pollinator of F. semicordata) using scanning/transmission electron microscopy. The oval apposition eyes contain 228–263 ommatidia, which are asymmetrically distributed between the left and right eyes. Each ommatidium comprises a biconvex corneal lens overlying a tetrapartite eucone crystalline cone; proximal cone cells reveal an interlaced labyrinth. Pigment cells encapsulate each ommatidium, and numerous pigment granules and mitochondria are present in both pigment and retinular cells. Nine retinular cells comprise a unit, with eight photoreceptors (R1–R8) forming the rhabdom from the cone base to the basal matrix; a ninth cell replaces R8 in the apical third of the rhabdom. Optical metrics, including F-number (1.1°), acceptance angle (10.0°), and ommatidial sensitivity (0.26 µm²/sr), indicate diurnal activity in bright environments. These adaptations suggest that their eyes are critical for processing visual cues during host interactions, which advances our understanding of multimodal sensory integration in fig–wasp mutualism. Full article

Bardet–Biedl syndrome (BBS) is a rare multisystem ciliopathy characterized by early-onset retinal degeneration and other vision-threatening ophthalmologic manifestations. This review synthesizes current knowledge on the ocular phenotype of BBS as well as emerging therapeutic approaches aimed at preserving visual function. Retinal degeneration, particularly early macular involvement and rod–cone dystrophy, remains the hallmark of BBS-related vision loss. Additional ocular manifestations, such as refractive errors, nystagmus, optic nerve abnormalities, and cataracts further contribute to visual morbidity. Experimental therapies—including gene-based interventions and pharmacologic strategies such as nonsense suppression and antioxidant approaches—have shown promise in preclinical models but require further validation. Early ophthalmologic care, including routine visual assessments, refractive correction, and low-vision rehabilitation, remains the standard of management. However, there are currently no effective therapies to halt or reverse retinal degeneration, which underscores the importance of emerging molecular and genetic interventions. Timely recognition and comprehensive ophthalmologic evaluation are essential to mitigate visual decline in BBS. Future efforts should focus on translating these approaches into clinical practice, enhancing early diagnosis, and promoting multidisciplinary collaboration to improve long-term outcomes for patients with BBS. Full article

The Na,K-ATPase is a heterodimeric ion pump consisting of various combinations of a catalytic α-subunit (α1, α2, α3, or α4, encoded by ATP1A1–ATP1A4) and a β-subunit (β1, β2, or β3, encoded by ATP1B1–ATP1B3). We have previously shown that Atp1b2 knock-out (ko) mice exhibit rapid photoreceptor cell degeneration, whereas Atp1b2^Atp1b1 knock-in (ki) mice, which express the β1-subunit instead of the β2-subunit under regulatory elements of the Atp1b2 gene, exhibit slowly progressive retinal dystrophy. Here, we performed a detailed analysis of the retinal phenotype of the Atp1b2^Atp1b1 ki mouse. We found that the number of cone photoreceptor cells in the mutant retinas was significantly reduced by postnatal day 28. The retinas of 4-month-old mice were almost devoid of cones. The early onset and rapid loss of cones was followed by a slowly progressive degeneration of rods. Other retinal cell types were unaffected. Nonradioactive in situ hybridization and immunohistochemistry revealed that wild-type photoreceptors expressed β3 and high levels of β2, while Atp1b2^Atp1b1 ki photoreceptor cells expressed β3 and low levels of transgenic β1. Additionally, levels of retinoschisin, a secreted retina-specific protein that interacts directly with the β2-subunit, were greatly reduced in mutant retinas. The results demonstrate that the β1-subunit can functionally compensate, at least in part, for the absence of the β2-subunit. The results also show that cones are more susceptible to Na,K-ATPase dysfunction than rods. Taken together, the present study identifies the Atp1b2^Atp1b1 ki mutant as a novel animal model of an early-onset and rapidly progressive cone–rod dystrophy. Full article

Müller glia exhibit a remarkable regenerative capacity in zebrafish through spontaneous reprogramming post-injury but remain limited in mammals. This review highlights the key mechanisms underlying Müller glia reprogramming, including gene regulatory networks, cytokine signaling, signal transduction pathways, epigenetic modifications, and transcriptional regulation. Cross-species analyses have uncovered conserved gene networks that suppress neurogenesis in mammals, while injury-induced transcriptional profiles reveal divergent regenerative strategies. Combinatorial approaches may enhance the reprogramming of mammalian Müller glia into functional neurons. Nevertheless, significant challenges remain, such as variability in the efficacy of direct reprogramming methods and the limited regeneration of cone photoreceptors, even in regenerative species. We conclude that targeting epigenetic barriers and species-specific regulatory pathways offers promising avenues for clinical translation in retinal disorders such as glaucoma and retinitis pigmentosa. Moving forward, research efforts should prioritize the functional integration of regenerated neurons and the development of standardized methodologies to accelerate therapeutic advancements. Full article

O-mannosylation is a post-translational modification required for the proper function of various proteins and critical for development and growth. POMGNT1 encodes the enzyme O-linked-mannose β-1,2-N-acetylglucosaminyltransferase 1, which catalyzes the second step in the synthesis of α-dystroglycan O-mannosyl glycans. Among POMGNT1-related α-dystroglycanopathies, muscle–eye–brain (MEB) disease presents with congenital muscular dystrophy, structural brain abnormalities, and retinal dystrophy. Defects in protein O-mannosylation due to biallelic loss-of-function POMGNT1 mutations produce disturbances in assembling and organizing the basal membrane in the neuroretinal system, involving both the central and peripheral nervous systems. In the retina, POMGNT1 is expressed in photoreceptors and is localized near the photoreceptor cilium basal body, a structure critical for protein transport. Recent studies have reported an isolated degenerative ocular phenotype without any involvement of muscular or neuronal tissues. Here, we report on a family with three siblings affected by an apparently isolated clinically variable retinal disease and sharing biallelic inactivating POMGNT1 variants. Notably, the rod-cone dystrophy phenotype in the three siblings varied significantly in onset, presentation, and severity. These findings provide further evidence of the clinical variability associated with defective POMGNT1 function. Full article

Goldmann–Favre syndrome (GFS) is a rare vitreoretinal degenerative disorder caused by mutations in the NR2E3 gene located on the short arm of chromosome 15. This condition, inherited in an autosomal recessive manner, was first described by Favre in two siblings, with Ricci later confirming its hereditary pattern. In GFS, rod photoreceptors are essentially replaced by S-cone photoreceptors. Enhanced S-Cone Syndrome (ESCS) and Goldmann–Favre syndrome are two distinct entities within the spectrum of retinal degenerative diseases, both caused by mutations in the NR2E3 gene. Despite sharing a common genetic basis, these conditions exhibit significantly different clinical phenotypes. ESCS is characterized by an excessive number of S-cones (blue-sensitive cones) with degeneration of rods and L-/M-cones, leading to increased sensitivity to blue light and early-onset night blindness. In contrast, GFS is considered a more severe form of ESCS, involving additional features such as retinal schisis, vitreous degeneration, and more pronounced visual impairment. GFS typically manifests in the first decade of life as night blindness (nyctalopia) and progressive visual acuity impairment. The clinical features include degenerative vitreous changes such as liquefaction, strands, and bands, along with macular and peripheral retinoschisis, posterior subcapsular cataract, atypical pigmentary dystrophy, and markedly abnormal or nondetectable electroretinograms (ERGs). Although peripheral retinoschisis is more common in GFS, central retinoschisis may also occur. Despite the consistent genetic basis, the phenotype of GFS can vary significantly among individuals. The differential diagnosis should consider diseases within the retinal degenerative spectrum, including retinitis pigmentosa, congenital retinoschisis, and secondary pigmentary retinopathy. Full article

Photoreceptor/retinal degeneration is the major cause of blindness. Induced and inherited mouse models of retinal degeneration are valuable tools for investigating disease mechanisms and developing therapeutic interventions. This study investigated the potential of the antioxidant resveratrol to relieve photoreceptor degeneration using mouse models. Clinical studies have shown a potential association between thyroid hormone (TH) signaling and age-related retinal degeneration. Excessive TH signaling induces oxidative stress/damage and photoreceptor death in mice. C57BL/6 (rod-dominant) and Nrl^−/− (cone-dominant) mice at postnatal day 30 (P30) received triiodothyronine (T3) via drinking water (20 µg/mL) with or without concomitant treatment with resveratrol via drinking water (120 µg/mL) for 30 days, followed by evaluation of photoreceptor degeneration, oxidative damage, and retinal stress responses. In experiments using Leber congenital amaurosis model mice, mother Rpe65^−/− and Rpe65^−/−/Nrl^−/− mice received resveratrol via drinking water (120 µg/mL) for 20 days and 10–13 days, respectively, beginning on the day when the pups were at P5, and pups were then evaluated for cone degeneration. Treatment with resveratrol significantly diminished the photoreceptor degeneration induced by T3 and preserved photoreceptors in Rpe65-deficient mice, manifested as preserved retinal morphology/outer nuclear layer thickness, increased cone density, reduced photoreceptor oxidative stress/damage and apoptosis, reduced upregulation of genes involved in cell death/inflammatory responses, and reduced macroglial cell activation. These findings demonstrate the role of oxidative stress in photoreceptor degeneration, associated with TH signaling and Rpe65 deficiency, and support the therapeutic potential of resveratrol/antioxidants in the management of retinal degeneration. Full article

Glucose-sensing ChREBP and MondoA are transcriptional factors involved in the lipogenic, inflammatory, and insulin signaling pathways implicated in metabolic disorders; however, limited ocular studies have been conducted on these proteins. We aimed to investigate the potential role of ChREBP in the pathogenesis of diabetic retinopathy (DR). We used diabetic human and mouse retinal cryosections analyzed by immunohistochemistry. qRT-PCR was performed to quantify gene expression. To explore the role of ChREBP in rods, we generated caChREBP^RP mice with constitutively active (ca) ChREBP. These mice underwent retinal functional testing, which was followed by proteomic analysis using LC-MS. Furthermore, ARPE-19 cells were infected with lentiviral particles expressing human ChREBP (ARPE-19^ChREBP) and subjected to global proteomics. Our results demonstrate that both proteins were expressed across the retina, although with distinct distribution patterns: MondoA was more prominently expressed in cones, while ChREBP was broadly expressed throughout the retina. Elevated expression of both proteins was observed in DR. This may have contributed to rod photoreceptor degeneration, as we observed diminished scotopic ERG amplitudes in caChREBP^RP mice at P35. The retinal proteomic landscape revealed a decline in the KEGG pathways associated with phototransduction, amino acid metabolism, and cell adhesion. Furthermore, rod-specific caChREBP induced TXNIP expression. Consistent with altered retinal proteomics, ARPE-19^ChREBP cells exhibit a metabolic shift toward increased glyoxylate signaling, sugar metabolism, and lysosomal activation. Our study demonstrates that ChREBP overexpression causes significant metabolic reprogramming triggering retinal functional loss in mice. Full article

Retinitis pigmentosa (RP) is a hereditary disease characterized by progressive vision loss ultimately leading to blindness. This condition is initiated by mutations in genes expressed in retinal cells, resulting in the degeneration of rod photoreceptors, which is subsequently followed by the loss of cone photoreceptors. Mutations in various genes expressed in the retina are associated with RP. Among them, mutations in the rhodopsin gene (RHO) are the most common cause of this condition. Due to the involvement of numerous genes and multiple mutations in a single gene, RP is a highly heterogeneous disease making the development of effective treatments particularly challenging. The progression of this disease involves complex cellular responses to restore cellular homeostasis, including the unfolded protein response (UPR) signaling, autophagy, and various cell death pathways. These mechanisms, however, often fail to prevent photoreceptor cell degradation and instead contribute to cell death under certain conditions. Current research focuses on the pharmacological modulation of the components of these pathways and the direct stabilization of mutated receptors as potential treatment strategies. Despite these efforts, the intricate interplay between these mechanisms and the diverse causative mutations involved has hindered the development of effective treatments. Advancing our understanding of the interactions between photoreceptor cell death mechanisms and the specific genetic mutations driving RP is critical to accelerate the discovery and development of therapeutic strategies for this currently incurable disease. Full article

In this study, we designed a biomimetic artificial visual system (AVS) inspired by biological visual system that can process RGB images. Our approach begins by mimicking the photoreceptor cone cells to simulate the initial input processing followed by a learnable dendritic neuron model to replicate ganglion cells that integrate outputs from bipolar and horizontal cell simulations. To handle multi-channel integration, we utilize a nonlearnable dendritic neuron model to simulate the lateral geniculate nucleus (LGN), which consolidates outputs across color channels, an essential function in biological multi-channel processing. Cross-validation experiments show that AVS demonstrates strong generalization across varied object–background configurations, achieving accuracy where traditional models like EfN-B0, ResNet50, and ConvNeXt typically fall short. Additionally, our results across different training-to-testing data ratios reveal that AVS maintains over 96% test accuracy even with limited training data, underscoring its robustness in low-data scenarios. This demonstrates the practical advantage of the AVS model in applications where large-scale annotated datasets are unavailable or expensive to curate. This AVS model not only advances biologically inspired multi-channel processing but also provides a practical framework for efficient, integrated visual processing in computational models. Full article

Background: This study aimed to analyze the potential pathogenic connection between metabolic factors, photoreceptor cell rearrangements, retinal microvascular perfusion, and functional parameters through multifocal electroretinography (mfERG) in type 1 diabetes mellitus (DM1). Methods: This prospective observational cohort study enrolled DM1 patients (40.5 ± 9.1 years) with mild nonproliferative diabetic retinopathy followed for 4 years. Patients were subjected to multimodal imaging, which included color fundus photography, optical coherence tomography (OCT), OCT angiography, adaptive optics (AO), and mfERG. OCTA slabs were analyzed using ImageJ software (software version 2.3.0/1.53f) to calculate perfusion density (PD) at both superficial (SCP) and deep (DCP) capillary plexuses, as well as flow deficit percentage (FD%) at the choriocapillaris (CC). To calculate cone metrics on AO at the parafovea, including cone density (CD), linear dispersion index (LDi), and heterogeneity packing index (Hpi%) in the parafovea, the images were post-processed using a MATLAB algorithm. The mfERG P1 implicit time (IT) and N1-P1 response amplitude density (RAD) from R1 (foveal area), R2 (parafoveal area), and the unified rings R1 + R2 were evaluated. Results: A total of 22 patients (22 eyes) were enrolled. No significant differences were noted in central mfERG amplitude and implicit time-averaged values (p > 0.05, all). The main factor influencing R1 IT was HbA1c, while R1 RAD was affected by Hpi and CC FD%. R1 + R2 IT was influenced by Hpi, LDi (p > 0.001, all), and modifications in the perfusion density in the SCP (p < 0.001) and DCP (p = 0.03) at the parafovea. In contrast, R1 + R2 RAD were associated with HbA1c (p = 0.02) and Hpi (p < 0.001). Conclusions: Microvascular changes and glucometabolic factors are key elements influencing the long-term morphofunctional alterations at the photoreceptor level in DM1. Full article

Photoreceptors in the mammalian retina convert light signals into electrical and molecular signals through phototransduction and transfer the visual inputs to second-order neurons via specialized ribbon synapses. Two kinds of photoreceptors, rods and cones, possess distinct morphology and function. Currently, we have limited knowledge about rod versus (vs.) cone synapse development and the associated genes. The transcription factor neural retina leucine zipper (NRL) determines the rod vs. cone photoreceptor cell fate and is critical for rod differentiation. Nrl knockout mice fail to form rods, generating all cone or S-cone-like (SCL) photoreceptors in the retina, whereas ectopic expression of Nrl using a cone-rod homeobox (Crx) promoter (CrxpNrl) forms all rods. Here, we examined rod and cone pre-synapse development, including axonal elongation, terminal shaping, and synaptic lamination in the outer plexiform layer (OPL) in the presence or absence of Nrl. We show that NRL loss and knockdown result in delayed OPL maturation and plasticity with aberrant dendrites of bipolar neurons. The integrated analyses of the transcriptome in developing rods and SCLs with NRL CUT&RUN and synaptic gene ontology analyses identified G protein subunit beta (Gnb) 1 and p21 (RAC1) activated kinase 5 (Pak5 or Pak7) transcripts were upregulated in developing rods and down-regulated in developing SCLs. Notably, Gnb1 and Gnb5 are rod dominant, and Gnb3 is enriched in cones. NRL binds to the genes of Gnb1, Gnb3, and Gnb5. NRL also regulates pre-synapse ribbon genes, and their expression is altered in rods and SCLs. Our study of histological and gene analyses provides new insights into the morphogenesis of photoreceptor pre-synapse development and regulation of associated genes in the developing retina. Full article

The visual system is essential for humans to perceive the environment. In the retina, rod and cone photoreceptor neurons are the initial sites where vision forms. The apical region of both cone and rod photoreceptors contains a light-sensing organelle known as the outer segment (OS), which houses tens of thousands of light-sensitive opsins. The OSs of photoreceptors are not static; they require rhythmic renewal to maintain normal physiological functions. Disruptions in OS renewal can lead to various genetic disorders, such as retinitis pigmentosa (RP). Understanding the patterns and molecular mechanisms of photoreceptor OS renewal remains one of the most intriguing topics in visual biology. This review aims to elucidate the structure of photoreceptor OSs, the molecular mechanisms underlying photoreceptor OS renewal, and the retinal diseases resulting from defects in this renewal process. Additionally, we will explore retinal diseases related to photoreceptor OS renewal and potential therapeutic strategies, concluding with a discussion on future research directions for OS renewal. Full article

Background/Objectives: Cone dystrophy with supernormal rod response (CDSRR) is a rare autosomal recessive retinal disorder characterized by a delayed and markedly decreased photoreceptor response. In this article, we aim to describe the clinical course and associated molecular findings in children with cone dystrophy with supernormal rod response associated with recessive mutations in the KCNV2 gene, which encodes a subunit (Kv8.2) of the voltage-gated potassium channel. Methods: The genetic testing of two patients included the next-generation sequencing of a retinal dystrophy panel and direct Sanger sequencing to confirm KCNV2 gene variants, in addition to an electroretinogram (ERG) and spectral domain optical coherence tomography (SD-OCT). Results: Cone dystrophy with supernormal rod response is associated with identified variants in the KCNV2 gene. The genetic analysis of the first case identified a compound heterozygous mutation in the KCNV2 gene, including a de novo nonsense duplication at cDNA position 1109, which led to the premature termination of the p.Lys371Ter codon in the second extracellular domain of the protein. Two patients showed changes in the full-field electroretinogram, especially in the first case, which demonstrated a close to supernormal total electroretinogram amplitude. This study increased the range of the KCNV2 mutation database, added an unreported de novo substitution pattern to KCNV2 gene variants, and linked it to the evaluated clinical studies. Conclusions: The initial clinical manifestations were varied, but both patients presented with hypermetropia and slight exotropia. The ERG findings are characteristic of KCNV2 mutations, and patients exhibited an increased b-wave latency in DA3.0 ERG (combined rod–cone response). Full article