RESUMEN
Purpose: To investigate the contributions of the microstructural and metabolic brain environment to glaucoma and their association with visual field (VF) loss patterns by using advanced diffusion magnetic resonance imaging (dMRI), proton magnetic resonance spectroscopy (MRS), and clinical ophthalmic measures. Methods: Sixty-nine glaucoma and healthy subjects underwent dMRI and/or MRS at 3 Tesla. Ophthalmic data were collected from VF perimetry and optical coherence tomography. dMRI parameters of microstructural integrity in the optic radiation and MRS-derived neurochemical levels in the visual cortex were compared among early glaucoma, advanced glaucoma, and healthy controls. Multivariate regression was used to correlate neuroimaging metrics with 16 archetypal VF loss patterns. We also ranked neuroimaging, ophthalmic, and demographic attributes in terms of their information gain to determine their importance to glaucoma. Results: In dMRI, decreasing fractional anisotropy, radial kurtosis, and tortuosity and increasing radial diffusivity correlated with greater overall VF loss bilaterally. Regionally, decreasing intra-axonal space and extra-axonal space diffusivities correlated with greater VF loss in the superior-altitudinal area of the right eye and the inferior-altitudinal area of the left eye. In MRS, both early and advanced glaucoma patients had lower gamma-aminobutyric acid (GABA), glutamate, and choline levels than healthy controls. GABA appeared to associate more with superonasal VF loss, and glutamate and choline more with inferior VF loss. Choline ranked third for importance to early glaucoma, whereas radial kurtosis and GABA ranked fourth and fifth for advanced glaucoma. Conclusions: Our findings highlight the importance of non-invasive neuroimaging biomarkers and analytical modeling for unveiling glaucomatous neurodegeneration and how they reflect complementary VF loss patterns.
Asunto(s)
Tomografía de Coherencia Óptica , Pruebas del Campo Visual , Campos Visuales , Humanos , Masculino , Femenino , Persona de Mediana Edad , Campos Visuales/fisiología , Tomografía de Coherencia Óptica/métodos , Anciano , Trastornos de la Visión/fisiopatología , Trastornos de la Visión/metabolismo , Imagen de Difusión por Resonancia Magnética , Glaucoma/fisiopatología , Glaucoma/metabolismo , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Glaucoma de Ángulo Abierto/metabolismo , Glaucoma de Ángulo Abierto/fisiopatología , Corteza Visual/metabolismo , Corteza Visual/diagnóstico por imagen , Espectroscopía de Protones por Resonancia Magnética , Adulto , Presión Intraocular/fisiologíaRESUMEN
OBJECTIVE: Surgery is a good treatment option for drug-resistant temporal lobe epilepsy (TLE). 2-deoxy-2-(18F) fluoro-D-glucose (FDG) positron emission tomography (PET) is used to detect epileptic foci as hypometabolic lesions in presurgical evaluation. Visual field defects (VFDs) in the contralateral homonymous upper quadrant are common postoperative complications in TLE. This study aimed to quantify VFDs using pattern deviation probability plots (PDPPs) and examine the effect of hypometabolism in FDG-PET on VFDs. METHODS: This study included 40 patients. Both visual fields were assessed using the Humphrey field analyzer preoperatively and 3 months and 2 years postoperatively. PDPPs with <0.5% confidence level counted in the contralateral homonymous upper quadrant. FDG-PET results were compared between groups with (15 patients) and without (24 patients) hypometabolism in the optic radiation. RESULTS: All 40 patients were evaluated by Humphrey field analyzer at 3 months postoperatively and 39 at 2 years postoperatively. The incidence of VFDs 3 months postoperatively was 35/40 (87.5%), and 17/40 (42.5%) patients had severe VFDs. In cases of surgery on the left temporal lobe, ipsilateral eyes appeared to be more significantly affected than contralateral eyes. VFDs were more severe in patients with FDG hypometabolism than in those without hypometabolism in posteromedial temporal and medial occipital cortex (P < 0.01); however, 85% of patients with FDG hypometabolism had a reduced VFD 2 years postoperatively. CONCLUSIONS: PDPP counting is useful for quantifying VFDs. Preoperative dysfunction indicated by preoperative FDG-PET in the posteromedial temporal and medial occipital cortex could enhance VFDs early after TLE surgery.
Asunto(s)
Epilepsia del Lóbulo Temporal , Fluorodesoxiglucosa F18 , Lóbulo Occipital , Tomografía de Emisión de Positrones , Complicaciones Posoperatorias , Lóbulo Temporal , Humanos , Epilepsia del Lóbulo Temporal/cirugía , Epilepsia del Lóbulo Temporal/diagnóstico por imagen , Epilepsia del Lóbulo Temporal/metabolismo , Femenino , Masculino , Adulto , Tomografía de Emisión de Positrones/métodos , Estudios Retrospectivos , Lóbulo Occipital/diagnóstico por imagen , Lóbulo Occipital/metabolismo , Lóbulo Occipital/cirugía , Lóbulo Temporal/metabolismo , Lóbulo Temporal/diagnóstico por imagen , Lóbulo Temporal/cirugía , Estudios de Seguimiento , Persona de Mediana Edad , Adulto Joven , Complicaciones Posoperatorias/metabolismo , Complicaciones Posoperatorias/diagnóstico por imagen , Campos Visuales/fisiología , Radiofármacos , Adolescente , Trastornos de la Visión/etiología , Trastornos de la Visión/diagnóstico por imagen , Trastornos de la Visión/metabolismo , Epilepsia Refractaria/cirugía , Epilepsia Refractaria/diagnóstico por imagen , Epilepsia Refractaria/metabolismoRESUMEN
Corneal alkali burn is one of the most devastating ophthalmic emergencies correlated with remarkable morbidity resulting in severe visual impairment. Appropriate intervention in the acute phase determines the eventual outcome for later corneal restoration treatment. Since the epithelium plays an essential role in inhibiting inflammation and promoting tissue repair, sustained anti-matrix metalloproteinases (MMPs) and pro-epithelialization are the prior remedies during the first week. In this study, a drug-loaded collagen membrane (Dox-HCM/Col) that could be sutured to overlay the burned cornea was developed to accelerate the early reconstruction. Doxycycline (Dox), a specific inhibitor of MMPs, was encapsulated in collagen membrane (Col) through hydroxypropyl chitosan microspheres (HCM) to develop Dox-HCM/Col, affording a preferable pro-epithelialization microenvironment and an in-situ controlled release. Results showed that loading HCM into Col prolonged the release time to 7 days, and Dox-HCM/Col could significantly suppress the expression of MMP-9 and -13 in vitro and in vivo. Furthermore, the membrane accelerated the corneal complete re-epithelialization and promoted early reconstruction within the first week. Overall, Dox-HCM/Col was a promising biomaterial membrane for treating alkali-burned cornea in the early stage, and our attempt may provide a clinically feasible method for the ocular surface reconstruction.
Asunto(s)
Quitosano , Lesiones de la Cornea , Quemaduras Oculares , Humanos , Doxiciclina/farmacología , Quitosano/metabolismo , Álcalis/metabolismo , Microesferas , Colágeno/metabolismo , Lesiones de la Cornea/tratamiento farmacológico , Lesiones de la Cornea/metabolismo , Córnea/metabolismo , Quemaduras Oculares/inducido químicamente , Quemaduras Oculares/tratamiento farmacológico , Quemaduras Oculares/metabolismo , Trastornos de la Visión/metabolismoRESUMEN
Inadequate wound healing of ocular surface injuries can lead to permanent visual impairment. The relaxin ligand-receptor system has been demonstrated to promote corneal wound healing through increased cell migration and modulation of extracellular matrix formation. Recently, C1q/tumor necrosis factor-related protein (CTRP) 8 was identified as a novel interaction partner of relaxin receptor RXFP1. Additional data also suggest a role for CTRP1 and CTRP6 in RXFP1-mediated cAMP signaling. However, the role of CTRP1, CTRP6 and CTRP8 at the ocular surface remains unclear. In this study, we investigated the effects of CTRP1, CTRP6, and CTRP8 on epithelial ocular surface wound closure and their dependence on the RXFP1 receptor pathway. CTRP1, CTRP6, and CTRP8 expression was analyzed by RT-PCR and immunohistochemistry in human tissues and cell lines derived from the ocular surface and lacrimal apparatus. In vitro ocular surface wound modeling was performed using scratch assays. We analyzed the effects of recombinant CTRP1, CTRP6, and CTRP8 on cell proliferation and migration in human corneal and conjunctival epithelial cell lines. Dependence on RXFP1 signaling was established by inhibiting ligand binding to RXFP1 using a specific anti-RXFP1 antibody. We detected the expression of CTRP1, CTRP6, and CTRP8 in human tissue samples of the cornea, conjunctiva, meibomian gland, efferent tear ducts, and lacrimal gland, as well as in human corneal, conjunctival, and meibomian gland epithelial cell lines. Scratch assays revealed a dose-dependent increase in the closure rate of surface defects in human corneal epithelial cells after treatment with CTRP1, CTRP6, and CTRP8, but not in conjunctival epithelial cells. Inhibition of RXFP1 fully attenuated the effect of CTRP8 on the closure rate of surface defects in human corneal epithelial cells, whereas the CTRP1 and CTRP6 effects were not completely suppressed. Conclusions: Our findings demonstrate a novel role for CTRP1, CTRP6, and CTRP8 in corneal epithelial wound closure and suggest an involvement of the relaxin receptor RXFP1 signaling pathway. This could be a first step toward new approaches for pharmacological and therapeutic intervention.
Asunto(s)
Lesiones de la Cornea , Aparato Lagrimal , Relaxina , Humanos , Complemento C1q/metabolismo , Ligandos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Aparato Lagrimal/metabolismo , Lesiones de la Cornea/metabolismo , Trastornos de la Visión/metabolismo , Relaxina/metabolismo , Receptores de Péptidos/genética , Receptores de Péptidos/metabolismoRESUMEN
Mutations in the PRKN gene are the major cause of autosomal recessive Parkinson's disease (PD). However, studies of parkin-/- mice did not show the loss of dopaminergic neurons and motor phenotypes at a young age. Whether pathological changes are associated with nonmotor symptoms of PD remains unclear. Visual impairment is one common nonmotor symptom in patients with PD. This study aimed to examine the effects of parkin-/- on mitochondria and synaptic structures in the retina of 6-month-old mice. Compared with wild-type mice, parkin-/- mice exhibited a slightly thickened retina. Also, the number of normal mitochondria (mito-5 grade) in rod spherules (RSs) significantly decreased (p < 0.01), the average area of mitochondria was significantly larger (p < 0.001), and the number of ribbons in RSs significantly decreased (p = 0.02). The RSs of parkin-/- mice showed severe swelling after flicker stimulation. Our study implicated that parkin-/- led to the impairment of mitochondria and abnormality of the synaptic structure in mouse retina at a young age, which damaged the synaptic transmission between photoreceptors and second-order retinal neurons and resulted in visual impairment.
Asunto(s)
Enfermedad de Parkinson , Ubiquitina-Proteína Ligasas , Ratones , Animales , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Mitocondrias/patología , Neuronas Dopaminérgicas/metabolismo , Enfermedad de Parkinson/genética , Retina/patología , Trastornos de la Visión/metabolismoRESUMEN
Despite decades of research, knowledge about the genes that are important for development and function of the mammalian eye and are involved in human eye disorders remains incomplete. During mammalian evolution, mammals that naturally exhibit poor vision or regressive eye phenotypes have independently lost many eye-related genes. This provides an opportunity to predict novel eye-related genes based on specific evolutionary gene loss signatures. Building on these observations, we performed a genome-wide screen across 49 mammals for functionally uncharacterized genes that are preferentially lost in species exhibiting lower visual acuity values. The screen uncovered several genes, including SERPINE3, a putative serine proteinase inhibitor. A detailed investigation of 381 additional mammals revealed that SERPINE3 is independently lost in 18 lineages that typically do not primarily rely on vision, predicting a vision-related function for this gene. To test this, we show that SERPINE3 has the highest expression in eyes of zebrafish and mouse. In the zebrafish retina, serpine3 is expressed in Müller glia cells, a cell type essential for survival and maintenance of the retina. A CRISPR-mediated knockout of serpine3 in zebrafish resulted in alterations in eye shape and defects in retinal layering. Furthermore, two human polymorphisms that are in linkage with SERPINE3 are associated with eye-related traits. Together, these results suggest that SERPINE3 has a role in vertebrate eyes. More generally, by integrating comparative genomics with experiments in model organisms, we show that screens for specific phenotype-associated gene signatures can predict functions of uncharacterized genes.
Asunto(s)
Proteínas del Ojo , Visión Ocular , Animales , Ceguera/genética , Ceguera/metabolismo , Proteínas del Ojo/genética , Proteínas del Ojo/metabolismo , Genoma , Humanos , Mamíferos/genética , Mamíferos/metabolismo , Ratones/genética , Ratones/metabolismo , Retina/metabolismo , Trastornos de la Visión/genética , Trastornos de la Visión/metabolismo , Visión Ocular/genética , Visión Ocular/fisiología , Pez Cebra/genética , Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
Bright light exposure in animals results in the selective degeneration of the outer retina, known as "retinal photic injury" (RPI). The susceptibility to RPI differs among rat strains. WKY rats display susceptibility to RPI with extensive retinal degeneration observed in the sagittal eye specimen, whereas LEW strain rats are resistant to it, showing only slight or no degeneration. In the present study, we first established an ethological screening method using the Morris water maze to discern differential susceptibility among the living rats. WKY and LEW were crossed to produce the first filial generation (F1) offspring. Maze-trained individuals were exposed to bright, white light. The screening test results demonstrated that the susceptibility to light-induced visual impairment in rats is a dominant Mendelian susceptibility trait, as F1 rats were susceptible to visual impairment like WKY rats. Therefore, F1 rats were backcrossed with recessive LEW to produce the first backcross offspring (BC1). Subsequent recurrent backcrossing while selecting for the susceptibility, indicated a segregation ratio of ca. 24% in BC1 and BC2 generations, indicating the involvement of two or more genes in the susceptibility. Further, microsatellite analysis of BC1-to-BC4 individuals using microsatellite markers mapped two susceptibility loci on chromosome segments 5q36 and 19q11-q12, named RPI susceptibility (Rpi)1 and Rpi2, respectively. This study provides an insight into mechanisms underlying differential susceptibility, which could help decipher the mechanism underlying the onset/progression of human age-related macular degeneration.
Asunto(s)
Luz/efectos adversos , Traumatismos Experimentales por Radiación/genética , Retina/efectos de la radiación , Degeneración Retiniana/genética , Trastornos de la Visión/genética , Animales , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Femenino , Masculino , Repeticiones de Microsatélite , Prueba del Laberinto Acuático de Morris , Sitios de Carácter Cuantitativo , Traumatismos Experimentales por Radiación/metabolismo , Traumatismos Experimentales por Radiación/fisiopatología , Ratas , Ratas Endogámicas Lew , Ratas Endogámicas WKY , Degeneración Retiniana/metabolismo , Degeneración Retiniana/fisiopatología , Trastornos de la Visión/metabolismo , Trastornos de la Visión/fisiopatologíaRESUMEN
One of the causes of nervous system degeneration is an excess of glutamate released upon several diseases. Glutamate analogs, like N-methyl-DL-aspartate (NMDA) and kainic acid (KA), have been shown to induce experimental retinal neurotoxicity. Previous results have shown that NMDA/KA neurotoxicity induces significant changes in the full field electroretinogram response, a thinning on the inner retinal layers, and retinal ganglion cell death. However, not all types of retinal neurons experience the same degree of injury in response to the excitotoxic stimulus. The goal of the present work is to address the effect of intraocular injection of different doses of NMDA/KA on the structure and function of several types of retinal cells and their functionality. To globally analyze the effect of glutamate receptor activation in the retina after the intraocular injection of excitotoxic agents, a combination of histological, electrophysiological, and functional tools has been employed to assess the changes in the retinal structure and function. Retinal excitotoxicity caused by the intraocular injection of a mixture of NMDA/KA causes a harmful effect characterized by a great loss of bipolar, amacrine, and retinal ganglion cells, as well as the degeneration of the inner retina. This process leads to a loss of retinal cell functionality characterized by an impairment of light sensitivity and visual acuity, with a strong effect on the retinal OFF pathway. The structural and functional injury suffered by the retina suggests the importance of the glutamate receptors expressed by different types of retinal cells. The effect of glutamate agonists on the OFF pathway represents one of the main findings of the study, as the evaluation of the retinal lesions caused by excitotoxicity could be specifically explored using tests that evaluate the OFF pathway.
Asunto(s)
Células Amacrinas/patología , Agonistas de Aminoácidos Excitadores/toxicidad , Ácido Glutámico/metabolismo , N-Metilaspartato/análogos & derivados , Células Ganglionares de la Retina/patología , Trastornos de la Visión/patología , Células Amacrinas/efectos de los fármacos , Células Amacrinas/metabolismo , Animales , Apoptosis , Ratones , Ratones Endogámicos C57BL , N-Metilaspartato/metabolismo , Receptores de Glutamato/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/metabolismo , Trastornos de la Visión/inducido químicamente , Trastornos de la Visión/metabolismoRESUMEN
To characterize the mechanisms by which the highly conserved exocyst trafficking complex regulates eye physiology in zebrafish and mice, we focused on Exoc5 (also known as sec10), a central exocyst component. We analyzed both exoc5 zebrafish mutants and retinal pigmented epithelium (RPE)-specific Exoc5 knockout mice. Exoc5 is present in both the non-pigmented epithelium of the ciliary body and in the RPE. In this study, we set out to establish an animal model to study the mechanisms underlying the ocular phenotype and to establish if loss of visual function is induced by postnatal RPE Exoc5-deficiency. Exoc5-/- zebrafish had smaller eyes, with decreased number of melanocytes in the RPE and shorter photoreceptor outer segments. At 3.5 days post-fertilization, loss of rod and cone opsins were observed in zebrafish exoc5 mutants. Mice with postnatal RPE-specific loss of Exoc5 showed retinal thinning associated with compromised visual function and loss of visual photoreceptor pigments. Abnormal levels of RPE65 together with a reduced c-wave amplitude indicate a dysfunctional RPE. The retinal phenotype in Exoc5-/- mice was present at 20 weeks, but was more pronounced at 27 weeks, indicating progressive disease phenotype. We previously showed that the exocyst is necessary for photoreceptor ciliogenesis and retinal development. Here, we report that exoc5 mutant zebrafish and mice with RPE-specific genetic ablation of Exoc5 develop abnormal RPE pigmentation, resulting in retinal cell dystrophy and loss of visual pigments associated with compromised vision. Together, these data suggest that exocyst-mediated signaling in the RPE is required for RPE structure and function, indirectly leading to photoreceptor degeneration.
Asunto(s)
Células Fotorreceptoras/patología , Degeneración Retiniana , Epitelio Pigmentado de la Retina/patología , Proteínas de Transporte Vesicular/fisiología , Trastornos de la Visión/patología , Animales , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Fotorreceptoras/metabolismo , Epitelio Pigmentado de la Retina/metabolismo , Trastornos de la Visión/metabolismo , Pez CebraRESUMEN
Traumatic brain injuries (TBI) of varied types are common across all populations and can cause visual problems. For military personnel in combat settings, injuries from blast exposures (bTBI) are prevalent and arise from a myriad of different situations. To model these diverse conditions, we are one of several groups modeling bTBI using mice in varying ways. Here, we report a refined analysis of retinal ganglion cell (RGC) damage in male C57BL/6J mice exposed to a blast-wave in an enclosed chamber. Ganglion cell layer thickness, RGC density (BRN3A and RBPMS immunoreactivity), cellular density of ganglion cell layer (hematoxylin and eosin staining), and axon numbers (paraphenylenediamine staining) were quantified at timepoints ranging from 1 to 17-weeks. RNA sequencing was performed at 1-week and 5-weeks post-injury. Earliest indices of damage, evident by 1-week post-injury, are a loss of RGC marker expression, damage to RGC axons, and increase in glial markers expression. Blast exposure caused a loss of RGC somas and axons-with greatest loss occurring by 5-weeks post-injury. While indices of glial involvement are prominent early, they quickly subside as RGCs are lost. The finding that axonopathy precedes soma loss resembles pathology observed in mouse models of glaucoma, suggesting similar mechanisms.
Asunto(s)
Traumatismos por Explosión/complicaciones , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/etiología , Trastornos de la Visión/etiología , Animales , Axones/metabolismo , Biomarcadores , Muerte Celular , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Ratones , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Factores de Tiempo , Tomografía de Coherencia Óptica , Trastornos de la Visión/diagnóstico , Trastornos de la Visión/metabolismoRESUMEN
Lipid metabolism-related gene mutations can cause retinitis pigmentosa, a currently untreatable blinding disease resulting from progressive neurodegeneration of the retina. Here, we demonstrated the influence of adiponectin receptor 1 (ADIPOR1) deficiency in retinal neurodegeneration using Adipor1 knockout (KO) mice. Adipor1 mRNA was observed to be expressed in photoreceptors, predominately within the photoreceptor inner segment (PIS), and increased after birth during the development of the photoreceptor outer segments (POSs) where photons are received by the visual pigment, rhodopsin. At 3 weeks of age, visual function impairment, specifically photoreceptor dysfunction, as recorded by electroretinography (ERG), was evident in homozygous, but not heterozygous, Adipor1 KO mice. However, although photoreceptor loss was evident at 3 weeks of age and progressed until 10 weeks, the level of visual dysfunction was already substantial by 3 weeks, after which it was retained until 10 weeks of age. The rhodopsin mRNA levels had already decreased at 3 weeks, suggesting that reduced rhodopsin may have contributed to early visual loss. Moreover, inflammation and oxidative stress were induced in homozygous KO retinas. Prior to observation of photoreceptor loss via optical microscopy, electron microscopy revealed that POSs were present; however, they were misaligned and their lipid composition, including docosahexaenoic acid (DHA), which is critical in forming POSs, was impaired in the retina. Importantly, the expression of Elovl2, an elongase of very long chain fatty acids expressed in the PIS, was significantly reduced, and lipogenic genes, which are induced under conditions of reduced endogenous DHA synthesis, were increased in homozygous KO mice. The causal relationship between ADIPOR1 deficiency and Elovl2 repression, together with upregulation of lipogenic genes, was confirmed in vitro. Therefore, ADIPOR1 in the retina appears to be indispensable for ELOVL2 induction, which is likely required to supply sufficient DHA for appropriate photoreceptor function and survival.
Asunto(s)
Elongasas de Ácidos Grasos/metabolismo , Metabolismo de los Lípidos/genética , Células Fotorreceptoras de Vertebrados/metabolismo , Receptores de Adiponectina/deficiencia , Trastornos de la Visión/metabolismo , Animales , Ácidos Docosahexaenoicos/metabolismo , Ratones , Ratones Noqueados , TransfecciónRESUMEN
Purpose: To test the hypothesis that acutely correcting a sustained presence of outer retina free radicals measured in vivo in 24-month-old mice corrects their reduced visual performance. Methods: Male C57BL/6J mice two and 24 months old were noninvasively evaluated for unremitted production of paramagnetic free radicals based on whether 1/T1 in retinal laminae are reduced after acute antioxidant administration (QUEnch-assiSTed [QUEST] magnetic resonance imaging [MRI]). Superoxide production was measured in freshly excised retina (lucigenin assay). Combining acute antioxidant administration with optical coherence tomography (i.e., QUEST OCT) tested for excessive free radical-induced shrinkage of the subretinal space volume. Combining antioxidant administration with optokinetic tracking tested for a contribution of uncontrolled free radical production to cone-based visual performance declines. Results: At two months, antioxidants had no effect on 1/T1 in vivo in any retinal layer. At 24 months, antioxidants reduced 1/T1 only in superior outer retina. No age-related change in retinal superoxide production was measured ex vivo, suggesting that free radical species other than superoxide contributed to the positive QUEST MRI signal at 24 months. Also, subretinal space volume did not show evidence for age-related shrinkage and was unresponsive to antioxidants. Finally, visual performance declined with age and was not restored by antioxidants that were effective per QUEST MRI. Conclusions: An ongoing uncontrolled production of outer retina free radicals as measured in vivo in 24 mo C57BL/6J mice appears to be insufficient to explain reductions in visual performance.
Asunto(s)
Antioxidantes/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Radicales Libres/metabolismo , Azul de Metileno/uso terapéutico , Ácido Tióctico/uso terapéutico , Trastornos de la Visión/tratamiento farmacológico , Acridinas/metabolismo , Factores de Edad , Animales , Inyecciones Intraperitoneales , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Nistagmo Optoquinético/fisiología , Retina/diagnóstico por imagen , Retina/enzimología , Superóxidos/metabolismo , Tomografía de Coherencia Óptica , Trastornos de la Visión/diagnóstico por imagen , Trastornos de la Visión/metabolismo , Trastornos de la Visión/fisiopatologíaRESUMEN
Purpose: The human PDZK1 gene is located in a genomic susceptibility region for neurodevelopmental disorders. A genome-wide association study identified links between PDZK1 polymorphisms and altered visual contrast sensitivity, an endophenotype for schizophrenia and autism spectrum disorder. The PDZK1 protein is implicated in neurological functioning, interacting with synaptic molecules including postsynaptic density 95 (PSD-95), N-methyl-d-aspartate receptors (NMDARs), corticotropin-releasing factor receptor 1 (CRFR1), and serotonin 2A receptors. The purpose of the present study was to elucidate the role of PDZK1. Methods: We generated pdzk1-knockout (pdzk1-KO) zebrafish using CRISPR/Cas-9 genome editing. Visual function of 7-day-old fish was assessed at behavioral and functional levels using the optomotor response and scotopic electroretinogram (ERG). We also quantified retinal morphology and densities of PSD-95, NMDAR1, CRFR1, and serotonin in the synaptic inner plexiform layer at 7 days, 4 weeks, and 8 weeks of age. Standard RT-PCR and nonsense-mediated decay interference treatment were also performed to assess genetic compensation in mutants. Results: Relative to wild-type, pdzk1-KO larvae showed spatial frequency tuning functions with increased amplitude (likely due to abnormal gain control) and reduced ERG b-waves (suggestive of inner retinal dysfunction). No synaptic phenotypes, but possible morphological retinal phenotypes, were identified. We confirmed that the absence of major histological phenotypes was not attributable to genetic compensatory mechanisms. Conclusions: Our findings point to a role for pdzk1 in zebrafish visual function, and our model system provides a platform for investigating other genes associated with abnormal visual behavior.
Asunto(s)
Técnicas de Inactivación de Genes , Dominios PDZ/genética , Desempeño Psicomotor/fisiología , Retina/fisiopatología , Trastornos de la Visión/genética , Proteínas de Pez Cebra/genética , Animales , Proteína 9 Asociada a CRISPR , Sensibilidad de Contraste/fisiología , Electrorretinografía , Técnicas de Genotipaje , Larva , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Retina/metabolismo , Serotonina/metabolismo , Trastornos de la Visión/metabolismo , Trastornos de la Visión/fisiopatología , Pez CebraRESUMEN
Acquired and inherited retinal disorders are responsible for vision loss in an increasing proportion of individuals worldwide. Photoreceptor (PR) death is central to the vision loss individuals experience in these various retinal diseases. Unfortunately, there is a lack of treatment options to prevent PR loss, so an urgent unmet need exists for therapies that improve PR survival and ultimately, vision. The retina is one of the most energy demanding tissues in the body, and this is driven in large part by the metabolic needs of PRs. Recent studies suggest that disruption of nutrient availability and regulation of cell metabolism may be a unifying mechanism in PR death. Understanding retinal cell metabolism and how it is altered in disease has been identified as a priority area of research. The focus of this review is on the recent advances in the understanding of PR metabolism and how it is critical to reduction-oxidation (redox) balance, the outer retinal metabolic ecosystem, and retinal disease. The importance of these metabolic processes is just beginning to be realized and unraveling the metabolic and redox pathways integral to PR health may identify novel targets for neuroprotective strategies that prevent blindness in the heterogenous group of retinal disorders.
Asunto(s)
Reprogramación Celular , Metabolismo Energético , Células Fotorreceptoras/metabolismo , Enfermedades de la Retina/metabolismo , Trastornos de la Visión/metabolismo , Visión Ocular , Animales , Muerte Celular , Humanos , Metaboloma , Metabolómica , Células Fotorreceptoras/patología , Enfermedades de la Retina/patología , Enfermedades de la Retina/fisiopatología , Enfermedades de la Retina/terapia , Trastornos de la Visión/patología , Trastornos de la Visión/fisiopatología , Trastornos de la Visión/terapiaRESUMEN
Ionising radiation interacts with lenses and retinae differently. In human lenses, posterior subcapsular cataracts are the predominant observation, whereas retinae of adults are comparably resistant to even relatively high doses. In this study, we demonstrate the effects of 2 Gy of low linear energy transfer ionising radiation on eyes of B6C3F1 mice aged postnatal day 2. Optical coherence tomography and Scheimpflug imaging were utilised for the first time to monitor murine lenses and retinae in vivo. The visual acuity of the mice was determined and histological analysis was conducted. Our results demonstrated that visual acuity was reduced by as much as 50 % approximately 9 months after irradiation in irradiated mice. Vision impairment was caused by retinal atrophy and inner cortical cataracts. These results help to further our understanding of the risk of ionising radiation for human foeti (â¼ 8 mo), which follow the same eye development stages as neonatal mice.
Asunto(s)
Catarata/etiología , Cristalino/efectos de la radiación , Traumatismos Experimentales por Radiación/etiología , Radiación Ionizante , Retina/efectos de la radiación , Enfermedades de la Retina/etiología , Trastornos de la Visión/etiología , Animales , Animales Recién Nacidos , Calbindina 2/metabolismo , Catarata/diagnóstico por imagen , Catarata/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Proteína Quinasa C-alfa/metabolismo , Dosis de Radiación , Traumatismos Experimentales por Radiación/diagnóstico por imagen , Traumatismos Experimentales por Radiación/metabolismo , Enfermedades de la Retina/diagnóstico por imagen , Enfermedades de la Retina/metabolismo , Rodopsina/metabolismo , Tomografía de Coherencia Óptica , Trastornos de la Visión/diagnóstico por imagen , Trastornos de la Visión/metabolismo , Agudeza Visual/fisiologíaRESUMEN
Multiple neuro-ophthalmological manifestations have been described in association with COVID-19. These symptoms and signs may be the result of a range of pathophysiological mechanisms throughout the course from acute illness to recovery phase. Optic nerve dysfunction, eye movement abnormalities and visual field defects have been described.
Asunto(s)
COVID-19/complicaciones , Síndrome de Liberación de Citoquinas/etiología , Enfermedades del Sistema Nervioso/etiología , Trastornos de la Visión/etiología , COVID-19/diagnóstico , COVID-19/metabolismo , Síndrome de Liberación de Citoquinas/diagnóstico , Síndrome de Liberación de Citoquinas/metabolismo , Humanos , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/metabolismo , Trastornos de la Visión/diagnóstico , Trastornos de la Visión/metabolismoRESUMEN
Mutations in NR2E3 cause retinitis pigmentosa (RP) and enhanced S-cone syndrome (ESCS) in humans. This gene produces a large isoform encoded in 8 exons and a previously unreported shorter isoform of 7 exons, whose function is unknown. We generated two mouse models by targeting exon 8 of Nr2e3 using CRISPR/Cas9-D10A nickase. Allele Δ27 is an in-frame deletion of 27â¯bp that ablates the dimerization domain H10, whereas allele ΔE8 (full deletion of exon 8) produces only the short isoform, which lacks the C-terminal part of the ligand binding domain (LBD) that encodes both H10 and the AF2 domain involved in the Nr2e3 repressor activity. The Δ27 mutant shows developmental alterations and a non-progressive electrophysiological dysfunction that resembles the ESCS phenotype. The ΔE8 mutant exhibits progressive retinal degeneration, as occurs in human RP patients. Our mutants suggest a role for Nr2e3 as a cone-patterning regulator and provide valuable models for studying mechanisms of NR2E3-associated retinal dystrophies and evaluating potential therapies.
Asunto(s)
Enfermedades Hereditarias del Ojo/genética , Mutación/genética , Receptores Nucleares Huérfanos/metabolismo , Degeneración Retiniana/genética , Retinitis Pigmentosa/metabolismo , Trastornos de la Visión/genética , Exones/genética , Enfermedades Hereditarias del Ojo/metabolismo , Humanos , Fenotipo , Isoformas de Proteínas/genética , Retina/metabolismo , Degeneración Retiniana/metabolismo , Retinitis Pigmentosa/genética , Trastornos de la Visión/metabolismoAsunto(s)
Fóvea Central/diagnóstico por imagen , Imagen Óptica , Enfermedades de la Retina/diagnóstico , Tomografía de Coherencia Óptica , Trastornos de la Visión/diagnóstico , Niño , Color , Consanguinidad , Fóvea Central/metabolismo , Fóvea Central/patología , Humanos , Masculino , Trastornos de la Pigmentación/diagnóstico , Trastornos de la Pigmentación/metabolismo , Trastornos de la Pigmentación/patología , Enfermedades de la Retina/metabolismo , Enfermedades de la Retina/patología , Túnez , Trastornos de la Visión/metabolismo , Trastornos de la Visión/patologíaRESUMEN
Human organoid models of the central nervous system, including the neural retina, are providing unprecedented opportunities to explore human neurodevelopment and neurodegeneration in controlled culture environments. In this Perspective, we discuss how the single-cell multi-omic toolkit has been used to identify features and limitations of brain and retina organoids and how these tools can be deployed to study congenital brain malformations and vision disorders in organoids. We also address how to improve brain and retina organoid protocols to revolutionize in vitro disease modeling.
Asunto(s)
Genómica/métodos , Trastornos del Neurodesarrollo/metabolismo , Organoides/metabolismo , Cultivo Primario de Células/métodos , Análisis de la Célula Individual/métodos , Trastornos de la Visión/metabolismo , Humanos , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Organoides/crecimiento & desarrollo , Organoides/patología , Trastornos de la Visión/genética , Trastornos de la Visión/patologíaRESUMEN
Background/Purpose: A prolactinoma is the most common pituitary adenoma, but it is relatively rare in childhood and adolescence. There is only limited research about the clinical spectrum, treatment, and outcomes of prolactinomas in childhood and adolescence. In this single-center cohort study, we assessed the clinical, hormonal, and neuroradiological characteristics and therapeutic outcomes of children and adolescents with prolactinomas. Methods: This retrospective cohort study included 25 patients with prolactinomas diagnosed before 19 years of age, who presented at Samsung Medical Center during a 15-year period (March 2005 to August 2019). Results: The median age at diagnosis was 16.9 (range 10.1-18.5) years, and 80% of the patients were female. The common clinical manifestations at diagnosis were galactorrhea (10/20, 50%) and amenorrhea (9/20, 45%) among females and visual field defects (3/5, 60%) and headaches (2/5, 40%) among males. In our cohort, macroadenomas accounted for 56% of cases, and the rate of overall responsiveness to dopamine agonists (DAs) was 56% (10/18). Male gender, the prolactin (PRL) level at diagnosis, and the presence of panhypopituitarism were positively correlated with maximum tumor diameter (r = 0.443, P = 0.026; r = 0.710, P < 0.001; and r = 0.623, P = 0.001, respectively). After the trans-sphenoidal approach (TSA), 53% (8/15) of patients showed normalization of the PRL level. Three patients, who underwent gamma knife surgery (GKS) owing to either resistance or intolerance to DAs or recurrence after the TSA, achieved a normal PRL level accompanied with marked tumor reduction and symptom remission. Conclusions: A macroprolactinoma is more prevalent than a microprolactinoma in children and adolescents than in adults. Male gender, increased PRL levels, and the presence of panhypopituitarism at diagnosis are closely related to macroprolactinomas in children and adolescents.