Optic nerve head component responses of the multifocal electroretinogram in MS.
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ABSTRACT: Objective
To employ a novel stimulation paradigm in order to elicit multifocal electroretinography (mfERG)-induced optic nerve head component (ONHC) responses, believed to be contingent upon the transformation in electrical transmission properties of retinal ganglion cell axons from membrane to saltatory conduction mechanisms, as they traverse the lamina cribrosa and obtain oligodendrocyte myelin. We further sought to characterize abnormalities in ONHC responses in eyes from patients with multiple sclerosis (MS).Methods
In 10 normal subjects and 7 patients with MS (including eyes with and without a history of acute optic neuritis), we utilized a novel mfERG stimulation paradigm that included interleaved global flashes in order to elicit the ONHC responses from 103 retinal patches of pattern-reversal stimulation.Results
The number of abnormal or absent ONHC responses was significantly increased in MS patient eyes compared to normal subject eyes (p < 0.001, by general estimating equation modeling, and accounting for age and within-subject, intereye correlations).Conclusion
Studying the relationship between ONHC abnormalities and alterations in validated structural and functional measures of the visual system may facilitate the ability to dissect and characterize the pathobiological mechanisms that contribute to tissue damage in MS, and may have utility to detect and monitor neuroprotective or restorative effects of novel therapies.
SUBMITTER: Frohman TC
PROVIDER: S-EPMC3775685 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To describe a novel neurophysiologic signature of the retinal ganglion cell and to elucidate its relationship to abnormalities in validated structural and functional measures of the visual system.We used multifocal electroretinogram-generated optic nerve head component (ONHC) responses from normal subjects (n = 18), patients with multiple sclerosis (MS) (n = 18), and those with glaucoma (n = 3). We then characterized the relationship between ONHC response abnormalities and performance on low-contrast visual acuity, multifocal visual-evoked potential-induced cortical responses, and average and quadrant retinal nerve fiber layer (RNFL) thicknesses, as measured by spectral-domain optical coherence tomography.Compared with the eyes of normal subjects, the eyes of patients with MS exhibited an increased number of abnormal or absent ONHC responses (p < 0.0001). For every 7-letter reduction in low-contrast letter acuity, there were corresponding 4.6 abnormal ONHC responses at 2.5% contrast (p < 0.0001) and 6.6 abnormalities at the 1.25% contrast level (p < 0.0001). Regarding average RNFL thickness, for each 10-?m thickness reduction, we correspondingly observed 6.8 abnormal ONHC responses (p = 0.0002). The most robust association was between RNFL thinning in the temporal quadrant and ONHC response abnormalities (p < 0.0001).Further characterization of ONHC abnormalities (those that are reversible and irreversible) may contribute to the development of novel neurotherapeutic strategies aimed at achieving neuroprotective, and perhaps even neurorestorative, effects in disorders that target the CNS in general, and MS in particular.
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Project description:PurposeTo delineate responses of optic nerve head astrocytes to sustained intraocular pressure (IOP) elevation in mice.MethodsWe elevated IOP for 1 day to 6 weeks by intracameral microbead injection in 4 strains of mice. Astrocyte alterations were studied by transmission electron microscopy (TEM) including immunogold molecular localization, and by laser scanning microscopy (LSM) with immunofluorescence for integrin β1, α-dystroglycan, and glial fibrillary acidic protein (GFAP). Astrocyte proliferation and apoptosis were quantified by Ki67 and TUNEL labeling, respectively.ResultsAstrocytes in normal optic nerve head expressed integrin β1 and α-dystroglycan by LSM and TEM immunogold labeling at electron dense junctional complexes that were found only on cell membrane zones bordering their basement membranes (BM) at the peripapillary sclera (PPS) and optic nerve head capillaries. At 1-3 days after IOP elevation, abnormal extracellular spaces appeared between astrocytes near PPS, and axonal vesical and mitochondrial accumulation indicated axonal transport blockade. By 1 week, abnormal spaces increased, new collagen formation occurred, and astrocytes separated from their BM, leaving cell membrane fragments. Electron dense junctional complexes separated or were absent at the BM. Astrocyte proliferation was modest during the first week, while only occasional apoptotic astrocytes were observed by TEM and TUNEL.ConclusionsAstrocytes normally exhibit junctions with their BM which are disrupted by extended IOP elevation. Responses include reorientation of cell processes, new collagen formation, and cell proliferation.
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Project description:Reactive gliosis is a complex process that involves profound changes in gene expression. We used microarray to indentify differentially expressed genes and to investigate the molecular mechanisms of reactive gliosis in optic nerve head in response to optic nerve crush injury. C57Bl/6 female mice were 6-8 weeks old at the time of optic nerve crush surgery. The optic nerve in the left eye was crush 1 mm behind the globe for 10 seconds and the right eye served as contralateral control. The animals were allowed to recover for 1 day, 3 day, 1 week, 3 weeks and 3 months before the optic nerve heads were collected. The naive control mice did not receive any surgery in either eye. Due to the small tissue size of the mouse optic nerve head, two optic nerve heads were pooled together for each microarray chip. The left eyes and the right eyes of two mice were combined respectively to form one pair of experiment and control samples. There were five biological replicates (10 mice) for each condition.
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Project description:Reactive gliosis is a complex process that involves profound changes in gene expression. We used microarray to indentify differentially expressed genes and to investigate the molecular mechanisms of reactive gliosis in optic nerve head in response to optic nerve crush injury.
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Project description:The electrical response of the retina was examined as a function of retinal region, using stimuli of various spatial frequencies in the first experiment. In the second experiment, the regional response of the retina to defocus at high and low spatial frequencies was investigated. Twenty three subjects were recruited for global flash multifocal electroretinogram (mfERG) in experiment 1. Black and white gratings (printed on plastic transparent sheets) of four spatial frequencies (SF), 0.24, 1.2, 2.4 and 4.8 cycle per degree were presented in front of the mfERG stimulation. The amplitudes and implicit times of the direct (DC) and induced (IC) components of mfERG responses were pooled into six concentric rings for analysis. There was low amplitude DC at low SF, which increased with increasing SF, and which decreased with increasing eccentricity. The IC was high in amplitude at all SF and reduced in amplitude with increasing eccentricity. Our findings suggested that outer and inner retina had different characteristics in processing spatial details. In experiment 2, Twenty-three young adults were recruited for mfERG measurement. The retinal electrical responses for low (0.24cpd) and high (4.8cpd) SF under fully corrected conditions of short-term negative defocus (-2D) and short term positive defocus (+2D) conditions were measured. There was a sign-dependent response to defocus in the DC response, mainly in peripheral regions. The sign dependent response at low SF was more obvious than that at high SF, and was located more peripherally. The IC response showed no clear trends for either defocus condition. The human retina seems to have a decoding system for optical defocus, which was tuned for low spatial frequency, and was located in the retinal near periphery.
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Project description:Injury to retinal ganglion cell (RGC) axons leads to selective loss of RGCs and vision. Previous studies have shown that exogenous neurotrophic factors promote RGC survival. We investigated the neuroprotective effects of oncostatin M (OSM), a member of the IL-6 family of cytokines, on pattern electroretinogram (PERG) and RGC survival after optic nerve crush (ON-crush) in the mouse. BALB/C mice received ON-crush in the left eyes for either 4-second or 1-second duration (4-s or 1-s). Fluoro-gold retrograde labeling was used to identify RGCs. RGC function was assessed by PERG measurement. OSM or CNTF protein was injected intravitreally immediately after ON-crush. OSM responsive cells were identified by localization of increased STAT3 phosphorylation. Significant higher RGC survival (46% of untreated control) was seen in OSM-treated eyes when assessed 2 weeks after 4-s ON-crush as compared to that (14% of untreated control) of the PBS-treated eyes (P<0.001). In addition, PERG amplitude was significantly higher in eyes treated with OSM or CNTF 1 week after 1-s ON-crush (36% of baseline) as compared with the amplitude of PBS-treated eyes (19% of the baseline, P = 0.003). An increase in STAT3 phosphorylation was localized in Müller layer after OSM treatment, suggesting that Müller cells mediate the effect of OSM. Our results demonstrate that one single injection of either OSM or CNTF after ON-crush improves RGC survival together with their electrophysiological activity. These data provide proof-of-concept for using neurotrophic factors OSM and CNTF for RGC degenerative diseases, including glaucoma and acute optic nerve trauma.
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Project description:A major risk factor for glaucomatous optic neuropathy is the level of intraocular pressure (IOP), which can lead to retinal ganglion cell axon injury and cell death. The optic nerve has a rostral unmyelinated portion at the optic nerve head followed by a caudal myelinated region. The unmyelinated region is differentially susceptible to IOP-induced damage in rodent models and in human glaucoma. While several studies have analyzed gene expression changes in the mouse optic nerve following optic nerve injury, few were designed to consider the regional gene expression differences that exist between these distinct areas. We performed bulk RNA-sequencing on the retina and on separately micro-dissected unmyelinated and myelinated optic nerve regions from naïve C57BL/6 mice, mice after optic nerve crush, and mice with microbead-induced experimental glaucoma (total = 36). Gene expression patterns in the naïve unmyelinated optic nerve showed significant enrichment of the Wnt, Hippo, PI3K-Akt, and transforming growth factor β pathways, as well as extracellular matrix–receptor and cell membrane signaling pathways, compared to the myelinated optic nerve and retina. Gene expression changes induced by both injuries were more extensive in the myelinated optic nerve than the unmyelinated region, and greater after nerve crush than glaucoma. Changes present three and fourteen days after injury largely subsided by six weeks. Gene markers of reactive astrocytes did not consistently differ between injury states. Overall, the transcriptomic phenotype of the mouse unmyelinated optic nerve was significantly different from immediately adjacent tissues, likely dominated by expression in astrocytes, whose junctional complexes are inherently important in responding to IOP elevation.
2023-09-06 | GSE241782 | GEO
Project description:The authors investigated the role of myosin light chain kinase (MYLK) and transforming growth factor beta (TGFbeta) receptor pathways in optic nerve head (ONH) astrocyte migration. They further investigated how the expression of these genes is altered by elevated hydrostatic pressure (HP).PCR was used to determine the isoforms of MYLK expressed in ONH astrocytes. siRNAs against MYLK (all isoforms) and TGFbeta receptor 2 (TGFBR2) were prepared and tested for effects on the migration of cultured ONH astrocytes. Finally, the effects of elevated HP (24-96 hours) on the expression of MYLK isoforms and selected TGFbeta pathway components were measured.Multiple isoforms of MYLK are present in ONH astrocytes from Caucasian (CA) and African American (AA) donors. Both populations express the short form (MYLK-130) and the long form (MYLK-210) of MYLK and a splicing variant within MYLK-210. MYLK-directed siRNA decreased MYLK expression and cell migration compared with control siRNA. siRNA directed against TGFbeta receptor 2 also decreased cell migration compared with control and decreased extracellular matrix genes regulated by TGFbeta signaling. Elevated HP increased the expression of MYLK-130 and MYLK-210 in both populations of astrocytes. However, TGFbeta2 was uniquely upregulated by exposure to elevated HP in CA compared with AA astrocytes.Differential expression of TGFbeta pathway genes and MYLK isoforms observed in populations of glaucomatous astrocytes applies to the elevated HP model system. MYLK may be a new target for intervention in glaucoma to alter reactive astrocyte migration in the ONH.
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Project description:PurposeThis article describes the first retinal histopathologic findings in a patient with Susac's syndrome (SS).DesignObservational case report.ParticipantA 51-year-old white woman diagnosed with SS.MethodsEyes from a 51-year-old white woman diagnosed with SS were obtained at autopsy. One retina was dissected and processed for adenosine diphosphatase (ADPase) flat embedding. Selected areas were processed further for transmission electron microscopy.Main outcome measuresHistopathologic examination using ADPase flat-embedding technique.ResultsThere were vaso-occlusive changes in the retinal periphery resulting in small areas of capillary dropout. Cross-sections demonstrated serous filled spaces between the retinal blood vessels and the internal limiting membrane. Lumens adjacent to these spaces appeared compressed and sometimes closed, but without thrombosis. Decreased ADPase activity in some peripheral blood vessels suggested endothelial cell dysfunction and vaso-occlusion. In the optic nerve head, numerous corpora amylacea were observed in the vicinity of capillaries with thickened walls and narrow lumens. Transmission electron microscopy demonstrated thickened and amorphous vascular basal lamina and open endothelial cell junctions in some retinal blood vessels.ConclusionsThe serous deposits with compression of retinal vessel lumens observed histologically probably represent the so-called string of pearls described clinically in SS. Chronic extension of these serous deposits along the vessel wall possibly are the cause of retinal arterial wall plaques as described by Gass and other investigators. In the optic nerve head, corpora amylacea are probably a result of microinfarcts resulting from optic nerve head capillary angiopathy. Accumulation of amorphous material in the basal lamina, loss of viable endothelial cells, and capillary dropout suggest that SS may be an endotheliopathy.
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Project description:BackgroundAstrocyte activation is a characteristic response to injury in the central nervous system, and can be either neurotoxic or neuroprotective, while the regulation of both roles remains elusive.MethodsTo decipher the regulatory elements controlling astrocyte-mediated neurotoxicity in glaucoma, we conducted a systems-level functional analysis of gene expression, proteomic and genetic data associated with reactive optic nerve head astrocytes (ONHAs).ResultsOur reconstruction of the molecular interactions affected by glaucoma revealed multi-domain biological networks controlling activation of ONHAs at the level of intercellular stimuli, intracellular signaling and core effectors. The analysis revealed that synergistic action of the transcription factors AP-1, vitamin D receptor and Nuclear Factor-kappaB in cross-activation of multiple pathways, including inflammatory cytokines, complement, clusterin, ephrins, and multiple metabolic pathways. We found that the products of over two thirds of genes linked to glaucoma by genetic analysis can be functionally interconnected into one epistatic network via experimentally-validated interactions. Finally, we built and analyzed an integrative disease pathology network from a combined set of genes revealed in genetic studies, genes differentially expressed in glaucoma and closely connected genes/proteins in the interactome.ConclusionOur results suggest several key biological network modules that are involved in regulating neurotoxicity of reactive astrocytes in glaucoma, and comprise potential targets for cell-based therapy.
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