Murine Autoimmune Optic Neuritis Is Not Phenotypically Altered by the Retinal Degeneration 8 Mutation

Stojic, Aleksandar; Fairless, Richard; Beck, Susanne; Sothilingam, Vithiyanjali; Weißgerber, Petra; Wissenbach, Ulrich; Gimmy, Valerie; Seeliger, Mathias W.; Flockerzi, Veit; Diem, Ricarda; Williams, Sarah K.

doi:10.1167/iovs.16-20419

Cited by 9 publications

(11 citation statements)

References 40 publications

(64 reference statements)

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“…: 078/15). A total of 44 female 16–18 weeks old C57BL/6JRj (Janvier, Le Genest-St Isle, France) [39, 40] mice were examined in this study. EAE was induced in 30 mice by immunisation with an emulsion of MOG 35–55 (Hooke Laboratories, Lawrence, MA, USA), in complete Freund’s adjuvant (CFA), injected subcutaneously into both flanks (0.2 mg/mouse), followed by intraperitoneal administration of pertussis toxin in phosphate-buffered saline (PBS) on day 0 of immunisation and again on day 1 (4 μg/mL/mouse/day).…”

Section: Methodsmentioning

confidence: 99%

Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis

Manogaran

Samardzija

Schad

et al. 2019

acta neuropathol commun

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The exact mechanisms and temporal sequence of neurodegeneration in multiple sclerosis are still unresolved. The visual pathway including its unmyelinated retinal axons, can serve as a prototypic model of neurodegeneration in experimental optic neuritis. We conducted a longitudinal study combining retinal imaging through optical coherence tomography (OCT) with immunohistochemical analyses of retinal and optic nerve tissue at various time points in experimental autoimmune encephalomyelitis (EAE). Inner retinal layer (IRL) thickness was measured in 30 EAE and 14 healthy control C57BL/6 J mice using OCT. Distribution of marker proteins was assessed by immunofluorescence staining and retinal mRNA levels were assayed using real-time PCR. Histological morphology was evaluated on light and electron microscopy images. Signs of inflammatory edema 11 days post immunisation coincided with IRL thickening, while neuro-axonal degeneration throughout the disease course contributed to IRL thinning observed after 20 days post immunisation. Retinal pathology, including axonal transport impairment, was observed early, prior to cellular infiltration (i.e. T-cells) in the optic nerve 11 days post immunisation. Yet, the effects of early retinal damage on OCT-derived readouts were outweighed by the initial inflammatory edema. Early microglial activation and astrocytosis was detected in the retina prior to retinal ganglion cell loss and persisted until 33 days post immunisation. Müller cell reactivity (i.e. aquaporin-4 and glutamine synthetase decrease) presented after 11 days post immunisation in the IRL. Severe neuro-axonal degeneration was observed in the optic nerve and retina until 33 days post immunisation. Initial signs of retinal pathology subsequent to early glial activity, suggests a need for prophylactic treatment of optic neuritis. Following early inflammation, Müller cells possibly respond to retinal pathology with compensatory mechanisms. Although the majority of the IRL damage observed is likely due to retrograde degeneration following optic neuritis, initial pathology, possibly due to gliosis, may contribute further to IRL thinning. These results add morphological substrate to our OCT findings. The extent and rapid onset of axonal and neuronal damage in this model appears relevant for testing interventions scaled to human optic neuritis. Electronic supplementary material The online version of this article (10.1186/s40478-019-0768-5) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis

Manogaran

Samardzija

Schad

et al. 2019

acta neuropathol commun

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“…Differences in the selected C57BL/6 mouse sub-strain could be relevant for explaining differences in the observed phenotypes. C57BL/6N carry a mutation in the Crumbs CRB1 gene that leads to the rd8 retinal degeneration phenotype 60,[77][78][79] . This degeneration phenotype in C57BL/6N mice strongly affects photoreceptors and might block ribbon-and active zone dynamics.…”

Section: Discussionmentioning

confidence: 99%

“…In the current study, we used the C57BL/6J sub-strain to avoid the rd8 retinal degeneration phenotype 79 . Furthermore, we also chose C57BL/6J mice because these mice perform better in visual tests than C57BL/6N mice 78 .…”

Section: Discussionmentioning

confidence: 99%

Synaptic ribbons foster active zone stability and illumination-dependent active zone enrichment of RIM2 and Cav1.4 in photoreceptor synapses

Dembla

Maxeiner

et al. 2020

Sci Rep

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Rod photoreceptor synapses use large, ribbon-type active zones for continuous synaptic transmission during light and dark. Since ribbons are physically connected to the active zones, we asked whether illumination-dependent changes of ribbons influence Cav1.4/RIM2 protein clusters at the active zone and whether these illumination-dependent effects at the active zone require the presence of the synaptic ribbon. We found that synaptic ribbon length and the length of presynaptic Cav1.4/RIM2 clusters are tightly correlated. Dark-adaptation did not change the number of ribbons and active zone puncta. However, mean ribbon length and length of presynaptic Cav1.4/RIM2 clusters increased significantly during dark-adaptation when tonic exocytosis is highest. In the present study, we identified by the analyses of synaptic ribbon-deficient RIBEYE knockout mice that synaptic ribbons are (1) needed to stabilize Cav1.4/RIM2 at rod photoreceptor active zones and (2) are required for the darkness-induced active zone enrichment of Cav1.4/RIM2. These data propose a role of the ribbon in active zone stabilization and suggest a homeostatic function of the ribbon in illumination-dependent active zone remodeling. The active zone of the presynaptic terminal controls central aspects of presynaptic communication 1,2. It is a protein-rich, electron-dense specialization of the plasma membrane at which synaptic vesicle fusion preferentially occurs. The active zone is strongly enriched in voltage-gated Cav-channels and active zone proteins, e.g. RIM-proteins, that attach the vesicle fusion machinery in close proximity to the Cav-channels for tight coupling creating rapidly reacting nanodomains 1,3-9. Ribbon synapses are continuously active chemical synapses with specialized active zones that are considered to promote both fast, transient and slow, continuous synaptic vesicle exocytosis 10,11. The active zone of ribbon synapses is extended by large electron-dense structures, synaptic ribbons, that recruit additional vesicles to the active zone. The basal row of ribbon-associated vesicles is positioned close to the Cav-channels and represents the fastest releasable vesicle pool 12 ideally suited to signal the onset of a stimulus. Synaptic vesicles tethered to the ribbon body, i.e. in some distance from the active zone, are considered to replenish empty release sites at the active zone with slower release kinetics providing information predominantly about the length of the stimulus 12,13. The main structural component of ribbons is the ribbon-specific protein RIBEYE 14,15. Photoreceptor ribbon synapses are the first synapses in the visual system at which light signals are transmitted to the inner retina. Light induces hyperpolarization of photoreceptors and a decrease of exocytosis at the synapse 16. Rod synapses represent the majority of photoreceptor synapses in the mouse retina and are built in a morphologically fairly uniform manner. They use a single large active zone with a single large ribbon. In EM cross-sections, rod ribbons typically ap...

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“…Full-field ERGs were performed on RIBEYE knock-out and wild-type mice according to previously published procedures. 14 , 15 Mice were dark adapted overnight and anesthetized with ketamine (150 mg/kg) and xylazine (10 mg/kg), and the pupils were dilated with 0.5% atropine (Ursapharm, Saarbrücken, Germany). ERGs were recorded using the UTAS Visual Diagnostic System (LKC Technologies, Gaithersburg, MD, USA) and a contact lens electrode with gold contact (LKC Technologies).…”

Section: Methodsmentioning

confidence: 99%

ERG Responses in Mice with Deletion of the Synaptic Ribbon Component RIBEYE

Fairless

Williams

Katiyar

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Purpose To determine the influence of RIBEYE deletion and the resulting absence of synaptic ribbons on retinal light signaling by electroretinography. Methods Full-field flash electroretinograms (ERGs) were recorded in RIBEYE knock-out (KO) and wild-type (WT) littermate mice under photopic and scotopic conditions, with oscillatory potentials (OPs) extracted by digital filtering. Flicker ERGs and ERGs following intravitreal injection of pharmacological agents were also obtained under scotopic conditions. Results The a-wave amplitudes were unchanged between RIBEYE KO and WT mice; however, the b-wave amplitudes were reduced in KOs under scotopic, but not photopic, conditions. Increasing stimulation frequency led to a greater reduction in RIBEYE KO b-wave amplitudes compared with WTs. Furthermore, we observed prominent, supernormal OPs in RIBEYE KO mice in comparison with WT mice. Following intravitreal injections with l -2 amino-4-phosphonobutyric acid and cis -2,3 piperidine dicarboxylic acid to block ON and OFF responses at photoreceptor synapses, OPs were completely abolished in both mice types, indicating a synaptic origin of the prominent OPs in the KOs. Conversely, tetrodotoxin treatment to block voltage-gated Na + channels/spiking neurons did not differentially affect OPs in WT and KO mice. Conclusions The decreased scotopic b-wave and decreased responses to increased stimulation frequencies are consistent with signaling malfunctions at photoreceptor and inner retinal ribbon synapses. Because phototransduction in the photoreceptor outer segments is unaffected in the KOs, their supernormal OPs presumably result from a dysfunction in retinal synapses. The relatively mild ERG phenotype in KO mice, particularly in the photopic range, is probably caused by compensatory mechanisms in retinal signaling pathways.

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Murine Autoimmune Optic Neuritis Is Not Phenotypically Altered by the Retinal Degeneration 8 Mutation

Abstract: The presence of the rd8 mutation in C57BL/6 mice does not affect the course of AON and should not provide a confounding factor in the interpretation of experimental results obtained in this model. However, it could be dangerous in other models of ocular pathology.

Cited by 9 publications

References 40 publications

Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis

Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis

Synaptic ribbons foster active zone stability and illumination-dependent active zone enrichment of RIM2 and Cav1.4 in photoreceptor synapses

ERG Responses in Mice with Deletion of the Synaptic Ribbon Component RIBEYE

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