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

Abstract

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.

Monitoring retinal changes with optical coherence tomography predicts neuronal loss in experimental autoimmune encephalomyelitis

“…The power analysis using our previously published results with alpha-lipoic acid [8] revealed that protective effects of 20% on the retinal structure could be detected with 14 animals per group, which is in line with other studies using similar methodology [9, 39, 40]. Interestingly, OKR analysis of visual function and RGC counting in retinal wholemounts showed less variance resulting in numbers as low as 3 animals per group in the power analysis to detect 15% protection of visual function and 25% protection of RGCs.…”

Comparison of different optomotor response readouts for visual testing in experimental autoimmune encephalomyelitis-optic neuritis

“…Optic neuritis (ON) is a major source of disability in patients with inflammatory central nervous system diseases such as multiple sclerosis, and trials on optic neuritis are increasingly being applied to evaluate neuroprotective strategies [ 1 ]. Myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis is reportedly associated with strong optic neuritis (EAEON) resulting in demyelination and axonal damage of the optic nerve and in the following degeneration of the inner retinal layers: retinal nerve fiber layer (axons), ganglion cell layer (neurons), and inner plexiform layer (dendritic arbor) [ 2 – 6 ]. Studies on preclinical models of experimental autoimmune encephalomyelitis optic neuritis (EAEON) are ideally suited to translationally evaluate the promise of clinical ON trials especially since more and more in vivo clinical readouts are being adapted to the preclinical setting [ 7 ].…”

Klotho Pathways, Myelination Disorders, Neurodegenerative Diseases, and Epigenetic Drugs

“…202 More than 70% of MS patients suffer vision loss as a secondary effect of optic neuritis disease progression. 160,203,204 In recent studies, Klotho was shown to accelerate remyelination in a cuprizone-mediated demyelination mouse model. 9,28 This important finding is refocusing attention on Klotho's role in neurodegeneration and research efforts are increasingly directed toward the develop-ment of MS treatments that promote remyelination and/or stimulate myelin repair.…”