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 com...
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| Format: | Article |
| Language: | English |
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BMC
2019-07-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-019-0768-5 |
| _version_ | 1811220310904537088 |
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| author | Praveena Manogaran Marijana Samardzija Anaïs Nura Schad Carla Andrea Wicki Christine Walker-Egger Markus Rudin Christian Grimm Sven Schippling |
| author_facet | Praveena Manogaran Marijana Samardzija Anaïs Nura Schad Carla Andrea Wicki Christine Walker-Egger Markus Rudin Christian Grimm Sven Schippling |
| author_sort | Praveena Manogaran |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T07:39:30Z |
| format | Article |
| id | doaj.art-e536027d293146d681d69fb41f02c59b |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-04-12T07:39:30Z |
| publishDate | 2019-07-01 |
| publisher | BMC |
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| series | Acta Neuropathologica Communications |
| spelling | doaj.art-e536027d293146d681d69fb41f02c59b2022-12-22T03:41:51ZengBMCActa Neuropathologica Communications2051-59602019-07-017112210.1186/s40478-019-0768-5Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosisPraveena Manogaran0Marijana Samardzija1Anaïs Nura Schad2Carla Andrea Wicki3Christine Walker-Egger4Markus Rudin5Christian Grimm6Sven Schippling7Department of Information Technology and Electrical Engineering, Swiss Federal Institute of TechnologyDepartment of Ophthalmology, Lab for Retinal Cell Biology, University of ZurichDepartment of Biology, University of ZurichNeuroimmunology and Multiple Sclerosis Research, Clinic for Neurology, University Hospital Zurich and University of ZurichNeuroimmunology and Multiple Sclerosis Research, Clinic for Neurology, University Hospital Zurich and University of ZurichDepartment of Information Technology and Electrical Engineering, Swiss Federal Institute of TechnologyDepartment of Ophthalmology, Lab for Retinal Cell Biology, University of ZurichNeuroimmunology and Multiple Sclerosis Research, Clinic for Neurology, University Hospital Zurich and University of ZurichAbstract 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.http://link.springer.com/article/10.1186/s40478-019-0768-5Optical coherence tomographyOptic neuritisRetinaExperimental autoimmune encephalomyelitisNeuro-axonal degenerationGliosis |
| spellingShingle | Praveena Manogaran Marijana Samardzija Anaïs Nura Schad Carla Andrea Wicki Christine Walker-Egger Markus Rudin Christian Grimm Sven Schippling Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis Acta Neuropathologica Communications Optical coherence tomography Optic neuritis Retina Experimental autoimmune encephalomyelitis Neuro-axonal degeneration Gliosis |
| title | Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis |
| title_full | Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis |
| title_fullStr | Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis |
| title_full_unstemmed | Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis |
| title_short | Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis |
| title_sort | retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis |
| topic | Optical coherence tomography Optic neuritis Retina Experimental autoimmune encephalomyelitis Neuro-axonal degeneration Gliosis |
| url | http://link.springer.com/article/10.1186/s40478-019-0768-5 |
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