Optic Neuritis and Retinal Ganglion Cell Loss in a Chronic Murine Model of Multiple Sclerosis

Kenneth S Shindler,Mahasweta Dutt,Thomas A Quinn

doi:10.3389/fneur.2011.00050

Abstract

Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are neurodegenerative diseases with characteristic inflammatory demyelination in the central nervous system, including the optic nerve. Neuronal and axonal damage is considered to be the main cause of long-term disability in patients with MS. Neuronal loss, including retinal ganglion cell (RGC) apoptosis in eyes with optic neuritis (ON), also occurs in EAE. However, there is significant variability in the clinical course and level of neuronal damage in MS and EAE. The current studies examine the mechanisms and kinetics of RGC loss in C57/BL6 mice immunized with myelin oligodendrocyte glycoprotein to induce a chronic EAE disease. Clinical progression of EAE was scored daily and vision was assessed by optokinetic responses. At various time points, RGCs were counted and optic nerves were examined for inflammatory cell infiltration. Almost all EAE mice develop ON by day 15 post-immunization; however, RGC loss is delayed in these mice. No RGC loss is detected 25 days post-immunization, whereas RGC numbers in EAE mice significantly and progressively decrease compared to controls from 35 to 50 days post-immunization. The delayed time course of RGC loss is in stark contrast to that reported in relapsing EAE, as well as in rats with chronic EAE. Results suggest that different clinical disease courses of optic nerve inflammation may trigger distinct mechanisms of neuronal damage, or RGCs in different rodent strains may have variable resistance to neuronal degeneration.

Highlights

Multiple sclerosis (MS) is an autoimmune-mediated neurodegenerative disease with characteristic inflammatory demyelination in the central nervous system (Constantinescu et al, 1998; Noseworthy et al, 2000)
Results of the current studies show that immunization of C57/BL6 mice with myelin oligodendrocyte glycoprotein (MOG) induces a chronic EAE disease course with a high incidence of optic neuritis (ON), consistent with prior studies
Retinal ganglion cell loss in this chronic EAE model is delayed by 2 weeks beyond the onset of optic nerve inflammation, making it distinct from other reported experimental ON models

Summary

Introduction

Multiple sclerosis (MS) is an autoimmune-mediated neurodegenerative disease with characteristic inflammatory demyelination in the central nervous system (Constantinescu et al, 1998; Noseworthy et al, 2000). Multiple sclerosis was considered primarily a demyelinating disease in the past, increasing evidence suggests disease progression and permanent disability in both MS and ON depend upon accumulated axon degeneration (Losseff et al, 1996; Fisher et al, 2006). Axonal degeneration measured by retinal imaging, including thinning of the retinal nerve fiber layer and decreased macular volume, occurs in patients after a single clinical episode of ON and correlates with the level of residual visual dysfunction (Steel and Waldock, 1998; Parisi et al, 1999; Trip et al, 2005; Costello et al, 2006; Fisher et al, 2006). The precise mechanisms leading to this neurodegeneration remain unknown

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