Influence of retinal NMDA receptor activity during autoimmune optic neuritis

Abstract

Autoimmune optic neuritis (AON), a model of multiple sclerosis‐associated optic neuritis, is accompanied by degeneration of retinal ganglion cells (RGCs) and optic nerve demyelination and axonal loss. In order to investigate the role of N‐methyl‐d‐aspartate (NMDA) receptors in mediating RGC degeneration, upstream changes in the optic nerve actin cytoskeleton and associated deterioration in visual function, we induced AON in Brown Norway rats by immunization with myelin oligodendrocyte glycoprotein. Subsequently, visual acuity was assessed by recording visual evoked potentials and electroretinograms prior to extraction of optic nerves for western blot analysis and retinas for quantification of RGCs. As previously reported, in Brown Norway rats RGC degeneration is observed prior to onset of immune cell infiltration and demyelination of the optic nerves. However, within the optic nerve, destabilization of the actin cytoskeleton could be seen as indicated by an increase in the globular to filamentous actin ratio. Interestingly, these changes could be mimicked by intravitreal injection of glutamate, and similarly blocked by application of the NMDA receptor blocker MK‐801, leading us to propose that prior to optic nerve lesion formation, NMDA receptor activation within the retina leads to retinal calcium accumulation, actin destabilization within the optic nerve as well as a deterioration of visual acuity during AON.

New actors in optic neuritis pathogenesis

“…Based on the clinical association between multiple sclerosis and optic neuritis, the most frequently employed experimental model for studying optic neuritis is experimental autoimmune encephalomyelitis (EAE), a reliable model of human multiple sclerosis, involving an immune‐mediated demyelination process. In the present report, Bojcevski et al induce autoimmune optic neuritis (AON) in female Brown Norway rats by immunisation with myelin oligodendrocyte glycoprotein (Bojcevski et al, 2020). Since RGCs are particularly susceptible to glutamate‐induced excitotoxicity, the authors examine the involvement of NMDA receptors on RGC loss, visual dysfunction, and optic nerve actin cytoskeleton network dynamics during the induction phase of AON (Bojcevski et al, 2020).…”

“…In the present report, Bojcevski et al induce autoimmune optic neuritis (AON) in female Brown Norway rats by immunisation with myelin oligodendrocyte glycoprotein (Bojcevski et al, 2020). Since RGCs are particularly susceptible to glutamate‐induced excitotoxicity, the authors examine the involvement of NMDA receptors on RGC loss, visual dysfunction, and optic nerve actin cytoskeleton network dynamics during the induction phase of AON (Bojcevski et al, 2020). The authors show a correlation in the timing of RGC degeneration with alterations in the optic nerve actin cytoskeleton dynamics and visual disturbances.…”

“…However, although steroids may increase the speed of visual recovery, the overall visual recuperation is not affected by treatment, which does not prevent axonal and RGC loss (Gal, Vedula, & Beck, 2015). Therefore, neuroprotective therapies for optic neuritis are still an unmet clinical demand (Bojcevski et al, 2020).…”

“…The authors show a correlation in the timing of RGC degeneration with alterations in the optic nerve actin cytoskeleton dynamics and visual disturbances. In particular, the authors demonstrate that the optic nerve globular to filamentous (G‐F) actin ratio and fractin levels increase, while gelsolin (an F‐actin‐binding protein) levels decrease along the disease progression (Bojcevski et al, 2020). At advanced (but not early) stages of AON, these findings correlate with transported protein (β amyloid precursor protein, synaptophysin, and kinesin) accumulation.…”

“…In addition, glutamate intravitreal injection induces a decrease in pattern visual evoked potential (an index of RGCs‐visual cortex pathway), and pattern electroretinogram (an index of RGC activity) amplitudes. In order to analyze the role of NMDA receptors in RGC degeneration and upstream optic nerve actin cytoskeletal changes, the authors intravitreally inject a potent NMDA receptor antagonist (MK‐801) into rats with AON (Bojcevski et al, 2020). MK‐801 partly avoids RGC dysfunction and loss (Figure 1), and completely prevents G/F‐actin ratio, fraction and gelsolin level changes induced by AON (Bojcevski et al, 2020).…”