Early Nodal and Paranodal Disruption in Autoimmune Optic Neuritis

Abstract

Disturbances in the nodes of Ranvier are an early phenomenon in many CNS disorders, including the autoimmune demyelinating disease multiple sclerosis (MS). Using an animal model of optic neuritis, a common early symptom of MS, we have investigated nodal and paranodal compartments in the optic nerve during disease progression. Both nodes and paranodes, as identified by immunohistochemistry against sodium channels (Nav) and Caspr, respectively, were observed to increase in length during the late induction phase of the disease, prior to onset of the demyelination and immune cell infiltration characteristic of optic neuritis. These changes were correlated with both axonal stress and microglial/macrophage activation, and were most apparent in the vicinity of the retrobulbar optic nerve head, the unmyelinated region of the optic nerve where retinal ganglion cell axons exit the retina. Using intravitreal glutamate injection as a model of a primary retinal insult, we demonstrate that this can induce similar nodal and paranodal changes. This may suggest that onset of neurodegeneration in the absence of demyelination, as reported in several studies into the nonaffected eyes of MS patients, may give rise to subtle disturbances in the axo-glial junction.

Non‐invasive visual evoked potentials to assess optic nerve involvement in the dark agouti rat model of experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein

“…During the follow‐up study of three weeks (experiment 1), even if motor deficits were mild, ONs have been pathologically involved, confirming previous works in which optic neuritis is a common feature of MOG‐EAE . Interestingly, a significant VEP delay appeared before the clinical onset of EAE (7 dpi), resembling what happens in some patients affected by MS, which could manifest visual impairments before the first motor deficits .…”

Early auto‐immune targeting of photoreceptor ribbon synapses in mouse models of multiple sclerosis

“…This was shown by various analyses of the optic nerve sourced from the same mice from which the retinas were assayed for synaptic alterations. Stojic et al () found that the paranodal region of the optic nerve is an early and sensitive marker for optic neuritis. Therefore, we screened the organization of the paranodal region of the optic nerve at day 9 after immunization by immunolabeling.…”

“…At that site, it forms a cis‐complex with contactin1 (CNTN1), a GPI‐anchored cell adhesion protein of the immunoglobulin superfamily (Zeng & Sanes, ). The pathophysiological importance of CASPR1/CNTN1 in MS has been attributed to the localization of these proteins in the myelin sheath at the paranodal region of the nodes of Ranvier present along myelinated axons (Coman et al , ) including the optic nerve (Stojic et al , ).…”

“…The pathophysiological importance of CASPR1/CNTN1 in MS has been attributed to the localization of these proteins in the myelin sheath at the paranodal region of the nodes of Ranvier present along myelinated axons (Coman et al, 2006) including the optic nerve (Stojic et al, 2018).…”

Structural adaption of axons during de‐ and remyelination in the Cuprizone mouse model

“…Alteration of numbers of the nodes of Ranvier have already been described under demyelinating conditions . In studies where complete demyelination was induced, clustering of sodium channel subunit Nav1.6 was lost or greatly reduced and did not return back to control levels, even after 6 weeks of remyelination .…”