Nodes of Ranvier in Glaucoma.

Nodes of Ranvier in Glaucoma.

Smith M A; Plyler E S; Dengler-Crish Christine M; Meier J; Crish S D

Neuroscience

2018

2018-10

Retinal ganglion cell axons of the DBA/2J mouse model of glaucoma, a model characterized by extensive neuroinflammation, preserve synaptic contacts with their subcortical targets for a time after onset of anterograde axonal transport deficits, axon terminal hypertrophy, and cytoskeletal alterations. Though retrograde axonal transport is still evident in these axons, it is unknown if they retain their ability to transmit visual information to the brain. Using a combination of in vivo multiunit electrophysiology, neuronal tract tracing, multichannel immunofluorescence, and transmission electron microscopy, we report that eye-brain signaling deficits precede transport loss and axonal degeneration in the DBA/2J retinal projection. These deficits are accompanied by node of Ranvier pathology - consisting of increased node length and redistribution of the voltage-gated sodium channel Nav1.6 that parallel changes seen early in multiple sclerosis (MS) axonopathy. Further, with age, axon caliber and neurofilament density increase without corresponding changes in myelin thickness. In contrast to these findings in DBA/2J mice, node pathologies were not observed in the induced microbead occlusion model of glaucoma - a model that lacks pre-existing inflammation. After one week of systemic treatment with fingolimod, an immunosuppressant therapy for relapsing-remitting MS, DBA/2J mice showed a substantial reduction in node pathology and mild effects on axon morphology. These data suggest that neurophysiological deficits in the DBA/2J may be due to defects in intact axons and targeting node pathology may be a promising intervention for some types of glaucoma.

Female; Male; Animals; Mice; *axonopathy; *axons; *neurodegeneration; *neurofilament; *node of Ranvier; *superior colliculus; Axons/pathology; Action Potentials; Inbred C57BL; Transgenic; Cytoskeleton/pathology; Glaucoma/metabolism/pathology/*physiopathology; Optic Nerve/metabolism/pathology; Ranvier's Nodes/*physiology/ultrastructure; Visual Pathways/metabolism/*physiopathology/ultrastructure; Voltage-Gated Sodium Channels/metabolism

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