Nodes of Ranvier in Glaucoma

Area of Science:

• Neuroscience
• Ophthalmology
• Cell Biology

Background:

• Glaucoma involves retinal ganglion cell (RGC) axon damage, but the precise timing of functional deficits relative to structural changes remains unclear.
• The DBA/2J mouse model exhibits neuroinflammation and RGC axon alterations, including transport deficits and terminal hypertrophy.
• Early functional impairments in RGCs may precede overt axonal degeneration, suggesting potential therapeutic targets before irreversible damage.

Purpose of the Study:

• To investigate the temporal relationship between eye-brain signaling deficits, axonal transport, and degeneration in the DBA/2J glaucoma model.
• To characterize the nature of early axonal pathology, specifically focusing on nodes of Ranvier and ion channel distribution.
• To evaluate the therapeutic potential of targeting node pathology using fingolimod in this glaucoma model.

Main Methods:

• In vivo multiunit electrophysiology to assess eye-brain signaling.
• Neuronal tract tracing to evaluate axonal projections.
• Multichannel immunofluorescence and transmission electron microscopy for ultrastructural analysis.
• Comparison with an induced microbead occlusion model of glaucoma lacking inflammation.

Main Results:

• Eye-brain signaling deficits were observed before significant axonal transport loss or degeneration in DBA/2J mice.
• Nodes of Ranvier showed pathology, including increased length and altered Na_v1.6 channel distribution, resembling early multiple sclerosis (MS) axonopathy.
• Axon caliber and neurofilament density increased with age, without changes in myelin thickness.
• No node pathology was found in the microbead occlusion model, highlighting the role of inflammation.
• Fingolimod treatment reduced node pathology and mildly affected axon morphology in DBA/2J mice.

Conclusions:

• Neurophysiological deficits in DBA/2J glaucoma occur in functionally impaired but structurally intact axons.
• Node of Ranvier pathology is a key feature of early glaucoma in this model and may be linked to neuroinflammation.
• Targeting nodes of Ranvier represents a potential therapeutic strategy for specific types of glaucoma, particularly those with an inflammatory component.