July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Node of Ranvier pathology in two mouse models of glaucoma
Author Affiliations & Notes
  • Matthew Alan Smith
    Pharmaceutical Sciences, Northeast Ohio Medical University, ROOTSTOWN, Ohio, United States
  • Emily Plyler
    Pharmaceutical Sciences, Northeast Ohio Medical University, ROOTSTOWN, Ohio, United States
    Biomedical Sciences, Kent State University, Kent, Ohio, United States
  • Christine M Dengler-Crish
    Pharmaceutical Sciences, Northeast Ohio Medical University, ROOTSTOWN, Ohio, United States
  • Samuel D Crish
    Pharmaceutical Sciences, Northeast Ohio Medical University, ROOTSTOWN, Ohio, United States
  • Footnotes
    Commercial Relationships   Matthew Smith, None; Emily Plyler, None; Christine Dengler-Crish, None; Samuel Crish, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 3743. doi:https://doi.org/
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      Matthew Alan Smith, Emily Plyler, Christine M Dengler-Crish, Samuel D Crish; Node of Ranvier pathology in two mouse models of glaucoma. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3743. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : We have previously reported that semifunctional retinal ganglion cell (RGC) axons persist after anterograde axonal transport deficits in two mouse models of glaucoma but little is known about these axons’ ability to transmit neuronal signals to their brain targets. In other neurodegenerative conditions that exhibit persistent axons, there are multiple alterations in axonal structure and physiology that can be protective or detrimental. One common defect occurs at nodes of Ranvier (NOR), specialized gaps in the myelin sheath that facilitate propagation of action potentials along axons. In multiple sclerosis (MS), extensive redistribution and differential expression of sodium channels (Nav) play a major role in optic nerve dysfunction. Very little is known about node of Ranvier function in glaucoma.

Methods : Using tract tracing, immunofluorescence, electron microscopy, and electrophysiology, we examined NOR in two common mouse models of chronic glaucoma, the DBA/2J mouse and the microbead occlusion model. We also investigated the effects of acute treatment with the MS drug fingolimod on axon structure and function.

Results : In agreement with previous work (and contrasting with MS) we did not find overt demyelination in glaucomatous optic nerves, however, RGC axons in DBA/2J mice animals exhibited substantial expansion of the nodal region – even at ages preceding glaucomatous pathology. Most intriguingly, as in MS, we found redistribution of the sodium channel Nav1.6; clusters of this channel were redistributed to the paranode (“split”), followed by loss of Nav1.6 immunoreactivity at NOR. These changes were accompanied by an inability to drive neurons in the retinorecipient superior colliculus (SC) with visual stimuli. One week of fingolimod treatment reversed node pathology and partially rescued neuronal signaling to the SC. We did not see node morphology change in the microbead model, but instead found reduced node density.

Conclusions : Node of Ranvier pathology may be an early defect in some forms of glaucoma. Immunosuppression can rescue this pathology in the DBA/2J mouse, an inflammatory glaucoma model. Addressing early NOR dysfunction may be a promising target for developing therapies that slow, stop, or reverse the progression of vision loss in this disease.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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