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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Neurosci. | doi: 10.3389/fnins.2019.01139

Impairment of Membrane Repolarization Accompanies Axon Transport Deficits in Glaucoma

 Rachel A. Fischer1,  Michael L. Risner2, Abigail L. Roux2, Lauren K. Wareham2 and  Rebecca M. Sappington2*
  • 1School of Medicine, Vanderbilt University, United States
  • 2Vanderbilt University Medical Center, United States

Glaucoma is a leading cause of blindness worldwide, resulting from degeneration of retinal ganglion cells (RGCs), which form the optic nerve. In glaucoma, axon transport deficits appear to precede structural degeneration of RGC axons. The period of time between the onset of axon transport deficits and the structural degeneration of RGC axons may represent a therapeutic window for the prevention of irreversible vision loss. However, it is unclear how deficits in axon transport relate to the electrophysiological capacity of RGCs to produce and maintain firing frequencies that encode visual stimuli. Here we examined the electrophysiological signature of individual RGCs in glaucomatous retina with respect to axon transport facility. Utilizing the Microbead Occlusion Model of murine ocular hypertension, we performed electrophysiological recordings of RGCs with and without deficits in anterograde axon transport. We found that RGCs with deficits in axon transport have a reduced ability to maintain spiking frequency that arises from elongation of the repolarization phase of the action potential. This repolarization phenotype arises from reduced cation flux and K+ dyshomeostasis that accompanies pressure-induced decreases in Na/K-ATPase expression and activity. In vitro studies with purified RGCs indicate that elevated pressure induces early internalization of Na/K-ATPase that, when reversed, stabilizes cation flux and prevents K+ dyshomeostasis. Furthermore, pharmacological inhibition of the Na/K-ATPase is sufficient to replicate pressure-induced cation influx and repolarization phase phenotypes in healthy RGCs. These studies suggest that deficits in axon transport also likely reflect impaired electrophysiological function of RGCs. Our findings further identify a failure to maintain electrochemical gradients and cation dyshomeostasis as an early phenotype of glaucomatous pathology in RGCs that may have significant baring on efforts to restore RGC health in diseased retina.

Keywords: Retina, Retinal ganglion cell (RGC), Glaucoma, Na/K +ATPase, Potassium, Microbead

Received: 24 Jul 2019; Accepted: 09 Oct 2019.

Copyright: © 2019 Fischer, Risner, Roux, Wareham and Sappington. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Rebecca M. Sappington, Vanderbilt University Medical Center, Nashville, 37232, Tennessee, United States,