Significance of Potassium Homeostasis for Neurodegeneration in Glaucoma
Fischer, Rachel Anne
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2019-09-05
Abstract
Vision loss during glaucoma results from degeneration of retinal ganglion cell (RGC) axons. Glaucoma produces deficits in axon transport in RGCs prior to structural degeneration, representing a potential therapeutic window to interrupt axonopathy and prevent irreversible vision loss. Furthermore, studies indicate that axon transport deficits are accompanied by electrophysiological impairment. Electrophysiological studies in the Microbead Occlusion Model of murine glaucoma reveal that RGCs with deficits in axon transport have a reduced ability to maintain spiking frequency that arises from impaired membrane repolarization. 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. Our findings identify a failure to maintain electrochemical gradients and cation dyshomeostasis as an early phenotype of glaucomatous pathology in RGCs.