Retinal Ganglion Cell Excitability and Adaptations to Ionic Stress in Glaucomatous Optic Neuropathy

Abstract

Neurodegenerative diseases are complex disorders that affect various regions and cells in the central nervous system, sharing common hallmark features of progression. Intrinsic and extrinsic stressors lead to shared mechanisms of neuron dysfunction and death. Glaucoma, the leading cause of irreversible vision loss worldwide, involves the progressive degeneration of retinal ganglion cells (RGCs) piqued by sensitivity to intraocular pressure. Despite numerous effective tools available for lowering pressure, there is a persistent need for the development of new tools that can protect RGCs from degenerative stress. Identifying targets for neuroprotective therapy requires an understanding of the pathophysiologic changes, protective and maladaptive, that occur early in disease. This work explores the relationship between disruptions in ion homeostasis, neuronal hyperexcitability, and intrinsic factors that may underlie RGC susceptibility to degeneration. We leveraged both in vivo and in vitro models to investigate electrophysiologic and structural properties of RGCs in healthy and diseased conditions. First, we performed ex vivo electrophysiologic recordings from healthy C57Bl6/J mice to delineate intrinsic excitability differences between two RGC subtypes which may correlate to degenerative vulnerability. Next, we applied a similar experimental approach in an inducible mouse model of glaucoma, evaluating the adaptive response of RGCs to prolonged stress. Finally, we evaluated structural properties of the RGC axon that regulate excitability in vivo and in vitro, exploring cell type specific differences and delineating a potential mechanism of RGC adaptation. These findings offer valuable insight into how RGCs modulate excitability in the face of prolonged stress, which may play an important role in preserving vision and offers potential therapeutic targets for early glaucomatous neurodegeneration. While the etiologies and pathophysiologic processes of different neurodegenerative diseases may vary, they share many common features of progression. Understanding how fundamental neurodegenerative stressors, such as those explored in this work, lead to shared features of dysfunction and death is critical for developing effective neuroprotective therapies.