Abstract
Purpose :
Retinal ganglion cell axonopathy in glaucoma is influenced by complex interplay with astrocyte processes which may reflect metabolic changes. Our goal is to understand how sensitivity to intraocular pressure (IOP) in glaucoma influences astrocyte distribution in the optic nerve early in progression and how these changes may relate to axon and visual function.
Methods :
In young (2 month) C57 mice, IOP was elevated unilaterally (30-35%) using microbead occlusion of aqueous flow. The contralateral eye received an equivalent volume saline injection as internal control. We monitored IOP for up to 4 weeks using Tono-Pen XL rebound tonometry and measured optokinetic nystagmus (OKN) using Optomotry (Cerebral Mechanics). Some eyes received intravitreal injection of cholera toxin B to measure anterograde axonal transport to the superior colliculus. Following perfusion, optic nerve cross-sections were analyzed for astrocyte process orientation using custom Matlab routines. We devised a metric to quantify the degree of parallelism between astrocyte processes and compared the results to optic nerve glycogen content, which is restricted to astrocytes.
Results :
Two weeks of microbead-induced IOP elevation resulted in measurable functional loss. Optokinetics and CTB labeling demonstrated a 15% loss in visual spatial contrast sensitivity (n=10, p=0.024) and a 40% deficit in anterograde axonal transport (n=7, p=0.018) compared to control. Four weeks of IOP elevation caused a 23% deficit in spatial contrast sensitivity (n=5, p=0.03) and a 55% deficit in axonal transport (n=5, p=0.002), as well as a 66% loss of optic nerve glycogen content. These changes mirror alterations in astrocyte morphology. Increased glial coverage after 4 weeks IOP elevation was associated with increased parallelism among astrocyte processes in the nerve (n=9, p=0.02).
Conclusions :
Early progression in glaucoma involves reorganization of optic nerve astrocyte processes without change in total coverage. With these changes, both functional axon transport from retina to brain and visual contrast sensitivity are diminished. Both measures further diminish with more extensive exposure to elevated IOP, which also diminishes glycogen content in the optic projection. These changes may reflect how astrocytes redistribute and utilize available energy stores when the optic nerve is stressed in glaucoma.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.