Genetic Dissection of Retinal Ganglion Cell Axon Function During Progression in Glaucoma
Michael L Risner PhD Vanderbilt University Medical Center, Dept of Ophthalmology and Visual Sciences
Co-authors: Silvia Pasini PhD David J Calkins PhD
Glaucomatous optic neuropathy is a leading cause of irreversible blindness. The disease affects retinal ganglion cells (RGCs) through sensitivity to intraocular pressure (IOP). A body of evidence supports the hypothesis of compartmentalized degeneration, where varied degenerative programs affect the different RGC components (soma, dendrites, and axon). Here, we examine how raising IOP affects axon function using genetic models of neuroprotection, including Bax-dependent apoptosis (Bax-/-) and slow Wallerian degeneration (Wlds).
We increased IOP unilaterally by microbead occlusion of the anterior chamber in 1- to 3-month old homozygous Bax-/-, Wlds (Wlds+/+), and C57 (WT) mice. An equivalent volume of PBS was injected into the contralateral eye as an internal control. IOP was monitored twice a week for 4 weeks using applanation tonometry. We then assessed physiology of different RGC types, anterograde transport along RGC axons, and spatial frequency threshold by optomotor response.
Following 4 weeks of raised IOP, light-evoked spike rate was significantly reduced in all WT RGC types analyzed (αON-S, αOFF-S, αOFF-T, p<0.05). Bax-/- and Wlds+/+ prevented this IOP-related reduction in RGC light responses. Increasing pressure significantly decreased anterograde axon transport to the brain in both WT and Bax-/- animals (p<0.001), but transport remained intact in Wlds+/+ animals. Ocular hypertension produced a significant decrease in spatial frequency threshold in both WT and Bax-/- animals (p<0.05), but acuity was unaffected by IOP in Wlds+/+ mice.
Based on our measures of RGC axon function, we find Wlds+/+ protects against IOP-related degradation of axon signaling.
Funding Sources: NEI R01EY024997, NEI P30EY008126, Glaucoma Research Foundation, Research to Prevent Blindness Inc
