Wld^S gene protects against deficits in visual acuity and axonal transport caused by ocular hypertension

Abstract

Purpose : 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 compartments (soma, dendrites, and axon). Early features of glaucoma include RGC axonal dysfunction and dendritic pruning, but the molecular mechanisms and the interdependence of their degeneration is still unknown. It has been shown that the slow Wallerian degeneration (Wld^s) gene delays axon degeneration from a wide variety of degeneration-inducing stimuli, including traumatic injury, Parkinson's disease, and ocular hypertension. Here we assess whether the Wld^s gene protects against deficits in visual acuity and anterograde axonal transport caused by increased IOP.

Methods : We increased IOP unilaterally by microbead occlusion of the anterior chamber in 1- to 3-month old homozygous Wld^s (Wld^s+/+) and wild type (Wld^{s -\-}) 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 assessed visual acuity by measuring the optokinetic response and compared these results to levels of intact anterograde transport to assess RGC axonal function.

Results : Microbead occlusion significantly elevated IOP in both the genotypes compared to respective controls (Wld^{s -/-} 19.24±1.45 vs 15.22±1.31 mmHg, p<0.001, n=30; Wld^{s +/+} 19.53±1.78 vs 14.54±1.26 mmHg, p<0.001, n=10). IOP elevation led to a significant deficit in visual acuity in Wld^s-\- mice starting 1 week post-injection (p<0.05, n=35), while in Wld^s+\+ mice the visual acuity of the microbead injected eyes was not significantly different from the respective control eyes for up to 4 weeks post-injection (p=0.31, n=5). Similarly, 4 weeks of IOP elevation caused a significant loss in the anterograde transport of cholera toxin b to the superior colliculus in Wld^s-\- mice (p=0.0013, n=5), while no significant deficit was detected in Wld^s+\+ mice (p=0.41, n=10).

Conclusions : Our results show that the Wld^s transgene prevents visual acuity loss and axon dysfunction caused by elevated IOP. Wld^s mice represent a useful tool to study the relationship between RGC axonal degeneration and dendritic pruning during glaucomatous progression.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.