Neuroprotection by Wld^S depends on retinal ganglion cell type and age in glaucoma

Early challenges to axonal physiology, active transport, and ultrastructure are endemic to age-related neurodegenerative disorders, including those affecting the optic nerve. Chief among these, glaucoma causes irreversible vision loss through sensitivity to intraocular pressure (IOP) that challenges retinal ganglion cell (RGC) axons, which comprise the optic nerve. Early RGC axonopathy includes distal to proximal progression that implicates a slow form of Wallerian degeneration. In multiple disease models, including inducible glaucoma, expression of the slow Wallerian degeneration (Wld^S) allele slows axon degeneration and confers protection to cell bodies.

Using an inducible model of glaucoma along with whole-cell patch clamp electrophysiology and morphological analysis, we tested if Wld^S also protects RGC light responses and dendrites and, if so, whether this protection depends upon RGC type. We induced glaucoma in young and aged mice to determine if neuroprotection by Wld^S on anterograde axonal transport and spatial contrast acuity depends on age.

We found Wld^S protects dendritic morphology and light-evoked responses of RGCs that signal light onset (αON-Sustained) during IOP elevation. However, IOP elevation significantly reduces dendritic complexity and light responses of RGCs that respond to light offset (αOFF-Sustained) regardless of Wld^S. As expected, Wld^S preserves anterograde axon transport and spatial acuity in young adult mice, but its protection is significantly limited in aged mice.

The efficacy of Wld^S in conferring protection to neurons and their axons varies by cell type and diminishes with age.