Current perspective on retinal remodeling: Implications for therapeutics

Abstract

The retinal degenerative diseases retinitis pigmentosa and age-related macular degeneration are a leading cause of irreversible vision loss. Both present with progressive photoreceptor degeneration that is further complicated by processes of retinal remodeling. In this perspective, we discuss the current state of the field of retinal remodeling and its implications for vision-restoring therapeutics currently in development. Here, we discuss the challenges and pitfalls retinal remodeling poses for each therapeutic strategy under the premise that understanding the features of retinal remodeling in totality will provide a basic framework with which therapeutics can interface. Additionally, we discuss the potential for approaching therapeutics using a combined strategy of using diffusible molecules in tandem with other vision-restoring therapeutics. We end by discussing the potential of the retina and retinal remodeling as a model system for more broadly understanding the progression of neurodegeneration across the central nervous system.

Keywords: age-related macular degeneration; neurodegeneration; retinal remodeling; retinitis pigmentosa; therapeutics.

FIGURE 1

Metabolic and receptor changes phase 1 remodeling in 3mo P347L rabbit: (A) top panel: 3-channel composite of metabolites taurine, glutamine and glutamate. Lower panels: individual metabolites taurine and glutamine. Arrows indicate neighboring Müller cells. (B) Theme map of cell types in a horizontal section of retina identified based on ionotropic glutamate receptor function. Phase 2 remodeling in 2yo P347L rabbit: (C) top panel: 3-channel composite of metabolites taurine, glutamine and glutamate. Lower panels: individual metabolites taurine and glutamine. Arrows indicate neighboring Müller cells. (D) Theme map of cell types in a horizontal section of retina identified based on ionotropic glutamate receptor function. Phase 3 remodeling in 4yo P347L rabbit: (E) top panel: 3-channel composite of metabolites taurine, glutamine, and glutamate. Lower panels: individual metabolites taurine and glutamine. Arrows indicate Müller cell devoid of taurine and containing reduced glutamine. Bracket indicates region of Müller cells with varying levels of small molecules.

FIGURE 2

Early and late-stage rewiring. Early rewiring in 10mo P347L rabbit: (A) 3D rendering of rod bipolar cell (RodBC) dendrites from RPC1. RodBC in blue, cone photoreceptor in pink, rod photoreceptor in purple, and indeterminate in yellow. (B) Pseudocolored TEM image of rod photoreceptor ribbon synapse onto RodBC rendered in panel (A). (C) Pseudocolored TEM image of indeterminate photoreceptor ribbon synapse onto RodBC rendered in panel (A). (D) Pseudocolored TEM image of Cone photoreceptor ribbon synapse onto RodBC rendered in panel (A). Scale bars: 500 nm late rewiring in the pnd 900 RCS rat: (E) TEM image of microneuroma extended over a blood vessel invading inner nuclear layer. (F) GABA, Glycine, and Glutamate channels overlayed on top of the region outlined with a box in panel (E). (G) Higher resolution image of region highlighted with box in panel (F). (H) Pseudocolored high-resolution image of area indicated with arrow in panel (G). Arrows indicate edges of gap junction found intact within microneuroma.