Mechanisms of Adaptive Remodeling and Their Therapeutic Potential in Glaucoma

PROJECT SUMMARY
Glaucoma blinds through degeneration of retinal ganglion cells (RGCs) and their axons in the optic
projection through sensitivity to intraocular pressure (IOP). Many patients continue to lose vision despite efforts
to manage IOP. Thus, an unmet clinical need is a treatment that addresses RGC degeneration directly. Our
long-term goal is to identify new therapeutic targets based on neuronal repair, protection, and restoration. In
the previous grant cycle, we leveraged transgenic mouse strains to discern interplay between RGC dendritic
pruning, axon degeneration, and astrocyte glia. We discovered two novel forms of adaptive remodeling that
boost and preserve RGC signaling and slow progression. With unilateral IOP elevation, metabolic redistribution
transfers metabolites from the unstressed optic nerve to the retina and nerve challenged by IOP elevation
through astrocyte networks. Conditional knock-out of the gap junction protein connexin 43 (Cx43) uncouples
this network and prevents redistribution. Finally, for individual RGCs exposed to elevated IOP, enhanced
excitability amplifies the light response, even as dendritic complexity diminishes, through reorganization of
voltage-gated sodium channels (NaV) in the unmyelinated axon segment. Both phenomena occur early and
are transient, as are their protective effects. Our objective in this competitive renewal is to build upon these
important results to discern how enhanced excitability and metabolic redistribution mechanistically relate to
axonal and dendritic degeneration and whether they can be enhanced to extend RGC survival. As a corollary,
we will test whether the transient nature of both forms of adaptation arises from metabolic and oxidative stress
to the astrocyte network and if boosting resources exogenously reduces this stress and extends visual
function. This hypothesis is supported by new preliminary data showing a dietary metabolite (pyruvate)
increases astrocyte glycogen in the optic nerve and enhances nerve excitation in response to elevated IOP,
suggesting that the two forms of adaptive remodeling may be linked. In our inducible glaucoma models, we will
utilize a cross-disciplinary approach that combines electrophysiological, cellular and in vivo imaging, and
transgenic tools. Aim 1 will determine the dependence of adaptive remodeling on axonopathy and dendritic
pruning. Aim 2 will characterize the interdependence between metabolic redistribution and enhanced
excitability and whether metabolic redistribution through astrocyte networks maps retinotopically to spatial
sectors of intact RGC axon and dendritic function. Finally, Aim 3 will test whether boosting metabolic
resources reduces astrocyte stress, extends adaptive remodeling, and slows progression in mouse and non-
human primate models of glaucoma. Building from results in the prior grant period, our innovative strategy will
elucidate how two novel, intrinsically compensatory adaptive processes utilize metabolic resources to promote
RGC survival in glaucoma. By translating results to our non-human primate model, we will test the therapeutic
value of targeting enhanced excitability and metabolic redistribution as clinical interventions.

Grant Number: 5R01EY024997-10
NIH Institute/Center: NIH
Principal Investigator: David Calkins