Abstract
Introduction: The complexity of the retina is a challenge to the design of neuroprosthetic devices. It is now clear that the neural retina is not a passive bystander in retinal degenerations (RDs) and that extensive remodeling occurs on tissue, cellular, synaptic and molecular scales (Jones et al. 2003 J Comp Neurol 464: 1–16, Marc et al. 2003 Prog Ret Eye Res 22: 607–655). All intervention schemata (genetic, cellular or bionic) for blinding diseases will have to address the ongoing processes of neuronal death, gene expression revision, neuronal rewiring, neuronal migration, and the formation new glial barriers. I will review the nature and scope of retinal remodeling, focusing on critical rewiring phenomena that may represent the greatest challenge to artificial vision. Indeed prosthetics may be the essential tools with which to repattern retinal circuits.
Methods: We have used computational molecular phenotyping (CMP) to screen over twenty RD models, comprehensively tracking all cell types. The CMP platform is based on a library of quantitative small molecule probes, nanoscale sample preparation, multichannel imaging and N-space pattern recognition analysis. The platform can be coupled with molecular tools (organic cation permeation) for mapping excitation histories of neurons. The systems screened include mixed forms of human retinitis pigmentosa, genetic rodent models (rat S344ter, P23H, and RCS; mouse rd1, GHL, TG9N, nr, or, chx10, p27kip1-chx10 dual mutant, pcd, rd2, rho-/-, rho deltaCTA, hrhoG) and the Sprague-Dawley light damage (LD) model.
Remodeling Processes: Remodeling occurs in three phases. In Phase 1, primary bipolar cell signaling pathways are revised in response to pre-death photoreceptor stress. In Phase 2, both glial and neuronal structures are extensively transformed during photoreceptor death. 3. In Phase 3, the deafferented neural retina enters an extended era of remodeling that includes neuronal death, gene revision, rewiring, and migration. Remarkably, in the absence of any photoreceptor drive, ganglion and amacrine cell networks are initially very active, revealing the existence of endogenous pathway drivers. Rewiring into arrays of resonant and corruptive ectopic micronetworks continues, suggesting that deafferented neurons are in search of synaptic partners. Indeed, bipolar cells lose their entire dendritic input module and permanently repress glutamate receptor expression. Ganglion cells engage in new connective patterns that undoubtedly corrupt their spatiotemporal attributes. Finally, progressive neuronal death in some models (including human RP) further degrades signaling.
Conclusions: The remnant neural retina engages in a wide range of reorganizations that are invisible to routine histological and physiologic probes. CMP and excitation mapping together reveal the presence of extensive negative remodeling, which appears partly driven by neuronal searches for excitation. In this respect, retinal remodeling resembles CNS sensory deafferentation responses and epileptogenic remodeling. On the single-cell level, this represents significant plasticity in mature survivor neurons. At the systems level, the aggregate effect is likely to be negative. These phenomena challenge every rescue scheme yet devised. Indeed, remodeling is part of the disease process and demands its own spectrum of interventions.