In rodent models of retinitis pigmentosa (RP), age-related macular dystrophy (AMD) and cone-rod dystrophies (CORD), late global negative remodeling of the remnant neural retina emerges and matches the transformations now known to occur in human RP and AMD. Following loss of the outer nuclear layer, new pathologies characteristic of CNS denervation and remodeling emerge, including: evolution of panretinal glial barriers, neuron migration, progressive neuronal loss, growth of new neurite fascicles and ectopic synaptic foci, and extensive rewiring. Remodeling and negative plasticity limit therapeutic windows for genetic, molecular, cellular and bionic rescue by compromising access, corrupting signaling and altering intercellular recognition. We propose (i) a comprehensive spatiotemporal analysis of remodeling to define sites and epochs of intercession; (ii) analysis of the nature of rewiring and anomalous synaptic plasticity; and (iii) exploration of possible mechanisms driving the emergent neural plasticity. ? ? Aim 1: Define the patterns and chronologies of remodeling in retinal degenerations with computational molecular phenotyping (CMP). The emergence and, most critically, the spatial patterning of glial seals, neuronal migration and microneuromas will constrain therapeutic windows and molecular strategies. ? ? Aim 2: Determine how remodeling retinas self-signal without photoreceptors and the extent to which novel circuitry is normal or aberrant. Characterize circuit remodeling with ultrastructural molecular phenotyping, excitation mapping, single unit recording and dialkylcarbocyanine dye imaging. Plasticity is a hallmark of CNS trauma responses and plastic rewiring delimits the functionality of survivor neuron cohorts. ? ? Aim 3: Test the hypotheses that (i) active recovery of Ca-based synaptic drive and (ii) changes in ? integrin/integrin receptor expression are major factors driving remodeling. We will attempt to modify the course of remodeling with surface-active substrates, ectopic current, and pharmacologic interventions. Restoring retinas must eventually involve guiding remodeled and implanted cells to assume functional architectures. Failing that, remodeling must be prevented or rescues instituted prior to remodeling onset. ? ?
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