During the last two decades it has become clear that the retina is not just a static network of neurons. Retinal neurons change their properties and connections during aging or disease in a process termed retinal remodeling or plasticity. However, mechanisms that mediate plasticity, as well as the impact of plasticity on light signaling in the retina and vision are still poorly defined. Our long-term goal is to advance the field of retinal remodeling towards development of vision restoration therapies with improved outcomes. This goal is achieved by (i) determining compensatory mechanisms in the retina that can promote vision, and (ii) quantifying the impact of remodeling on the retinal output and vision during photoreceptor degenerative disease. Our central hypothesis is that a partial loss of sensory input from rods increases the gain of transmission of the remaining input to rod bipolar cells (RBCs) in the retina to promote vision, whereas extensive loss of the sensory input leads to a corruption of the light signal transmission and exacerbation of vision loss. This central hypothesis will be tested in a mouse model of autosomal dominant retinitis pigmentosa caused by the rhodopsin P23H mutation. The rationale of this project is that delineating a compensatory mechanism in the retina will yield an accessible target for promoting vision in photoreceptor degenerative diseases where this does not happen naturally. Secondly, new knowledge about the impact and time course of constructive and destructive remodeling in the retina on vision will generate critical information about the expected outcomes of vision restoration therapies. The central hypothesis will be tested in two specific aims: 1) Determine the mechanism underlying the increase of rod - RBC signal transmission at early stages of retinal degenerative disease; and 2) Determine the impact of inner retinal remodeling on light signal transmission during photoreceptor degenerative disease. In the first aim, a working hypothesis that rod – RBC transmission is potentiated in P23H mice via synaptotagmin-1 (Syt1)-dependent pathway in rod synaptic terminal will be tested by using P23H mice with a rod-specific deletion of Syt1 and in vivo/ex vivo Electroretinogram as well as patch clamp physiology. In addition, these mice will be used to determine the impact of this compensatory mechanism on vision using behavior methods. In the second aim, genetic silencing of photoreceptors and optogenetics will be used together with ganglion cell multielectrode array electrophysiology in P23H mice to evaluate the impact of inner retina remodeling on ganglion cell output during photoreceptor degeneration from early to late-stage disease. This innovative work 1) challenges current dogma of destructive remodeling by asserting that in some retinal degenerative diseases, the retina compensates for the loss of photoreceptors to maintain stable output and vision; and 2) applies genetic and optogenetic tools to determine the causal role of remodeling on retinal output signal and vision. The proposed research is significant because it will transform our understanding of plasticity in the retina and how it impacts retinal function and vision, critical knowledge required for restoring normal vision at different stages of blinding disease.

Narrative The proposed research is relevant to public health because it reveals a compensatory plasticity mechanism induced by cell death that could be harnessed as a treatment strategy to promote vision in photoreceptor degenerative diseases where compensation does not naturally occur. Secondly, this work will define the time course of constructive and destructive remodeling in the inner retina to better understand expected prognoses of retinitis pigmentosa diseases and their treatment outcomes by photoreceptor or optogenetic rescue therapies. Thus, this research is relevant to NEI’s goal to understand how plasticity and rewiring impacts signaling between photoreceptors and neurons and how this could be harnessed in degenerative disease and injury.