Rod photoreceptor death is a significant cause of human blindness, and much research effort has been expended towards their rescue or replacement using gene or stem cell therapy. However, rod death is followed by secondary changes in the inner retina such as dendritic remodeling, cell migration, and rewiring. The extent to which this reorganization obstructs the potential for recovery of vision following photoreceptor rescue is not known. The objective of this proposal is to examine signal processing in the affected retina following the genetic rescue of rods. To this end, we have created a mouse model of retinal degeneration caused by loss of expression of the ?-subunit of the cyclic nucleotide-gated (CNG?1) channel, a model for autosomal recessive retinitis pigmentosa in humans. The novelty of this mouse model is that CNG?1 can be expressed from the endogenous locus in all affected CNGB1-/- rods upon tamoxifen(TX)-inducible Cre- mediated recombination, leading to rod rescue. This proposal utilizes this mouse line to determine the impact of rescuing rod function on retinal signal processing.
In Aim 1 we will examine how the structure and function of rod photoreceptors recovers following the restoration of CNG?1 expression. In particular we will examine the extent of functional recovery when TM is administered in mice with increasing severity of retinal degeneration, as this may identify a critical window for the efficacy of rod recovery and halting further degeneration.
In Aim 2 we will examine how the synapse between rods and their primary postsynaptic partner, rod bipolar cells, is reformed following rod rescue. Synapses between rods and rod bipolar cells form retinal circuits that regulate our night vision. Finally, in Aim 3 we will evaluate how rod rescue impacts the function of retinal ganglion cells, which are the sole conduit for signals from the retina to reach higher brain areas. The central hypothesis is that while light sensitivity will recover substantially with rod rescue, some deficits in retinal signaling will persist and worsen at late rescue ages due to secondary changes in retinal circuits. These studies will define the window of opportunity for therapeutic intervention and provide a foundation for future studies aimed at reversing the negative effects of neural remodeling.
Genetic and environmental injuries to rod photoreceptor cells underlie many forms of human blindness. Rod death leads to rewiring of the downstream retinal circuit, but how this remodeled circuit processes input from rods after rescue by gene therapy, or replacement by stem cell therapy, is not known. Our project addresses this important question so that future strategies for full restoration of visual function can be developed.
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