It is well recognized that the photoreceptor synaptic terminal responds to injury and disease by making structural changes. In retinal detachment the rod axon retracts toward the cell body, thereby uncoupling the first synapse in the visual pathway, whereas in human and animal retinal degenerations, the photoreceptors grow long neurites or make new synapses with other retinal cells. Although these changes are harmful to the retina and lead to further structural remodeling by second and third order retinal neurons, these changes also hold out promise that retinal transplantation is possible since they show that photoreceptor synapses are capable of structural plasticity. This proposal examines the mechanisms involved in synaptic changes in amphibian and mammalian photoreceptor cells and has the following specific aims: 1) to test the hypothesis that RhoA activation initiates axonal retraction of rod photoreceptors after retinal detachment and 2) to test the hypothesis that cytokines released by reactive glia stimulate remodeling in retinal injury and work through RhoA-dependent pathways. Rod and cone photoreceptors will be treated with antagonists and agonists of RhoA. Synaptic plasticity will be examined by immunocytochemistry, confocal laser scanning microscopy, and image analysis. Microinjecting extracellular factors directly onto axon terminals of isolated photoreceptors followed by conventional and video time-lapse microscopy, will test exogenous factors and the role of glial cells in synaptic restructuring. These projects explore the fundamental mechanisms involved in the plasticity of the photoreceptor synapse after retinal detachment and hope to provide a rational basis for future repair of the retina by manipulation of endogenous cellular pathways and/or reduction of glial cell activation.
Retinal degeneration, whether it is caused by retinal detachment, hereditary disease, or age, causes a dramatic rewiring of the retina that can harm the retina even before photoreceptors begin to die. Understanding the mechanisms, which cause this restructuring, could reduce these changes and help maintain normal vision for a longer period of time during retinal disease. After loss of photoreceptors, transplantation of photoreceptors may be desired. Understanding synaptic plasticity by rod and cone cells will promote successful synaptic integration of a transplant.
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