Primary open-angle glaucoma (POAG) is a leading cause of blindness. Clinically, most cases of POAG are characterized by an increase in intraocular pressure (IOP), progressive changes in the structure of the optic disc, and visual field defects. While numerous studies have focused on the degenerative effects that chronic elevation of IOP has on fibers in the optic nerve, few data are available concerning the pattern or the time course of glaucomatous neuropathy that occurs within the primate retina or its central target, the dorsal lateral geniculate nucleus (LGN). The overall goal of the proposed research is to define the temporal relation between the onset and progression of glaucoma measured clinically, and the degeneration of retinal ganglion cells and LGN neurons. Since no previous glaucoma-related study has examined the morphology of single ganglion cells, a necessary first step is to identify those structural features that characterize ganglion cell degeneration in the glaucomatous eye. To do this, the somata and dendritic fields of ganglion cells in the retinae of normal monkeys and monkeys with clinically well-defined, experimentally-induced, glaucoma will be compared by labeling single ganglion cells intracellularly in an in vitro retinal preparation. Once the structural features characteristic of ganglion cell degeneration are defined, the next series of experiments will determine the duration of increased intraocular pressure that produces the earliest detectable changes in ganglion cell morphology. Single ganglion cells will be injected in the retinae of monkeys that have had the pressure in one eye elevated for a period of time ranging from 2 weeks to 3 months. The focus of these experiments, which is the central goal of the proposed studies, is to define the temporal relation between clinically recognizable glaucomatous neuropathy and the onset and progression of retinal ganglion cell degeneration, thus establishing the level of neuronal damage that may precede, as well as accompany, the clinical stages of the disease. The proposed work also will address the possibility that glaucoma affects different classes of ganglion cells, and therefore different functional visual channels selectively. Previous studies, based on Niss1-staining of cell bodies, have suggested that large ganglion cells (presumably parasol cells-M pathway) may be more vulnerable than the smaller, midget, ganglion cells (P pathway). Since intracellular dye injection stains not only the cell body but also the dendritic tree of ganglion cells, the proposed experiments make it possible to determine unequivocally whether parasol cells are affected preferentially during the early stages of glaucoma. Further, since midget and parasol cells project to different layers of the LGN, comparison of the neuronal changes in the parvo- and magnocellular layers of the LGN, which receive input from midget and parasol ganglion cells respectively, will provide additional information regarding possible selective effects of glaucoma. Because the M and P pathways subserve different visual functions, the results of these experiments have the potential to direct the future development of more sensitive and specific tests for the early detection of glaucoma. The results also will serve as the basis for later exploring new treatments aimed at mitigating or preventing glaucoma-induced ganglion cell degeneration, by delivering neuroprotectants to the glaucomatous eye.
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