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Liang Feng, Yan Zhao, Miho Yoshida, Sarah Lindstrom, Ted S. Kim, Jianhua Cang, John B. Troy, Xiaorong Liu; Subtype- and Location- Dependent Degeneration of Retinal Ganglion Cells in a Mouse Model of Ocular Hypertension. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6602.
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Glaucoma, a group of neurodegenerative diseases characterized by selective loss of retinal ganglion cells (RGCs), is one of the leading causes of blindness worldwide. Unfortunately, it is not well understood how RGCs degenerate and die with the progression of glaucoma. In this study, we examined the progressive destruction of RGC structure and function before their death in a mouse model of experimental glaucoma.
Because glaucoma is often associated with elevated intraocular pressure (IOP), we have adopted a mouse model of glaucoma using laser photocoagulation to induce ocular hypertension. Combining the ocular hypertension model with transgenic Thy-1-YFP mouse line, in which a small number of RGCs were labeled with yellow fluorescence protein, we investigated the dendritic atrophy of RGCs. Next, using a 256-channel multi-electrode array (MEA) to record visual responses of large population of RGCs, we examined their functional degeneration in glaucomatous eyes.
We first confirmed a sustained IOP elevation and a gradual RGC loss in laser-treated mice. We next demonstrated that the dendritic shrinkage of RGCs started from the vertical axis of the glaucomatous eyes, and preceded RGC soma shrinkage. Based on the lamination pattern of RGC dendrites in the inner plexiform layer, we classified RGCs into ON, OFF, and ON-OFF three subgroups. We found that ON cells were more susceptible to the IOP elevation than ON-OFF cells in the superior and inferior quadrants. A subgroup ON RGCs labeled by SMI-32 antibody exhibited a significant decrease in the dendritic coverage area in the laser-treated eyes, further supporting that the dendritic atrophy of RGCs is subtype-dependent in glaucoma. Using the MEA recordings, we found a higher mean spontaneous firing rate and fewer light-responsive cells in glaucomatous eyes compared to controls. We also confirmed a decrease in the visual acuity and contrast sensitivity of glaucomatous eyes using the optomotor behavioral test.
Taken together, our data demonstrate the subtype- and location- dependent degeneration of RGCs in mice with ocular hypertension. Our study establishes a valuable model system for the understanding and early prevention of RGC degeneration and vision loss in glaucoma.
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