Glaucoma is a disease of the visual system often characterized by pressure-induced damage to the optic nerve. This results not only in a loss of ganglion cells from the retina, but also degeneration of their target neurons in the lateral geniculate nucleus (LGN) of the thalamus. While numerous studies have shown that direct application of neurotrophic factors to the eye can reduce ganglion cell loss following optic nerve injury, an important issue that has not been addressed is whether 'rescued'neurons retain their normal structural and functional properties, and thus were worth saving. The first specific aim of this proposal is to compare the morphologies and visual response properties of ganglion cells from normal eyes with those from eyes that have received either an optic nerve injury alone, or nerve injury combined with intraocular treatment of brain-derived neurotrophic factor (BDNF), a potent neuroprotectant in the eye. The basic mechanism underlying the progressive neuropathy that characterizes glaucoma is thought to be a reduction in the level of trophic material retinal ganglion cells receive from their target neurons in the LGN due to the nerve injury. This results not only from pressure-induced blockage of axonal transport within the nerve, but also the progressive loss of target neurons, and thus trophic factor levels, within the LGN itself. At present, however, no data are available concerning the extent to which treatment beyond the eye might enhance and/or prolong ganglion cell survival compared with treatment of the eye alone. The second specific aim of this study will examine the neuroprotective effects that application of BDNF to both the eye and thalamus has on retinal ganglion cell and LGN neuron survival following different durations post nerve injury. In all cases, the structural and functional integrity of the retina, as well as the entire central visual pathway, will be assessed using non-invasive electroretinographic and visual evoked methods, and with intracellular recording and labeling of single ganglion cells using our isolated, living retina, preparation. The proposed studies represent a continuation of our previous work concerning optic nerve injury and retinal ganglion cell degeneration. They will provide new and important information concerning the functional integrity of ganglion cells following trophic factor-based rescue, and they will advance our understanding of the extent to which new treatment strategies for long-term ganglion cell survival and central visual pathway stability also should include treatment beyond the eye itself.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Agarwal, Neeraj
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Michigan State University
Anatomy/Cell Biology
Schools of Medicine
East Lansing
United States
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Weber, Arthur J; Harman, Christine D (2013) BDNF treatment and extended recovery from optic nerve trauma in the cat. Invest Ophthalmol Vis Sci 54:6594-604
Weber, Arthur J; Viswanathan, Suresh; Ramanathan, Chidambaram et al. (2010) Combined application of BDNF to the eye and brain enhances ganglion cell survival and function in the cat after optic nerve injury. Invest Ophthalmol Vis Sci 51:327-34
Weber, A J; Harman, C D; Viswanathan, S (2008) Effects of optic nerve injury, glaucoma, and neuroprotection on the survival, structure, and function of ganglion cells in the mammalian retina. J Physiol 586:4393-400
Weber, Arthur J; Harman, Christine D (2008) BDNF preserves the dendritic morphology of alpha and beta ganglion cells in the cat retina after optic nerve injury. Invest Ophthalmol Vis Sci 49:2456-63
Weber, Arthur J; Harman, Christine D (2005) Structure-function relations of parasol cells in the normal and glaucomatous primate retina. Invest Ophthalmol Vis Sci 46:3197-207
Chen, Hao; Weber, Arthur J (2004) Brain-derived neurotrophic factor reduces TrkB protein and mRNA in the normal retina and following optic nerve crush in adult rats. Brain Res 1011:99-106
Chen, Hao; Weber, Arthur J (2002) Expression of glial fibrillary acidic protein and glutamine synthetase by Muller cells after optic nerve damage and intravitreal application of brain-derived neurotrophic factor. Glia 38:115-25
Weber, A J; Zelenak, D (2001) Experimental glaucoma in the primate induced by latex microspheres. J Neurosci Methods 111:39-48
Chen, H; Weber, A J (2001) BDNF enhances retinal ganglion cell survival in cats with optic nerve damage. Invest Ophthalmol Vis Sci 42:966-74
Weber, A J; Chen, H; Hubbard, W C et al. (2000) Experimental glaucoma and cell size, density, and number in the primate lateral geniculate nucleus. Invest Ophthalmol Vis Sci 41:1370-9

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