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The Journal of Neuroscience, January 9, 2008, 28(2):548-561; doi:10.1523/JNEUROSCI.3714-07.2008

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Neurobiology of Disease
Retinal Ganglion Cells Downregulate Gene Expression and Lose Their Axons within the Optic Nerve Head in a Mouse Glaucoma Model

Ileana Soto,^1,4 Ericka Oglesby,⁴ Brian P. Buckingham,⁵ Janice L. Son,⁴ Elisha D. O. Roberson,^3,4 Michael R. Steele,⁶ Denise M. Inman,⁵ Monica L. Vetter,⁶ Philip J. Horner,⁵ and Nicholas Marsh-Armstrong^1,2,4

¹Solomon H. Snyder Department of Neuroscience, ²Department of Ophthalmology, ³Graduate Program in Human Genetics, Johns Hopkins University School of Medicine, and ⁴Kennedy Krieger Research Institute, Baltimore, Maryland 21205, ⁵Department of Neurological Surgery, University of Washington, Seattle, Washington 98104, and ⁶Department of Neurobiology and Anatomy, University of Utah, Salt Lake, Utah 84132

Correspondence should be addressed to Dr. Nicholas Marsh-Armstrong, Kennedy Krieger Research Institute, 707 North Broadway, Baltimore, MD 21205. Email: marsh-armstrong{at}kennedykrieger.org

Little is known about molecular changes occurring within retinal ganglion cells (RGCs) before their death in glaucoma. Taking advantage of the fact that -synuclein (Sncg) mRNA is expressed specifically and highly in adult mouse RGCs, we show in the DBA/2J mouse model of glaucoma that there is not only a loss of cells expressing this gene, but also a downregulation of gene expression of Sncg and many other genes within large numbers of RGCs. This downregulation of gene expression within RGCs occurs together with reductions in FluoroGold (FG) retrograde transport. Surprisingly, there are also large numbers of Sncg-expressing cells without any FG labeling, and among these many that have a marker previously associated with disconnected RGCs, accumulation of phosphorylated neurofilaments in their somas. These same diseased retinas also have large numbers of RGCs that maintain the intraocular portion while losing the optic nerve portion of their axons, and these disconnected axons terminate within the optic nerve head. Our data support the view that RGC degeneration in glaucoma has two separable stages: the first involves atrophy of RGCs, whereas the second involves an insult to axons, which causes the degeneration of axon portions distal to the optic nerve head but does not cause the immediate degeneration of intraretinal portions of axons or the immediate death of RGCs.

Key words: retinal ganglion cell; axonal transport; axoplasmic transport; glaucoma; synuclein; axonopathy; DBA/2J

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Received March 30, 2007; revised Nov. 14, 2007; accepted Nov. 23, 2007.

Correspondence should be addressed to Dr. Nicholas Marsh-Armstrong, Kennedy Krieger Research Institute, 707 North Broadway, Baltimore, MD 21205. Email: marsh-armstrong{at}kennedykrieger.org

This article has been cited by other articles:

				A. Bosco, D. M. Inman, M. R. Steele, G. Wu, I. Soto, N. Marsh-Armstrong, W. C. Hubbard, D. J. Calkins, P. J. Horner, and M. L. Vetter Reduced Retina Microglial Activation and Improved Optic Nerve Integrity with Minocycline Treatment in the DBA/2J Mouse Model of Glaucoma Invest. Ophthalmol. Vis. Sci., April 1, 2008; 49(4): 1437 - 1446. [Abstract] [Full Text] [PDF]

				B. P. Buckingham, D. M. Inman, W. Lambert, E. Oglesby, D. J. Calkins, M. R. Steele, M. L. Vetter, N. Marsh-Armstrong, and P. J. Horner Progressive Ganglion Cell Degeneration Precedes Neuronal Loss in a Mouse Model of Glaucoma J. Neurosci., March 12, 2008; 28(11): 2735 - 2744. [Abstract] [Full Text] [PDF]

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