Quantitative Analysis of Retinal Ganglion Cell (RGC) Loss in Aging DBA/2NNia Glaucomatous Mice: Comparison with RGC Loss in Aging C57/BL6 Mice

Danias, John; Lee, Kevin C.; Zamora, Maria-Florencia; Chen, Bin; Shen, Fran; Filippopoulos, Theodoros; Su, Yanling; Goldblum, David; Podos, Steven M.; Mittag, Thomas W.

doi:10.1167/iovs.02-1101

Cited by 191 publications

(186 citation statements)

References 26 publications

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“…This is consistent with findings of a considerable number of surviving axons in older optic nerves, even with diminished physiological activity (Fig. 6B) (14,17,36).…”

Section: Discussionsupporting

confidence: 92%

“…2), so additional pathogenic mechanisms must be at work early (30,36). Retrograde transport from the SC to the retina in the DBA/2 is maintained at 20% to 30% capacity up to 18 mo of age (16,17). Anterograde transport is challenged considerably earlier, with complete failure to the SC at 11 to 12 mo and to all RGC targets in the brain after 12 mo (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…DBA/2 mice present agedependent elevations in IOP as a result of pigmentary dispersion in the anterior eye that are linked to RGC degeneration (14,15). Retrograde transport from the SC persists as late as 18 months of age in the DBA/2 mouse (16,17). Here we examine anterograde transport from the retina to the superior colliculus (SC), the primary projection site for RGCs in the rodent brain (18,19).…”

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confidence: 99%

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Distal axonopathy with structural persistence in glaucomatous neurodegeneration

Crish

Sappington

Inman

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

313

487

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An early hallmark of neuronal degeneration is distal transport loss and axon pathology. Glaucoma involves the degeneration of retinal ganglion cell (RGC) neurons and their axons in the optic nerve. Here we show that, like other neurodegenerations, distal axon injury appears early in mouse glaucoma. Where RGC axons terminate in the superior colliculus, reduction of active transport follows a retinotopic pattern resembling glaucomatous vision loss. Like glaucoma, susceptibility to transport deficits increases with age and is not necessarily associated with elevated ocular pressure. Transport deficits progress distal-to-proximal, appearing in the colliculus first followed by more proximal secondary targets and then the optic tract. Transport persists through the optic nerve head before finally failing in the retina. Although axon degeneration also progresses distal-to-proximal, myelinated RGC axons and their presynaptic terminals persist in the colliculus well after transport fails. Thus, distal transport loss is predegenerative and may represent a therapeutic target.axon transport | optic neuropathy | retinal ganglion cell | glaucoma | optic nerve

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“…This is consistent with findings of a considerable number of surviving axons in older optic nerves, even with diminished physiological activity (Fig. 6B) (14,17,36).…”

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Distal axonopathy with structural persistence in glaucomatous neurodegeneration

Crish

Sappington

Inman

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

313

487

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“…Loss of RGCs in Tg mice was less pronounced than that in DBA/2 mice, which develop a progressive form of secondary angle-closure glaucoma (John et al, 1998). By the age of 15 months, there is an ϳ50% decrease in the number of RGCs in total retinas of DBA/2NNia mice compared with C57BL/6 mice (Danias et al, 2003). Enhanced damage of the RGC layer in the DBA/2 strain, compared with our Tg mice, correlates with a more dramatic increase in IOP, which, in most DBA/2J mice was 6 -7 mmHg higher than in control mice by the age of 9 months (Libby et al, 2005).…”

mentioning

confidence: 52%

Expression of Mutated Mouse Myocilin Induces Open-Angle Glaucoma in Transgenic Mice

Senatorov¹,

Malyukova²,

Fariss³

et al. 2006

J. Neurosci.

139

112

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“…This result may be due to the advanced age (~ 18 months old at the time of sacrifice) as well as the gender and strain difference. A sex difference has been reported for the susceptibility of DBA mice (John 1998) to glaucoma and the age-related decline of RGC numbers has been documented for several rat and mouse strains (Kawai 2001;Danias 2003). Our results on the total RGC counts in normal B-N rat eyes are less than those determined by Cepurna et al (Cepurna 1988) who used the same strain and estimated the total RGC count of B-N rats to be ~100K by a sampling count of the optic nerve axons.…”

Section: Discussionmentioning

confidence: 99%

Characterization of retinal damage in the episcleral vein cauterization rat glaucoma model

Danias

Shen

Kavalarakis

et al. 2006

Experimental Eye Research

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Episcleral vein cauterization (EVC) is used in rats to generate a glaucoma model with high intraocular pressure (IOP). The long-term retinal damage in this glaucoma model however, has not been accurately quantified. We report the location and amount of retinal ganglion cell (RGC) damage caused by (EVC) induced IOP elevation in two rat strains.IOP was raised in one eye of Wistar(N=5) and Brown-Norway(B-N)(N=7) rats by EVC and monitored monthly until IOP in contralateral eyes equalized at 5 months post-surgery. Animals were maintained for 3.5-4.5 additional months. B-N rats(N=7) that had no EVC served as controls for this strain. Scotopic flash ERGs were recorded at baseline and just prior to euthanasia. Automated counts of all retrogradely labeled RGCs in retinal flat-mounts were determined and compared between contralateral eyes. RGC density maps were constructed and RGC size distribution was determined.Oscillatory potentials in the group of eyes which had elevated IOP were decreased at the time of euthanasia, when IOP had returned to normal. A group of normal B-N rats had similar RGC counts between contralateral eyes. In the experimental group the mean number of RGCs was not significantly different between control and experimental eyes, but 1 of 5 Wistar and 2 of 7 B-N experimental eyes had at least 30% fewer RGCs from contralateral control eyes. Total retinal area in B-N experimental eyes was higher compared with contralateral eyes. Cumulative IOP exposure of the experimental eyes was modestly correlated with RGC loss while oscillatory potentials appeared to be inversely related to RGC loss. In retinas with extensive (>30% RGC loss) but not complete damage, smaller cells were preserved better than larger ones.The above results indicate that RGC loss in both Wistar and B-N strains is variable after a prolonged elevation of IOP via EVC. Such variability despite equivalent IOP levels and ERG abnormalities, suggests unknown factors that can protect IOP-stressed RGCs. Identification and enhancement of such factors could prove useful for glaucoma therapy.

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Quantitative Analysis of Retinal Ganglion Cell (RGC) Loss in Aging DBA/2NNia Glaucomatous Mice: Comparison with RGC Loss in Aging C57/BL6 Mice

Abstract: Age-related RGC loss of up to 50% can occur in the C57 mouse by 18 months of age. The loss does not proceed linearly with age, as is often assumed, and differs both in extent and locational pattern from pathologic RGC loss secondary to glaucoma in DBA/2NNia mouse retinas.

Cited by 191 publications

References 26 publications

Distal axonopathy with structural persistence in glaucomatous neurodegeneration

Distal axonopathy with structural persistence in glaucomatous neurodegeneration

Expression of Mutated Mouse Myocilin Induces Open-Angle Glaucoma in Transgenic Mice

Characterization of retinal damage in the episcleral vein cauterization rat glaucoma model

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