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Progressive ganglion cell loss and optic nerve degeneration in DBA/2J mice is variable and asymmetric.

Schlamp CL, Li Y, Dietz JA, Janssen KT, Nickells RW - BMC Neurosci (2006)

Bottom Line: Degeneration appears to follow a retrograde course with axons dying from their proximal ends toward the globe.Some nerves also exhibit focal preservation of tracts of axons generally in the nasal peripheral region.Similar to what we observe in the optic nerves, ganglion cell loss is often asymmetric between the eyes of the same animal.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI, USA. clschlamp@wisc.edu

ABSTRACT

Background: Glaucoma is a chronic neurodegenerative disease of the retina, characterized by the degeneration of axons in the optic nerve and retinal ganglion cell apoptosis. DBA/2J inbred mice develop chronic hereditary glaucoma and are an important model system to study the molecular mechanisms underlying this disease and novel therapeutic interventions designed to attenuate the loss of retinal ganglion cells. Although the genetics of this disease in these mice are well characterized, the etiology of its progression, particularly with respect to retinal degeneration, is not. We have used two separate labeling techniques, post-mortem DiI labeling of axons and ganglion cell-specific expression of the betaGeo reporter gene, to evaluate the time course of optic nerve degeneration and ganglion cell loss, respectively, in aging mice.

Results: Optic nerve degeneration, characterized by axon loss and gliosis is first apparent in mice between 8 and 9 months of age. Degeneration appears to follow a retrograde course with axons dying from their proximal ends toward the globe. Although nerve damage is typically bilateral, the progression of disease is asymmetric between the eyes of individual mice. Some nerves also exhibit focal preservation of tracts of axons generally in the nasal peripheral region. Ganglion cell loss, as a function of the loss of betaGeo expression, is evident in some mice between 8 and 10 months of age and is prevalent in the majority of mice older than 10.5 months. Most eyes display a uniform loss of ganglion cells throughout the retina, but many younger mice exhibit focal loss of cells in sectors extending from the optic nerve head to the retinal periphery. Similar to what we observe in the optic nerves, ganglion cell loss is often asymmetric between the eyes of the same animal.

Conclusion: A comparison of the data collected from the two cohorts of mice used for this study suggests that the initial site of damage in this disease is to the axons in the optic nerve, followed by the subsequent death of the ganglion cell soma.

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βGeo staining pattern of DBA/2JR3/+ mice showing distinct patterns of ganglion cell loss. (A) A retinal lobe of a young mouse showing normal staining for βGeo activity. (B) A retinal lobe from an older mouse (9 months), showing regional loss of ganglion cells in a sector of retina with adjacent regions of normal retina. (C) A retinal lobe from an old mouse (11.5 months) showing diffuse loss of ganglion cells generally uniformly across the retina. In this cohort of mice, the pattern of cell loss seen in the example in (B) was exhibited principally in middle-aged mice (8–9 months), with early signs of degeneration. Bar = 0.5 mm.
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Figure 7: βGeo staining pattern of DBA/2JR3/+ mice showing distinct patterns of ganglion cell loss. (A) A retinal lobe of a young mouse showing normal staining for βGeo activity. (B) A retinal lobe from an older mouse (9 months), showing regional loss of ganglion cells in a sector of retina with adjacent regions of normal retina. (C) A retinal lobe from an old mouse (11.5 months) showing diffuse loss of ganglion cells generally uniformly across the retina. In this cohort of mice, the pattern of cell loss seen in the example in (B) was exhibited principally in middle-aged mice (8–9 months), with early signs of degeneration. Bar = 0.5 mm.

Mentions: Using the R3 marker also allowed us to examine the pattern of cell loss over the whole retina. Essentially two patterns of loss were observed (Fig. 7). Mice aged between 8.5 and 10 months often showed regional cell loss, typically in wedge-shaped patterns extending from the optic nerve to peripheral retina. Older mice often exhibited more uniform cell loss, suggesting that areas of regional loss may coalesce as the disease progresses. For statistical analysis, we selected all the retinas that were scored as 1.5 or greater as being eyes with at least some degree of damage. Scores for individual lobes were compared to determine if particular regions of the retina were more susceptible than others to degeneration. No significant association was found (P = 0.75, ANOVA) indicating that regional loss occurred randomly around the retina. We then compared scores for peripheral and central retinal regions. In this analysis, we also found that cells were not preferentially lost in either retinal region (P values ranged from 0.72 to 0.99 by ANOVA, when individual regions of the retinas were tested separately).


Progressive ganglion cell loss and optic nerve degeneration in DBA/2J mice is variable and asymmetric.

Schlamp CL, Li Y, Dietz JA, Janssen KT, Nickells RW - BMC Neurosci (2006)

βGeo staining pattern of DBA/2JR3/+ mice showing distinct patterns of ganglion cell loss. (A) A retinal lobe of a young mouse showing normal staining for βGeo activity. (B) A retinal lobe from an older mouse (9 months), showing regional loss of ganglion cells in a sector of retina with adjacent regions of normal retina. (C) A retinal lobe from an old mouse (11.5 months) showing diffuse loss of ganglion cells generally uniformly across the retina. In this cohort of mice, the pattern of cell loss seen in the example in (B) was exhibited principally in middle-aged mice (8–9 months), with early signs of degeneration. Bar = 0.5 mm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC1621073&req=5

Figure 7: βGeo staining pattern of DBA/2JR3/+ mice showing distinct patterns of ganglion cell loss. (A) A retinal lobe of a young mouse showing normal staining for βGeo activity. (B) A retinal lobe from an older mouse (9 months), showing regional loss of ganglion cells in a sector of retina with adjacent regions of normal retina. (C) A retinal lobe from an old mouse (11.5 months) showing diffuse loss of ganglion cells generally uniformly across the retina. In this cohort of mice, the pattern of cell loss seen in the example in (B) was exhibited principally in middle-aged mice (8–9 months), with early signs of degeneration. Bar = 0.5 mm.
Mentions: Using the R3 marker also allowed us to examine the pattern of cell loss over the whole retina. Essentially two patterns of loss were observed (Fig. 7). Mice aged between 8.5 and 10 months often showed regional cell loss, typically in wedge-shaped patterns extending from the optic nerve to peripheral retina. Older mice often exhibited more uniform cell loss, suggesting that areas of regional loss may coalesce as the disease progresses. For statistical analysis, we selected all the retinas that were scored as 1.5 or greater as being eyes with at least some degree of damage. Scores for individual lobes were compared to determine if particular regions of the retina were more susceptible than others to degeneration. No significant association was found (P = 0.75, ANOVA) indicating that regional loss occurred randomly around the retina. We then compared scores for peripheral and central retinal regions. In this analysis, we also found that cells were not preferentially lost in either retinal region (P values ranged from 0.72 to 0.99 by ANOVA, when individual regions of the retinas were tested separately).

Bottom Line: Degeneration appears to follow a retrograde course with axons dying from their proximal ends toward the globe.Some nerves also exhibit focal preservation of tracts of axons generally in the nasal peripheral region.Similar to what we observe in the optic nerves, ganglion cell loss is often asymmetric between the eyes of the same animal.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI, USA. clschlamp@wisc.edu

ABSTRACT

Background: Glaucoma is a chronic neurodegenerative disease of the retina, characterized by the degeneration of axons in the optic nerve and retinal ganglion cell apoptosis. DBA/2J inbred mice develop chronic hereditary glaucoma and are an important model system to study the molecular mechanisms underlying this disease and novel therapeutic interventions designed to attenuate the loss of retinal ganglion cells. Although the genetics of this disease in these mice are well characterized, the etiology of its progression, particularly with respect to retinal degeneration, is not. We have used two separate labeling techniques, post-mortem DiI labeling of axons and ganglion cell-specific expression of the betaGeo reporter gene, to evaluate the time course of optic nerve degeneration and ganglion cell loss, respectively, in aging mice.

Results: Optic nerve degeneration, characterized by axon loss and gliosis is first apparent in mice between 8 and 9 months of age. Degeneration appears to follow a retrograde course with axons dying from their proximal ends toward the globe. Although nerve damage is typically bilateral, the progression of disease is asymmetric between the eyes of individual mice. Some nerves also exhibit focal preservation of tracts of axons generally in the nasal peripheral region. Ganglion cell loss, as a function of the loss of betaGeo expression, is evident in some mice between 8 and 10 months of age and is prevalent in the majority of mice older than 10.5 months. Most eyes display a uniform loss of ganglion cells throughout the retina, but many younger mice exhibit focal loss of cells in sectors extending from the optic nerve head to the retinal periphery. Similar to what we observe in the optic nerves, ganglion cell loss is often asymmetric between the eyes of the same animal.

Conclusion: A comparison of the data collected from the two cohorts of mice used for this study suggests that the initial site of damage in this disease is to the axons in the optic nerve, followed by the subsequent death of the ganglion cell soma.

Show MeSH
Related in: MedlinePlus