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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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Graph of the mean (± SEM) severity score for individual optic nerves of mice as a function of age. This cohort of DBA/2J mice showed a steep increase in the prevalence of optic nerve degeneration at 9 months of age.
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Figure 2: Graph of the mean (± SEM) severity score for individual optic nerves of mice as a function of age. This cohort of DBA/2J mice showed a steep increase in the prevalence of optic nerve degeneration at 9 months of age.

Mentions: To quantify the extent of optic nerve degeneration in these mice, the pattern of label in each nerve was scored by 2 masked observers as described in the Methods. The time course of degeneration was then estimated by graphing the mean scores (± SEM) of nerves at each age (Fig. 2). Only a few mice aged 8 months or younger showed signs of degeneration using this labeling method. After 8 months the average level of degeneration rose dramatically and peaked at 11 months of age. The general pattern of age-related degeneration, as indicated by the DiI labeling technique, suggested that axonal degeneration followed a die-back pattern from the proximal end of the optic nerve to the distal end. To assess this pattern, we examined several nerves in different stages of disease histologically in transverse sections. Figure 3 shows a panel of silver stained sections taken at different intervals along 4 nerves. Surprisingly, nerves with early to moderate signs of degeneration using the DiI method (i.e., grades 2 and 3 nerves) showed mostly normal axon tracts throughout most of their length, but contained intermittent regions of degeneration beginning posterior of the lamina. These regions were marked by swollen axons and axonal fragments and could be found throughout the nerve, but were more prevalent in the proximal segment. Regions of degeneration were much more extensive in grade 4 nerves, while grade 5 nerves exhibited fewer axonal fragments and an increase in gliosis and connective tissue deposition.


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)

Graph of the mean (± SEM) severity score for individual optic nerves of mice as a function of age. This cohort of DBA/2J mice showed a steep increase in the prevalence of optic nerve degeneration at 9 months of age.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1621073&req=5

Figure 2: Graph of the mean (± SEM) severity score for individual optic nerves of mice as a function of age. This cohort of DBA/2J mice showed a steep increase in the prevalence of optic nerve degeneration at 9 months of age.
Mentions: To quantify the extent of optic nerve degeneration in these mice, the pattern of label in each nerve was scored by 2 masked observers as described in the Methods. The time course of degeneration was then estimated by graphing the mean scores (± SEM) of nerves at each age (Fig. 2). Only a few mice aged 8 months or younger showed signs of degeneration using this labeling method. After 8 months the average level of degeneration rose dramatically and peaked at 11 months of age. The general pattern of age-related degeneration, as indicated by the DiI labeling technique, suggested that axonal degeneration followed a die-back pattern from the proximal end of the optic nerve to the distal end. To assess this pattern, we examined several nerves in different stages of disease histologically in transverse sections. Figure 3 shows a panel of silver stained sections taken at different intervals along 4 nerves. Surprisingly, nerves with early to moderate signs of degeneration using the DiI method (i.e., grades 2 and 3 nerves) showed mostly normal axon tracts throughout most of their length, but contained intermittent regions of degeneration beginning posterior of the lamina. These regions were marked by swollen axons and axonal fragments and could be found throughout the nerve, but were more prevalent in the proximal segment. Regions of degeneration were much more extensive in grade 4 nerves, while grade 5 nerves exhibited fewer axonal fragments and an increase in gliosis and connective tissue deposition.

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