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B.K. Armstrong, L.A. Kehler, R.M. Sappington, D.J. Calkins; Müller Cell Activation Correlates with Photoreceptor Loss in DBA/2 Mice . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1562.
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© ARVO (1962-2015); The Authors (2016-present)
Glaucoma leads to visual field loss through a confluence of apoptotic and inflammatory events, which can include expression of glial fibrillary acidic protein (GFAP) by Müller cells. In age–related macular degeneration (AMD), activation of Müller cells correlates with photoreceptor loss. Using the DBA/2 mouse model of glaucoma, we examined region–specific changes in the expression of GFAP and correlated these changes with age and intraocular pressure (IOP). We also explored the relationship between Müller cell activation and photoreceptor number.
We harvested the retinas from 3 and 6 month old DBA/2 mice, whose IOP was measured monthly from 2 months of age using a Tono–pen, and examined GFAP expression and localization using immunohistochemistry in vertical paraffin sections. To quantify the region–specific localization of GFAP, we designated 250 µm intervals from the optic nerve head to the ora serrata and measured the labeled area. Using digital microscopy, we correlated GFAP localization with photoreceptor density and compared these values across different ages and IOP.
GFAP localization was particularly intense centrally near the optic nerve head and peripherally near the ora serrata. Between these regions, GFAP label was minimal and limited to astrocytes within the nerve fiber layer. GFAP localization near the ora serrata increased in Müller cells with increasing age and IOP. At 3 months of age, GFAP localization increased 3.5 fold near the ora serrata relative to other regions; at 6 months, this same localization increased 8–fold. In age–matched DBA/2 mice, GFAP expression increased near the ora serrata as average IOP increased. We found that as GFAP localization increased near the ora serrata, the density of photoreceptor nuclei within that region decreased. In young DBA/2 mice with relatively low IOP, there was a reduction in photoreceptor density of 30% at the ora serrata relative to other regions versus a 70% reduction in older and higher IOP DBA/2 for the same region.
Although retinal ganglion cell death is a major component of glaucomatous pathology, these data reveal that Müller glia and photoreceptors near the retinal margin may also contribute to disease progression. In particular, the modest loss of photoreceptors we observe in the DBA/2 may signal similarities to other ocular diseases, such as AMD. Furthermore, the regionally specific activation of GFAP near the ora serrata suggests that a breach in the blood retina barrier and peripheral inflammation could also be an important mechanism in this animal model of glaucoma.
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