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. 2007 Dec 31;179(7):1523–1537. doi: 10.1083/jcb.200706181

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Copyright © 2007, The Rockefeller University Press

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Figure 4. — Early damage to RGC axons occurs at the lamina. RGC axons were analyzed for glaucomatous damage at different locations as they extend across the retina and exit the eye. Damage was assessed in the nerve fiber layer (NFL), the prelamina, and glial lamina regions of the optic nerve. All mice were 11 mo old and had no or early glaucoma based on analysis of the retro-orbital optic nerve. (A–C) D2-Gpnmb ⁺ no glaucoma controls, the axons were healthy and had normal morphology at all locations based on electron microscopy. Only rare damaged axons were detected. This rare age-related damage occurs in aged mice of various strains that do not develop glaucoma. (D–F) The axons of age- and sex-matched DBA/2J mice with early glaucoma did not differ from controls at any intraocular location, as they extended from the cell body to the lamina. At the glial lamina, however, dystrophic neurites (F, arrows) were readily detected. (G and H) The dystrophic neurites (arrows) consisted of swollen and damaged axon segments containing an accumulation of organelles including swollen mitochondria (arrowhead). (I and J) Due to the accumulation and disorganization of axonal contents, dystrophic neurites were also detected using a combination of both nonphosphorylated (Smi32) and phosphorylated (Smi34) neurofilament antibodies (green). They were visible as abnormally large and bright staining, damaged axon regions (arrows) in the lamina. Although dystrophic neurites labeled with each antibody (not depicted), we used the combination to maximize the intensity of staining. GFAP-positive astrocytes are shown in red. (K and L) Counting dystrophic neurites indicates that the first site of morphological damage to the intraocular RGC axon occurs in the lamina. The average number of dystrophic neurites (DNs) per EM field in the lamina was significantly higher in DBA/2J mice with no or early glaucoma compared with the no glaucoma D2-Gpnmb ⁺ controls (K, left panel, P < 0.001, t test, n = 8 eyes per genotype). This clearly demonstrates that dystrophic neurites are part of the glaucoma process and not just age-related changes. Comparing the indicated regions, the number of dystrophic neurites was highest in the lamina (P < 0.001). (L) Neurofilament and GFAP staining were used to assess serial, optic nerve cross sections extending from the nerve fiber layer at the retinal surface and into the lamina. Counting neurofilament-stained dystrophic neurites confirmed the EM findings. The values for individual DBA/2J eye show that at this age some eyes were at an early stage of glaucoma with significantly more dystrophic neurites than control mice (P < 0.001 comparing the lamina region of DBA/2J to D2-Gpnmb ⁺; n = 9 per genotype). (A–H) Bars, 2 μm. (I–J) Bars, 20 μm.