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G. Wu, D. Inman, P. Horner, D.J. Calkins; Selective Loss of Large–Caliber Axons in the Optic Nerve of the DBA/2J Mouse With Modest Increases in Intraocular Pressure . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1829.
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© ARVO (1962-2015); The Authors (2016-present)
Intraocular pressure (IOP) in the DBA2J mouse increases with age due to pigmentary dispersion. This increase is associated with the loss of retinal ganglion cell (RGC) axons in the optic nerve. We investigated quantitatively how modest differences in IOP across young and aged mice correlate with the number, size distribution and ultrastructural pathology of RGC axons.
We used the Tono–Pen XL to obtain monthly IOP measurements from our colony of 400+ DBA2J mice at 2–11 months of age. We harvested optic nerve proximal to the eyecup from samples of young (4–5 months, n=9) and aged (9–11 months, n=10) eyes demonstrating modest differences in IOP. Each nerve was processed for histological cross–sectioning and electron microscopy. From 1–2 um semi–thin sections, we obtained measurements of total axon number using an automated microscopy system equipped for high–resolution imaging. A similar algorithm sampled and measured the cross–sectional area of 2000–14,000 individual axons for each nerve. We photographed 60–70 nm ultra–thin sections under a Philips CM–12, 120 keV transmission electron microscope.
Mean axonal area varied between 0.25–0.45 sq. um and was strongly predicted by the total number of axons in each nerve. Axonal area dropped significantly as the total number of axons decreased across both age groups (Pearson’s r = 0.71; p<0.001). The normalized distribution of axonal areas for nerves from young eyes with IOPs higher than the colony average for that group (mean: 20.6 mmHG) demonstrated a 25% shift to lower values compared to the normalized distribution of areas for young eyes with 18% lower IOPs (mean: 17.4 mmHG). This shift entailed a 23% loss of axons with areas greater than the mean, compared to an 11% loss of axons with areas less than the mean (p<0.01). Similarly, for aged eyes, modestly higher IOP (mean: 21.2 mmHG) induced a 20% shift in the distribution of axon areas to lower values compared to the distribution for eyes with lower IOP (mean: 18.0). This shift entailed a three–fold greater loss of axons with areas greater than the mean than of axons with areas less than the mean (p<0.01). Ultrastructural pathology in the highest IOP nerves included intra–axonal swelling and distortion, thinning of myelin, and development of multi–laminar sheaths around collapsed axons.
These data indicate that even modest increases in IOP among age–matched eyes can induce loss of axons and support the hypothesis that large–caliber axons are more susceptible to pressure–induced pathology than smaller axons.
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