Optic nerve damage in mice with a targeted type I collagen mutation.

PURPOSE: Transgenic (Col1a1(r/r)) mice gradually develop elevated intraocular pressure (IOP) with open angles. The present study was undertaken to evaluate optic nerve axonal loss with time in these mice.

METHODS

The IOP of transgenic (Col1a1(r/r)) mice and control wild-type (Col1a1(+/+)) mice was measured at 7, 12, 16, 24, 36, and 54 weeks of age using a microneedle method. Transgenic Col1a1(r/r) and control Col1a1(+/+) mice at 24 and 54 weeks of age were randomly selected and their optic nerves were processed conventionally for electron microscopy. Optic nerve cross-sections were collected 300 micro m posterior to the globe. Low (200X) and high (10,000X) magnification images were collected systematically and were masked before analysis. For each nerve, cross-sectional area was measured in low magnification images, and axonal number was counted in high magnification images.

RESULTS

Mean IOP of the transgenic Col1a1(r/r) mice was significantly higher than that of the control Col1a1(+/+) mice at 16, 24, 36, and 54 weeks by 21%, 42%, 41%, and 33% respectively (P < 0.05). The mean axonal density and total axonal number in the transgenic Col1a1(r/r) mice at 54 weeks of age (n = 10) was significantly less than those in the control Col1a1(+/+) mice at 24 weeks (n = 5) and 54 weeks (n = 5; P = 0.0081 and P = 0.020, respectively, analysis of variance, P < 0.05 for pair-wise comparisons). The mean axonal density and total axonal number in the transgenic Col1a1(r/r) mice at 54 weeks also were significantly less than in the transgenic Col1a1(r/r) mice at 24 weeks (n = 10). Mean axonal loss between 24 and 54 weeks of age in the transgenic Col1a1(r/r) mice was 28.7%.

CONCLUSIONS

Transgenic Col1a1(r/r) mice develop sustained elevation of IOP and progressive optic nerve axon loss. This suggests that these mice may be useful as a mouse model of primary open angle glaucoma as well as for assessing the relationship between collagen type I metabolism and optic nerve axon loss.