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Hangjing Wu, Abudi Nashabi, Frances Clark, Samyukta Reddy, John Kuchtey, Rachel W Kuchtey; Increased susceptibility to glaucomatous optic nerve damage in microfibril deficient mice. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3705.
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© ARVO (1962-2015); The Authors (2016-present)
Our previous identification of a disease-causing mutation in a microfibril-associated gene (ADAMTS10) in a dog glaucoma model suggested that microfibril defects may cause glaucoma. We investigated an established microfibril deficient mouse line and found they had enlarged optic nerves and optic nerve axons at normal intraocular pressure (IOP). Here, we use microbead injection to induce elevated IOP, to test the hypothesis that microfibril deficient mice have increased susceptibility to pressure-induced optic nerve damage.
To induce IOP elevation, the anterior chamber of the right eye of 7 months old microfibril deficient and WT mice was injected with microbeads, with contralateral eye as control. IOP was measured every 3-7 days in both eyes by TonoLab. Mice were sacrificed 4 months post-injection. Phase-contrast images of PPD-stained optic nerve sections were acquired and total axon numbers and axon areas determined using AxonJ. IOP responses were quantified by integrating delta IOP over time. A linear regression model was used to analyze the relationship between axon loss and integrated IOP.
Microfibril deficient mice had significantly lower IOP responses compared to WT (444 vs 725 mmHg*days, n=21 and 31, respectively, p=0.02). Despite lower IOP responses, microfibril deficient mice had significantly higher mean axon loss (17.7%, n=18) than did WT mice (7.1%, n=29, linear regression model). In un-injected eyes of microfibril deficient mice, the optic nerves and optic nerve axons were enlarged compared to WT (p=0.02, t-test and p<0.001, Mann-Whitney, respectively). In bead-injected eyes of both genotypes, optic nerve area decreased compared to control (p=0.02 and 0.03, paired t-test). While in WT, the distribution of axon sizes shifted towards larger diameters in injected eyes (p<0.001), microfibril deficient mice had similar axon size distributions in both eyes (p=0.46, Mann-Whitney).
Microfibril deficient mice have greater axon loss at lower induced pressures compared to WT, suggesting that microfibril deficiency leads to increased susceptibility to IOP-induced glaucomatous optic nerve damage. Expansion of the optic nerve and optic nerve axons may play a role in increased susceptibility.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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