June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Glaucomatous retinal dysfunction and optic nerve phenotype in microfibril deficient mice
Author Affiliations & Notes
  • Hang Jing Wu
    Vanderbilt Eye Institute, Nashville, Tennessee, United States
  • George Naratadam
    Vanderbilt Eye Institute, Nashville, Tennessee, United States
  • Ralph Hazelwood
    Vanderbilt Eye Institute, Nashville, Tennessee, United States
  • Abudi Nashabi
    Vanderbilt Eye Institute, Nashville, Tennessee, United States
  • John Kuchtey
    Vanderbilt Eye Institute, Nashville, Tennessee, United States
  • Rachel W Kuchtey
    Vanderbilt Eye Institute, Nashville, Tennessee, United States
  • Footnotes
    Commercial Relationships   Hang Jing Wu, None; George Naratadam, None; Ralph Hazelwood, None; Abudi Nashabi, None; John Kuchtey, None; Rachel Kuchtey, None
  • Footnotes
    Support  NIH Grant EY020894
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 5854. doi:
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      Hang Jing Wu, George Naratadam, Ralph Hazelwood, Abudi Nashabi, John Kuchtey, Rachel W Kuchtey; Glaucomatous retinal dysfunction and optic nerve phenotype in microfibril deficient mice. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5854.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Our previous identification of a disease-causing mutation in a microfibril-associated gene (ADAMTS10) in a dog glaucoma model, led us to a hypothesis that microfibril defects may cause glaucoma. Here, we investigated retinal function in an established microfibril deficient mouse line which carries the tight skin (Tsk) mutation to test our hypothesis.

Methods : Retinal function was evaluated at 3 and 16 months of age by positive scotopic threshold response (pSTR) and a- and b-wave responses in flash electroretinography (ERG) experiments. Visual acuity threshold was assessed by optokinetic reflex (OKR). Whole mount retinas were stained for Brn3a to assess number of retinal ganglion cell (RGC) bodies at 16 months of age. Cross-sections of the optic nerves from the same cohort were stained with P-Phenylene Diamine (PPD) for manual axon quantification and area measurement using ImageJ. Two-tailed Student’s t-test was used for statistical analysis. Results are presented as mean ± SD.

Results : The pSTR, as well as a- and b-wave amplitudes, were decreased in Tsk+/- mice as compared to wild type (wt) at 3 and 16 months of age, with prolonged latency at 16 months of age. The pSTR amplitudes normalized to the b-wave showed no significant difference at 3 months of age, but progressed to significant decrease for Tsk+/- at 16 months (0.12 ± 0.06 vs 0.23 ± 0.08, n = 9 and 22, Tsk+/-, wt, respectively, p < 0.001). Tsk+/- mice (n = 26) progressed to 20.9% decrease in acuity threshold compared to wt (n = 11, p < 0.001) at 16 months of age. Although density of Brn3a+ RGCs was not different, axon number was significantly lower in Tsk+/- mice (41,040 ± 2,851 vs 44,389 ± 4,413, n = 19 and 9, Tsk+/-, wt, respectively, p < 0.05). At 16 months, optic nerve cross-sectional area was expanded by 22.5% in Tsk+/- mice (0.15 ± 0.02 mm2, n = 11) compared to wt (0.12 ± 0.02 mm2, n = 21, p < 0.01). The distribution of axon cross-sectional area was similar at 6 months, but shifted to larger size in Tsk+/- mice at 16 months (Figure).

Conclusions : Reduction in the normalized pSTR amplitude and decrease in visual acuity threshold indicates inner retinal dysfunction progresses with advanced age in microfibril deficient Tsk+/- mice. Retinal dysfunction is accompanied by persistent RGC cell bodies, axon loss, nerve expansion and axon enlargement, suggesting microfibril defects cause glaucoma.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

 

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