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Enlarged Optic Nerve Axons and Reduced Visual Function in Mice with Defective Microfibrils.
eNeuro. 2018 Sep-Oct; 5(5)E

Abstract

Glaucoma is a leading cause of irreversible vision loss due to retinal ganglion cell (RGC) degeneration that develops slowly with age. Elevated intraocular pressure (IOP) is a significant risk factor, although many patients develop glaucoma with IOP in the normal range. Mutations in microfibril-associated genes cause glaucoma in animal models, suggesting the hypothesis that microfibril defects contribute to glaucoma. To test this hypothesis, we investigated IOP and functional/structural correlates of RGC degeneration in mice of either sex with abnormal microfibrils due to heterozygous Tsk mutation of the fibrilin-1 gene (Fbn1Tsk /+). Although IOP was not affected, Fbn1Tsk /+ mice developed functional deficits at advanced age consistent with glaucoma, including reduced RGC responses in electroretinogram (ERG) experiments. While RGC density in the retina was not affected, the density of RGC axons in the optic nerve was significantly reduced in Fbn1Tsk /+ mice. However, reduced axon density correlated with expanded optic nerves, resulting in similar numbers of axons in Fbn1Tsk /+ and control nerves. Axons in the optic nerves of Fbn1Tsk /+ mice were significantly enlarged and axon diameter was strongly correlated with optic nerve area, as has been reported in early pathogenesis of the DBA/2J mouse model of glaucoma. Our results suggest that microfibril abnormalities can lead to phenotypes found in early-stage glaucomatous neurodegeneration. Thinning of the elastic fiber-rich pia mater was found in Fbn1Tsk /+ mice, suggesting mechanisms allowing for optic nerve expansion and a possible biomechanical contribution to determination of axon caliber.

Authors+Show Affiliations

Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN 37232-8808.Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN 37232-8808.Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN 37232-8808.Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN 37232-8808. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232-0022.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30406200

Citation

Wu, Hang-Jing, et al. "Enlarged Optic Nerve Axons and Reduced Visual Function in Mice With Defective Microfibrils." ENeuro, vol. 5, no. 5, 2018.
Wu HJ, Hazlewood RJ, Kuchtey J, et al. Enlarged Optic Nerve Axons and Reduced Visual Function in Mice with Defective Microfibrils. eNeuro. 2018;5(5).
Wu, H. J., Hazlewood, R. J., Kuchtey, J., & Kuchtey, R. W. (2018). Enlarged Optic Nerve Axons and Reduced Visual Function in Mice with Defective Microfibrils. ENeuro, 5(5). https://doi.org/10.1523/ENEURO.0260-18.2018
Wu HJ, et al. Enlarged Optic Nerve Axons and Reduced Visual Function in Mice With Defective Microfibrils. eNeuro. 2018 Sep-Oct;5(5) PubMed PMID: 30406200.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enlarged Optic Nerve Axons and Reduced Visual Function in Mice with Defective Microfibrils. AU - Wu,Hang-Jing, AU - Hazlewood,Ralph J, AU - Kuchtey,John, AU - Kuchtey,Rachel W, Y1 - 2018/10/30/ PY - 2018/07/03/received PY - 2018/10/13/accepted PY - 2018/11/9/entrez PY - 2018/11/9/pubmed PY - 2019/4/20/medline KW - biomechanical property KW - glaucoma KW - microfibril KW - optic nerve KW - retinal ganglion cells KW - visual function JF - eNeuro JO - eNeuro VL - 5 IS - 5 N2 - Glaucoma is a leading cause of irreversible vision loss due to retinal ganglion cell (RGC) degeneration that develops slowly with age. Elevated intraocular pressure (IOP) is a significant risk factor, although many patients develop glaucoma with IOP in the normal range. Mutations in microfibril-associated genes cause glaucoma in animal models, suggesting the hypothesis that microfibril defects contribute to glaucoma. To test this hypothesis, we investigated IOP and functional/structural correlates of RGC degeneration in mice of either sex with abnormal microfibrils due to heterozygous Tsk mutation of the fibrilin-1 gene (Fbn1Tsk /+). Although IOP was not affected, Fbn1Tsk /+ mice developed functional deficits at advanced age consistent with glaucoma, including reduced RGC responses in electroretinogram (ERG) experiments. While RGC density in the retina was not affected, the density of RGC axons in the optic nerve was significantly reduced in Fbn1Tsk /+ mice. However, reduced axon density correlated with expanded optic nerves, resulting in similar numbers of axons in Fbn1Tsk /+ and control nerves. Axons in the optic nerves of Fbn1Tsk /+ mice were significantly enlarged and axon diameter was strongly correlated with optic nerve area, as has been reported in early pathogenesis of the DBA/2J mouse model of glaucoma. Our results suggest that microfibril abnormalities can lead to phenotypes found in early-stage glaucomatous neurodegeneration. Thinning of the elastic fiber-rich pia mater was found in Fbn1Tsk /+ mice, suggesting mechanisms allowing for optic nerve expansion and a possible biomechanical contribution to determination of axon caliber. SN - 2373-2822 UR - https://www.unboundmedicine.com/medline/citation/30406200/Enlarged_Optic_Nerve_Axons_and_Reduced_Visual_Function_in_Mice_with_Defective_Microfibrils_ L2 - http://eneuro.org/cgi/pmidlookup?view=long&pmid=30406200 DB - PRIME DP - Unbound Medicine ER -