June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Investigating temporal mechanisms of retinal interneuron loss and dysfunction caused by Atrx deficiency
Author Affiliations & Notes
  • Pamela S Lagali
    Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada
  • Brandon Y. H. Zhao
    Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  • Adam Baker
    Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada
  • Stuart G. Coupland
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada
    Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  • Keqin Yan
    Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  • David J. Picketts
    Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  • Catherine Tsilfidis
    Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada
  • Footnotes
    Commercial Relationships   Pamela S Lagali, None; Brandon Zhao, None; Adam Baker, None; Stuart Coupland, None; Keqin Yan, None; David Picketts, None; Catherine Tsilfidis, None
  • Footnotes
    Support  Foundation Fighting Blindness-Canada
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 5904. doi:
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      Pamela S Lagali, Brandon Y. H. Zhao, Adam Baker, Stuart G. Coupland, Keqin Yan, David J. Picketts, Catherine Tsilfidis; Investigating temporal mechanisms of retinal interneuron loss and dysfunction caused by Atrx deficiency. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5904.

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

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Abstract

Purpose : Deficiency of the chromatin remodeling protein Atrx in the mouse retina causes the selective loss of amacrine and horizontal cells and inner retinal dysfunction. Onset of the neurodegenerative phenotype coincides with both eye opening and developmental maturation of retinal interneurons and their circuitry. We aim to determine the contributions of these biological processes in causing the cellular and functional defects observed in Atrx-deficient mice. Here we interrogate the influence of light-dependent visual signaling on the survival of inhibitory interneurons in the mouse retina to determine the relevance of eye-opening on triggering the Atrx-knockout phenotype.

Methods : Retina-specific Atrx conditional knockout (cKO) mice were generated using Chx10-GFP/Cre-IRES-AP and Atrx-floxed lines. Photic input was blocked in the Atrx cKO mice using two separate paradigms: 1) genetic deficiency of metabotropic glutamate receptor 6 (Grm6) in Chx10Cre+/-;Atrxf/y;Grm6nob4 triple transgenic mice, and 2) a dark-rearing regime. Retinal immunohistochemistry and enumeration of amacrine and horizontal cells were performed for both light deprivation paradigms. Scotopic electroretinography was performed for adult dark-reared Atrx cKO mice and controls to measure scotopic a-wave, b-wave, and oscillatory potential amplitudes.

Results : The Atrx cKO mice contained one-third fewer amacrine and horizontal cells compared to wildtype controls. The Grm6nob4 mice exhibited a 10-15% reduction in the retinal inhibitory interneuron population relative to wildtype mice. The number of retinal interneurons was further reduced in the Atrx/Grm6 double mutants compared to Atrx cKO mice. Deficits were observed in the scotopic b-wave and oscillatory potential amplitudes of dark-reared Atrx cKO mice similar to light-exposed counterparts.

Conclusions : The loss of retinal inhibitory interneurons in Atrx cKO mice is exacerbated by the blockage of light signaling through the ON pathway in Atrx/Grm6 double mutant mice. Visual deprivation by dark-rearing also does not rescue the functional deficiency caused by Atrx deletion. Our results indicate a protective effect of visual signaling on the retinal interneuron population and suggest that the temporal features of the Atrx cKO phenotype are not directly related to light exposure upon eye opening but rather coincident developmental processes impacting the inner retinal circuitry.

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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