June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Up-regulation of connexin36 in retinal neurons amplifies gap junction-mediated neurodegeneration in glaucoma.
Author Affiliations & Notes
  • Sandeep Kumar
    SUNY College of Optometry, New York, New York, United States
  • Hari Ramakrishnan
    SUNY College of Optometry, New York, New York, United States
  • Kaushambi Roy
    SUNY College of Optometry, New York, New York, United States
  • Abram Akopian
    SUNY College of Optometry, New York, New York, United States
  • Stewart A Bloomfield
    SUNY College of Optometry, New York, New York, United States
  • Footnotes
    Commercial Relationships   Sandeep Kumar, None; Hari Ramakrishnan, None; Kaushambi Roy, None; Abram Akopian, None; Stewart Bloomfield, None
  • Footnotes
    Support  NIH Grants EY007360 and EY026024
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 2551. doi:
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      Sandeep Kumar, Hari Ramakrishnan, Kaushambi Roy, Abram Akopian, Stewart A Bloomfield; Up-regulation of connexin36 in retinal neurons amplifies gap junction-mediated neurodegeneration in glaucoma.. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2551.

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

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Abstract

Purpose : We reported earlier that blockade of gap junctions (GJs) can preserve the normal structure and function of the retina and optic nerve in a mouse model of glaucoma (ARVO 2016). Here we examined the expression of the GJ subunits connexin36 (Cx36) and connexin45 (Cx45), which are highly expressed in retinal neurons, to determine their selective contribution to bystander cell death in glaucoma.

Methods : Experimental glaucoma was induced in C57BL/6 (WT) and connexin knockout (KO) mice by intracameral injection of polystyrene microbeads. Retinal and optic nerve structure was assessed histologically and the ERG and VEP were recorded to evaluate retinal and cortical function. Immunohistochemistry was used to determine any changes in the expression and distribution of Cx36 and Cx45 associated with glaucoma.

Results : Genetic ablation of Cx36 produced significant protection of retinal and optic nerve structure and function. This was indicated by a dramatic reduction in the loss of retinal ganglion and amacrine cells in glaucomatous Cx36 KO mice. Further, ablation of Cx36 prevented attenuation of ERG and VEP components in glaucomatous animals. Genetic deletion of both Cx36 and Cx45 provided no further improvement in neuroprotection than knocking out Cx36 alone. We next compared the distribution of Cx36 and Cx45 immunolabeling in control and glaucomatous retinas to reveal any changes that could instruct their differential roles in promoting bystander cell death. Eight weeks after microbead injection we observed a significant up-regulation of Cx36 expression in the IPL, but found no change in Cx45 immunolabeling compared to control levels. Application of the GJ blocker MFA to glaucomatous eyes prevented the up-regulation of Cx36. Finally, we found that ablation of Cx36-expressing GJs prevented the deterioration of visually guided behavior seen in glaucoma as indicated by a preservation of spatial acuity and contrast sensitivity at control levels.

Conclusions : We found that Cx36-, but not Cx45-expressing GJs play a critical role in cell and vision loss associated with glaucoma. There is an up-regulation in the expression of Cx36 in the inner retina, which can amplify the bystander effect and the subsequent neurodegeneration. Taken together, these results reveal Cx36-expressing neuronal GJs as key targets for novel neuroprotective therapies to prevent structural and functional deficits in 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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