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Inhibiting retinoic acid mitigates vision loss in a mouse model of retinal degeneration

View ORCID ProfileMichael Telias, View ORCID ProfileKevin Sit, Daniel Frozenfar, Benjamin Smith, Arjit Misra, View ORCID ProfileMichael J Goard, View ORCID ProfileRichard H Kramer
doi: https://doi.org/10.1101/2021.08.09.455683
Michael Telias
1Department of Molecular and Cell Biology, University of California, Berkeley, USA
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Kevin Sit
2Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, USA
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Daniel Frozenfar
1Department of Molecular and Cell Biology, University of California, Berkeley, USA
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Benjamin Smith
1Department of Molecular and Cell Biology, University of California, Berkeley, USA
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Arjit Misra
3Department of Bioengineering, University of California, Berkeley, USA
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Michael J Goard
2Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, USA
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  • For correspondence: michael.goard@lifesci.ucsb.edu rhkramer@berkeley.edu
Richard H Kramer
1Department of Molecular and Cell Biology, University of California, Berkeley, USA
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  • For correspondence: michael.goard@lifesci.ucsb.edu rhkramer@berkeley.edu
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Abstract

In degenerative retinal disorders, rod and cone photoreceptors die, causing vision impairment and blindness. Downstream neurons survive but undergo morphological and physiological remodeling, with some retinal ganglion cells (RGC) exhibiting heightened spontaneous firing. Retinoic acid (RA) has been implicated as the key signaling molecule that induces RGC hyperactivity, obscuring RGC light responses and reducing light avoidance behaviors triggered by residual rods and cones. However, evidence that RA-dependent remodeling corrupts image-forming vision has been lacking. Here we show that disulfiram, an FDA-approved drug that inhibits RA synthesis, and BMS 493, an RA receptor (RAR) inhibitor, reduce RGC hyperactivity and augment image detection in visually impaired mice. Functional imaging of visual cortical neurons shows that disulfiram and BMS 493 sharpen orientation-tuning and strengthen response fidelity to naturalistic scenes. These findings establish a causal link between RA-induced retinal hyperactivity and vision impairment and define molecular targets and candidate drugs for boosting image-forming vision in retinal degeneration.

Competing Interest Statement

M.T. and R.H.K. filed, through the University of California, a patent application for mitigating visual decline with retinoic acid inhibitors.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted August 10, 2021.
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Inhibiting retinoic acid mitigates vision loss in a mouse model of retinal degeneration
Michael Telias, Kevin Sit, Daniel Frozenfar, Benjamin Smith, Arjit Misra, Michael J Goard, Richard H Kramer
bioRxiv 2021.08.09.455683; doi: https://doi.org/10.1101/2021.08.09.455683
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Inhibiting retinoic acid mitigates vision loss in a mouse model of retinal degeneration
Michael Telias, Kevin Sit, Daniel Frozenfar, Benjamin Smith, Arjit Misra, Michael J Goard, Richard H Kramer
bioRxiv 2021.08.09.455683; doi: https://doi.org/10.1101/2021.08.09.455683

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