Retinoic acid inhibitors mitigate vision loss in a mouse model of retinal degeneration

Rod and cone photoreceptors degenerate in retinitis pigmentosa (RP). While downstream neurons survive, they undergo physiological changes, including accelerated spontaneous firing in retinal ganglion cells (RGCs). Retinoic acid (RA) is the molecular trigger of RGC hyperactivity, but whether this int...

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Autores principales: Telias, Michael, Sit, Kevin K., Frozenfar, Daniel, Smith, Benjamin, Misra, Arjit, Goard, Michael J., Kramer, Richard H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8932665/
https://www.ncbi.nlm.nih.gov/pubmed/35302843
http://dx.doi.org/10.1126/sciadv.abm4643
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author Telias, Michael
Sit, Kevin K.
Frozenfar, Daniel
Smith, Benjamin
Misra, Arjit
Goard, Michael J.
Kramer, Richard H.
author_facet Telias, Michael
Sit, Kevin K.
Frozenfar, Daniel
Smith, Benjamin
Misra, Arjit
Goard, Michael J.
Kramer, Richard H.
author_sort Telias, Michael
collection PubMed
description Rod and cone photoreceptors degenerate in retinitis pigmentosa (RP). While downstream neurons survive, they undergo physiological changes, including accelerated spontaneous firing in retinal ganglion cells (RGCs). Retinoic acid (RA) is the molecular trigger of RGC hyperactivity, but whether this interferes with visual perception is unknown. Here, we show that inhibiting RA synthesis with disulfiram, a deterrent of human alcohol abuse, improves behavioral image detection in vision-impaired mice. In vivo Ca(2+) imaging shows that disulfiram sharpens orientation tuning of visual cortical neurons and strengthens fidelity of responses to natural scenes. An RA receptor inhibitor also reduces RGC hyperactivity, sharpens cortical representations, and improves image detection. These findings suggest that photoreceptor degeneration is not the only cause of vision loss in RP. RA-induced corruption of retinal information processing also degrades vision, pointing to RA synthesis and signaling inhibitors as potential therapeutic tools for improving sight in RP and other retinal degenerative disorders.
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spelling pubmed-89326652022-03-31 Retinoic acid inhibitors mitigate vision loss in a mouse model of retinal degeneration Telias, Michael Sit, Kevin K. Frozenfar, Daniel Smith, Benjamin Misra, Arjit Goard, Michael J. Kramer, Richard H. Sci Adv Neuroscience Rod and cone photoreceptors degenerate in retinitis pigmentosa (RP). While downstream neurons survive, they undergo physiological changes, including accelerated spontaneous firing in retinal ganglion cells (RGCs). Retinoic acid (RA) is the molecular trigger of RGC hyperactivity, but whether this interferes with visual perception is unknown. Here, we show that inhibiting RA synthesis with disulfiram, a deterrent of human alcohol abuse, improves behavioral image detection in vision-impaired mice. In vivo Ca(2+) imaging shows that disulfiram sharpens orientation tuning of visual cortical neurons and strengthens fidelity of responses to natural scenes. An RA receptor inhibitor also reduces RGC hyperactivity, sharpens cortical representations, and improves image detection. These findings suggest that photoreceptor degeneration is not the only cause of vision loss in RP. RA-induced corruption of retinal information processing also degrades vision, pointing to RA synthesis and signaling inhibitors as potential therapeutic tools for improving sight in RP and other retinal degenerative disorders. American Association for the Advancement of Science 2022-03-18 /pmc/articles/PMC8932665/ /pubmed/35302843 http://dx.doi.org/10.1126/sciadv.abm4643 Text en Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Neuroscience
Telias, Michael
Sit, Kevin K.
Frozenfar, Daniel
Smith, Benjamin
Misra, Arjit
Goard, Michael J.
Kramer, Richard H.
Retinoic acid inhibitors mitigate vision loss in a mouse model of retinal degeneration
title Retinoic acid inhibitors mitigate vision loss in a mouse model of retinal degeneration
title_full Retinoic acid inhibitors mitigate vision loss in a mouse model of retinal degeneration
title_fullStr Retinoic acid inhibitors mitigate vision loss in a mouse model of retinal degeneration
title_full_unstemmed Retinoic acid inhibitors mitigate vision loss in a mouse model of retinal degeneration
title_short Retinoic acid inhibitors mitigate vision loss in a mouse model of retinal degeneration
title_sort retinoic acid inhibitors mitigate vision loss in a mouse model of retinal degeneration
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8932665/
https://www.ncbi.nlm.nih.gov/pubmed/35302843
http://dx.doi.org/10.1126/sciadv.abm4643
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