PT  - JOURNAL ARTICLE
AU  - Telias, Michael
AU  - Sit, Kevin
AU  - Frozenfar, Daniel
AU  - Smith, Benjamin
AU  - Misra, Arjit
AU  - Goard, Michael J
AU  - Kramer, Richard H
TI  - Inhibiting retinoic acid mitigates vision loss in a mouse model of retinal degeneration
AID  - 10.1101/2021.08.09.455683
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.08.09.455683
4099  - http://biorxiv.org/content/early/2021/08/10/2021.08.09.455683.short
4100  - http://biorxiv.org/content/early/2021/08/10/2021.08.09.455683.full
AB  - 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 StatementM.T. and R.H.K. filed, through the University of California, a patent application for mitigating visual decline with retinoic acid inhibitors.