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Published on: September 16, 2020
Retinoic acid inhibitors mitigate vision loss in a mouse model of retinal degeneration
Michael Telias1, Kevin K Sit2, Daniel Frozenfar1
1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
Abstract:
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 Ca2+ 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.
Insights
In retinitis pigmentosa (RP), inhibiting retinoic acid (RA) synthesis with disulfiram improves vision in mice. This suggests RA signaling contributes to vision loss in RP, offering new therapeutic targets.
Area of Science:
- Neuroscience
- Ophthalmology
- Pharmacology
Background:
- Retinitis pigmentosa (RP) involves photoreceptor degeneration, leading to vision loss.
- Surviving retinal ganglion cells (RGCs) exhibit hyperactivity, triggered by retinoic acid (RA).
- The impact of RA-induced RGC hyperactivity on visual perception in RP remains unclear.
Purpose of the Study:
- To investigate the role of RA in visual dysfunction in RP.
- To evaluate the therapeutic potential of inhibiting RA synthesis or signaling for vision restoration in RP.
Main Methods:
- Utilized disulfiram to inhibit RA synthesis in a mouse model of RP.
- Administered an RA receptor inhibitor to assess its effects.
- Performed in vivo Ca2+ imaging to analyze neural activity in the visual cortex.
- Assessed behavioral image detection capabilities in treated mice.
Main Results:
- Disulfiram treatment improved behavioral image detection in vision-impaired mice.
- Inhibition of RA synthesis sharpened orientation tuning and enhanced response fidelity in visual cortical neurons.
- RA receptor inhibition also reduced RGC hyperactivity, improved cortical representations, and enhanced image detection.
Conclusions:
- Photoreceptor degeneration is not the sole cause of vision loss in RP; RA-driven retinal information processing errors also contribute.
- RA-induced hyperactivity corrupts visual information, degrading vision in RP.
- Inhibitors of RA synthesis and signaling represent promising therapeutic strategies for RP and other retinal degenerative diseases.
