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Bristol Denlinger, Zachary Helft, Michael Telias, Casey Thornton, Richard H Kramer; Blocking retinal remodeling improves light sensitivity in vision-impaired mice. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4451.
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© ARVO (1962-2015); The Authors (2016-present)
In many blinding diseases at least some photoreceptors persist for years during the progression of retinal degeneration. We hypothesize that visual impairment may derive not only from photoreceptor loss, but also from retinoic acid (RA)-mediated retinal ganglion cell (RGC) hyperactivity imposing background noise. Blocking RA signaling, reducing spontaneous firing, might improve responses and enhance visual performance.
Retinas were isolated from WT, rd1 and rd10 mice of varying ages. For extracellular recordings, a flat-mounted retina was placed RGC layer down onto a Multi-Electrode Array (MEA). Light flashes were used to measure photosensitivity before and after application of 100μM BENAQ and a synaptic blocker cocktail, to isolate the RGCs. To measure RGC permeability, retinas were treated with YO-PRO-1 and imaged. A dual fluorescent protein reporter was used to detect and measure RA signaling.Using 6 week old rd10 mice, when degeneration is incomplete, one eye was injected with BMS-493 and the other with vehicle. At 3-7 days post injection, we evaluated retinal sensitivity with MEA recordings with light flashes of varying intensities.
Spontaneous firing, BENAQ photosensitivity and RGC permeability increased with the progression of degeneration. RA signaling in RGCs was weaker in rd10 compared to rd1 retinas.BMS-treated rd10 retinas showed a transient increase in firing in response to a flash of dim light, whereas vehicle-treated retinas showed no response to the same flash, associated with a decrease in background firing in darkness. A BMS augmented light response was observed in all 5 mice tested, comparing across drug- and vehicle-injected eyes (p=0.02). Measuring the response over a variety of intensities revealed a leftward shift in the midpoint of the intensity vs. response curve and an increase in the peak response (BMS I50=0.35μW, Max=4.77; Vehicle I50=1.73μW, Max=3.68). Also, response threshold was lower for BMS-injected than for vehicle-injected eyes (0.2μW vs. 0.85μW).
Our results have shown that blocking RA leads to enhanced visual responses of RGCs suggesting a therapeutic strategy for improving low-level vision before photoreceptor degeneration is complete. By reducing the background noise, treatment with RA blockers enables RGCs to more effectively encode visual information, lowering light detection threshold and increasing the gain of visual information processing.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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