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Zachary Helft, Bristol Denlinger, Michael Telias, Casey Thornton, Richard H Kramer; Retinoic acid mediates electrophysiological remodeling during retinal degeneration. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3973.
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© ARVO (1962-2015); The Authors (2016-present)
In retinitis pigmentosa (RP) and age-related macular degeneration (AMD), downstream retinal neurons survive and the axons of retinal ganglion cells (RGCs) remain intact. Retinal prostheses can either directly or indirectly impart artificial light responses onto RGCs and restore light-elicited behavioral responses but rely on the integrity of remaining synaptic connections. However, while RGCs survive, they exhibit electrophysiological remodeling resulting in heightened spontaneous activity, permeability, and permissiveness to azobenzene photoswitches. Understanding the mechanism of remodeling would lead to a better understanding of disease pathology and could enhance remaining vision or the efficacy of visual prosthetics.
Rd1 and rd10 mice and S334Ter rats were used as models of retinal degeneration. Multi-electrode array recordings were used to determine the hyperactivity and photosensitivity of RGCs in isolated retinae. YO-PRO-1 loading was used as a probe of cell permeability. Pharmacological agents to either enhance or inhibit retinoic acid (RA) signaling including the production, breakdown, or receptor activity were intravitreally injected 3-7 days pre-assessment. A dual-fluorescent reporter was used to measure RA-driven transcription in-vivo.
Blocking RA signaling in rd1 retinae reduced the number of RGCs loading YO-PRO-1 (29% vs 6.1%, p<0.001), reduced the efficacy of photoswitches (PI=0.63 vs 0.15, p=0.002), and lowered spontaneous activity (5.1Hz to 2.7Hz, p=0.002). Co-injecting all-trans RA with liarozole, a drug which inhibits RA breakdown, increased YO-PRO-1 labeling in wt RGCs from 3.7% to 20% (p<0.001) and enabled photosensitization using photoswitches (PI=0.08 vs 0.61, p=0.002). A dual-fluorescent protein reporter showed increased RA receptor-mediated transcription in both rd1 mice and S334Ter rats.
RA-mediated signaling is both necessary and sufficient to cause remodeling of RGCs following photoreceptor degeneration as measured by permeability, hyperactivity, and permissiveness to photoswitches. Heightened RA signaling is conserved over two different mammalian models of retinal degeneration. By identifying the signal for electrophysiological remodeling, hyperactivity of RGCs can be reduced in order to unmask any remaining light responses as well as enhance the efficacy of restored vision imparted by retinal prosthetics.
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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