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Zhuo-Hua Pan, Qi Lu, Mitchell Fenner, Tushar Harishkumar Ganjawala, Gary W Abrams; Impact of retinal degeneration on restoring functional vision by optogenetics in rd mice. Invest. Ophthalmol. Vis. Sci. 2019;60(9):6438.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the impact of retinal degeneration on the ability or efficacy of optogenetic vision restoration with behavioral assessments.
Two retinal degenerative mouse models, rd1 (C3H/HeJ and C57BL/6J-Pde6brd1-2J/J) and rd10 (B6.CXB1Pde6brd10/J) mice, were used. A triple knock-out (TKO; Gnat1-/-Cnga3-/-Opn4-/-) blind mouse model which exhibits no apparent photoreceptor degeneration was used as control (Lu et al., 2018). Optogenetic vision restoration was achieved by the expression of a highly light-sensitive CoChR mutant (CoChR-H94E/L112C/K264T; CoChRm) fused to GFP with a CAG promoter delivered by AAV2 vector via intravitreal administration. Virus vectors were injected at the age of ≥1 month and experiments were performed at least 1 month after virus injection. Histology and immunochemistry were performed to evaluate the state of retinal degeneration and the expression of CoChRm-GFP. Multi-electrode array recordings were performed to examine CoChR-mediated light responses from retinal ganglion cells (RGCs) in retinal whole-mounts. Visual functions were assessed by optomotor response (OMR; Lu et al., 2018) and visual water task (VWT; Prusky et al., 2000) behavioral tests.
Robust expression of CoChRm-GFP was observed in all three mouse models, predominantly in RGCs. The CoChRm-mediated light responses of RGCs, including light sensitivity, were comparable between rd and TKO mice. Restoration of functional vision with contrast sensitivity and visual acuity assessed by OMR and/or VWT was observed in CoChRm-treated TKO mice under ambient light conditions. In contrast, restoration of OMR was not observed in CoChRm-treated rd1 mice with light intensities up to 1 x 1016 photons/cm2s. CoChR-treated rd1 mice also failed to be trained to distinguish between a sine-wave grating (~0.1 cycle/degree) and homogeneous gray by VWT. For rd10 mice, CoChRm-mediated OMR were observed at the age of ≥5 months when untreated rd10 mice no longer show OMR. However, the efficacy of the CoChRm-restored OMR in rd10 mice was much worse than that in TKO mice and continued to decline with animal aging.
Restoration of functional vision can be achieved in TKO mice and partially in rd10 mice but not in rd1 mice. Our results indicate that the ability or efficacy of optogenetic vision restoration in rd mouse models is critically dependent on the severity and stage of retinal degeneration.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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