Abstract
Retinitis pigmentosa results in blindness due to degeneration of photoreceptors, but spares other retinal cells, leading to the hope that expression of light-activated signaling proteins in the surviving cells could restore vision. We used a retinal G protein-coupled receptor, mGluR2, which we chemically engineered to respond to light. In retinal ganglion cells (RGCs) of blind rd1 mice, photoswitch-charged mGluR2 (“SNAG-mGluR2”) evoked robust OFF responses to light, but not in wild-type retinas, revealing selectivity for RGCs that have lost photoreceptor input. SNAG-mGluR2 enabled animals to discriminate parallel from perpendicular lines and parallel lines at varying spacing. Simultaneous viral delivery of the inhibitory SNAG-mGluR2 and excitatory light-activated ionotropic glutamate receptor LiGluR yielded a distribution of expression ratios, restoration of ON, OFF and ON-OFF light responses and improved visual acuity. Thus, SNAG-mGluR2 restores patterned vision and combinatorial light response diversity provides a new logic for enhanced-acuity retinal prosthetics.
Highlights
We found that simultaneous transfection with adeno-associated viruses (AAVs) for these engineered receptors leads to retinal ganglion cells (RGCs) that display a range of ON, OFF, and ON-OFF light responses
We turned to our chemically and genetically engineered light-activated version of metabotropic glutamate receptor 2 (mGluR2), a class C G protein-coupled receptors (GPCRs) that is natively expressed in retinal neurons and implicated in the diverse modulatory effects of visual perception[25]
We demonstrate the translational potential for retinal gene therapy of a light-gated GPCR engineered from a metabotropic glutamate receptor
Summary
Though these approaches lack the diversity of the visual responses found in normal vision, most have succeeded in restoring light-evoked activity in visual cortex[18, 8], pupillary reflex[11, 14, 19], and discrimination of light from dark[7, 11, 12, 14, 16, 18,19,20] It remains to be determined whether these systems support image recognition. SNAG-mGluR2 produced little or no light response in the RGCs of wt mice, suggesting that, in the degenerating retina, it may selectively act in RGCs whose upstream circuit has lost its photoreceptor cell input. Using a new visually-guided image discrimination paradigm, we show that rd[1] mice expressing SNAG-mGluR2 are capable of distinguishing light from dark, but can discriminate between static light patterns of equal luminance, a critical benchmark for vision restoration
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