Abstract
Inherited and age-related retinal degenerative diseases cause progressive loss of rod and cone photoreceptors, leading to blindness, but spare downstream retinal neurons, which can be targeted for optogenetic therapy. However, optogenetic approaches have been limited by either low light sensitivity or slow kinetics, and lack adaptation to changes in ambient light, and not been shown to restore object vision. We find that the vertebrate medium wavelength cone opsin (MW-opsin) overcomes these limitations and supports vision in dim light. MW-opsin enables an otherwise blind retinitis pigmenotosa mouse to discriminate temporal and spatial light patterns displayed on a standard LCD computer tablet, displays adaption to changes in ambient light, and restores open-field novel object exploration under incidental room light. By contrast, rhodopsin, which is similar in sensitivity but slower in light response and has greater rundown, fails these tests. Thus, MW-opsin provides the speed, sensitivity and adaptation needed to restore patterned vision.
Highlights
Inherited and age-related retinal degenerative diseases cause progressive loss of rod and cone photoreceptors, leading to blindness, but spare downstream retinal neurons, which can be targeted for optogenetic therapy
A number of light-sensitive signaling proteins have been tested, including two microbial opsins, the ion channel channelrhodopsin and ion pump halorhodopsin[13,14,15,16,17,18], chemically engineered mammalian receptors[19,20] and two G-protein coupled receptor (GPCR) opsins that are native to the retina, rhodopsin of rod photoreceptor cells and melanopsin of intrinsically photosensitive retinal ganglion cells[21,22,23,24,25]
We find that, when virally delivered to retinal ganglion cells (RGCs), medium wavelength cone opsin (MW-opsin) is as sensitive to light as rhodopsin under physiological stimulation parameters, but displays 10-fold faster kinetics
Summary
Inherited and age-related retinal degenerative diseases cause progressive loss of rod and cone photoreceptors, leading to blindness, but spare downstream retinal neurons, which can be targeted for optogenetic therapy. A number of light-sensitive signaling proteins have been tested, including two microbial opsins, the ion channel channelrhodopsin and ion pump halorhodopsin[13,14,15,16,17,18], chemically engineered mammalian receptors[19,20] and two G-protein coupled receptor (GPCR) opsins that are native to the retina, rhodopsin of rod photoreceptor cells and melanopsin of intrinsically photosensitive retinal ganglion cells[21,22,23,24,25] These light-gated systems, when delivered to the surviving neurons of the blind retina using adeno-associated viruses (AAVs), restore light sensitivity, transmission of light-driven activity to higher order visual centers in the brain, and both innate and learned visually guided behaviors. Rhodopsin under the same behavioral parameters performed no better than blind animals
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