Abstract
The advent of optogenetics has ushered in a new era in neuroscience where spatiotemporal control of neurons is possible through light application. These tools used to study neural circuits can also be used therapeutically to restore vision. In order to recapitulate the broad spectral and light sensitivities along with high temporal sensitivity found in human vision, researchers have identified and developed new optogenetic tools. There are two major kinds of optogenetic effectors employed in vision restoration: ion channels and G-protein coupled receptors (GPCRs). Ion channel based optogenetic therapies require high intensity light that can be unsafe at lower wavelengths, so work has been done to expand and red-shift the excitation spectra of these channels. Light activatable GPCRs are much more sensitive to light than their ion channel counterparts but are slower kinetically in terms of both activation and inactivation. This review article examines the latest optogenetic ion channel and GPCR candidates for vision restoration based on light and temporal sensitivity.
Highlights
After the popularization of optogenetic tools in neuroscience began in the early 2000s (Nagel et al, 2003, 2005; Boyden et al, 2005), researchers began evaluating their use in a novel in vivo application: vision restoration
While HaloR requires 20 times more light than ChR2, which already requires an unsafe amount of light, this study importantly shows that the retina can produce multiple types of light responses without bipolar cell transduction
Discovered and developed optogenetics have improved upon the original ChR2 studies
Summary
After the popularization of optogenetic tools in neuroscience began in the early 2000s (Nagel et al, 2003, 2005; Boyden et al, 2005), researchers began evaluating their use in a novel in vivo application: vision restoration. ReaChR, which used the N-terminus of ChiEF to facilitate membrane trafficking, the transmembrane domain from VChR2 to increase expression, and a L171I point mutation to reduce desensitization above 600 nm, has a red-shifted activation spectrum with a peak excitation ∼600 nm and is capable of generating photocurrent at 630 nm (Figure 2B; Lin et al, 2013) In mice this channel could produce spiking frequencies up to 30 Hz in ganglion cells and 22 Hz in macaque retinal explants (Sengupta et al, 2016). When delivered intravitreally to the ganglion cell layer (Lin et al, 2008), or subretinally to outer retinal cells (De Silva et al, 2017), melanopsin treated retinas are three fold more light sensitive than any microbial opsin, only requiring 1012 photons cm−2 s−1 to generate a signal (Figure 2C). In order for any of these therapies to be a viable option for people, non-transgenic routes must be pursued
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