Ambient light optogenetics for vision restoration

Hundreds of novel opsins have been characterized since the advent of optogenetics, but low experimental throughput has limited the scale of opsin engineering campaigns. We modified an automated patch-clamp system with a multispectral light source and a custom light path to enable high-throughput electrophysiological measurements of opsin functional properties. Using this approach, we screened over 1,750 opsins from a range of families. We discovered that the F240A mutation of the light-gated potassium channel WiChR abolished potassium selectivity, turning it into a sensitive excitatory channel that we dubbed “WAChR”. We systematically mutated WAChR and identified variants that expand the frontier of speed-sensitivity tradeoffs. Multiple WAChR variants produced large inward currents in response to indoor ambient office light, and responded to irradiances as low as 15nW/mm2, something that we did not observe with other ultra-sensitive opsins. In vivo recording from the mouse cortex confirmed that WAChRs exhibit enhanced sensitivity in neurons. These ambient-light sensitive channels should be broadly useful for neuroscience research and vision restoration therapies.