Using a bistable animal opsin for switchable and scalable optogenetic inhibition of neurons

There is no consensus on the best inhibitory optogenetic tool. Since Gi/o signalling is a native mechanism of neuronal inhibition, we asked whether Lamprey Parapinopsin (Lamplight), a Gi/o-coupled bistable animal opsin, could be used for optogenetic silencing. We show that short (405 nm) and long (525 nm) wavelength pulses repeatedly switch Lamplight between stable signalling active and inactive states, respectively, and that combining these wavelengths can be used to achieve intermediate levels of activity. These properties can be applied to produce switchable neuronal hyperpolarisation and suppression of spontaneous spike firing in the mouse hypothalamic suprachiasmatic nucleus. Expressing Lamplight in (predominantly) ON bipolar cells can photosensitise retinas following advanced photoreceptor degeneration, with 405 and 525 nm stimuli producing responses of opposite sign in the output neurons of the retina. We conclude that bistable animal opsins can co-opt endogenous signalling mechanisms to allow optogenetic inhibition that is scalable, sustained and reversible.

Automated summary

There is no consensus on the best inhibitory optogenetic tool. Gi/o signalling is a native mechanism of neuronal inhibition, and Lamprey Parapinopsin (Lamplight) can be used for optogenetic silencing by switching between stable signalling active and inactive states with different wavelengths. The properties of Lamplight can be applied to achieve switchable neuronal hyperpolarisation and suppression of spontaneous spike firing in specific brain regions. Expressing Lamplight in ON bipolar cells can photosensitise retinas following advanced photoreceptor degeneration, showing potential for scalable, sustained, and reversible optogenetic inhibition.