Journal
EMBO REPORTS
Volume 22, Issue 5, Pages -Publisher
WILEY
DOI: 10.15252/embr.202051866
Keywords
bistable; GPCR; neuronal inhibition; opsins; optogenetics
Categories
Funding
- Human Frontier Science Program [RGP0034/2014]
- Medical Research Council [MR/N012992/1, MR/S026266/1]
- Bekker Programme by the Polish National Agency for Academic Exchange [PPN/BEK/2018/1/00192]
- David Sainsbury Fellowship from National Centre for the Replacement Refinement & Reduction of Animals in Research [NC/P001505/1]
- Fight for Sight Fellowship [5047/5048]
- Dean's Prize Fellowship from The University of Manchester
- Biotechnology and Biological Sciences Research Council [BB/S01764X/1]
- BBSRC [BB/S01764X/1] Funding Source: UKRI
- MRC [MR/N012992/1, MR/S026266/1] Funding Source: UKRI
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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.
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.
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