A bistable inhibitory optoGPCR for multiplexed optogenetic control of neural circuits

Jonas Wietek*, Adrianna Nozownik, Mauro Pulin, Inbar Saraf-Sinik, Noa Matosevich, Raajaram Gowrishankar, Asaf Gat, Daniela Malan, Bobbie J. Brown, Julien Dine, Bibi Nusreen Imambocus, Rivka Levy, Kathrin Sauter, Anna Litvin, Noa Regev, Suraj Subramaniam, Khalid Abrera, Dustin Summarli, Eva Madeline Goren, Gili MizrachiEyal Bitton, Asaf Benjamin, Bryan A. Copits, Philipp Sasse, Benjamin R. Rost, Dietmar Schmitz, Michael R. Bruchas, Peter Soba, Meital Oren-Suissa, Yuval Nir, J. Simon Wiegert, Ofer Yizhar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Information is transmitted between brain regions through the release of neurotransmitters from long-range projecting axons. Understanding how the activity of such long-range connections contributes to behavior requires efficient methods for reversibly manipulating their function. Chemogenetic and optogenetic tools, acting through endogenous G-protein-coupled receptor pathways, can be used to modulate synaptic transmission, but existing tools are limited in sensitivity, spatiotemporal precision or spectral multiplexing capabilities. Here we systematically evaluated multiple bistable opsins for optogenetic applications and found that the Platynereis dumerilii ciliary opsin (PdCO) is an efficient, versatile, light-activated bistable G-protein-coupled receptor that can suppress synaptic transmission in mammalian neurons with high temporal precision in vivo. PdCO has useful biophysical properties that enable spectral multiplexing with other optogenetic actuators and reporters. We demonstrate that PdCO can be used to conduct reversible loss-of-function experiments in long-range projections of behaving animals, thereby enabling detailed synapse-specific functional circuit mapping.

Original languageEnglish
Pages (from-to)1275-1287
Number of pages13
JournalNature Methods
Issue number7
StatePublished - Jul 2024


FundersFunder number
European Horizon 2020 Program
Joseph and Wolf Lebovic Charitable Foundation
Azrieli Foundation
National Institutes of Health1U01NS128537-01
National Institutes of Health
European Research CouncilH2020-RIA DEEPER 101016787, 819496, 810580
European Research Council
Deutsche ForschungsgemeinschaftSPP 1665, SFB 958, SFB 1315, SPP 1926, EXC-2049 – 390688087
Deutsche Forschungsgemeinschaft
ERC-2016-StG714762, ERC-2019-STG 850784
European Molecular Biology OrganizationALTF 378-2019
European Molecular Biology Organization


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