A bistable inhibitory optoGPCR for multiplexed optogenetic control of neural circuits PMID: 38811857

Target-related Cytokines

2026-09-23

A bistable inhibitory optoGPCR for multiplexed optogenetic control of neural circuits

Nat Methods. 2024 Jul;21(7):1275-1287. doi: 10.1038/s41592-024-02285-8.

Jonas Wietek ¹ ² ³ , Adrianna Nozownik ⁴ ⁵ , Mauro Pulin ⁴ ⁶ , Inbar Saraf-Sinik ⁷ ⁸ , Noa Matosevich ⁹ , Raajaram Gowrishankar ¹⁰ ¹¹ , Asaf Gat ⁷ ⁸ , Daniela Malan ¹² , Bobbie J Brown ¹³ , Julien Dine ⁷ ⁸ ¹⁴ , Bibi Nusreen Imambocus ¹⁵ , Rivka Levy ⁷ ⁸ , Kathrin Sauter ⁴ , Anna Litvin ⁷ ⁸ , Noa Regev ¹⁶ , Suraj Subramaniam ⁷ ⁸ , Khalid Abrera ¹⁰ , Dustin Summarli ¹⁰ , Eva Madeline Goren ⁹ ¹⁷ , Gili Mizrachi ⁷ ⁸ , Eyal Bitton ⁷ ⁸ , Asaf Benjamin ⁷ ⁸ , Bryan A Copits ¹³ , Philipp Sasse ¹² , Benjamin R Rost ¹⁸ ¹⁹ , Dietmar Schmitz ¹⁸ ¹⁹ ²⁰ ²¹ ²² , Michael R Bruchas ¹⁰ ¹¹ ²³ , Peter Soba ¹⁵ ²⁴ , Meital Oren-Suissa ⁷ ⁸ , Yuval Nir ⁹ ¹⁶ ²⁵ , J Simon Wiegert ⁴ ²⁶ , Ofer Yizhar ²⁷ ²⁸

Affiliations

1. Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel. [email protected].
2. Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel. [email protected].
3. Neuroscience Research Center, Charité - Universitätsmedizin Berlin, Berlin, Germany. [email protected].
4. Center for Molecular Neurobiology, Hamburg, Germany.
5. Paris Brain Institute, Institut du Cerveau (ICM), CNRS UMR 7225, INSERM U1127, Sorbonne Université, Paris, France.
6. Laboratory of Sensory Processing, Brain Mind Institute, Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
7. Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel.
8. Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel.
9. Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
10. Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA.
11. Center for Excellence in the Neurobiology of Addiction, Pain and Emotion, University of Washington, Seattle, WA, USA.
12. Institut für Physiologie I, University of Bonn, Bonn, Germany.
13. Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA.
14. Boehringer Ingelheim Pharma GmbH & Co. KG; CNS Diseases, Biberach an der Riss, Germany.
15. LIMES-Institute, University of Bonn, Bonn, Germany.
16. Department of Physiology and Pharmacology, Tel Aviv University, Tel Aviv, Israel.
17. University of Michigan, Ann Arbor, MI, USA.
18. German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.
19. Neuroscience Research Center, Charité - Universitätsmedizin Berlin, Berlin, Germany.
20. Bernstein Center for Computational Neuroscience, Berlin, Germany.
21. Einstein Center for Neurosciences, Berlin, Germany.
22. Max Delbrück Center for Molecular Medicine, Berlin, Germany.
23. Department of Pharmacology, University of Washington, Seattle, WA, USA.
24. Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
25. Department of Biomedical Engineering, Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel.
26. MCTN, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany.
27. Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel. [email protected].
28. Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel. [email protected].

Abstract

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.