@article{1708f2d80773455a979a612da93683f0,
title = "A photoswitchable GPCR-based opsin for presynaptic inhibition",
abstract = "Optical manipulations of genetically defined cell types have generated significant insights into the dynamics of neural circuits. While optogenetic activation has been relatively straightforward, rapid and reversible synaptic inhibition has proven more elusive. Here, we leveraged the natural ability of inhibitory presynaptic GPCRs to suppress synaptic transmission and characterize parapinopsin (PPO) as a GPCR-based opsin for terminal inhibition. PPO is a photoswitchable opsin that couples to Gi/o signaling cascades and is rapidly activated by pulsed blue light, switched off with amber light, and effective for repeated, prolonged, and reversible inhibition. PPO rapidly and reversibly inhibits glutamate, GABA, and dopamine release at presynaptic terminals. Furthermore, PPO alters reward behaviors in a time-locked and reversible manner in vivo. These results demonstrate that PPO fills a significant gap in the neuroscience toolkit for rapid and reversible synaptic inhibition and has broad utility for spatiotemporal control of inhibitory GPCR signaling cascades.",
keywords = "chemogenetics, inhibitory opsin, neuronal inhibition, optogenetics, synaptic inhibition",
author = "Copits, {Bryan A.} and Raaj Gowrishankar and O'Neill, {Patrick R.} and Li, {Jun Nan} and Girven, {Kasey S.} and Yoo, {Judy J.} and Xenia Meshik and Parker, {Kyle E.} and Spangler, {Skylar M.} and Elerding, {Abigail J.} and Brown, {Bobbie J.} and Shirley, {Sofia E.} and Ma, {Kelly K.L.} and Vasquez, {Alexis M.} and Stander, {M. Christine} and Vani Kalyanaraman and Vogt, {Sherri K.} and Samineni, {Vijay K.} and Tommaso Patriarchi and Lin Tian and N. Gautam and Sunahara, {Roger K.} and Gereau, {Robert W.} and Bruchas, {Michael R.}",
note = "Funding Information: This work was supported by a NIH BRAIN Initiative grant R01 MH111520 (M.R.B and R.K.S.); NIH R21 DA049569 (B.A.C. and P.R.O.), K01 DA042219 (P.R.O.), K01 DK115634 (V.K.S.), T32DA007278 (K.S.G.), R35 GM122577 (N.G.), and P30DA048736 (M.R.B.); the Mary Gates Research Fellowship (A.J.E.); and Scan Design Research Foundation (S.E.S.). We would like to especially thank Akihisa Terakita and Mitsumasa Koyanagi for initial advice in working with parapinopsin, Yu-Qing Cao for advice in recording Ca 2+ channel currents, and Ben Suter for suggestions in building LED systems. We also thank Mathias Mahn, Simon Wiegert, and Ofer Yizhar for helpful comments and discussion on the manuscript and Fletcher Austin and Paul Gaetano for insightful discussions. This work was also supported by the Hope Center Viral Vectors Core at Washington University School of Medicine. Funding Information: This work was supported by a NIH BRAIN Initiative grant R01 MH111520 (M.R.B and R.K.S.); NIH R21 DA049569 (B.A.C. and P.R.O.), K01 DA042219 (P.R.O.), K01 DK115634 (V.K.S.), T32DA007278 (K.S.G.), R35 GM122577 (N.G.), and P30DA048736 (M.R.B.); the Mary Gates Research Fellowship (A.J.E.); and Scan Design Research Foundation (S.E.S.). We would like to especially thank Akihisa Terakita and Mitsumasa Koyanagi for initial advice in working with parapinopsin, Yu-Qing Cao for advice in recording Ca2+ channel currents, and Ben Suter for suggestions in building LED systems. We also thank Mathias Mahn, Simon Wiegert, and Ofer Yizhar for helpful comments and discussion on the manuscript and Fletcher Austin and Paul Gaetano for insightful discussions. This work was also supported by the Hope Center Viral Vectors Core at Washington University School of Medicine. Conceptualization, B.A.C. P.R.O. R.G. R.W.G. and M.R.B.; Methodology, B.A.C. R.G. P.R.O. J.J.Y. X.M. K.E.P. V.K.S. R.K.S. R.W.G. and M.R.B.; Investigation, B.A.C. R.G. P.R.O. J.-N.L. K.S.G. J.J.Y. X.M. K.E.P. S.M.S. A.M.V. A.J.E. S.E.S. B.J.B. K.K.L.M. and V.K.S.; Resources, M.C.S. V.K. and S.K.V.; Writing – original draft, B.A.C.; Writing – review & editing, B.A.C. R.G. P.R.O. R.W.G. and M.R.B.; Visualization, B.A.C. R.G. P.R.O. R.W.G. and M.R.B.; Supervision, B.A.C. P.R.O. N.G. R.K.S. R.W.G. and M.R.B.; Funding acquisition, B.A.C. P.R.O. N.G. R.K.S. R.W.G. and M.R.B. R.W.G and M.R.B. are cofounders of Neurolux Inc. a neuroscience technology company, but no related technology was used in this study. All other authors declare no competing interests. We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper received support from a program designed to increase minority representation in science. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = jun,
day = "2",
doi = "10.1016/j.neuron.2021.04.026",
language = "English",
volume = "109",
pages = "1791--1809.e11",
journal = "Neuron",
issn = "0896-6273",
number = "11",
}