A photoswitchable GPCR-based opsin for presynaptic inhibition

• Published in: Neuron (Cambridge, Mass.) Vol. 109; no. 11; pp. 1791 - 1809.e11
• Main Authors: Copits, Bryan A., Gowrishankar, Raaj, O’Neill, Patrick R., Li, Jun-Nan, Girven, Kasey S., Yoo, Judy J., Meshik, Xenia, Parker, Kyle E., Spangler, Skylar M., Elerding, Abigail J., Brown, Bobbie J., Shirley, Sofia E., Ma, Kelly K.L., Vasquez, Alexis M., Stander, M. Christine, Kalyanaraman, Vani, Vogt, Sherri K., Samineni, Vijay K., Patriarchi, Tommaso, Tian, Lin, Gautam, N., Sunahara, Roger K., Gereau, Robert W., Bruchas, Michael R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02-06-2021; Elsevier Limited
• Subjects: Animals; chemogenetics; Dopamine; Dopamine - metabolism; Exocytosis; Fish Proteins - genetics; Fish Proteins - metabolism; G protein-coupled receptors; gamma-Aminobutyric Acid - metabolism; Glutamic Acid - metabolism; HEK293 Cells; HeLa Cells; Humans; Inhibition; inhibitory opsin; Lasers; Light; Localization; Male; Mice; Nervous system; Neural Inhibition; Neural networks; neuronal inhibition; optogenetics; Optogenetics - methods; Presynapse; Presynaptic Terminals - metabolism; Presynaptic Terminals - physiology; Proteins; Receptors, G-Protein-Coupled - metabolism; Reinforcement; Reward; Rod Opsins - genetics; Rod Opsins - metabolism; synaptic inhibition; Synaptic Transmission; γ-Aminobutyric acid; neuronal inhibition; optogenetics; chemogenetics; synaptic inhibition; inhibitory opsin
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2021.04.026

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.
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•Parapinopsin (PPO) is a photoswitchable Gi-coupled opsin activated by blue light•At cell bodies, PPO inhibits neuronal activity to suppress reward-seeking behaviors•PPO reversibly inhibits neurotransmitter release at axon terminals•Photoinhibition of projections in vivo rapidly and reversibly alters mouse behavior
Optical approaches to rapidly and reversibly inhibit neuronal projections have lagged behind those for activation. Copits et al. identify a photoswitchable GPCR-based opsin that couples to inhibitory effectors. This opsin leverages the natural ability of presynaptic GPCRs to inhibit transmitter release, providing an alternative strategy to manipulate distinct synaptic projections.