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Copits, BA;Gowrishankar, R;O'Neill, PR;Li, JN;Girven, KS;Yoo, JJ;Meshik, X;Parker, KE;Spangler, SM;Elerding, AJ;Brown, BJ;Shirley, SE;Ma, KKL;Vasquez, AM;Stander, MC;Kalyanaraman, V;Vogt, SK;Samineni, VK;Patriarchi, T;Tian, L;Gautam, N;Sunahara, RK;Gereau, RW;Bruchas, MR;
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.