A Comprehensive Optogenetic Pharmacology Toolkit for In Vivo Control of GABAA Receptors and Synaptic Inhibition

• Published in: Neuron (Cambridge, Mass.) Vol. 88; no. 5; pp. 879 - 891
• Main Authors: Lin, Wan-Chen, Tsai, Ming-Chi, Davenport, Christopher M., Smith, Caleb M., Veit, Julia, Wilson, Neil M., Adesnik, Hillel, Kramer, Richard H.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 02.12.2015
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2015.10.026

Exogenously expressed opsins are valuable tools for optogenetic control of neurons in circuits. A deeper understanding of neural function can be gained by bringing control to endogenous neurotransmitter receptors that mediate synaptic transmission. Here we introduce a comprehensive optogenetic toolkit for controlling GABAA receptor-mediated inhibition in the brain. We developed a series of photoswitch ligands and the complementary genetically modified GABAA receptor subunits. By conjugating the two components, we generated light-sensitive versions of the entire GABAA receptor family. We validated these light-sensitive receptors for applications across a broad range of spatial scales, from subcellular receptor mapping to in vivo photo-control of visual responses in the cerebral cortex. Finally, we generated a knockin mouse in which the “photoswitch-ready” version of a GABAA receptor subunit genomically replaces its wild-type counterpart, ensuring normal receptor expression. This optogenetic pharmacology toolkit allows scalable interrogation of endogenous GABAA receptor function with high spatial, temporal, and biochemical precision. •Tools for optogenetic pharmacology are introduced for all GABAA receptors•Photo-control is rapid, reversible, and isoform specific in mouse brain•Photo-control is exerted on synaptic inhibition ex vivo or in vivo•Photo-control can be applied to endogenous GABAA receptors in a transgenic mouse Lin, Tsai et al. introduce a chemical-genetic toolkit for photo-controlling individual types of GABAA receptors, which mediate inhibitory synaptic transmission in the brain. Photo-control of inhibition operates with spatial, temporal, and biochemical precision, allowing subcellular-to-systems-level analysis.