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

作者：Lin Wan Chen; Tsai Ming Chi; Davenport Christopher M; Smith Caleb M; Veit Julia; Wilson Neil M; Adesnik Hillel; Kramer Richard H^*

来源：Neuron, 2015, 88(5): 1-13.

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 GABA(A) receptor-mediated inhibition in the brain. We developed a series of photo-switch ligands and the complementary genetically modified GABA(A) receptor subunits. By conjugating the two components, we generated light-sensitive versions of the entire GABA(A) receptor family. We validated these light-sensitive receptors for applications across a broad range of spatial scales, from subcellular receptor mapping to in vivo photocontrol of visual responses in the cerebral cortex. Finally, we generated a knockin mouse in which the "photoswitch-ready'' version of a GABA(A) receptor subunit genomically replaces its wild-type counterpart, ensuring normal receptor expression. This optogenetic pharmacology toolkit allows scalable interrogation of endogenous GABA(A) receptor function with high spatial, temporal, and biochemical precision.

• 出版日期2015-12-2