A Comprehensive Optogenetic Pharmacology Toolkit for In Vivo Control of GABA(A) Receptors and Synaptic Inhibition

Neuron. 2015 Dec 2;88(5):879-891. doi: 10.1016/j.neuron.2015.10.026. Epub 2015 Nov 19.


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 photoswitch 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 photo-control 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / drug effects
  • Binding Sites / physiology
  • Brain / cytology*
  • Cells, Cultured
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • In Vitro Techniques
  • Mice, Knockout
  • Mutation / genetics
  • Neural Inhibition / drug effects
  • Neural Inhibition / physiology*
  • Optogenetics / methods*
  • Patch-Clamp Techniques
  • Phosphines / pharmacology
  • Photic Stimulation
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism*
  • Synapsins / genetics
  • Synapsins / metabolism
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / genetics
  • Synaptic Transmission / physiology*
  • gamma-Aminobutyric Acid / pharmacology


  • Phosphines
  • Receptors, GABA-A
  • Synapsins
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • tris(2-carboxyethyl)phosphine
  • gamma-Aminobutyric Acid