Optical Interrogation of Metabotropic Glutamate Receptor‐Mediated Modulation of Cortical Circuits using Optimized Photoswitchable Tethered Ligands

G protein‐coupled receptors (GPCRs) form a large family of membrane bound receptors that initiate intracellular responses which control cellular signaling cascades to contribute to a wide range of biological functions. The metabotropic glutamate receptors (mGluRs) consist of an eight‐member family of class C GPCRs that respond to the excitatory neurotransmitter glutamate and serve as promising pharmacological targets for a range of neurological and psychiatric disorders. Studies targeting mGluR2 and mGluR3, the group II Gi/o‐coupled subfamily of mGluRs, have shown that they are strong modulators of frontal cortex activity and associated behaviors. However, the lack of spatiotemporal precision and specificity of classical pharmacological and genetic approaches has limited our mechanistic understanding of these receptors. Here we report an improved chemical optogenetic toolkit that permits the reversible and repeatable activation of group II mGluRs with genetic targeting, subtype‐specificity and spatiotemporal precision in vivo . Through introduction of branches and tuning of azobenzene photophysics, we have produced a family of tethered photoswitchable glutamate compounds that enable dual control and visualization of mGluRs in vivo with robust speed and efficiency. We use these tools to probe the effects of mGluR2 activation within different cell‐types and corticolimbic circuits while probing behaviors associated with anxiety, depression and cognitive disorders.