SST-INs display unique patterns of transcript expression, splicing variants, and cell signaling pathways relative to other types of neurons in the PFC [1]. Based on this, there exists tremendous potential to harness endogenous cell type-specific mechanisms to manipulate discrete PFC microcircuits via conventional neuropharmacology. To this end, G protein-coupled receptors (GPCRs) deserve our continued attention as pharmacologically accessible targets for therapeutic intervention. GPCRs are generally expressed at the cell surface, where they respond to neurotransmitters, hormones, and other signals by initiating amplified cascades of intracellular signaling. While many widely expressed GPCRs have been explored as targets for psychiatric medications, INs contain vast untapped potential to modulate neurocircuit function through receptors with unique or limited expression patterns. For example, mGlu1 metabotropic glutamate receptors are enriched in SST-INs and expressed in those cells as an uncommon splicing variant. We recently discovered that mGlu1 receptors potentiate excitatory transmission on SST-INs but not neighboring pyramidal cells. Consistent with these actions, small molecule modulators conferred microcircuit-specific effects on PFC microcircuit function and disease-relevant behaviors. Studies from our labs and others leveraging chemogenetics confirm that GPCR-based manipulation of PFC SST-INs can modulate disease-relevant behaviors in animal models [6].

These new and cutting-edge examples provide exciting proof-of-concept that GPCR modulation of SST-INs can be efficacious in preclinical models related to disease. Moving forward, some less-abundant receptor subtypes for acetylcholine, monoamines, and SST itself, represent potentially straightforward paths to develop microcircuit-specific GPCR modulators. Contemporary single-cell transcriptomics studies offer extraordinary, unbiased insight into candidate GPCRs expressed in limited populations of INs as well. Leveraging these valuable datasets to develop means to modulate SST-INs and other IN subtypes will provide great opportunities for developing breakthrough treatments for psychiatric disease.

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