Mechanism-guided identification of antidepressant G protein-coupled receptor drug targets

Depression is a psychiatric disorder that is widely thought to be driven by dysregulation at the molecular and synaptic levels that disrupts the function of discrete neural circuits which, ultimately, drive behavioral symptoms. While therapeutic approaches have typically been based on the serendipitous identification of symptom-alleviating compounds, a deeper understanding of the mechanisms underlying the pathophysiology and treatment of depression is needed to guide the development of new therapeutics. Here we decipher mechanisms of action of the fast-acting antidepressant ketamine to enable the identification of new G protein-coupled receptor (GPCR) antidepressant targets. We find that the behavioral effects of ketamine rely on agonism of mu-opioid receptors, which are enriched in somatostatin-expressing interneurons (Sst+ INs) in the medial prefrontal cortex (mPFC). Chronic stress drives presynaptic hypertrophy of mPFC Sst+ INs and excessive inhibition of pyramidal neurons, which is rescued by ketamine. Driven by these findings, we use RNA sequencing to identify a plethora of mPFC Sst+ IN-enriched GPCRs and validate the antidepressant potential of novel GPCR targets. Synergistic targeting of multiple Sst+ IN-enriched GPCRs enables potent antidepressant-like responses with a reduced side effect profile compared to ketamine. Together this study provides new mechanistic insights with promise to improve antidepressant strategies while revealing a general approach to identifying new therapeutic GPCR targets for brain disorders.