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

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.