Mechanism-guided identification of antidepressant G protein-coupled receptor drug targets.
Hermany Munguba, Anisul Arefin, Ryota Hasegawa, Luca Posa, Giovanna R Romano, Teja N Peddada, Alexander Donatelle, Ashna Singh, Vanessa A Gutzeit, Akshara Vijay, Prerana Vaddi, Melanie Kristt, Daniel Shaver, Shanjida Hoque, Johannes Broichhagen, Joseph M Stujenske, Francis S Lee, Evan O'brien, Joshua Levitz, Conor Liston
Cell April 30, 2026 Peer reviewed DOI: 10.1016/j.cell.2026.04.006 via PubMed
Summary
The study reveals that the fast-acting antidepressant ketamine exerts its effects through mu-opioid receptors in somatostatin-expressing interneurons in the medial prefrontal cortex. Chronic stress leads to changes in these interneurons that ketamine can reverse, suggesting a potential mechanism for its antidepressant action. Additionally, by using RNA sequencing, the study identifies GPCRs enriched in these interneurons, highlighting a strategy for developing new antidepressants with fewer side effects.
Study at a glance
| Population | somatostatin-expressing interneurons in the medial prefrontal cortex |
|---|---|
| Key finding | Ketamine's behavioral effects depend on mu-opioid receptors in somatostatin-expressing interneurons, which are affected by chronic stress. |
Abstract
Depression is driven by dysfunction in discrete neural circuits, but a deeper understanding of the underlying molecular and synaptic mechanisms is needed to guide the development of therapeutics. Here, we decipher the mechanisms of action of the fast-acting antidepressant ketamine to enable the identification of G protein-coupled receptor (GPCR) antidepressant targets. We find that the behavioral effects of ketamine rely on mu-opioid receptors (MORs), 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. Motivated by these findings, we use RNA sequencing to identify mPFC Sst+ IN-enriched GPCRs and validate the antidepressant potential of promising targets. Synergistic targeting of multiple GPCRs enables potent antidepressant-like responses with reduced side effects. Together, these findings reveal a general approach to identifying therapeutic GPCR targets for brain disorders.