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 DOI: 10.1016/j.cell.2026.04.006 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mouse models |
| Intervention | Ketamine |
| Topics | Ketamine Neuroplasticity |
| Keywords | Gpcr Antidepressant Neuromodulation Opioid receptor Photopharmacology Prefrontal cortex Somatostatin interneuron Two-photon imaging |
| Citations | 4 |
| Key findings | Ketamine's behavioral effects require mu-opioid receptors on somatostatin-expressing interneurons in the medial prefrontal cortex, and chronic stress-induced presynaptic hypertrophy of these interneurons is rescued by ketamine. |
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.
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Citations in the library
Cited by 3
- Ketamine Modulates Endogenous Opioid Peptide Signaling and Reduces Heroin-Seeking in Male Long-Evans Rats bioRxiv (Cold Spring Harbor Laboratory) September 6, 2026
- Structural basis of opioid receptor activation by PCP and ketamine Nature Structural & Molecular Biology June 22, 2026
- Astrocytic μ-δ opioid receptor heterodimers mediate the antidepressant effects of ketamine’s metabolite bioRxiv June 3, 2026
Cites 32
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression American Journal of Psychiatry October 1, 2015
and 27 more in the library