Brain region-specific action of ketamine as a rapid antidepressant.
Min Chen, Shuangshuang Ma, Hanxiao Liu, Yiyan Dong, Jingxiang Tang, Zheyi Ni, Yi Tan, Chenchi Duan, Hui Li, Hefeng Huang, Yulong Li, Xiaohua Cao, Christopher J Lingle, Yan Yang, Hailan Hu
Science August 9, 2024 DOI: 10.1126/science.ado7010 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Depressive-like mice |
| Intervention | Ketamine injection |
| Topics | Esketamine Ketamine |
| Keywords | Depression treatment Ketamine therapy Brain research Psychopharmacology |
| Citations | 87 |
| Key findings | Ketamine's antidepressant action in depressive-like mice depends on blocking NMDARs specifically in the lateral habenula, not the hippocampus. |
Abstract
Ketamine has been found to have rapid and potent antidepressant activity. However, despite the ubiquitous brain expression of its molecular target, the N-methyl-d-aspartate receptor (NMDAR), it was not clear whether there is a selective, primary site for ketamine's antidepressant action. We found that ketamine injection in depressive-like mice specifically blocks NMDARs in lateral habenular (LHb) neurons, but not in hippocampal pyramidal neurons. This regional specificity depended on the use-dependent nature of ketamine as a channel blocker, local neural activity, and the extrasynaptic reservoir pool size of NMDARs. Activating hippocampal or inactivating LHb neurons swapped their ketamine sensitivity. Conditional knockout of NMDARs in the LHb occluded ketamine's antidepressant effects and blocked the systemic ketamine-induced elevation of serotonin and brain-derived neurotrophic factor in the hippocampus. This distinction of the primary versus secondary brain target(s) of ketamine should help with the design of more precise and efficient antidepressant treatments.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| 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 Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 29
- Rapid hippocampal synaptic potentiation induced by ketamine metabolite (2R,6R)-hydroxynorketamine persistently primes synaptic plasticity. Neuropsychopharmacology May 1, 2025
- Ketamine Reverses Chronic Stress‐Induced Behavioral Changes via the Expression of Ca 2+ ‐Permeable AMPA Receptors in Mice The FASEB Journal August 26, 2025
- The therapeutic potential of psilocybin beyond psychedelia through shared mechanisms with ketamine. Molecular Psychiatry July 7, 2025
- Locking away depression. Science August 9, 2024
- Rapid antidepressant potential of nitrous oxide: current state and major questions. Molecular Psychiatry June 1, 2026
and 24 more in the library
Cites 19
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate British Journal of Pharmacology June 1, 1983
- Ketamine: a paradigm shift for depression research and treatment Neuron March 1, 2019
and 14 more in the library