Ketamine exerts its sustained antidepressant effects via cell-type-specific regulation of Kcnq2.
J. Lopez, M. Lücken, E. Brivio, Stoyo Karamihalev, A. Kos, Carlo de Donno, Asaf Benjamin, Huanqing Yang, Alec L W Dick, R. Stoffel, C. Flachskamm, Andrea Ressle, Simone Roeh, R. Huettl, Andrea Parl, Carola Eggert, B. Novak, Yu Yan, K. Yeoh, Maria Holzapfel, B. Hauger, D. Harbich, B. Schmid, R. D. Giaimo, C. Turck, M. Schmidt, J. Deussing, M. Eder, J. Dine, F. Theis, Alon Chen
Neuron May 1, 2022 DOI: 10.1016/j.neuron.2022.05.001 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | Ketamine Retigabine Escitalopram |
| Dose | single sub-anesthetic dose |
| Topics | Esketamine Ketamine |
| Citations | 78 |
| Key points | Kcnq2 gene in glutamatergic neurons of the ventral hippocampus regulates ketamine's sustained antidepressant effects, and adjunctive retigabine augments these effects specifically for ketamine, not escitalopram. |
Abstract
A single sub-anesthetic dose of ketamine produces a rapid and sustained antidepressant response, yet the molecular mechanisms responsible for this remain unclear. Here, we identified cell-type-specific transcriptional signatures associated with a sustained ketamine response in mice. Most interestingly, we identified the Kcnq2 gene as an important downstream regulator of ketamine action in glutamatergic neurons of the ventral hippocampus. We validated these findings through a series of complementary molecular, electrophysiological, cellular, pharmacological, behavioral, and functional experiments. We demonstrated that adjunctive treatment with retigabine, a KCNQ activator, augments ketamine's antidepressant-like effects in mice. Intriguingly, these effects are ketamine specific, as they do not modulate a response to classical antidepressants, such as escitalopram. These findings significantly advance our understanding of the mechanisms underlying the sustained antidepressant effects of ketamine, with important clinical implications.
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 30
- The Antidepressant Actions of Ketamine and its Enantiomers Pharmacology & Therapeutics May 1, 2023
- Ketamine: Mechanisms and Relevance to Treatment of Depression. Annual Review of Medicine September 20, 2023
- Arketamine, a new rapid-acting antidepressant: A historical review and future directions Neuropharmacology August 14, 2022
- Brain region-specific action of ketamine as a rapid antidepressant. Science August 9, 2024
- Psychedelics and Neural Plasticity: Therapeutic Implications. Journal of Neuroscience November 1, 2022
and 25 more in the library
Cites 13
- 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
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism American Journal of Psychiatry August 29, 2018
- Ketamine: a paradigm shift for depression research and treatment Neuron March 1, 2019
and 8 more in the library