Sustained antidepressant effects of ketamine metabolite involve GABAergic inhibition-mediated molecular dynamics in aPVT glutamatergic neurons
Ayako Kawatake-Kuno, Haiyan Li, Hiromichi Inaba, Momoka Hikosaka, Erina Ishimori, Takatoshi Ueki, Y. Garkun, Hirofumi Morishita, S. Narumiya, Naoya Oishi, Gen Ohtsuki, Toshiya Murai, Shusaku Uchida
Neuron February 1, 2024 DOI: 10.1016/j.neuron.2024.01.023 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Repeatedly stressed animal models |
| Interventions | (2S 6S)-hydroxynorketamine |
| Topics | Esketamine Ketamine |
| Key points | The authors report that (2S,6S)-hydroxynorketamine's sustained antidepressant-like behavioral effects in repeatedly stressed animal models involve neurobiological changes in the anterior paraventricular nucleus of the thalamus, including enhanced GABAA receptor-mediated tonic currents, nuclear export of KDM6, replacement by EZH2, increased H3K27me3 levels, and suppressed transcription of genes associated with G-protein-coupled receptor signaling. They propose these mechanisms may inform next-generation pharmacotherapies for sustained remission of stress-related psychiatric disorders. |
Abstract
Summary Despite the rapid and sustained antidepressant effects of ketamine and its metabolites, their underlying cellular and molecular mechanisms are not fully understood. Here, we demonstrate that the sustained antidepressant-like behavioral effects of (2S,6S)-hydroxynorketamine (HNK) in repeatedly stressed animal models involve neurobiological changes in the anterior paraventricular nucleus of the thalamus (aPVT). Mechanistically, (2S,6S)-HNK induces mRNA expression of extrasynaptic GABAA receptors, and subsequently enhances GABAA receptor-mediated tonic currents, leading to the nuclear export of histone demethylase KDM6 and its replacement by histone methyltransferase EZH2. This process increases H3K27me3 levels, which in turn suppresses the transcription of genes associated with G-protein-coupled receptor signaling. Thus, our findings shed light on the comprehensive cellular and molecular mechanisms in aPVT underlying the sustained antidepressant behavioral effects of ketamine metabolites. The present study may support the development of potentially effective next-generation pharmacotherapies to promote sustained remission of stress-related psychiatric disorders.
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 10
- Repurposing Ketamine in the Therapy of Depression and Depression-Related Disorders: Recent Advances and Future Potential. Aging and disease April 29, 2024
- Low-dose ketamine improved brain network integrity among patients with treatment-resistant depression and suicidal ideation. Psychiatry Research March 1, 2025
- Neural signaling mechanisms in depression: bridging classical monoamine hypotheses, animal models, and emerging antidepressant strategies Frontiers in Cell and Developmental Biology March 25, 2026
- Cortical Mechanisms Contributing to Ketamine-Induced Dissociation The Neuroscientist December 26, 2025
- Inhibition of SERT and NMDAR synergistically confers rapid antidepressant effects of ketamine National Science Review September 5, 2025
and 5 more in the library
Cites 10
- 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
- Ketamine: a paradigm shift for depression research and treatment Neuron March 1, 2019
- Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor Molecular Psychiatry May 7, 2021
and 5 more in the library