Neuregulin signaling mediates the acute and sustained antidepressant effects of subanesthetic ketamine
Steven F. Grieco, X. Qiao, Kevin Johnston, Lujia Chen, Renetta R. Nelson, Cary Lai, Todd C. Holmes, Xiangmin Xu
Translational Psychiatry February 24, 2021 DOI: 10.1038/s41398-021-01255-4 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Basic experimental animal study Peer reviewed |
|---|---|
| Population | Adult mice |
| Intervention | Ketamine |
| Dose | single low-dose ketamine treatment |
| Duration | Up to one week |
| Measures | forced swim test |
| Topics | Esketamine Ketamine |
| Key findings | A single low-dose ketamine treatment reduced depression-like behavior in the forced swim test in adult mice and rapidly downregulated NRG1 in parvalbumin-expressing inhibitory neurons of the medial prefrontal cortex, with decreased synaptic inhibition to excitatory neurons persisting up to a week. The authors propose that ketamine's acute and lasting antidepressant effects are mediated by rapid, sustained cortical disinhibition via PV-specific NRG1/ErbB4 signaling. |
Abstract
Subanesthetic ketamine evokes rapid antidepressant effects in human patients that persist long past ketamine’s chemical half-life of ~2 h. Ketamine’s sustained antidepressant action may be due to modulation of cortical plasticity. We find that ketamine ameliorates depression-like behavior in the forced swim test in adult mice, and this depends on parvalbumin-expressing (PV) neuron-directed neuregulin-1 (NRG1)/ErbB4 signaling. Ketamine rapidly downregulates NRG1 expression in PV inhibitory neurons in mouse medial prefrontal cortex (mPFC) following a single low-dose ketamine treatment. This NRG1 downregulation in PV neurons co-tracks with the decreases in synaptic inhibition to mPFC excitatory neurons for up to a week. This results from reduced synaptic excitation to PV neurons, and is blocked by exogenous NRG1 as well as by PV targeted ErbB4 receptor knockout. Thus, we conceptualize that ketamine’s effects are mediated through rapid and sustained cortical disinhibition via PV-specific NRG1 signaling. Our findings reveal a novel neural plasticity-based mechanism for ketamine’s acute and long-lasting antidepressant effects.
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 7
- Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor Molecular Psychiatry May 7, 2021
- Psychedelics and Neural Plasticity: Therapeutic Implications. Journal of Neuroscience November 1, 2022
- Uncovering the Underlying Mechanisms of Ketamine as a Novel Antidepressant Frontiers in Pharmacology July 7, 2022
- New perspective on sustained antidepressant effect: focus on neurexins regulating synaptic plasticity Cell Death Discovery May 1, 2024
- Transient peripheral blood transcriptomic response to ketamine treatment in children with ADNP syndrome. Translational Psychiatry July 25, 2024
and 2 more in the library
Cites 14
- 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
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
and 9 more in the library