Ketamine and its metabolite 2R,6R‐hydroxynorketamine promote ocular dominance plasticity and release tropomyosin‐related kinase B from inhibitory control without reducing perineuronal nets enwrapping parvalbumin interneurons
Cecilia Cannarozzo, Anna Rubiolo, Plínio Casarotto, Eero Castrén
March 1, 2023 DOI: 10.1111/ejn.15929 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study |
|---|---|
| Population | Monocularly deprived mice; in vitro assays |
| Interventions | Ketamine 2R |
| Dose | 3 or 20 mg/kg ketamine |
| Duration | Three injections throughout the 7-day monocular deprivation regimen |
| Topics | Esketamine Ketamine |
| Key findings | Ketamine and R,R-HNK facilitated ocular dominance shifts in monocularly deprived mice, with R,R-HNK showing a higher effect size than ketamine. Neither altered perineuronal net levels, but both disrupted TRKB-PTPσ interaction in vitro. The authors propose that these drugs promote juvenile-like plasticity by directly binding TRKB and releasing it from PTPσ regulation without reducing PNNs. |
Abstract
Ketamine has been described as a fast‐acting antidepressant, exerting effects in depressed patients and in preclinical models with a rapid onset of action. The typical antidepressant fluoxetine is known to induce plasticity in the adult rodent visual cortex, as assessed by a shift in ocular dominance, a classical model of brain plasticity, and a similar effect has been described for ketamine and its metabolite 2R,6R‐hydroxynorketamine (R,R‐HNK). Here, we demonstrate that ketamine (at 3 or 20 mg/kg) and R,R‐HNK facilitated the shift in ocular dominance in monocularly deprived mice, after three injections, throughout the 7‐day monocular deprivation regimen. Notably, the comparison between the treatments indicates a higher effect size of R,R‐HNK compared with ketamine. Treatment with ketamine or R,R‐HNK failed to influence the levels of perineuronal nets (PNNs) surrounding parvalbumin‐positive interneurons. However, we observed in vitro that both ketamine and R,R‐HNK are able to disrupt the tropomyosin‐related kinase B (TRKB) interaction with the protein tyrosine phosphatase sigma (PTPσ), which upon binding to PNNs dephosphorylates TRKB. These results support a model where diverse drugs promote the reinstatement of juvenile‐like plasticity by directly binding TRKB and releasing it from PTPσ regulation, without necessarily reducing PNNs deposits.
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 12
- Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Nature Neuroscience June 1, 2023
- Psychedelics and Neural Plasticity: Therapeutic Implications. Journal of Neuroscience November 1, 2022
- Rethinking the role of TRKB in the action of antidepressants and psychedelics. Trends in Neurosciences November 1, 2024
- Fluoxetine and Ketamine Enhance Extinction Memory and Brain Plasticity by Triggering the p75 Neurotrophin Receptor Proteolytic Pathway. Biological Psychiatry February 1, 2025
- Beyond NMDA Receptors: A Narrative Review of Ketamine's Rapid and Multifaceted Mechanisms in Depression Treatment. International Journal of Molecular Sciences December 20, 2024
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Cites 8
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- 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 Rapid-Acting Antidepressants: A Window into a New Neurobiology for Mood Disorder Therapeutics Annual Review of Medicine October 23, 2014
- Antidepressant-relevant concentrations of the ketamine metabolite (2R,6R)-hydroxynorketamine do not block NMDA receptor function Proceedings of the National Academy of Sciences February 22, 2019
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