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PreprintCited by 2Treatment of Major DepressionNeuroscience and Neuropharmacology ResearchNeurogenesis and neuroplasticity mechanisms

Ketamine and its metabolite 2R,6R-hydroxynorketamine promote ocular dominance plasticity and release TRKB from inhibitory control without changing perineuronal nets enwrapping parvalbumin interneurons

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Cannarozzo, Cecilia, Rubiolo, Anna, Casarotto, Plinio, Castrén, Eero·2022·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/2022.04.06.487292
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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 3 injections, throughout the 8-days regimen. Notably, the comparison between the treatments indicates a higher effect size of R,R-HNK compared to 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 affecting PNNs deposits.

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  • Both ketamine and R,R-HNK reactivate ODP in the murine visual cortex but do so with a much faster time scale than fluoxetine.

    “Using the same model, both ketamine and its metabolite R,R-HNK also reactivate ODP in the murine visual cortex but do so with a much faster time scale than fluoxetine does, consistent with their faster onset of antidepressant-like effects (Casarotto et al., 2021;Cannarozzo et al., 2022).”

    From Psychedelics and Neural Plasticity: Therapeutic Implications (2022) · cites this paper as Cannarozzo et al., 2022

  • R,R-HNK produces an ODP response comparable to that of fluoxetine, but preliminary data suggest the size of the effects of ketamine is more restricted, albeit significant.

    “R,R-HNK produces an ODP response comparable to that of fluoxetine, but preliminary data suggest that the size of the effects of ketamine is more restricted, albeit significant (Cannarozzo et al., 2022)”

    From Psychedelics and Neural Plasticity: Therapeutic Implications (2022) · cites this paper as Cannarozzo et al., 2022

  • Ketamine promotes ocular dominance plasticity in the binocular primary visual cortex (bV1).

    “The ability of ketamine to promote ODP in the binocular primary visual cortex (bV1) has recently been reported (Grieco et al., 2020;Casarotto et al., 2021, Cannarozzo et al., 2022).”

    From Psychedelics and Neural Plasticity: Therapeutic Implications (2022) · cites this paper as Cannarozzo et al., 2022

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Cited by

Sorted by citations

  • Psychedelics and Neural Plasticity: Therapeutic Implications

    Grieco, S. F., Castrén, E., Knudsen, G. M., Kwan, A. C., Olson, D. E., Zuo, Y., Holmes, T. C., & Xu, X. (2022) · The Journal of Neuroscience · doi:10.1523/jneurosci.1121-22.2022 · Cited by 82 · see citing works

    “R,R-HNK produces an ODP response comparable to that of fluoxetine, but preliminary data suggest that the size of the effects of ketamine is more restricted, albeit significant (Cannarozzo et al., 2022), perhaps because ketamine inhibits NMDARs, which is known to restrict ODP (Sawtell et al.”
    InfluentialSelf-citation

Authors
Cannarozzo, C., Rubiolo, A., Casarotto, P., & Castrén, E.
Affiliations
University of Helsinki (FI)
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2022-04-09
DOI
10.1101/2022.04.06.487292
OpenAlex
W4223443187
Cited by
2
References
4
Citations by year
2023: 1 · 2022: 1
Type
posted content
Language
en
Open access
Licence
cc-by-nc-nd
Locations
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
Funders
  • EU Joint Programme – Neurodegenerative Disease Research (301225, 643417)
  • Academy of Finland (307416, 294710)
  • Suomen Kulttuurirahasto (00210254)
  • Jane ja Aatos Erkon Säätiö (307416, 643417, 322742)
  • Päivikki ja Sakari Sohlbergin Säätiö
  • Sigrid Juséliuksen Säätiö (307416, 322742, 643417)
  • FP7 Ideas: European Research Council (322742)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
ketamine, (2R,6R)-hydroxynorketamine, ocular dominance plasticity, TrkB, PTPσ, perineuronal nets, parvalbumin interneurons, monocular deprivation, visual cortex, rapid-acting antidepressants, synaptic plasticity

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