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Cited by 63Neuroscience and Neuropharmacology ResearchTreatment of Major DepressionAnesthesia and Neurotoxicity Research

Metaplastic Effects of Subanesthetic Ketamine on CA1 Hippocampal Function

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Izumi, Yukitoshi, Zorumski, Charles F.·2014·Neuropharmacology
DOI 10.1016/j.neuropharm.2014.08.002PMC PMC4188808
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Abstract

Ketamine is a non-competitive N-methyl-d-aspartate receptor (NMDAR) antagonist of interest in neuropsychiatry. In the present studies, we examined the effects of subanesthetic, low micromolar ketamine on excitatory postsynaptic potentials (EPSPs), population spikes (PSs) and synaptic plasticity in the CA1 region of rat hippocampal slices. Ketamine acutely inhibited NMDAR-mediated synaptic responses with half-maximal effects near 10 μM. When administered for 15-30 min at 1-10 μM, ketamine had no effect on baseline dendritic AMPA receptor-mediated EPSPs, but persistently enhanced somatic EPSPs in the pyramidal cell body layer and augmented PS firing. Acute low micromolar ketamine also had no effect on the induction of long-term potentiation (LTP) but blocked long-term depression (LTD). Following 30 min administration of 1-10 μM ketamine, however, a slowly developing and persistent form of LTP inhibition was observed that took two hours following ketamine washout to become manifest. This LTP inhibition did not result from prolonged or enhanced NMDAR inhibition during drug washout. Effects of low ketamine on somatic EPSPs and LTP were not mimicked by a high ketamine concentration that completely inhibited NMDARs, and both of these effects were blocked by co-administration of low ketamine with a low concentration of the competitive NMDAR antagonist, 2-amino-5-phosphonovalerate or inhibitors of nitric oxide synthase. These results indicate that concentrations of ketamine relevant to psychotropic and psychotomimetic effects have complex metaplastic effects on hippocampal function that involve activation of unblocked NMDARs during ketamine exposure.

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  • mTOR activation is crucial for ketamine's sustained antidepressant effects but likely does not contribute to the rapid antidepressant response.

    “While mTOR activation is crucial for ketamine’s sustained antidepressant effects, it likely does not contribute to the rapid antidepressant response [89].”

    From Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review (2024) · cites this paper as [89]

    The Introduction links mTOR to ketamine-related synaptic changes, but does not distinguish its role in sustained versus rapid antidepressant effects. The Results and Discussion report that mTOR inhibition did not alter ketamine’s effect on LTP in hippocampal slices; they do not test either phase of the antidepressant response. No passage found supports the claimed temporal distinction. (LLM, conf=0.77)

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  • Ketamine's activation of mTORC1 occurs downstream of BDNF signaling and is not directly linked to its initial synaptic engagement.

    “Research suggests that ketamine’s activation of mTORC1 occurs downstream of BDNF signaling and is not directly linked to its initial synaptic engagement [89].”

    From Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review (2024) · cites this paper as [89]

    The Introduction links both mTOR and BDNF to ketamine-associated synaptic changes, but does not establish an order between them. The Results and Discussion report that mTOR inhibition did not alter ketamine’s effect on LTP in CA1 slices; they do not test whether mTORC1 activation follows BDNF signaling or whether it is linked to initial synaptic engagement. Searched our copy for BDNF–mTOR signaling order and rapamycin’s effects. (LLM, conf=0.75)

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Authors
Izumi, Y., & Zorumski, C. F.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Zorumski, Charles F.
ORCID
Venue
Neuropharmacology
Publisher
Elsevier BV
Published
2014-11
Volume
86
Pages
273-281
ISSN
0028-3908 (ISSN-L)
DOI
10.1016/j.neuropharm.2014.08.002
PMC
PMC4188808
OpenAlex
W2020785500
Cited by
63
References
65
Citations by year
2026: 5 · 2025: 5 · 2024: 5 · 2023: 4 · 2022: 1 · 2021: 6 · 2020: 8 · 2019: 4 · 2018: 12 · 2017: 2 · 2016: 5 · 2015: 4 · 2014: 2
FWCI
1.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuropharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (AA017413, MH077791)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Developmental Neuroscience › Anesthesia and Neurotoxicity Research
Keywords
ketamine, metaplasticity, hippocampal CA1, NMDA receptor antagonism, subanesthetic ketamine, long-term potentiation, long-term depression, synaptic plasticity, excitatory postsynaptic potentials, population spike, AMPA receptors, nitric oxide synthase, 2-amino-5-phosphonovalerate, pyramidal neurons
MeSH terms
Animals, Dendrites, Dose-Response Relationship, Drug, Ketamine, Male, Nitric Oxide, Synapses, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Long-Term Potentiation, Receptors, AMPA, Excitatory Amino Acid Antagonists, Nitric Oxide Synthase, Excitatory Postsynaptic Potentials, Long-Term Synaptic Depression, Tissue Culture Techniques, CA1 Region, Hippocampal

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