Age dependence of the rapid antidepressant and synaptic effects of acute NMDA receptor blockade
Open accessAbstract
Ketamine is a N-methyl-D-aspartate receptor (NMDAR) antagonist that produces rapid antidepressant responses in individuals with major depressive disorder. The antidepressant action of ketamine has been linked to blocking NMDAR activation at rest, which inhibits eukaryotic elongation factor 2 kinase leading to desuppression of protein synthesis and synaptic potentiation in the CA1 region of the hippocampus. Here, we investigated ketamine mediated antidepressant response and the resulting synaptic potentiation in juvenile animals. We found that ketamine did not produce an antidepressant response in juvenile animals in the novelty suppressed feeding or the forced swim test. In addition ketamine application failed to trigger synaptic potentiation in hippocampal slices obtained from juvenile animals, unlike its action in slices from adult animals. The inability of ketamine to trigger an antidepressant response or subsequent synaptic plasticity processes suggests a developmental component to ketamine mediated antidepressant efficacy. We also show that the NMDAR antagonist AP5 triggers synaptic potentiation in mature hippocampus similar to the action of ketamine, demonstrating that global competitive blockade of NMDARs is sufficient to trigger this effect. These findings suggest that global blockade of NMDARs in developmentally mature hippocampal synapses are required for the antidepressant efficacy of ketamine.
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A 30-min treatment of slice preparations with ketamine potentiates synaptic efficacy in the Schaffer collateral pathway from CA3 to CA1 subregions of the hippocampus.
“Recent work has shown that a 30-min treatment of slice preparations with ketamine potentiates synaptic efficacy in the Schaffer collateral pathway from CA3 to CA1 subregions of the hippocampus (Autry et al., 2011; Nosyreva et al., 2013, 2014).”
From BDNF - a key transducer of antidepressant effects (2016) · cites this paper as Nosyreva et al., 2014
The Results section reports that 30 minutes of ketamine treatment potentiated Schaffer collateral–CA1 responses in mature hippocampal slices. It also reports no significant potentiation in juvenile slices, so the unqualified claim about slice preparations omits an important age-dependent limit. (LLM, conf=0.88)
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- Authors
- Nosyreva, E., Autry, A. E., Kavalali, E. T., & Monteggia, L. M.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Monteggia, Lisa M.
- Venue
- Frontiers in Molecular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2014-12-01
- Volume
- 7
- Pages
- 94-94
- ISSN
- 1662-5099 (ISSN-L)
- PMC
- PMC4249453
- OpenAlex
- W2166563700
- Cited by
- 51
- References
- 31
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 2 · 2022: 3 · 2021: 8 · 2020: 4 · 2019: 3 · 2018: 7 · 2017: 10 · 2016: 6 · 2015: 2
- FWCI
- 4.37
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Molecular Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Brain and Behavior Research Foundation
- International Mental Health Research Organization
- National Institutes of Health (MH070727, MH066198)
- National Institute of Mental Health (R01MH066198, R01MH070727)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- ketamine, NMDA receptor antagonism, rapid antidepressant response, major depressive disorder, synaptic potentiation, hippocampus, CA1, juvenile animals, AP5, eEF2K, protein synthesis, synaptic plasticity, novelty-suppressed feeding, forced swim test
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