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Cited by 313Neuroscience and Neuropharmacology ResearchMemory and Neural MechanismsNicotinic Acetylcholine Receptors Study

LTP requires a reserve pool of glutamate receptors independent of subunit type

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Granger, Adam J., Shi, Yun, Lu, Wei, Cerpas, Manuel, Nicoll, Roger A.·2013·Nature
DOI 10.1038/nature11775PMC PMC3998843
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Abstract

Long-term potentiation (LTP) of synaptic transmission is thought to be an important cellular mechanism underlying memory formation. A widely accepted model posits that LTP requires the cytoplasmic carboxyl tail (C-tail) of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GluA1. To find the minimum necessary requirement of the GluA1 C-tail for LTP in mouse CA1 hippocampal pyramidal neurons, we used a single-cell molecular replacement strategy to replace all endogenous AMPA receptors with transfected subunits. In contrast to the prevailing model, we found no requirement of the GluA1 C-tail for LTP. In fact, replacement with the GluA2 subunit showed normal LTP, as did an artificially expressed kainate receptor not normally found at these synapses. The only conditions under which LTP was impaired were those with markedly decreased AMPA receptor surface expression, indicating a requirement for a reserve pool of receptors. These results demonstrate the synapse's remarkable flexibility to potentiate with a variety of glutamate receptor subtypes, requiring a fundamental change in our thinking with regard to the core molecular events underlying synaptic plasticity.

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  • Deletion of the CTD of GluA1 yields LTP indistinguishable from neighboring control cells.

    “Experiments in which the CTD of GluA1 is deleted (Refs. 273–275, but see Refs. 276, 277) express LTP that is indistinguishable from that in neighboring control cells.”

    From Synaptic memory and CaMKII (2023) · cites this paper as [273]

    In “No GluA1 C-tail domains are required for LTP” (page unavailable), two GluA1 C-tail truncations produced LTP comparable to control cells, and complete C-tail truncation rescued LTP when paired with GluA2. But “LTP requires a reserve pool of AMPARs” (page unavailable) reports substantially impaired LTP when completely truncated GluA1ΔC was used alone. The claim omits this condition-dependent result. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In the absence of preferred AMPAR variants, less preferred variants, or even kainate receptors, may substitute, although this may be only the case for the most robust LTP induction protocols.

    “Our proposed hierarchy suggests that in the absence of preferred AMPAR variants, less preferred variants, or even kainate receptors, may substitute, although this is may be only the case for the most robust LTP induction protocols (Granger et al., 2013).”

    From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Granger et al., 2013

    The Introduction and the section “GluK1 is sufficient for mediating LTP” report normal LTP after AMPARs were replaced with GluA2 or kainate receptors. The Methods specify the induction protocol, but the paper does not compare protocols or suggest that substitution works only with the most robust ones. The proposed hierarchy is the citing authors’ framing, not a finding attributed to this source. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Forms of LTP, LTD and homeostatic scaling have been shown to be intact in knock-out mice of different AMPAR subunits as well as in molecular replacement experiments.

    “Forms of LTP, LTD and homeostatic scaling have been shown to be intact in knock-out mice of different AMPAR subunits as well as in using molecular replacement experiments (Huganir and Nicoll, 2013, Granger et al., 2013, Ancona Esselmann et al., 2017).”

    From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Granger et al., 2013

    The Introduction and the section “LTP requires a reserve pool of AMPARs” report normal LTP with some molecular replacements and with GluA2 or GluA3 deletion. But the latter section reports impaired LTP after GluA1 deletion, so the knockout claim is too broad. The paper does not establish intact LTD or homeostatic scaling in these experiments. (LLM, conf=0.91)

    Experimental — accuracy not yet measured

  • Truncated receptors void of any cytoplasmic tail can rescue the depletion of endogenous GluA1-3.

    “a recent study suggests that truncated receptors void of any cytoplasmic tail can rescue the depletion of endogenous GluA1-3 (Granger et al., 2013).”

    From Barriers in the brain: resolving dendritic spine morphology and compartmentalization (2014) · cites this paper as Granger et al., 2013

  • LTP has been shown to occur in the absence of certain AMPAR subunits.

    “As described above, LTP has been shown to occur in the absence of certain AMPAR subunits (Granger et al., 2013).”

    From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Granger et al., 2013

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Authors
Granger, A. J., Shi, Y., Lu, W., Cerpas, M., & Nicoll, R. A.
Affiliations
University of California, San Francisco (US)
Corresponding author
Nicoll, Roger A.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2012-12-12
Volume
493
Issue
7433
Pages
495-500
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature11775
PMC
PMC3998843
OpenAlex
W2171341930
Cited by
313
References
42
Citations by year
2026: 6 · 2025: 14 · 2024: 15 · 2023: 14 · 2022: 17 · 2021: 32 · 2020: 19 · 2019: 15 · 2018: 35 · 2017: 32 · 2016: 28 · 2015: 18 · 2014: 30 · 2013: 36 · 2012: 2
FWCI
11.34
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Science Foundation
  • National Institutes of Health
  • National Institute of Mental Health (R01MH070957)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Keywords
long-term potentiation, AMPA receptors, GluR2 subunit, kainate receptors, synaptic plasticity, AMPA receptor trafficking, receptor surface expression, CA1 pyramidal neurons, glutamate receptor subtypes, memory formation
MeSH terms
Animals, Models, Neurological, Synaptic Transmission, Synapses, Gene Deletion, Protein Structure, Tertiary, Long-Term Potentiation, Receptors, AMPA, Receptors, Kainic Acid, Kainic Acid Receptors, Protein Subunits, Protein Transport, Mice, Receptors, Ionotropic Glutamate

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