Cited by 261Neuroscience and Neuropharmacology ResearchMemory and Neural MechanismsTreatment of Major Depression

Specific Roles of AMPA Receptor Subunit GluR1 (GluA1) Phosphorylation Sites in Regulating Synaptic Plasticity in the CA1 Region of Hippocampus

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Lee, Hey-Kyoung, Takamiya, Kogo, He, Kaiwen, Song, Lihua, Huganir, Richard L.·2010·Journal of Neurophysiology

Abstract

Activity-dependent changes in excitatory synaptic transmission in the CNS have been shown to depend on the regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). In particular, several lines of evidence suggest that reversible phosphorylation of AMPAR subunit glutamate receptor 1 (GluR1, also referred to as GluA1 or GluR-A) plays a role in long-term potentiation (LTP) and long-term depression (LTD). We previously reported that regulation of serines (S) 831 and 845 on the GluR1 subunit may play a critical role in bidirectional synaptic plasticity in the Schaffer collateral inputs to CA1. Specifically, gene knockin mice lacking both S831 and S845 phosphorylation sites ("double phosphomutants"), where both serine residues were replaced by alanines (A), showed a faster decaying LTP and a deficit in LTD. To determine which of the two phosphorylation sites was responsible for the phenotype, we have now generated two lines of gene knockin mice: one that specifically lacks S831 (S831A mutants) and another that lacks only S845 (S845A mutants). We found that S831A mutants display normal LTP and LTD, whereas S845A mutants show a specific deficit in LTD. Taken together with our previous results from the "double phosphomutants," our data suggest that either S831 or S845 alone may support LTP, whereas the S845 site is critical for LTD expression.

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Crossref · 10.1152/jn.00835.2009

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  • GluA1 S845/831A and S845A knock-in mice are deficient in LTD, but S831A mice express normal LTD, indicating that LTD requires regulation of only S845 phosphorylation.

    “GluA1 S845/831A and S845A knock-in mice are deficient in LTD, but S831A mice express normal LTD, further indicating that LTD requires regulation of only S845 phosphorylation”
  • Dephosphorylation and endocytosis of the extrasynaptic GluA1 pool is required for LTD, explaining why S845A knock-in mice that lack this receptor pool are deficient in LTD.

    “dephosphorylation and endocytosis of this pool of GluA1 is required for LTD, explaining why S845A knock-in mice that lack this receptor pool are deficient in LTD”
  • LTD is impaired in GluA1-S845A knock-in mice, where S845 phosphorylation stabilizes GluA1 homomers in extrasynaptic locations where they exchange in and out of the synapse but are removed by LTD.

    “LTD is impaired in GluA1-S845A knock-in mice (Lee et al., 2010), where it was found that S845 phosphorylation stabilizes GluA1 homomers in extrasynaptic locations where they exchange in and out of the synapse but are removed by LTD”
  • Replacement by alanine of either S831 or S845 does not affect LTP.

    “A further issue is that replacement by alanine of either one of these residues does not affect LTP (271)”

    From Synaptic memory and CaMKII (2023) · cites this paper as [271]

  • GluA1 S845 dephosphorylation is critical for hippocampal LTD, as the GluA1 S845A mutation results in impaired LTD.

    “GluA1 S845 dephosphorylation is critical for hippocampal LTD, as the GluA1 S845A mutation results in impaired LTD (Lee et al., 2003, Lee et al., 2010), indicating that the induction of LTD requires PKA phosphorylation of GluA1 even though receptors are eventually dephosphorylated (Huganir and Nicoll, 2013).”

    From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Lee et al., 2010

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Authors
Lee, H.-K., Takamiya, K., He, K., Song, L., & Huganir, R. L.
Affiliations
  • Howard Hughes Medical Institute (US)
  • University of Maryland, College Park (US)
Corresponding author
Huganir, Richard L.
Venue
Journal of Neurophysiology
Published
2010-01
Volume
103
Issue
1
Pages
479-489
ISSN
  • 0022-3077 (ISSN-L)
  • 1522-1598
OpenAlex
W2162552344
Cited by
261
References
65
Citations by year
2026: 6 · 2025: 9 · 2024: 13 · 2023: 13 · 2022: 17 · 2021: 14 · 2020: 18 · 2019: 17 · 2018: 18 · 2017: 11 · 2016: 24 · 2015: 22 · 2014: 19 · 2013: 23 · 2012: 13
FWCI
5.13
Type
journal article
Language
en
Open access
Locations
  • Journal of Neurophysiology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Eye Institute (R01EY014882)
  • National Institute of Neurological Disorders and Stroke (R01NS036715)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
GluR1, AMPA receptors, GluR1 phosphorylation, long-term potentiation, long-term depression, bidirectional synaptic plasticity, hippocampal CA1, Schaffer collaterals, excitatory synaptic transmission
MeSH terms
Aging, Amino Acid Sequence, Animals, Base Sequence, Male, Mice, Inbred C57BL, Mice, Transgenic, Molecular Sequence Data, Mutation, Synaptic Transmission, Neurons, Phosphorylation, Synapses, Long-Term Potentiation, Receptors, AMPA, Long-Term Synaptic Depression, Mice, Gene Knock-In Techniques, CA1 Region, Hippocampal, In Vitro Techniques

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