Phosphorylation of the AMPA Receptor GluR1 Subunit Is Required for Synaptic Plasticity and Retention of Spatial Memory
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Plasticity of the nervous system is dependent on mechanisms that regulate the strength of synaptic transmission. Excitatory synapses in the brain undergo long-term potentiation (LTP) and long-term depression (LTD), cellular models of learning and memory. Protein phosphorylation is required for the induction of many forms of synaptic plasticity, including LTP and LTD. However, the critical kinase substrates that mediate plasticity have not been identified. We previously reported that phosphorylation of the GluR1 subunit of AMPA receptors, which mediate rapid excitatory transmission in the brain, is modulated during LTP and LTD. To test if GluR1 phosphorylation is necessary for plasticity and learning and memory, we generated mice with knockin mutations in the GluR1 phosphorylation sites. The phosphomutant mice show deficits in LTD and LTP and have memory defects in spatial learning tasks. These results demonstrate that phosphorylation of GluR1 is critical for LTD and LTP expression and the retention of memories.
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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”
From AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca<sup>2+</sup>-Permeable AMPA Receptors (2012) · cites this paper as Lee et al., 2003
Using a stronger 1 Hz paired-pulse protocol, LTD was still strongly impaired in ΔPIX compared to WT slices.
“Using a stronger LTD induction protocol that delivers a 1 Hz paired-pulse with a 50 ms inter-pulse interval, which was also shown to be NMDAR-dependent in mice (Lee et al., 2003), LTD was still strongly impaired in ΔPIX compared to WT slices”
From AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca<sup>2+</sup>-Permeable AMPA Receptors (2012) · cites this paper as Lee et al., 2003
Only the double phosphonull mutant of S831 and S845 partially impaired LTP in adult, but not young, mice.
“only the double phosphonull mutant partially impaired LTP in adult, but not young, mice (272).”
From Synaptic memory and CaMKII (2023) · cites this paper as [272]
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., 2003
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Self-citation
- Authors
- Lee, H.-K., Takamiya, K., Han, J.-S., Man, H., Kim, C.-H., Rumbaugh, G., Yu, S., Ding, L., He, C., Petralia, R. S., Wenthold, R. J., Gallagher, M., & Huganir, R. L.
- Affiliations
- Howard Hughes Medical Institute (US)
- Johns Hopkins University (US)
- National Institutes of Health (US)
- Corresponding author
- Huganir, Richard L.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2003-03
- Volume
- 112
- Issue
- 5
- Pages
- 631-643
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2168319429
- Cited by
- 802
- References
- 4
- Citations by year
- 2026: 14 · 2025: 13 · 2024: 22 · 2023: 24 · 2022: 26 · 2021: 40 · 2020: 43 · 2019: 31 · 2018: 42 · 2017: 33 · 2016: 38 · 2015: 48 · 2014: 55 · 2013: 35 · 2012: 37
- FWCI
- 13.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R01 MH61108-02)
- Robert Packard Center for ALS Research, Johns Hopkins University
- Howard Hughes Medical Institute
- 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 › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- GluR1, AMPA receptors, receptor phosphorylation, synaptic plasticity, long-term potentiation, long-term depression, spatial memory, learning and memory, excitatory synapses, kinase substrates
- MeSH terms
- Animals, Cell Membrane, Cells, Cultured, Female, Hippocampus, Immunohistochemistry, Male, Memory Disorders, Mice, Inbred C57BL, Microscopy, Electron, Mutation, Neural Pathways, Synaptic Transmission, Phosphorylation, Synapses, Long-Term Potentiation, Receptors, AMPA, Mice, Knockout, Protein Transport, Long-Term Synaptic Depression, Mice
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