NMDA Induces Long-Term Synaptic Depression and Dephosphorylation of the GluR1 Subunit of AMPA Receptors in Hippocampus
Open accessAbstract
Brief bath application of N-methyl-D-aspartate (NMDA) to hippocampal slices produces long-term synaptic depression (LTD) in CA1 that is (1) sensitive to postnatal age, (2) saturable, (3) induced postsynaptically, (4) reversible, and (5) not associated with a change in paired pulse facilitation. Chemically induced LTD (Chem-LTD) and homosynaptic LTD are mutually occluding, suggesting a common expression mechanism. Using phosphorylation site-specific antibodies, we found that induction of chem-LTD produces a persistent dephosphorylation of the GluR1 subunit of AMPA receptors at serine 845, a cAMP-dependent protein kinase (PKA) substrate, but not at serine 831, a substrate of protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII). These results suggest that dephosphorylation of AMPA receptors is an expression mechanism for LTD and indicate an unexpected role of PKA in the postsynaptic modulation of excitatory synaptic transmission.
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Protein phosphatases PP1, PP2A, and CaN dephosphorylate GluA1 S845 and remove receptors by endocytosis during LTD.
“while protein phosphatases PP1, PP2A, and CaN (also known as PP2B) dephosphorylate GluA1 S845 and remove receptors by endocytosis during LTD”
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., 1998
Brief bath application of NMDA produces a form of chemical LTD (cLTD) that is similar to homosynaptic LTD induced by LFS.
“Brief bath application of NMDA produces a form of chemical LTD (cLTD) that is similar to homosynaptic LTD induced by LFS”
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., 1998
Both LFS and NMDA-cLTD induce selective dephosphorylation of GluA1 S845, but not S831, through activation of CaN and other phosphatases.
“both of these stimulation methods induce selective dephosphorylation of GluA1 S845, but not S831, through activation of CaN and other phosphatases”
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., 1998
During LTD, S845 is dephosphorylated by activation of CaN, PP1 and PP2A, removed from synapses, and endocytosed from the extrasynaptic membrane.
“During LTD, S845 is dephosphorylated by activation of CaN, PP1 and PP2A, removed from synapses, and endocytosed from the extrasynaptic membrane”
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., 1998
Acute 5-minute activation of NMDA receptors is known to induce a sustained depression of synaptic strength.
“We next tested an acute 5-minute activation of NMDARs, known to induce a sustained depression of synaptic strength20,21.”
From A trans-synaptic nanocolumn aligns neurotransmitter release to receptors (2016) · cites this paper as [20]
During LTD, GluA1 T840 is dephosphorylated by PP1/PP2A and S845 by CaN.
“GluA1 undergoes dephosphorylation of T840 and S845 during LTD by protein phosphatases PP1/PP2A and CaN, respectively (Delgado et al., 2007, Toda and Huganir, 2015, Lee et al., 1998, Sanderson et al., 2016).”
From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Lee et al., 1998
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- Authors
- Lee, H.-K., Kameyama, K., Huganir, R. L., & Bear, M. F.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Bear, Mark F
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 1998-11
- Volume
- 21
- Issue
- 5
- Pages
- 1151-1162
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2109208582
- Cited by
- 668
- References
- 6
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 15 · 2023: 17 · 2022: 19 · 2021: 33 · 2020: 26 · 2019: 29 · 2018: 24 · 2017: 23 · 2016: 24 · 2015: 29 · 2014: 34 · 2013: 31 · 2012: 26
- FWCI
- 9.03
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuron (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- 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
- NMDA, long-term depression, AMPA receptors, GluR1 subunit, receptor dephosphorylation, protein kinase A, hippocampal CA1, postsynaptic modulation, excitatory synaptic transmission, paired-pulse facilitation
- MeSH terms
- Animals, Hippocampus, Male, Synaptic Transmission, Phosphorylation, Synapses, Time, N-Methylaspartate, Receptors, AMPA, Rats, Long-Evans, Rats, In Vitro Techniques
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