The C-terminal tails of endogenous GluA1 and GluA2 differentially contribute to hippocampal synaptic plasticity and learning
Open accessAbstract
Long-term potentiation (LTP) and depression (LTD) at glutamatergic synapses are intensively investigated processes for understanding the synaptic basis for learning and memory, but the underlying molecular mechanisms remain poorly understood. We have made three mouse lines where the C-terminal domains (CTDs) of endogenous AMPA receptors (AMPARs), the principal mediators of fast excitatory synaptic transmission, are specifically exchanged. These mice display profound deficits in synaptic plasticity without any effects on basal synaptic transmission. Our study reveals that the CTDs of GluA1 and GluA2, the key subunits of AMPARs, are necessary and sufficient to drive NMDA receptor-dependent LTP and LTD, respectively. In addition, these domains exert differential effects on spatial and contextual learning and memory. These results establish dominant roles of AMPARs in governing bidirectional synaptic and behavioral plasticity in the CNS.
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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 [276]
Cites
AMPA Receptor Trafficking and Synaptic Plasticity
Malinow, R., & Malenka, R. C. (2002) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.25.112701.142758 · Cited by 2,588 · see citing works
Long-term depression in the CNS
Collingridge, G. L., Peineau, S., Howland, J. G., & Wang, Y. T. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2867 · Cited by 926 · see citing works
Self-citationAhmadian, G., Ju, W., Liu, L., Wyszynski, M., Lee, S. H., Dunah, A. W., Taghibiglou, C., Wang, Y., Lu, J., Wong, T. P., et al. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600126 · Cited by 296 · see citing works
Synaptic transmission and plasticity in the absence of AMPA glutamate receptor GluR2 and GluR3
Meng, Y., Zhang, Y., & Jia, Z. (2003) · Neuron · doi:10.1016/s0896-6273(03)00368-4 · Cited by 251 · see citing works
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The AMPA Receptor Code of Synaptic Plasticity
Diering, G. H., & Huganir, R. L. (2018) · Neuron · doi:10.1016/j.neuron.2018.10.018 · Cited by 844 · see citing works
Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels
Hansen, K. B., Wollmuth, L. P., Bowie, D., Furukawa, H., Menniti, F. S., Sobolevsky, A. I., Swanson, G. T., Swanger, S. A., Greger, I. H., Nakagawa, T., et al. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000131 · Cited by 686 · see citing works
Nicoll, R. A., & Schulman, H. (2023) · Physiological Reviews · doi:10.1152/physrev.00034.2022 · Cited by 126 · see citing works
“276, 277) express LTP that is indistinguishable from that in neighboring control cells.”
ResultVisualizing synaptic plasticity in vivo by large-scale imaging of endogenous AMPA receptors
Graves, A. R., Roth, R. H., Tan, H. L., Zhu, Q., Bygrave, A. M., Lopez-Ortega, E., Hong, I., Spiegel, A. C., Johnson, R. C., Vogelstein, J. T., et al. (2021) · eLife · doi:10.7554/elife.66809 · Cited by 84 · see citing works
Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain
Howard, P. G., Zou, P., Zhang, Y., Huang, F., Tesic, V., Wu, C. Y.-C., & Lee, R. H.-C. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.114973 · Cited by 13 · see citing works
- Authors
- Zhou, Z., Liu, A., Xia, S., Leung, C., Qi, J., Meng, Y., Xie, W., Park, P., Collingridge, G. L., & Jia, Z.
- Affiliations
- University of Toronto (CA)
- Southeast University (CN)
- Nantong University (CN)
- Mount Sinai Hospital (CA)
- Corresponding author
- Collingridge, Graham L.
- Jia, Zhengping
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2017-12-11
- Volume
- 21
- Issue
- 1
- Pages
- 50-62
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W2774694784
- Cited by
- 132
- References
- 4
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 11 · 2023: 15 · 2022: 12 · 2021: 24 · 2020: 22 · 2019: 20 · 2018: 13
- FWCI
- 7.37
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-05-11)
- Open access
- Licence
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Explore Bristol Research (publishedVersion, other-oa)
- 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
- AMPA receptors, GluR1, GluA2, C-terminal domain, long-term potentiation, long-term depression, NMDA receptor, synaptic plasticity, hippocampus, spatial learning, contextual learning, memory, glutamatergic synapses
- MeSH terms
- Protein Domains, Animals, Glycine, Hippocampus, Learning, Mice, Inbred C57BL, Mice, Transgenic, Neuronal Plasticity, Peptide Fragments, Quinoxalines, Synapses, Tetrodotoxin, Valine, Long-Term Potentiation, Receptors, AMPA, Excitatory Amino Acid Antagonists, Glutamic Acid, Maze Learning, Sodium Channel Blockers, Long-Term Synaptic Depression, Mice
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