CoChat
Sign Up
Cited by 660Neuroscience and Neuropharmacology ResearchReceptor Mechanisms and SignalingNicotinic Acetylcholine Receptors Study

Subunit Composition of Synaptic AMPA Receptors Revealed by a Single-Cell Genetic Approach

Open access
Lu, Wei, Shi, Yun, Jackson, Alexander C., Bjorgan, Kirsten, During, Matthew J., Sprengel, Rolf, Seeburg, Peter H., Nicoll, Roger A.·2009·Neuron
DOI 10.1016/j.neuron.2009.02.027PMC PMC3632349
Open this paper in CoChat — free account

Abstract

The precise subunit composition of synaptic ionotropic receptors in the brain is poorly understood. This information is of particular importance with regard to AMPA-type glutamate receptors, the multimeric complexes assembled from GluA1-A4 subunits, as the trafficking of these receptors into and out of synapses is proposed to depend upon the subunit composition of the receptor. We report a molecular quantification of synaptic AMPA receptors (AMPARs) by employing a single-cell genetic approach coupled with electrophysiology in hippocampal CA1 pyramidal neurons. In contrast to prevailing views, we find that GluA1A2 heteromers are the dominant AMPARs at CA1 cell synapses (approximately 80%). In cells lacking GluA1, -A2, and -A3, synapses are devoid of AMPARs, yet synaptic NMDA receptors (NMDARs) and dendritic morphology remain unchanged. These data demonstrate a functional dissociation of AMPARs from trafficking of NMDARs and neuronal morphogenesis. This study provides a functional quantification of the subunit composition of AMPARs in the CNS and suggests novel roles for AMPAR subunits in receptor trafficking.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.neuron.2009.02.027

Cites

8 of 8 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Most AMPARs in CA1 hippocampal pyramidal cells are tetraheteromeric assemblies of either GluA1/GluA2 or GluA2/GluA3 subunits, with a preponderance of GluA1/GluA2.

    “Most AMPARs in CA1 hippocampal pyramidal cells are tetraheteromeric assemblies of either GluA1/GluA2 subunits or GluA2/GluA3 subunits with a preponderance of GluA1/GluA2 subunits (264–266).”

    From Synaptic memory and CaMKII (2023) · cites this paper as [264]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 75

  1. Adesnik H Nicoll RA 2007 Conservation of glutamate receptor 2-containing AMPA receptors during long-term potentiation J Neurosci 27 4598 4602 17460072 PMC6672988
  2. Andrasfalvy BK Magee JC 2004 Changes in AMPA receptor currents following LTP induction on rat CA1 pyramidal neurones J Physiol 559 543 554 15235093 PMC1665120
  3. Andrasfalvy BK Smith MA Borchardt T Sprengel R Magee JC 2003 Impaired regulation of synaptic strength in hippocampal neurons from GluR1-deficient mice J Physiol 552 35 45 12878757 PMC2343312
  4. Ayalon G Segev E Elgavish S Stern-Bach Y 2005 Two regions in the N-terminal domain of ionotropic glutamate receptor 3 form the subunit oligomerization interfaces that control subtype-specific receptor assembly J Biol Chem 280 15053 15060 15703162
  5. Ayalon G Stern-Bach Y 2001 Functional assembly of AMPA and kainate receptors is mediated by several discrete protein-protein interactions Neuron 31 103 113 11498054
  6. Bats C Groc L Choquet D 2007 The interaction between Stargazin and PSD-95 regulates AMPA receptor surface trafficking Neuron 53 719 734 17329211
  7. Baude A Nuzzer Z Molnar E McIlhinney RAJ Somogyi P 1995 High-resolution immunogold localization of AMPA type glutamate receptor subunits at synaptic and non-snaptic sites in rat hipppocampus Neuroscience 69 1031 1055 8848093
  8. Beique JC Lin DT Kang MG Aizawa H Takamiya K Huganir RL 2006 Synapse-specific regulation of AMPA receptor function by PSD-95 Proc Natl Acad Sci U S A 103 19535 19540 17148601 PMC1748260
  9. Bellone C Nicoll RA 2007 Rapid bidirectional switching of synaptic NMDA receptors Neuron 55 779 785 17785184
  10. Bredt DS Nicoll RA 2003 AMPA receptor trafficking at excitatory synapses Neuron 40 361 379 14556714
  11. Bureau I Bischoff S Heinemann SF Mulle C 1999 Kainate receptor-mediated responses in the CA1 field of wild-type and GluR6-deficient mice J Neurosci 19 653 663 9880586 PMC6782223
  12. Burnashev N Monyer H Seeburg PH Sakmann B 1992 Divalent ion permeability of AMPA receptor channels is dominated by the edited form of a single subunit Neuron 8 189 198 1370372
  13. Carmignoto G Vicini S 1992 Activity-dependent decrease in NMDA receptor responses during development of the visual cortex Science 258 1007 1011 1279803
  14. Castillo PE Malenka RC Nicoll RA 1997 Kainate receptors mediate a slow postsynaptic current in hippocampal CA3 neurons Nature 388 182 186 9217159
  15. Chen L Chetkovich DM Petralia RS Sweeney NT Kawasaki Y Wenthold RJ Bredt DS Nicoll RA 2000 Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms Nature 408 936 943 11140673
  16. Cho CH St-Gelais F Zhang W Tomita S Howe JR 2007 Two families of TARP isoforms that have distinct effects on the kinetic properties of AMPA receptors and synaptic currents Neuron 55 890 904 17880893
  17. Collingridge GL Isaac JT Wang YT 2004 Receptor trafficking and synaptic plasticity Nat Rev Neurosci 5 952 962 15550950
  18. Collingridge GL Olsen RW Peters J Spedding M 2008 A nomenclature for ligand-gated ion channels Neuropharmacology PMC2847504 18655795
  19. Cull-Candy S Kelly L Farrant M 2006 Regulation of Ca2+-permeable AMPA receptors:synaptic plasticity and beyond Curr Opin Neurobiol 16 277 280 16713244
  20. Dingledine R Borges K Bowie D Traynelis SF 1999 The glutamate receptor ion channels Pharmacol Rev 51 7 61 10049997
  21. Elias GM Funke L Stein V Grant SG Bredt DS Nicoll RA 2006 Synapse-Specific and Developmentally Regulated Targeting of AMPA Receptors by a Family of MAGUK Scaffolding Proteins Neuron 52 307 320 17046693
  22. Engblom D Bilbao A Sanchis-Segura C Dahan L Perreau-Lenz S Balland B Parkitna JR Lujan R Halbout B Mameli M 2008 Glutamate receptors on dopamine neurons control the persistence of cocaine seeking Neuron 59 497 508 18701074
  23. Geiger JR Melcher T Koh DS Sakmann B Seeburg PH Jonas P Monyer H 1995 Relative abundance of subunit mRNAs determines gating and Ca2+ permeability of AMPA receptors in principal neurons and interneurons in rat CNS Neuron 15 193 204 7619522
  24. Greger IH Khatri L Ziff EB 2002 RNA editing at arg607 controls AMPA receptor exit from the endoplasmic reticulum Neuron 34 759 772 12062022
  25. Greger IH Ziff EB Penn AC 2007 Molecular determinants of AMPA receptor subunit assembly Trends Neurosci 30 407 416 17629578
  26. Hashimoto K Fukaya M Qiao X Sakimura K Watanabe M Kano M 1999 Impairment of AMPA receptor function in cerebellar granule cells of ataxic mutant mouse stargazer J Neurosci 19 6027 6036 10407040 PMC6783074
  27. Hayashi Y Shi SH Esteban JA Piccini A Poncer JC Malinow R 2000 Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction Science 287 2262 2267 10731148
  28. Hestrin S Nicoll RA Perkel DJ Sah P 1990 Analysis of excitatory synaptic action in pyramidal cells using whole- cell recording from rat hippocampal slices J Physiol 422 203 225 1972190 PMC1190128
  29. Hoffman DA Sprengel R Sakmann B 2002 Molecular dissection of hippocampal theta-burst pairing potentiation Proc Natl Acad Sci U S A 99 7740 7745 12032353 PMC124338
  30. Hollmann M Heinemann S 1994 Cloned glutamate receptors Annu Rev Neurosci 17 31 108 8210177
  31. Hsieh H Boehm J Sato C Iwatsubo T Tomita T Sisodia S Malinow R 2006 AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss Neuron 52 831 843 17145504 PMC1850952
  32. Isaac JT Ashby M McBain CJ 2007 The role of the GluR2 subunit in AMPA receptor function and synaptic plasticity Neuron 54 859 871 17582328
  33. Isaac JT Nicoll RA Malenka RC 1995 Evidence for silent synapses: implications for the expression of LTP Neuron 15 427 434 7646894
  34. Jensen V Kaiser KM Borchardt T Adelmann G Rozov A Burnashev N Brix C Frotscher M Andersen P Hvalby O 2003 A juvenile form of postsynaptic hippocampal long-term potentiation in mice deficient for the AMPA receptor subunit GluR-A J Physiol 553 843 856 14555717 PMC2343614
  35. Jia Z Agopyan N Miu P Xiong Z Henderson J Gerlai R Taverna FA Velumian A MacDonald J Carlen P 1996 Enhanced LTP in mice deficient in the AMPA receptor GluR2 Neuron 17 945 956 8938126
  36. Jonas P 2000 The Time Course of Signaling at Central Glutamatergic Synapses News Physiol Sci 15 83 89 11390884
  37. Kaspar BK Vissel B Bengoechea T Crone S Randolph-Moore L Muller R Brandon EP Schaffer D Verma IM Lee KF 2002 Adeno-associated virus effectively mediates conditional gene modification in the brain Proc Natl Acad Sci U S A 99 2320 2325 11842206 PMC122363
  38. Kerchner GA Nicoll RA 2008 Silent synapses and the emergence of a postsynaptic mechanism for LTP Nat Rev Neurosci 9 813 825 18854855 PMC2819160
  39. Koh DS Burnashev N Jonas P 1995 Block of native Ca(2+)-permeable AMPA receptors in rat brain by intracellular polyamines generates double rectification J Physiol 486 Pt 2 305 312 7473198 PMC1156522
  40. Kopec CD Real E Kessels HW Malinow R 2007 GluR1 links structural and functional plasticity at excitatory synapses J Neurosci 27 13706 13718 18077682 PMC6673607
  41. Lee HK Takamiya K Han JS Man H Kim CH Rumbaugh G Yu S Ding L He C Petralia RS 2003 Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory Cell 112 631 643 12628184
  42. Liao D Hessler NA Malinow R 1995 Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice Nature 375 400 404 7760933
  43. Luscher C Xia H Beattie EC Carroll RC von Zastrow M Malenka RC Nicoll RA 1999 Role of AMPA receptor cycling in synaptic transmission and plasticity Neuron 24 649 658 10595516
  44. Luthi A Chittajallu R Duprat F Palmer MJ Benke TA Kidd FL Henley JM Isaac JT Collingridge GL 1999 Hippocampal LTD expression involves a pool of AMPARs regulated by the NSF-GluR2 interaction Neuron 24 389 399 10571232
  45. Mansour M Nagarajan N Nehring RB Clements JD Rosenmund C 2001 Heteromeric AMPA receptors assemble with a preferred subunit stoichiometry and spatial arrangement Neuron 32 841 853 11738030
  46. Mayer ML Armstrong N 2004 Structure and function of glutamate receptor ion channels Annu Rev Physiol 66 161 181 14977400
  47. McKinney RA Capogna M Durr R Gahwiler BH Thompson SM 1999 Miniature synaptic events maintain dendritic spines via AMPA receptor activation Nat Neurosci 2 44 49 10195179
  48. Megias M Emri Z Freund TF Gulyas AI 2001 Total number and distribution of inhibitory and excitatory synapses on hippocampal CA1 pyramidal cells Neuroscience 102 527 540 11226691
  49. Nicoll RA Tomita S Bredt DS 2006 Auxiliary subunits assist AMPA-type glutamate receptors Science 311 1253 1256 16513974
  50. Oh MC Derkach VA 2005 Dominant role of the GluR2 subunit in regulation of AMPA receptors by CaMKII Nat Neurosci 8 853 854 15924137
  51. Osten P Stern-Bach Y 2006 Learning from stargazin: the mouse, the phenotype and the unexpected Curr Opin Neurobiol 16 275 280 16678401
  52. Panicker S Brown K Nicoll RA 2008 Synaptic AMPA receptor subunit trafficking is independent of the C terminus in the GluR2-lacking mouse Proc Natl Acad Sci U S A 105 1032 1037 18195349 PMC2242677
  53. Passafaro M Nakagawa T Sala C Sheng M 2003 Induction of dendritic spines by an extracellular domain of AMPA receptor subunit GluR2 Nature 424 677 681 12904794
  54. Philpot BD Sekhar AK Shouval HZ Bear MF 2001 Visual experience and deprivation bidirectionally modify the composition and function of NMDA receptors in visual cortex Neuron 29 157 169 11182088
  55. Saglietti L Dequidt C Kamieniarz K Rousset MC Valnegri P Thoumine O Beretta F Fagni L Choquet D Sala C 2007 Extracellular interactions between GluR2 and N-cadherin in spine regulation Neuron 54 461 477 17481398
  56. Sans N Vissel B Petralia RS Wang YX Chang K Royle GA Wang CY O’Gorman S Heinemann SF Wenthold RJ 2003 Aberrant formation of glutamate receptor complexes in hippocampal neurons of mice lacking the GluR2 AMPA receptor subunit J Neurosci 23 9367 9373 14561864 PMC6740562
  57. Schnell E Sizemore M Karimzadegan S Chen L Bredt DS Nicoll RA 2002 Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number Proc Natl Acad Sci U S A 99 13902 13907 12359873 PMC129795
  58. Seeburg PH 1993 The TINS/TiPS Lecture. The molecular biology of mammalian glutamate receptor channels Trends Neurosci 16 359 365 7694406
  59. Shepherd JD Huganir RL 2007 The cell biology of synaptic plasticity: AMPA receptor trafficking Annu Rev Cell Dev Biol 23 613 643 17506699
  60. Shi S Hayashi Y Esteban JA Malinow R 2001 Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons Cell 105 331 343 11348590
  61. Shimshek DR Bus T Kim J Mihaljevic A Mack V Seeburg PH Sprengel R Schaefer AT 2005 Enhanced odor discrimination and impaired olfactory memory by spatially controlled switch of AMPA receptors PLoS Biol 3 e354 16216087 PMC1255741
  62. Sommer B Kohler M Sprengel R Seeburg PH 1991 RNA editing in brain controls a determinant of ion flow in glutamate-gated channels Cell 67 11 19 1717158
  63. Song I Kamboj S Xia J Dong H Liao D Huganir RL 1998 Interaction of the N-ethylmaleimide-sensitive factor with AMPA receptors Neuron 21 393 400 9728920
  64. Soto D Coombs ID Kelly L Farrant M Cull-Candy SG 2007 Stargazin attenuates intracellular polyamine block of calcium-permeable AMPA receptors Nat Neurosci 10 1260 1267 17873873 PMC2430330
  65. Spruston N Jonas P Sakmann B 1995 Dendritic glutamate receptor channels in rat hippocampal CA3 and CA1 pyramidal neurons J Physiol 482 Pt 2 325 352 7536248 PMC1157732
  66. Tichelaar W Safferling M Keinanen K Stark H Madden DR 2004 The Three-dimensional Structure of an Ionotropic Glutamate Receptor Reveals a Dimer-of-dimers Assembly J Mol Biol 344 435 442 15522296
  67. Tsuzuki K Lambolez B Rossier J Ozawa S 2001 Absolute quantification of AMPA receptor subunit mRNAs in single hippocampal neurons J Neurochem 77 1650 1659 11413248
  68. Tu L Deutsch C 1999 Evidence for dimerization of dimers in K+ channel assembly Biophys J 76 2004 2017 10096897 PMC1300175
  69. Turetsky D Garringer E Patneau DK 2005 Stargazin modulates native AMPA receptor functional properties by two distinct mechanisms J Neurosci 25 7438 7448 16093395 PMC6725298
  70. Venkitaramani DV Chin J Netzer WJ Gouras GK Lesne S Malinow R Lombroso PJ 2007 Beta-amyloid modulation of synaptic transmission and plasticity J Neurosci 27 11832 11837 17978019 PMC2671021
  71. Washburn MS Dingledine R 1996 Block of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors by polyamines and polyamine toxins J Pharmacol Exp Ther 278 669 678 8768718
  72. Wenthold RJ Petralia RS Blahos J II Niedzielski AS 1996 Evidence for multiple AMPA receptor complexes in hippocampal CA1/CA2 neurons J Neurosci 16 1982 1989 8604042 PMC6578515
  73. Zamanillo D Sprengel R Hvalby O Jensen V Burnashev N Rozov A Kaiser KM Koster HJ Borchardt T Worley P 1999 Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning Science 284 1805 1811 10364547
  74. Zhu JJ Esteban JA Hayashi Y Malinow R 2000 Postnatal synaptic potentiation: delivery of GluR4-containing AMPA receptors by spontaneous activity Nat Neurosci 3 1098 1106 11036266
  75. Ziff EB 2007 TARPs and the AMPA Receptor Trafficking Paradox Neuron 53 627 633 17329203

Cited by

Sorted by citations

Authors
Lu, W., Shi, Y., Jackson, A. C., Bjorgan, K., During, M. J., Sprengel, R., Seeburg, P. H., & Nicoll, R. A.
Affiliations
  • University of California, San Francisco (US)
  • The Ohio State University (US)
  • Max Planck Society (DE)
Corresponding author
Nicoll, Roger A.
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2009-04
Volume
62
Issue
2
Pages
254-268
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2009.02.027
PMC
PMC3632349
OpenAlex
W1494623690
Cited by
660
References
8
Citations by year
2026: 26 · 2025: 32 · 2024: 27 · 2023: 39 · 2022: 35 · 2021: 53 · 2020: 49 · 2019: 33 · 2018: 49 · 2017: 42 · 2016: 41 · 2015: 26 · 2014: 40 · 2013: 37 · 2012: 38
FWCI
17.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Max Planck Institute for Plasma Physics (submittedVersion)
  • Max Planck Digital Library (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
  • Social Neuroscience
Funders
National Institute of Mental Health (F32MH081430, R01MH070957, R01MH080379)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Keywords
AMPA receptors, GluR1, GluA2, GluA3, GluA4, receptor subunit composition, CA1 pyramidal neurons, NMDA receptor, dendritic morphology, ionotropic glutamate receptors
MeSH terms
Animals, Animals, Newborn, Biophysics, Electric Stimulation, Hippocampus, Membrane Potentials, Mice, Transgenic, Models, Neurological, Neurons, Receptors, Neurotransmitter, Receptors, AMPA, Patch-Clamp Techniques, Excitatory Amino Acid Antagonists, Glutamic Acid, Excitatory Postsynaptic Potentials, Protein Subunits, Protein Transport, Green Fluorescent Proteins, Mice, In Vitro Techniques

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review