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Cited by 38Neuroscience and Neuropharmacology ResearchNicotinic Acetylcholine Receptors StudyReceptor Mechanisms and Signaling

AMPA receptor anchoring at CA1 synapses is determined by N-terminal domain and TARP γ8 interactions

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Watson, Jake F., Pinggera, Alexandra, Ho, Hinze, Greger, Ingo H.·2021·Nature Communications
DOI 10.1038/s41467-021-25281-4PMC PMC8382838

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Abstract

AMPA receptor (AMPAR) abundance and positioning at excitatory synapses regulates the strength of transmission. Changes in AMPAR localisation can enact synaptic plasticity, allowing long-term information storage, and is therefore tightly controlled. Multiple mechanisms regulating AMPAR synaptic anchoring have been described, but with limited coherence or comparison between reports, our understanding of this process is unclear. Here, combining synaptic recordings from mouse hippocampal slices and super-resolution imaging in dissociated cultures, we compare the contributions of three AMPAR interaction domains controlling transmission at hippocampal CA1 synapses. We show that the AMPAR C-termini play only a modulatory role, whereas the extracellular N-terminal domain (NTD) and PDZ interactions of the auxiliary subunit TARP γ8 are both crucial, and each is sufficient to maintain transmission. Our data support a model in which γ8 accumulates AMPARs at the postsynaptic density, where the NTD further tunes their positioning. This interplay between cytosolic (TARP γ8) and synaptic cleft (NTD) interactions provides versatility to regulate synaptic transmission and plasticity.

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  • Synaptic capture of AMPARs requires the PDZ domain interaction between TARPs and PSD-95.

    “It is also agreed that the synaptic capture of AMPARs requires the PDZ domain interaction between TARPs and PSD-95 (275, 279, 294, 440).”

    From Synaptic memory and CaMKII (2023) · cites this paper as [275]

    The Introduction describes TARP–PSD-95 PDZ binding as a major mechanism of AMPAR localization, but the Discussion explicitly rejects it as a universal requirement. It reports that the GluA2 N-terminal domain can support synaptic anchoring even without γ8 PDZ ligands. (LLM, conf=0.89)

    Checked by a reasoning model — may be wrong.

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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 [275]

    The Discussion (page unavailable) says the GluA1 CTD PDZ ligand is not required for synaptic potentiation, which supports a narrower version of the claim. It does not report that deleting the entire GluA1 CTD produces LTP indistinguishable from neighboring control cells; it says the CTD’s requirement for synaptic plasticity needs further investigation. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

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  1. [2]Pinggera, A., Watson, J. F. & Greger, I. H. AMPA Receptors. eLS vol. 1 635–644 (Wiley, 2020).
  2. [3]Malinow R Mainen ZF Hayashi Y LTP mechanisms: from silence to four-lane traffic Curr. Opin. Neurobiol. 2000 10 352 357 10.1016/S0959-4388(00)00099-4 10851179 · DOI
  3. [4]Nicoll RA A brief history of long-term potentiation Neuron 2017 93 281 290 10.1016/j.neuron.2016.12.015 28103477 · DOI · Paper page
  4. [6]Penn AC Hippocampal LTP and contextual learning require surface diffusion of AMPA receptors Nature. 2017 549 384 388 10.1038/nature23658 28902836 PMC5683353 · DOI · Paper page
  5. [7]Choquet D Linking nanoscale dynamics of AMPA receptor organization to plasticity of excitatory synapses and learning J. Neurosci. 2018 38 9318 9329 10.1523/JNEUROSCI.2119-18.2018 30381423 PMC6705996 · DOI · Paper page
  6. [8]MacGillavry HD Song Y Raghavachari S Blanpied TA Nanoscale scaffolding domains within the postsynaptic density concentrate synaptic ampa receptors Neuron. 2013 78 615 622 10.1016/j.neuron.2013.03.009 23719161 PMC3668352 · DOI · Paper page
  7. [9]Nair D Super-resolution imaging reveals that AMPA receptors inside synapses are dynamically organized in nanodomains regulated by PSD95 J. Neurosci. 2013 33 13204 13224 10.1523/JNEUROSCI.2381-12.2013 23926273 PMC6619720 · DOI · Paper page
  8. [12]Xie, X., Liaw, J. S., Baudry, M. & Berger, T. W. Novel expression mechanism for synaptic potentiation: alignment of presynaptic release site and postsynaptic receptor. Proc. Natl. Acad. Sci. USA. 94, 6983–6988 (1997). PMC21271 9192678
  9. [13]Greger IH Watson JF Cull-Candy SG Structural and functional architecture of AMPA-type glutamate receptors and their auxiliary proteins Neuron. 2017 94 713 730 10.1016/j.neuron.2017.04.009 28521126 · DOI · Paper page
  10. [14]Lu W Subunit composition of synaptic AMPA receptors revealed by a single-cell genetic approach Neuron. 2009 62 254 268 10.1016/j.neuron.2009.02.027 19409270 PMC3632349 · DOI · Paper page
  11. [15]Schwenk J Regional diversity and developmental dynamics of the AMPA-receptor proteome in the mammalian brain Neuron 2014 84 41 54 10.1016/j.neuron.2014.08.044 25242221 · DOI
  12. [16]Rouach N TARP γ-8 controls hippocampal AMPA receptor number, distribution and synaptic plasticity Nat. Neurosci. 2005 8 1525 1533 10.1038/nn1551 16222232 · DOI
  13. [17]Schnell E Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number Proc. Natl Acad. Sci. 2002 99 13902 13907 10.1073/pnas.172511199 12359873 PMC129795 · DOI · Paper page
  14. [19]Sheng, M. & Kim, E. The postsynaptic organization of synapses. Cold Spring Harb. Perspect. Biol. 3, a005678 (2011). PMC3225953 22046028
  15. [20]Sumioka A PDZ binding of TARPγ-8 controls synaptic transmission but not synaptic plasticity Nat. Neurosci. 2011 14 1410 1412 10.1038/nn.2952 22002768 PMC3206644 · DOI
  16. [21]Patriarchi, T., Buonarati, O. R. & Hell, J. W. Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca 2+/CaMKII signaling. EMBO J. 37, e99771 (2018). PMC6187224 30249603
  17. [22]Shepherd JD Huganir RL The cell biology of synaptic plasticity: AMPA receptor trafficking Annu. Rev. Cell Dev. Biol. 2007 23 613 643 10.1146/annurev.cellbio.23.090506.123516 17506699 · DOI · Paper page
  18. [23]Barry MF Ziff EB Receptor trafficking and the plasticity of excitatory synapses Curr. Opin. Neurobiol. 2002 12 279 286 10.1016/S0959-4388(02)00329-X 12049934 · DOI
  19. [24]Hayashi Y Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction Science. 2000 287 2262 2267 10.1126/science.287.5461.2262 10731148 · DOI · Paper page
  20. [25]Shi SH Hayashi Y Esteban JA Malinow R Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons Cell. 2001 105 331 343 10.1016/S0092-8674(01)00321-X 11348590 · DOI · Paper page
  21. [26]Granger AJ Shi Y Lu W Cerpas M Nicoll RA LTP requires a reserve pool of glutamate receptors independent of subunit type Nature. 2013 493 495 500 10.1038/nature11775 23235828 PMC3998843 · DOI · Paper page
  22. [27]Zhou Z The C-terminal tails of endogenous GluA1 and GluA2 differentially contribute to hippocampal synaptic plasticity and learning Nat. Neurosci. 2018 21 50 65 10.1038/s41593-017-0030-z 29230056 · DOI · Paper page
  23. [30]Jiang, C. H., Wei, M., Zhang, C. & Shi, Y. S. The amino-terminal domain of GluA1 mediates LTP maintenance via interaction with neuroplastin-65. Proc. Natl. Acad. Sci. USA. 118, e2019194118 (2021). PMC7936340 33627404
  24. [31]O’Brien RJ Synaptic clustering of AMPA receptors by the extracellular immediate- early gene product Narp Neuron 1999 23 309 323 10.1016/S0896-6273(00)80782-5 10399937 · DOI · Paper page
  25. [32]García-Nafría J Herguedas B Watson JF Greger IH The dynamic AMPA receptor extracellular region: a platform for synaptic protein interactions J. Physiol. 2016 594 5449 5458 10.1113/JP271844 26891027 PMC5043031 · DOI
  26. [33]Panicker S Brown K Nicoll RA Synaptic AMPA receptor subunit trafficking is independent of the C terminus in the GluR2-lacking mouse Proc. Natl Acad. Sci. 2008 105 1032 1037 10.1073/pnas.0711313105 18195349 PMC2242677 · DOI
  27. [34]Mack V Conditional restoration of hippocampal synaptic potentiation in Glur-A-deficient mice Science. 2001 292 2501 2504 10.1126/science.1059365 11431570 · DOI
  28. [35]Zamanillo D Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning Science. 1999 284 1805 1811 10.1126/science.284.5421.1805 10364547 · DOI · Paper page
  29. [36]Park P The role of calcium-permeable AMPARs in long-term potentiation at principal neurons in the rodent hippocampus Front. Synaptic Neurosci. 2018 10 42 10.3389/fnsyn.2018.00042 30524263 PMC6262052 · DOI
  30. [37]Lee HK Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory Cell. 2003 112 631 643 10.1016/S0092-8674(03)00122-3 12628184 · DOI · Paper page
  31. [38]Shi Y Lu W Milstein AD Nicoll RA The stoichiometry of AMPA receptors and TARPs varies by Neuronal Cell Type Neuron. 2009 62 633 640 19524523 PMC3119531
  32. [40]Arimori T Fv-clasp: an artificially designed small antibody fragment with improved production compatibility, stability, and crystallizability Structure. 2017 25 1611 1622.e4 10.1016/j.str.2017.08.011 28919443 · DOI
  33. [41]Ankerst, M., Breunig, M. M., Kriegel, H. P. & Sander, J. OPTICS: ordering points to identify the clustering structure (ACM Press, 1999).
  34. [43]Daszykowski, M., Walczak, B. & Massart, D. L. Looking for natural patterns in analytical data. 2. Tracing local density with OPTICS. J. Chem. Inf. Comput. Sci. 10.1021/ci010384s (2002). 12086507 · DOI
  35. [44]Malinow R Malenka RC AMPA receptor trafficking and synaptic plasticity Annu. Rev. Neurosci. 2002 25 103 126 10.1146/annurev.neuro.25.112701.142758 12052905 · DOI · Paper page
  36. [46]Bats C Groc L Choquet D The Interaction between stargazin and PSD-95 regulates AMPA receptor surface trafficking Neuron. 2007 53 719 734 10.1016/j.neuron.2007.01.030 17329211 · DOI · Paper page
  37. [47]Opazo P CaMKII triggers the diffusional trapping of surface AMPARs through phosphorylation of stargazin Neuron. 2010 67 239 252 10.1016/j.neuron.2010.06.007 20670832 · DOI
  38. [48]Inamura M Differential localization and regulation of stargazin-like protein,??-8 and stargazin in the plasma membrane of hippocampal and cortical neurons Neurosci. Res. 2006 55 45 53 10.1016/j.neures.2006.01.004 16516319 · DOI
  39. [49]Park J CaMKII phosphorylation of TARPγ-8 is a mediator of LTP and learning and memory Neuron. 2016 92 75 83 10.1016/j.neuron.2016.09.002 27667007 PMC5059846 · DOI · Paper page
  40. [50]Menuz K Kerchner GA O’Brien JL Nicoll RA Critical role for TARPs in early development despite broad functional redundancy Neuropharmacology. 2009 56 22 29 10.1016/j.neuropharm.2008.06.037 18634809 PMC3111090 · DOI
  41. [51]Park P On the Role of Calcium-Permeable AMPARs in Long-Term Potentiation and Synaptic Tagging in the Rodent Hippocampus Front. Synaptic Neurosci. 2019 11 4 10.3389/fnsyn.2019.00004 30923499 PMC6426746 · DOI
  42. [52]Cull-Candy S Kelly L Farrant M Regulation of Ca2+-permeable AMPA receptors: synaptic plasticity and beyond Curr. Opin. Neurobiol. 2006 16 288 297 10.1016/j.conb.2006.05.012 16713244 · DOI
  43. [53]Li, S. et al. Release sites are positioned to activate NMDA receptors. bioRxiv 2020.05.01.072157. 10.1101/2020.05.01.072157 (2020). · DOI
  44. [55]Chen H Tang A-H Blanpied TA Burrone J Holzbaur E Subsynaptic spatial organization as a regulator of synaptic strength and plasticity Transsynaptic alignment can control synaptic function Curr. Opin. Neurobiol. 2018 51 147 153 10.1016/j.conb.2018.05.004 29902592 PMC6295321 · DOI
  45. [56]Heine M Holcman D Asymmetry between pre- and postsynaptic transient nanodomains shapes neuronal communication Trends Neurosci. 2020 43 182 196 10.1016/j.tins.2020.01.005 32101710 · DOI
  46. [57]Heine M Surface mobility of postsynaptic AMPARs tunes synaptic transmission Science. 2008 320 201 205 10.1126/science.1152089 18403705 PMC2715948 · DOI · Paper page
  47. [58]Perez de Arce K Topographic mapping of the synaptic cleft into adhesive nanodomains Neuron. 2015 88 1165 1172 10.1016/j.neuron.2015.11.011 26687224 PMC4687029 · DOI
  48. [59]Biederer T Kaeser PS Blanpied TA Transcellular nanoalignment of synaptic function Neuron. 2017 96 680 696 10.1016/j.neuron.2017.10.006 29096080 PMC5777221 · DOI · Paper page
  49. [60]Bhouri M Deletion of LRRTM1 and LRRTM2 in adult mice impairs basal AMPA receptor transmission and LTP in hippocampal CA1 pyramidal neurons Proc. Natl Acad. Sci. USA. 2018 115 E5382 E5389 10.1073/pnas.1803280115 29784826 PMC6003336 · DOI
  50. [61]Dai J Aoto J Südhof TC Alternative splicing of presynaptic neurexins differentially controls postsynaptic NMDA and AMPA receptor responses Neuron. 2019 102 993 1008.e5 10.1016/j.neuron.2019.03.032 31005376 PMC6554035 · DOI
  51. [62]Farhy-Tselnicker I Astrocyte-secreted glypican 4 regulates release of neuronal pentraxin 1 from axons to induce functional synapse formation Neuron. 2017 96 428 445.e13 10.1016/j.neuron.2017.09.053 29024665 PMC5663462 · DOI · Paper page
  52. [65]Kim CH Persistent hippocampal CA1 LTP in mice lacking the C-terminal PDZ ligand of GluR1 Nat. Neurosci. 2005 8 985 987 10.1038/nn1432 16007085 · DOI
  53. [66]Kerr JM Blanpied TA Subsynaptic AMPA receptor distribution is acutely regulated by actin-driven reorganization of the postsynaptic density J. Neurosci. 2012 32 658 673 10.1523/JNEUROSCI.2927-11.2012 22238102 PMC3596168 · DOI
  54. [67]Kristensen AS Mechanism of Ca2+/calmodulin-dependent kinase II regulation of AMPA receptor gating Nat. Neurosci. 2011 14 727 735 10.1038/nn.2804 21516102 PMC3102786 · DOI · Paper page
  55. [68]Buonarati OR Hammes EA Watson JF Greger IH Hell JW Mechanisms of postsynaptic localization of AMPA-type glutamate receptors and their regulation during long-term potentiation Sci. Signal. 2019 12 eaar6889 10.1126/scisignal.aar6889 30600260 PMC7175813 · DOI
  56. [70]Roth RH Cortical Synaptic AMPA Receptor Plasticity during Motor Learning Neuron. 2020 105 895 908.e5 10.1016/j.neuron.2019.12.005 31901303 PMC7060107 · DOI
  57. [71]Hruska M Synaptic nanomodules underlie the organization and plasticity of spine synapses Nat. Neurosci. 2018 21 671 682 10.1038/s41593-018-0138-9 29686261 PMC5920789 · DOI · Paper page
  58. [72]Beaudoin, G. M. J. et al. Culturing pyramidal neurons from the early postnatal mouse hippocampus and cortex. Nat. Protoc. 10.1038/nprot.2012.099 (2012). 22936216 · DOI
  59. [73]Stoppini L Buchs PA Muller D A simple method for organotypic cultures of nervous tissue J. Neurosci. Methods. 1991 37 173 182 10.1016/0165-0270(91)90128-M 1715499 · DOI
  60. [74]García-Nafría J Watson JF Greger IH IVA cloning: a single-tube universal cloning system exploiting bacterial In Vivo Assembly Sci. Rep. 2016 6 27459 10.1038/srep27459 27264908 PMC4893743 · DOI
  61. [75]Howarth M Takao K Hayashi Y Ting AY Targeting quantum dots to surface proteins in living cells with biotin ligase Proc. Natl Acad. Sci. USA. 2005 102 7583 7588 10.1073/pnas.0503125102 15897449 PMC1129026 · DOI
  62. [76]Ho H Fowle A Coetzee M Greger IH Watson JF An inhalation anaesthesia approach for neonatal mice allowing streamlined stereotactic injection in the brain J. Neurosci. Methods. 2020 342 108824 10.1016/j.jneumeth.2020.108824 32569783 PMC7369625 · DOI
  63. [77]Rathenberg J Nevian T Witzemann V High-efficiency transfection of individual neurons using modified electrophysiology techniques J. Neurosci. Methods. 2003 126 91 98 10.1016/S0165-0270(03)00069-4 12788505 · DOI
  64. [78]Elegheert, J. et al. Lentiviral transduction of mammalian cells for fast, scalable and high-level production of soluble and membrane proteins. Nat. Protoc. 10.1038/s41596-018-0075-9 (2018). PMC6364805 30455477 · DOI
  65. [79]Huang B Wang W Bates M Zhuang X Three-dimensional super-resolution imaging by stochastic optical reconstruction microscopy Science. 2008 319 810 813 10.1126/science.1153529 18174397 PMC2633023 · DOI
  66. [80]Sun, Y., Smirnov, M., Kamasawa, N. & Yasuda, R. Rapid ultrastructural changes of PSD and extrasynaptic axon-spine interface membrane during LTP induced in single dendritic spine. J. Neuro. Sci. 10.1101/840629 (2019). · DOI

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Authors
Watson, J. F., Pinggera, A., Ho, H., & Greger, I. H.
Affiliations
  • Institute of Science and Technology Austria (AT)
  • MRC Laboratory of Molecular Biology (GB)
Corresponding author
Greger, Ingo H.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-08-23
Volume
12
Issue
1
Pages
5083-5083
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-021-25281-4
PMC
PMC8382838
OpenAlex
W3195715762
Cited by
38
References
13
Citations by year
2026: 4 · 2025: 5 · 2024: 9 · 2023: 9 · 2022: 6 · 2021: 4 · 2020: 1
FWCI
3.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Apollo
  • Apollo (cc-by)
Funders
  • RCUK | Biotechnology and Biological Sciences Research Council (BB/N002113/1)
  • RCUK | Medical Research Council (MC_U105174197)
  • RCUK | MRC | Medical Research Foundation (MC_U105174197)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
AMPA receptors, N-terminal domain, postsynaptic density, hippocampal CA1 synapses, synaptic transmission, synaptic plasticity, super-resolution imaging
MeSH terms
Protein Domains, Amino Acid Sequence, Animals, Fluorescent Dyes, Mice, Inbred C57BL, Models, Neurological, Mutation, Synaptic Transmission, Neuronal Plasticity, Neurons, Nuclear Proteins, Protein Binding, Synapses, Receptors, AMPA, Imaging, Three-Dimensional, Mice, Protein Multimerization, CA1 Region, Hippocampal

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