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Cited by 310Neuroscience and Neuropharmacology ResearchGenetics and Neurodevelopmental DisordersReceptor Mechanisms and Signaling

PSD-95 family MAGUKs are essential for anchoring AMPA and NMDA receptor complexes at the postsynaptic density

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Chen, Xiaobing, Levy, Jonathan M., Hou, Austin, Winters, Christine, Azzam, Rita, Sousa, Alioscka A., Leapman, Richard D., Nicoll, Roger A. +1 more·2015·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1517045112PMC PMC4687590
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Abstract

Significance: The postsynaptic density (PSD) at the glutamatergic excitatory synapse is a macromolecular machine that underlies synaptic transmission and information storage. Membrane-associated guanylate kinases (MAGUKs), the major scaffolding proteins at the PSD, are positively correlated with synaptic maturation and strength, but how MAGUKs sustain the strength of synaptic transmission remains unclear. Here, we remove three MAGUK proteins from neurons and find significant reductions in synaptic transmission by AMPARs and NMDARs with a concomitant reduction in PSD sizes and core scaffold and transmembrane structures. Our results show how MAGUKs anchor and organize both types of glutamate receptors, thereby regulating the strength of excitatory synapses.

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Crossref · 10.1073/pnas.1517045112

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  • On average there are approximately 250 PSD-95 molecules in the PSD and approximately 50 AMPARs, although this number is highly variable.

    “On average there are ∼250 PSD-95 molecules in the PSD (65) and, on average, ∼50 AMPARs, although this number is highly variable (143, 290, 291).”

    From Synaptic memory and CaMKII (2023) · cites this paper as [143]

    The Analysis of AMPAR- and NMDAR-Type Structures by EM Tomography section reports variability in AMPAR counts, including a relationship with PSD size, but estimates 105 ± 52 AMPARs in an average-sized PSD—not approximately 50. The ∼250 PSD-95 figure has a separate citation in the citing sentence and is not attributed to this paper. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The number of NMDARs at spine synapses and perhaps filopodia synapses is much less variable, averaging roughly 20, and this number is largely independent of PSD size.

    “The number of NMDARs at spine synapses and perhaps filopodia synapses is much less variable, averaging roughly 20, and this number is largely independent of PSD size (143, 438, 439).”

    From Synaptic memory and CaMKII (2023) · cites this paper as [143]

    The Analysis of AMPAR- and NMDAR-Type Structures by EM Tomography reports 23 ± 5 NMDAR-type structures in controls, nearly constant across PSD sizes; the Discussion estimates 20–30 per PSD. The study examined spine synapses, but our copy does not establish that the same pattern holds at filopodia synapses, even tentatively. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The number of AMPARs at dendritic spine synapses is highly variable but averages roughly 50, and this number strongly correlates with the size of the PSD.

    “The number of AMPARs at dendritic spine synapses is highly variable but averages roughly 50 (143, 438, 439), and this number strongly correlates with the size of the PSD.”

    From Synaptic memory and CaMKII (2023) · cites this paper as [143]

    The Analysis of AMPAR- and NMDAR-Type Structures by EM Tomography reports a strong positive correlation between AMPAR-type structure count and PSD diameter (r = 0.87; Fig. 6A). It estimates 105 ± 52 AMPARs in an average-size PSD, not an average of roughly 50. Page numbers were not supplied for these passages. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Given roughly 20-30 NMDARs in the PSD and ∼100 holoenzymes (∼1,200 CaMKII subunits), after NMDAR activation only a small fraction of subunits per holoenzyme would be directly bound to GluN2B.

    “since there are roughly 20–30 NMDARs in the PSD (66, 143) and ∼100 holoenzymes [∼1,200 CaMKII subunits (65)], after NMDAR activation only a small fraction of subunits per holoenzyme would be directly bound to GluN2B.”

    From Synaptic memory and CaMKII (2023) · cites this paper as [143]

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Research works printed but not linked: 22

  1. [57]Miledi R (1966) Strontium as a substitute for calcium in the process of transmitter release at the neuromuscular junction. Nature 212(5067):1233 -1234.
  2. [59]Petersen JD, et al. (2003) Distribution of postsynaptic density (PSD)-95 and Ca2 + /calmodulin-dependent protein kinase II at the PSD. J Neurosci 23(35):11270 -11278.
  3. [61]Meyer D, Bonhoeffer T, Scheuss V (2014) Balance and stability of synaptic structures during synaptic plasticity. Neuron 82(2):430 -443.
  4. [62]Hohmann-Marriott MF, et al. (2009) Nanoscale 3D cellular imaging by axial scanning transmission electron tomography. Nat Methods 6(10):729 -731.
  5. [63]Sousa AA, Azari AA, Zhang G, Leapman RD (2011) Dual-axis electron tomography of biological specimens: Extending the limits of specimen thickness with bright-field STEM imaging. J Struct Biol 174(1):107 -114.
  6. [64]Sobolevsky AI, Rosconi MP, Gouaux E (2009) X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature 462(7274):745 -756.
  7. [65]Nakagawa T, Cheng Y, Ramm E, Sheng M, Walz T (2005) Structure and different conformational states of native AMPA receptor complexes. Nature 433(7025):545 -549.
  8. [66]Lee CH, et al. (2014) NMDA receptor structures reveal subunit arrangement and pore architecture. Nature 511(7508):191 -197.
  9. [67]Chen X, Winters CA, Reese TS (2008) Life inside a thin section: Tomography. J Neurosci 28(38):9321 -9327.
  10. [68]Kharazia VN, Weinberg RJ (1999) Immunogold localization of AMPA and NMDA receptors in somatic sensory cortex of albino rat. J Comp Neurol 412(2):292 -302.
  11. [69]Sobczyk A, Scheuss V, Svoboda K (2005) NMDA receptor subunit-dependent [Ca2 + ] signaling in individual hippocampal dendritic spines. J Neurosci 25(26):6037 -6046.
  12. [70]Zito K, Scheuss V, Knott G, Hill T, Svoboda K (2009) Rapid functional maturation of nascent dendritic spines. Neuron 61(2):247 -258.
  13. [72]Masugi-Tokita M, Shigemoto R (2007) High-resolution quantitative visualization of glutamate and GABA receptors at central synapses. Curr Opin Neurobiol 17(3):387 -393.
  14. [73]Elias GM, Nicoll RA (2007) Synaptic trafficking of glutamate receptors by MAGUK scaffolding proteins. Trends Cell Biol 17(7):343 -352.
  15. [74]Bekkers JM, Stevens CF (1989) NMDA and non-NMDA receptors are co-localized at individual excitatory synapses in cultured rat hippocampus. Nature 341(6239):230 -233.
  16. [76]Nimchinsky EA, Yasuda R, Oertner TG, Svoboda K (2004) The number of glutamate receptors opened by synaptic stimulation in single hippocampal spines. J Neurosci 24(8):2054 -2064.
  17. [77]Bernard V, Bolam JP (1998) Subcellular and subsynaptic distribution of the NR1 subunit of the NMDA receptor in the neostriatum and globus pallidus of the rat: Colocalization at synapses with the GluR2/3 subunit of the AMPA receptor. Eur J Neurosci 10(12):3721 -3736.
  18. [79]DeGiorgis JA, Galbraith JA, Dosemeci A, Chen X, Reese TS (2006) Distribution of the scaffolding proteins PSD-95, PSD-93, and SAP97 in isolated PSDs. Brain Cell Biol 35(4-6):239 -250.
  19. [82]Kerr JM, Blanpied TA (2012) Subsynaptic AMPA receptor distribution is acutely regulated by actin-driven reorganization of the postsynaptic density. J Neurosci 32(2):658 -673.
  20. [83]Shi Y, Lu W, Milstein AD, Nicoll RA (2009) The stoichiometry of AMPA receptors and TARPs varies by neuronal cell type. Neuron 62(5):633 -640.
  21. [85]Kremer JR, Mastronarde DN, McIntosh JR (1996) Computer visualization of threedimensional image data using IMOD. J Struct Biol 116(1):71 -76.
  22. [86]Harlow ML, Ress D, Stoschek A, Marshall RM, McMahan UJ (2001) The architecture of active zone material at the frog ' s neuromuscular junction. Nature 409(6819): 479 -484. aspects of synaptic Proc Natl

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Authors
Chen, X., Levy, J. M., Hou, A., Winters, C., Azzam, R., Sousa, A. A., Leapman, R. D., Nicoll, R. A., & Reese, T. S.
Affiliations
  • National Institutes of Health (US)
  • University of California, San Francisco (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2015-11-24
Volume
112
Issue
50
Pages
E6983-92
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1517045112
PMC
PMC4687590
OpenAlex
W2178843014
Cited by
310
References
9
Citations by year
2026: 26 · 2025: 30 · 2024: 40 · 2023: 28 · 2022: 38 · 2021: 37 · 2020: 30 · 2019: 19 · 2018: 27 · 2017: 23 · 2016: 12
FWCI
9.64
Type
journal article
Language
en
Open access
Licence
www.pnas.org/site/misc/userlicense.xhtml (vor)
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS intramural fund)
  • HHS | NIH | National Institute of Biomedical Imaging and Bioengineering (NIBIB intramural fund)
  • HHS | NIH | National Institute of Mental Health (5R01MH080379-07)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
PSD-95, PSD-93, SAP102, membrane-associated guanylate kinase, postsynaptic density, AMPA receptors, NMDA receptor, synaptic scaffolding, silent synapses, synaptic transmission
MeSH terms
Disks Large Homolog 4 Protein, Animals, Cells, Cultured, Membrane Proteins, Receptors, N-Methyl-D-Aspartate, Receptors, AMPA, Intracellular Signaling Peptides and Proteins, Rats, Gene Knockdown Techniques, Post-Synaptic Density

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