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Probing the Lateral Diffusion of Individual Neurotransmitter Receptors

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Part of the book series: Advances in Atom and Single Molecule Machines ((AASMM))

Abstract

Synaptic transmission is a highly dynamic and regulated process in which electrical information is transferred between two neurons by means of a chemical transmitter that diffuses from the presynaptic element to reach, bind, and activate the neurotransmitter receptors located at postsynaptic side. Traditionally, postsynaptic receptors have been considered fixed in front of the releasing site, but over the last decade, compelling evidence has shown that they diffuse in the plane of the neuronal membrane, thus adding a further level of complexity to synaptic neurotransmission. The development of new technologies that allow a close inspection of the diffusive properties of receptors at synapses have revealed that the receptors dynamics is not only part of a “constitutive recycling” but also is responsible for the fast tuning of the receptor number at synapses both in basal conditions and in response to external stimuli, being therefore a major determinant of synaptic plasticity. In this section, we will review the techniques used to study the lateral mobility of individual receptors and the recent advances in the comprehension of the role of receptor diffusion in neuronal synaptic computation.

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References

  1. Adesnik H, Nicoll RA, England PM (2005) Photoinactivation of native AMPA receptors reveals their real-time trafficking. Neuron 48(6):977–985

    Article  Google Scholar 

  2. Ashby MC, De La Rue SA, Ralph GS, Uney J, Collingridge GL, Henley JM (2004) Removal of AMPA receptors (AMPARs) from synapses is preceded by transient endocytosis of extrasynaptic AMPARs. J Neurosci 24(22):5172–5176

    Article  Google Scholar 

  3. Axelrod D, Koppel DE, Schlessinger J, Elson E, Webb WW (1976) Mobility measurement by analysis of fluorescence photobleaching recovery kinetics. Biophys J 16(9):1055–1069

    Article  Google Scholar 

  4. Bannai H, Lévi S, Schweizer C, Inoue T, Launey T, Racine V, Sibarita JB, Mikoshiba K, Triller A (2009) Activity-dependent tuning of inhibitory neurotransmission based on GABAAR diffusion dynamics. Neuron 62(5):670–682

    Article  Google Scholar 

  5. Barberis A, Petrini EM, Mozrzymas JW (2011) Impact of synaptic neurotransmitter concentration time course on the kinetics and pharmacological modulation of inhibitory synaptic currents. Front Cell Neurosci 5:6

    Article  Google Scholar 

  6. Bats C, Groc L, Choquet D (2007) The interaction between Stargazin and PSD-95 regulates AMPA receptor surface trafficking. Neuron 53(5):719–734

    Article  Google Scholar 

  7. Berciaud S, Cognet L, Blab GA, Lounis B (2004) Photothermal heterodyne imaging of individual nonfluorescent nanoclusters and nanocrystals. Phys Rev Lett 93(25):257402

    Article  ADS  Google Scholar 

  8. Blanpied TA, Scott DB, Ehlers MD (2002) Dynamics and regulation of clathrin coats at specialized endocytic zones of dendrites and spines. Neuron 36(3):435–449

    Article  Google Scholar 

  9. Bogdanov Y, Michels G, Armstrong-Gold C, Haydon PG, Lindstrom J, Pangalos M, Moss SJ (2006) Synaptic GABAA receptors are directly recruited from their extrasynaptic counterparts. EMBO J 25:4381–4389

    Article  Google Scholar 

  10. Borgdorff AJ, Choquet D (2002) Regulation of AMPA receptor lateral movements. Nature 417(6889):649–653

    Article  ADS  Google Scholar 

  11. Bredt DS, Nicoll RA (2003) AMPA receptor trafficking at excitatory synapses. Neuron 40(2):361–379

    Article  Google Scholar 

  12. Carroll RC, Beattie EC, von Zastrow M, Malenka RC (2001) Role of AMPA receptor endocytosis in synaptic plasticity. Nat Rev Neurosci 2(5):315–324

    Article  Google Scholar 

  13. Cherubini E, Conti F (2001) Generating diversity at GABAergic synapses. Trends Neurosci 24(3):155–162

    Google Scholar 

  14. Choquet D, Triller A (2003) The role of receptor diffusion in the organization of the postsynaptic membrane. Nat Rev Neurosci 4(4):251–265

    Article  Google Scholar 

  15. Choquet D, Triller A (2013) The dynamic synapse. Neuron 80(3):691–703. doi:10.1016/j.neuron.2013.10.013

    Article  Google Scholar 

  16. Clements JD (1996) Transmitter time course in the synaptic cleft: its role in central synaptic function. Trends Neurosci 19:163–171

    Article  Google Scholar 

  17. Clements JD, Lester RA, Tong G, Jahr CE, Westbrook GL (1992) The time course of glutamate in the synaptic cleft. Science 258:1498–1501

    Article  ADS  Google Scholar 

  18. De Angelis F, Liberale C, Coluccio ML, Cojoc G, Di Fabrizio E (2011) Emerging fabrication techniques for 3D nano-structuring in plasmonics and single molecule studies. Nanoscale 3(7):2689–2696

    Article  ADS  Google Scholar 

  19. Genin E, Carion O, Mahler B, Dubertret B, Arhel N, Charneau P, Doris E, Mioskowski C (2008) CrAsH-quantum dot nanohybrids for smart targeting of proteins. J Am Chem Soc 130(27):8596–8597. doi: 10.1021/ja802987q (Epub 13 Jun 2008)

  20. Giannone G, Hosy E, Levet F, Constals A, Schulze K, Sobolevsky AI, Rosconi MP, Gouaux E, Tampé R, Choquet D, Cognet L (2010) Dynamic superresolution imaging of endogenous proteins on living cells at ultra-high density. Biophys J 99(4):1303–1310. doi:10.1016/j.bpj.2010.06.005

    Article  Google Scholar 

  21. Giannone G, Hosy E, Sibarita JB, Choquet D, Cognet L (2013) High-content super-resolution imaging of live cell by uPAINT. Methods Mol Biol 950:95–110

    Google Scholar 

  22. Giugni A, Torre B, Toma A, Francardi M, Malerba M, Alabastri A, Proietti Zaccaria R, Stockman MI, Di Fabrizio E (2013) Hot-electron nanoscopy using adiabatic compression of surface plasmons. Nat Nanotechnol 8(11):845–852

    Google Scholar 

  23. Groc L, Lafourcade M, Heine M, Renner M, Racine V, Sibarita JB, Lounis B, Choquet D, Cognet L (2007) Surface trafficking of neurotransmitter receptor: comparison between single-molecule/quantum dot strategies. J Neurosci 27(46):12433–12437

    Article  Google Scholar 

  24. Hannan S, Wilkins ME, Thomas P, Smart TG (2013) Tracking cell surface mobility of GPCRs using α-bungarotoxin-linked fluorophores. Methods Enzymol 521:109–129

    Article  Google Scholar 

  25. Harata NC, Aravanis AM, Tsien RW (2006) Kiss-and-run and full-collapse fusion as modes of exo-endocytosis in neurosecretion. J Neurochem 97(6):1546–1570

    Article  Google Scholar 

  26. Hastie P, Ulbrich MH, Wang HL, Arant RJ, Lau AG, Zhang Z, Isacoff EY, Chen L (2013) AMPA receptor/TARP stoichiometry visualized by single-molecule subunit counting. Proc Natl Acad Sci USA 110(13):5163–5168. doi:10.1073/pnas.1218765110 (Epub 11 Mar 2013)

    Article  ADS  Google Scholar 

  27. Heine M, Groc L, Frischknecht R, Beique JC, Lounis B, Rumbaugh G, Huganir RL, Cognet L, Choquet D (2008) Surface mobility of postsynaptic AMPARs tunes synaptic transmission. Science 320:201–205

    Article  ADS  Google Scholar 

  28. Holcman D, Triller A (2006) Modeling synaptic dynamics driven by receptor lateral diffusion. Biophys J 91(7):2405–2415

    Article  Google Scholar 

  29. Howarth M, Takao K, Hayashi Y, Ting AY (2005) Targeting quantum dots to surface proteins in living cells with biotin ligase. Proc Natl Acad Sci USA 102(21):7583–7588 (Epub 16 May 2005)

    Article  ADS  Google Scholar 

  30. Howarth M, Liu W, Puthenveetil S, Zheng Y, Marshall LF, Schmidt MM, Wittrup KD, Bawendi MG, Ting AY (2008) Monovalent, reduced-size quantum dots for imaging receptors on living cells. Nat Methods 5(5):397–399

    Article  Google Scholar 

  31. Hoze N, Nair D, Hosy E, Sieben C, Manley S, Herrmann A, Sibarita JB, Choquet D, Holcman D (2012) Heterogeneity of AMPA receptor trafficking and molecular interactions revealed by superresolution analysis of live cell imaging. Proc Natl Acad Sci USA 109(42):17052–17057. doi: 10.1073/pnas.1204589109 (Epub 3 Oct 2012)

  32. Iyer G, Michalet X, Chang YP, Pinaud FF, Matyas SE, Payne G, Weiss S (2008) High affinity scFv-hapten pair as a tool for quantum dot labeling and tracking of single proteins in live cells. Nano Lett 8(12):4618–4623. doi:10.1021/nl8032284

    Article  ADS  Google Scholar 

  33. Jacob TC, Bogdanov YD, Magnus C, Saliba RS, Kittler JT, Haydon PG, Moss SJ (2005) Gephyrin regulates the cell surface dynamics of synaptic GABAA receptors. J Neurosci 25:10469–10478

    Article  Google Scholar 

  34. Jones MV, Sahara Y, Dzubay JA, Westbrook GL (1995) Desensitized states prolong GABAA channel responses to brief agonist pulses. Neuron 15(1):181–191

    Google Scholar 

  35. Jones MV, Westbrook GL (1998) Defining affinity with the GABAA receptor. J Neurosci 18(21):8590–8604

    Google Scholar 

  36. Kim J, Park HY, Kim J, Ryu J, Kwon do Y, Grailhe R, Song R (2008) Ni-nitrilotriacetic acid-modified quantum dots as a site-specific labeling agent of histidine-tagged proteins in live cells. Chem Commun (Camb) (16):1910–1912. doi: 10.1039/b719434j (Epub 19 Feb 2008)

  37. Kusumi A, Nakada C, Ritchie K, Murase K, Suzuki K, Murakoshi H, Kasai RS, Kondo J, Fujiwara T (2005) Paradigm shift of the plasma membrane concept from the two-dimensional continuum fluid to the partitioned fluid: high-speed single-molecule tracking of membrane molecules. Annu Rev Biophys Biomol Struct 34:351–378

    Article  Google Scholar 

  38. Lasne D, Blab GA, Berciaud S, Heine M, Groc L, Choquet D, Cognet L, Lounis B (2006) Single nanoparticle photothermal tracking (SNaPT) of 5-nm gold beads in live cells. Biophys J 91(12):4598–4604

    Article  Google Scholar 

  39. Lu YM, Mansuy IM, Kandel ER, Roder J (2000) Calcineurin-mediated LTD of GABAergic inhibition underlies the increased excitability of CA1 neurons associated with LTP. Neuron 26(1):197–205

    Article  Google Scholar 

  40. Makino H, Malinow R (2009) AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis. Neuron 64(3):381–390

    Article  Google Scholar 

  41. Malinow R, Malenka RC (2002) AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci 25:103–126 (Epub 4 Mar 2002)

    Article  Google Scholar 

  42. Manley S, Gillette JM, Patterson GH, Shroff H, Hess HF, Betzig E (2008) Lippincott-Schwartz High-density mapping of single-molecule trajectories with photoactivated localization microscopy. J. Nat Methods. 5(2):155–157

    Article  Google Scholar 

  43. Manley S, Gillette JM, Lippincott-Schwartz J (2010) Single-particle tracking photoactivated localization microscopy for mapping single-molecule dynamics. Methods Enzymol 475:109–120. doi:10.1016/S0076-6879(10)75005-9

    Article  Google Scholar 

  44. Meier J, Vannier C, Sergé A, Triller A, Choquet D (2001) Fast and reversible trapping of surface glycine receptors by gephyrin. Nat Neurosci 4(3):253–260

    Article  Google Scholar 

  45. Mott DD, Rojas A, Fisher JL, Dingledine RJ, Benveniste M (2010) Subunit-specific desensitization of heteromeric kainate receptors. J Physiol 588(Pt 4):683–700

    Article  Google Scholar 

  46. Muir J, Arancibia-Carcamo IL, MacAskill AF, Smith KR, Griffin LD, Kittler JT (2010) NMDA receptors regulate GABAA receptor lateral mobility and clustering at inhibitory synapses through serine 327 on the γ2 subunit. Proc Natl Acad Sci USA 107(38):16679–16684

    Article  ADS  Google Scholar 

  47. Nair D, Hosy E, Petersen JD, Constals A, Giannone G, Choquet D, Sibarita JB (2013) Super-resolution imaging reveals that AMPA receptors inside synapses are dynamically organized in nanodomains regulated by PSD95. J Neurosci 33:13204–13224

    Google Scholar 

  48. Opazo P, Labrecque S, Tigaret CM, Frouin A, Wiseman PW, De Koninck P, Choquet D (2010) CaMKII triggers the diffusional trapping of surface AMPARs through phosphorylation of stargazin. Neuron 67(2):239–252

    Article  Google Scholar 

  49. Opazo P, Sainlos M, Choquet D (2012) Regulation of AMPA receptor surface diffusion by PSD-95 slots. Curr Opin Neurobiol 22(3):453–460

    Article  Google Scholar 

  50. Owen DM, Williamson D, Rentero C, Gaus K (2009) Quantitative microscopy: protein dynamics and membrane organisation. Traffic. 10(8):962–971

    Article  Google Scholar 

  51. Perestenko PV, Henley JM (2003) Characterization of the intracellular transport of GluR1 and GluR2 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor subunits in hippocampal neurons. J Biol Chem 278(44):43525–43532 Epub 2003 Aug 8

    Article  Google Scholar 

  52. Petralia RS, Wang YX, Wenthold RJ (2003) Internalization at glutamatergic synapses during development. Eur J Neurosci 18(12):3207–3217

    Article  Google Scholar 

  53. Petrini EM, Lu J, Cognet L, Lounis B, Ehlers MD, Choquet D (2009) Endocytic trafficking and recycling maintain a pool of mobile surface AMPA receptors required for synaptic potentiation. Neuron 63(1):92–105

    Article  Google Scholar 

  54. Raether H (1988) Surface plasmons. Springer, New York

    Google Scholar 

  55. Renner M, Choquet D, Triller A (2009) Control of the postsynaptic membrane viscosity. J Neurosci 29(9):2926–2937. doi:10.1523/JNEUROSCI.4445-08.2009

    Article  Google Scholar 

  56. Saliba RS, Kretschmannova K, Moss SJ (2012) Activity-dependent phosphorylation of GABAA receptors regulates receptor insertion and tonic current. EMBO J 31(13):2937–2951. doi: 10.1038/emboj.2012.109

  57. Saxton MJ, Jacobson K (1997) Single-particle tracking: applications to membrane dynamics. Annu Rev Biophys Biomol Struct 26:373–399

    Article  Google Scholar 

  58. Schwille P, Haupts U, Maiti S, Webb WW (1999) Molecular dynamics in living cells observed by fluorescence correlation spectroscopy with one- and two-photon excitation. Biophys J 77(4):2251–2265

    Article  Google Scholar 

  59. Sekine-Aizawa Y, Huganir RL (2004) Imaging of receptor trafficking by using alpha-bungarotoxin-binding-site-tagged receptors. Proc Natl Acad Sci USA 101(49):17114–17119 (Epub 24 Nov 2004)

    Article  ADS  Google Scholar 

  60. Sergé A, Fourgeaud L, Hémar A, Choquet D (2002) Receptor activation and homer differentially control the lateral mobility of metabotropic glutamate receptor 5 in the neuronal membrane. J Neurosci 22(10):3910–3920

    Google Scholar 

  61. Shi SH, Hayashi Y, Petralia RS, Zaman SH, Wenthold RJ, Svoboda K, Malinow R (1999) Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science 284(5421):1811–1816

    Article  Google Scholar 

  62. Shrivastava AN, Rodriguez PC, Triller A, Renner M (2013) Dynamic micro-organization of P2X7 receptors revealed by PALM based single particle tracking. Front Cell Neurosci 26(7):232. doi:10.3389/fncel.2013.00232

    Google Scholar 

  63. So MK, Yao H, Rao J (2008) HaloTag protein-mediated specific labeling of living cells with quantum dots. Biochem Biophys Res Commun 374(3):419–423

    Article  Google Scholar 

  64. Specht CG, Izeddin I, Rodriguez PC, El Beheiry M, Rostaing P, Darzacq X, Dahan M, Triller A (2013) Quantitative nanoscopy of inhibitory synapses: counting gephyrin molecules and receptor binding sites. Neuron 79(2):308–321. doi:10.1016/j.neuron.2013.05.013

    Article  Google Scholar 

  65. Szobota S, Gorostiza P, Del Bene F, Wyart C, Fortin DL, Kolstad KD, Tulyathan O, Volgraf M, Numano R, Aaron HL, Scott EK, Kramer RH, Flannery J, Baier H, Trauner D, Isacoff EY (2007) Remote control of neuronal activity with a light-gated glutamate receptor. Neuron 54(4):535–545

    Article  Google Scholar 

  66. Tardin C, Cognet L, Bats C, Lounis B, Choquet D (2003) Direct imaging of lateral movements of AMPA receptors inside synapses. EMBO J 22(18):4656–4665

    Article  Google Scholar 

  67. Thomas P, Mortensen M, Hosie AM, Smart TG (2005) Dynamic mobility of functional GABAA receptors at inhibitory synapses. Nat Neurosci 8:889–897

    Article  Google Scholar 

  68. Tovar KR, Westbrook GL (2002) Mobile NMDA receptors at hippocampal synapses. Neuron 34(2):255–264

    Article  Google Scholar 

  69. Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R (2010) Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev 62(3):405–496. doi:10.1124/pr.109.002451

    Article  Google Scholar 

  70. Triller A, Choquet D (2005) Surface trafficking of receptors between synaptic and extrasynaptic membranes: and yet they do move! Trends Neurosci 28(3):133–139

    Article  Google Scholar 

  71. Triller A, Choquet D (2008) New concepts in synaptic biology derived from single-molecule imaging. Neuron 59(3):359–374

    Article  Google Scholar 

  72. Wang Q, Liu L, Pei L, Ju W, Ahmadian G, Lu J, Wang Y, Liu F, Wang YT (2003) Control of synaptic strength, a novel function of Akt. Neuron 38(6):915–928

    Article  Google Scholar 

  73. Weiss S (1999) Fluorescence spectroscopy of single biomolecules. Science 283(5408):1676–1683

    Article  ADS  Google Scholar 

  74. Zucker RS, Regehr WG (2002) Short-term synaptic plasticity. Annu Rev Physiol 64:355–405

    Google Scholar 

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Correspondence to Andrea Barberis .

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Petrini, E.M., Barberis, A. (2014). Probing the Lateral Diffusion of Individual Neurotransmitter Receptors. In: Benfenati, F., Di Fabrizio, E., Torre, V. (eds) Novel Approaches for Single Molecule Activation and Detection. Advances in Atom and Single Molecule Machines. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-43367-6_11

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