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Regulation of AMPA receptor lateral movements

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Abstract

An essential feature in the modulation of the efficacy of synaptic transmission is rapid changes in the number of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors at post-synaptic sites on neurons1,2,3,4. Regulation of receptor endo- and exocytosis has been shown to be involved in this process5,6,7,8,9,10,11,12,13,14. Whether regulated lateral diffusion of receptors in the plasma membrane also participates in receptor exchange to and from post-synaptic sites remains unknown. We analysed the lateral mobility of native AMPA receptors containing the glutamate receptor subunit GluR2 in rat cultured hippocampal neurons, using single-particle tracking and video microscopy. Here we show that AMPA receptors alternate within seconds between rapid diffusive and stationary behaviour. During maturation of neurons, stationary periods increase in frequency and length, often in spatial correlation with synaptic sites. Raising intracellular calcium, a central element in synaptic plasticity, triggers rapid receptor immobilization and local accumulation on the neuronal surface. We suggest that calcium influx prevents AMPA receptors from diffusing, and that lateral receptor diffusion to and from synaptic sites acts in the rapid and controlled regulation of receptor numbers at synapses.

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References

  1. 1

    Hayashi, Y. et al. Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science 287, 2262–2267 (2000)

  2. 2

    Shi, S. H. et al. Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science 284, 1811–1816 (1999)

  3. 3

    Carroll, R. C., Lissin, D. V., von Zastrow, M., Nicoll, R. A. & Malenka, R. C. Rapid redistribution of glutamate receptors contributes to long-term depression in hippocampal cultures. Nature Neurosci. 2, 454–460 (1999)

  4. 4

    Shi, S., Hayashi, Y., Esteban, J. A. & Malinow, R. Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons. Cell 105, 331–343 (2001)

  5. 5

    Carroll, R. C., Beattie, E. C., von Zastrow, M. & Malenka, R. C. Role of AMPA receptor endocytosis in synaptic plasticity. Nature Rev. Neurosci. 2, 315–324 (2001)

  6. 6

    Luthi, A. et al. Hippocampal LTD expression involves a pool of AMPARs regulated by the NSF–GluR2 interaction. Neuron 24, 389–399 (1999)

  7. 7

    Beattie, E. C. et al. Regulation of AMPA receptor endocytosis by a signalling mechanism shared with LTD. Nature Neurosci. 3, 1291–1300 (2000)

  8. 8

    Lin, J. W. et al. Distinct molecular mechanisms and divergent endocytotic pathways of AMPA receptor internalization. Nature Neurosci. 3, 1282–1290 (2000)

  9. 9

    Wang, Y. T. & Linden, D. J. Expression of cerebellar long-term depression requires postsynaptic clathrin-mediated endocytosis. Neuron 25, 635–647 (2000)

  10. 10

    Man, Y. H. et al. Regulation of AMPA receptor-mediated synaptic transmission by clathrin-dependent receptor internalization. Neuron 25, 649–662 (2000)

  11. 11

    Lu, W. et al. Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons. Neuron 29, 243–254 (2001)

  12. 12

    Sheng, M. & Lee, S. H. AMPA receptor trafficking and the control of synaptic transmission. Cell 105, 825–828 (2001)

  13. 13

    Noel, J. et al. Surface expression of AMPA receptors in hippocampal neurons is regulated by an NSF-dependent mechanism. Neuron 23, 365–376 (1999)

  14. 14

    Luscher, C. et al. Role of AMPA receptor cycling in synaptic transmission and plasticity. Neuron 24, 649–658 (1999)

  15. 15

    Simson, R., Sheets, E. D. & Jacobson, K. Detection of temporary lateral confinement of membrane proteins using single-particle tracking analysis. Biophys. J. 69, 989–993 (1995)

  16. 16

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

  17. 17

    Fletcher, T. L., De Camilli, P. & Banker, G. Synaptogenesis in hippocampal cultures: evidence indicating that axons and dendrites become competent to form synapses at different stages of neuronal development. J. Neurosci. 14, 6695–6706 (1994)

  18. 18

    Kiss, J. Z. & Muller, D. Contribution of the neural cell adhesion molecule to neuronal and synaptic plasticity. Rev. Neurosci. 12, 297–310 (2001)

  19. 19

    Simson, R. et al. Structural mosaicism on the submicron scale in the plasma membrane. Biophys. J. 74, 297–308 (1998)

  20. 20

    Nusser, Z. AMPA and NMDA receptors: similarities and differences in their synaptic distribution. Curr. Opin. Neurobiol. 10, 337–341 (2000)

  21. 21

    Sergé, A., Fourgeaud, L., Hémar, A. & Choquet, D. Receptor activation and homer differentially control the lateral mobility of mGluR5 in the neuronal membrane. J. Neurosci. (in the press)

  22. 22

    Pickard, L., Noel, J., Henley, J. M., Collingridge, G. L. & Molnar, E. Developmental changes in synaptic AMPA and NMDA receptor distribution and AMPA receptor subunit composition in living hippocampal neurons. J. Neurosci. 20, 7922–7931 (2000)

  23. 23

    Benmerah, A., Poupon, V., Cerf-Bensussan, N. & Dautry-Varsat, A. Mapping of Eps15 domains involved in its targeting to clathrin-coated pits. J. Biol. Chem. 275, 3288–3295 (2000)

  24. 24

    Ghosh, A. & Greenberg, M. E. Calcium signalling in neurons: molecular mechanisms and cellular consequences. Science 268, 239–247 (1995)

  25. 25

    Yang, S. N., Tang, Y. G. & Zucker, R. S. Selective induction of LTP and LTD by postsynaptic [Ca2 +]i elevation. J. Neurophysiol. 81, 781–787 (1999)

  26. 26

    Liu, S. Q. & Cull-Candy, S. G. Synaptic activity at calcium-permeable AMPA receptors induces a switch in receptor subtype. Nature 405, 454–458 (2000)

  27. 27

    Lee, H. K., Barbarosie, M., Kameyama, K., Bear, M. F. & Huganir, R. L. Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature 405, 955–959 (2000)

  28. 28

    Malinow, R., Mainen, Z. F. & Hayashi, Y. LTP mechanisms: from silence to four-lane traffic. Curr. Opin. Neurobiol. 10, 352–357 (2000)

  29. 29

    Hémar, A., Olivo, J. C., Williamson, E., Saffrich, R. & Dotti, C. G. Dendroaxonal transcytosis of transferrin in cultured hippocampal and sympathetic neurons. J. Neurosci. 17, 9026–9034 (1997)

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Acknowledgements

This work was supported by grants from the Centre National de la Recherche Scientifique and the Conseil Régional d'Aquitaine. A.J.B. was supported by the Fondation pour la Recherche Médicale and an EC (European Commission) Marie Curie Training fellowship. We thank P. Osten for his gift of GluR2–GFP cDNA, A. Benmerah for the gift of the Esp15–GFP cDNA, and R.-M. Mège for the gift of anti-N-Cam. We thank P. Ascher for his support during early phases of this work; C. Mulle, A. Hémar and L. Cognet for their comments on the manuscript; and F. Rossignol for cultures of hippocampal neurons.

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Competing interests

The authors declare that they have no competing financial interests.

Correspondence to Daniel Choquet.

Supplementary information

  1. Legends to supplementary movies 1 - 3 (DOC 20 kb)

  2. Supplementary movie 1 - GluR2 (AVI 3687 kb)

  3. Supplementary movie 2 - GluR-FLASH (AVI 3626 kb)

  4. Supplementary movie 3 - GluR2-Doublebeads (AVI 4133 kb)

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DOI

https://doi.org/10.1038/nature00780

Further reading

Figure 1: Lateral mobility of GluR2 decreases during neuronal maturation.
Figure 2: GluR2 stops reversibly at synaptic sites.
Figure 3: Spontaneous neuronal activity modulates GluR2 mobility.
Figure 4: Local rises in intracellular calcium decrease GluR2 mobility and accumulate GluR2.

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