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Integrins mediate functional pre- and postsynaptic maturation at a hippocampal synapse

Nature volume 411, pages 317–321 (2001)Cite this article

Abstract

Coordinated signalling between presynaptic terminals and their postsynaptic targets is essential for the development and function of central synapses. In addition to diffusible molecules1, this bidirectional flow of information could involve direct interactions through cell-adhesion molecules2,3. Here, we show that one class of cell-adhesion molecule, the integrins, are required for the functional maturation of hippocampal synapses in vitro. At immature synapses, a high probability of glutamate release (Pr) was correlated with the expression of postsynaptic NMDA (N-methyl-D-aspartate) receptors containing the NR2B subunit. The activity-dependent reduction in Pr and a switch in the subunit composition of synaptic NMDA receptors was prevented by chronic blockade with peptides containing the integrin-binding site Arg-Gly-Asp (RGD), or by a functional antibody against the β3 integrin subunit. Active synapses, monitored by the uptake of antibodies against the intraluminal domain of synaptotagmin I, also had β3 subunit immunoreactivity. Our results provide evidence that integrin-mediated signalling is essential for the orchestrated maturation of central excitatory synapses.

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Figure 1: Presynaptic and postsynaptic properties are determined by synaptic activity.
Figure 2: Block of integrins prevents synaptic maturation.
Figure 3: Role of β3-containing integrins in coordinated pre- and postsynaptic function.
Figure 4: Working model for role of integrins in synaptic maturation.

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References

  1. Fitzsimonds, R. M. & Poo, M. M. Retrograde signaling in the development and modification of synapses. Physiol. Rev. 78, 143–170 (1998).

    Article  CAS  Google Scholar 

  2. Kohmura, N. et al. Diversity revealed by a novel family of cadherins expressed in neurons at a synaptic complex. Neuron 20, 1137–1151 (1998).

    Article  CAS  Google Scholar 

  3. Song, J. Y., Ichtchenko, K., Sudhof, T. C. & Brose, N. Neuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses. Proc. Natl Acad. Sci. USA 96, 1100–1105 (1999).

    Article  ADS  CAS  Google Scholar 

  4. Rosenmund, C., Clements, J. D. & Westbrook, G. L. Nonuniform probability of glutamate release at a hippocampal synapse. Science 262, 754–757 (1993).

    Article  ADS  CAS  Google Scholar 

  5. Hessler, N. A., Shirke, A. M. & Malinow, R. The probability of transmitter release at a mammalian central synapse. Nature 366, 569–572 (1993).

    Article  ADS  CAS  Google Scholar 

  6. Murthy, V. N., Sejnowski, T. J. & Stevens, C. F. Heterogeneous release properties of visualized individual hippocampal synapses. Neuron 18, 599–612 (1997).

    Article  CAS  Google Scholar 

  7. Bolshakov, V. Y. & Siegelbaum, S. A. Regulation of hippocampal transmitter release during development and long-term potentiation. Science 269, 1730–1734 (1995).

    Article  ADS  CAS  Google Scholar 

  8. Chavis, P. & Westbrook, G. L. ‘Pure’ NR2B-containing synapses have a high release probability in cultured hippocampal neurons. Soc. Neurosci. Abs. (1998).

  9. Williams, K., Russell, S. L., Shen, Y. M. & Molinoff, P. B. Developmental switch in the expression of NMDA receptors occurs in vivo and in vitro. Neuron 10, 267–278 (1993).

    Article  CAS  Google Scholar 

  10. Williams, K. Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. Mol. Pharm. 44, 851–859 (1993).

    CAS  Google Scholar 

  11. Vicini, S. et al. Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors. J. Neurophysiol. 79, 555–566 (1998).

    Article  CAS  Google Scholar 

  12. Tovar, K. R. & Westbrook, G. L. The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro. J. Neurosci. 19, 4180–4188 (1999).

    Article  CAS  Google Scholar 

  13. Staubli, U., Chun, D. & Lynch, G. Time-dependent reversal of long-term potentiation by an integrin antagonist. J. Neurosci. 18, 3460–3469 (1998).

    Article  CAS  Google Scholar 

  14. Grotewiel, M. S., Beck, C. D., Wu, K. H., Zhu, X. R. & Davis, R. L. Integrin-mediated short-term memory in Drosophila. Nature 391, 455–460 (1998).

    Article  ADS  CAS  Google Scholar 

  15. Aplin, A. E., Howe, A., Alahari, S. K. & Juliano, R. L. Signal transduction and signal modulation by cell adhesion receptors: the role of integrins, cadherins, immunoglobulin-cell adhesion molecules, and selectins. Pharmacol. Rev. 50, 197–263 (1998).

    CAS  PubMed  Google Scholar 

  16. Ruoslahti, E. RGD and other recognition sequences for integrins. Annu. Rev. Cell Dev. Biol. 12, 697–715 (1996).

    Article  CAS  Google Scholar 

  17. Tang, L., Hung, C. P. & Schuman, E. M. A role for the cadherin family of cell adhesion molecules in hippocampal long-term potentiation. Neuron 20, 1165–1175 (1998).

    Article  CAS  Google Scholar 

  18. Pinkstaff, J. K., Detterich, J., Lynch, G. & Gall, C. Integrin subunit gene expression is regionally differentiated in adult brain. J. Neurosci. 19, 1541–1556 (1999).

    Article  CAS  Google Scholar 

  19. Pfaff, M., McLane, M. A., Beviglia, L., Niewiarowski, S. & Timpl, R. Comparison of disintegrins with limited variation in the RGD loop in their binding to purified integrins alpha IIb beta 3, alpha V beta 3 and alpha 5 beta 1 and in cell adhesion inhibition. Cell. Adhes. Commun. 2, 491–501 (1994).

    Article  CAS  Google Scholar 

  20. Chavis, P., Mollard, P., Bockaert, J. & Manzoni, O. Visualization of cyclic AMP-regulated presynaptic activity at cerebellar granule cells. Neuron 20, 773–781 (1998).

    Article  CAS  Google Scholar 

  21. Schlaepfer, D. D. & Hunter, T. Integrin signalling and tyrosine phosphorylation: just the FAKs? Trends Cell Biol. 8, 151–157 (1998).

    Article  CAS  Google Scholar 

  22. Boyer, C., Schikorski, T. & Stevens, C. F. Comparison of hippocampal dendritic spines in culture and in brain. J. Neurosci. 18, 5294–5300 (1998).

    Article  CAS  Google Scholar 

  23. Schikorski, T. & Stevens, C. F. Quantitative ultrastructural analysis of hippocampal excitatory synapses. J. Neurosci. 17, 5858–5867 (1997).

    Article  CAS  Google Scholar 

  24. Lau, L. F. & Huganir, R. L. Differential tyrosine phosphorylation of N-methyl-D-aspartate receptor subunits. J. Biol. Chem. 270, 20036–20041 (1995).

    Article  CAS  Google Scholar 

  25. Blaess, S., Kammerer, R. A. & Hall, H. Structural analysis of the sixth immunoglobulin-like domain of mouse neural cell adhesion molecule L1 and its interactions with alpha(v)beta3, alpha(IIb)beta3, and alpha5beta1 integrins. J. Neurochem. 71, 2615–2625 (1998).

    Article  CAS  Google Scholar 

  26. Luthi, A., Laurent, J. P., Figurov, A., Muller, D. & Schachner, M. Hippocampal long-term potentiation and neural cell adhesion molecules L1 and NCAM. Nature 372, 777–779 (1994).

    Article  ADS  CAS  Google Scholar 

  27. Scheiffele, P., Fan, J., Choih, J., Fetter, R. & Serafini, T. Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons. Cell 101, 657–669 (2000).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank G. Alonso, K. Tovar and A. Puel for discussions and O. Manzoni, C. Jahr and J. Bockaert for critical reading of the manuscript. We also thank A. Miller for technical support and M. Passama for the artwork. This work was supported by NIH (G.L.W.), the Human Frontiers Science Program, INSERM, and by FRM (P.C.).

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  1. Pascale Chavis

    Present address: CNRS UPR 9023, 141 rue de la Cardonille, 34094, Montpellier Cedex, 05, France

  2. Pascale Chavis: Correspondence and request for materials should be addressed to P.C.

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  1. Vollum Institute Oregon Health Sciences, University Portland, 97201, Oregon, USA

    Pascale Chavis & Gary Westbrook

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  2. Gary Westbrook
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Correspondence to Pascale Chavis.

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Chavis, P., Westbrook, G. Integrins mediate functional pre- and postsynaptic maturation at a hippocampal synapse. Nature 411, 317–321 (2001). https://doi.org/10.1038/35077101

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