Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Hippocampal plasticity requires postsynaptic ephrinBs

Nature Neuroscience volume 7, pages 33–40 (2004)Cite this article

Abstract

Chemical synapses contain specialized pre- and postsynaptic structures that regulate synaptic transmission and plasticity. EphB receptor tyrosine kinases are important molecular components in this process. Previously, EphB receptors were shown to act postsynaptically, whereas their transmembrane ligands, the ephrinBs, were presumed to act presynaptically. Here we show that in mouse hippocampal CA1 neurons, the Eph/ephrin system is used in an inverted manner: ephrinBs are predominantly localized postsynaptically and are required for synaptic plasticity. We further demonstrate that EphA4, a candidate receptor, is also critically involved in long-term plasticity independent of its cytoplasmic domain, suggesting that ephrinBs are the active signaling partner. This work raises the intriguing possibility that depending on the type of synapse, Eph/ephrins can be involved in activity-dependent plasticity in converse ways, with ephrinBs on the pre- or the postsynaptic side.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Postsynaptic expression of ephrinBs.
Figure 2: Forebrain-specific removal of ephrinB2.
Figure 3: Ultrastructure of synapses in mutant mice.
Figure 4: EphrinBs are critical for LTP.
Figure 5: EphrinBs are required for LTD.
Figure 6: Signaling-independent requirement of EphA4 in LTP and LTD.

Similar content being viewed by others

References

  1. Henderson, J.T. et al. The receptor tyrosine kinase EphB2 regulates NMDA-dependent synaptic function. Neuron 32, 1041–1056 (2001).

    Article  CAS  Google Scholar 

  2. Grunwald, I.C. et al. Kinase-independent requirement of EphB2 receptors in hippocampal synaptic plasticity. Neuron 32, 1027–1040 (2001).

    Article  CAS  Google Scholar 

  3. Contractor, A. et al. Trans-synaptic Eph receptor-ephrin signaling in hippocampal mossy fiber LTP. Science 296, 1864–1869 (2002).

    Article  CAS  Google Scholar 

  4. Wilkinson, D.G. Multiple roles of EPH receptors and ephrins in neural development. Nat. Rev. Neurosci. 2, 155–164 (2001).

    Article  CAS  Google Scholar 

  5. Palmer, A. & Klein, R. Multiple roles of ephrins in morphogenesis, neuronal networking, and brain function. Genes Dev. 17, 1429–1450 (2003).

    Article  CAS  Google Scholar 

  6. Dalva, M.B. et al. EphB receptors interact with NMDA receptors and regulate excitatory synapse formation. Cell 103, 945–956 (2000).

    Article  CAS  Google Scholar 

  7. Takasu, M.A., Dalva, M.B., Zigmond, R.E. & Greenberg, M.E. Modulation of NMDA receptor-dependent calcium influx and gene expression through EphB receptors. Science 295, 491–495 (2002).

    Article  CAS  Google Scholar 

  8. Kullander, K. & Klein, R. Mechanisms and functions of Eph and ephrin signalling. Nat. Rev. Mol. Cell. Biol. 3, 475–486 (2002).

    Article  CAS  Google Scholar 

  9. Cho, K.O., Hunt, C.A. & Kennedy, M.B. The rat brain postsynaptic density fraction contains a homolog of the Drosophila discs-large tumor suppressor protein. Neuron 9, 929–942 (1992).

    Article  CAS  Google Scholar 

  10. Walikonis, R.S. et al. Identification of proteins in the postsynaptic density fraction by mass spectrometry. J. Neurosci. 20, 4069–4080 (2000).

    Article  CAS  Google Scholar 

  11. Chen, L. et al. Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408, 936–943 (2000).

    Article  CAS  Google Scholar 

  12. Dong, H. Zhang, P., Liao, D. & Huganir, R.L. Characterization, expression, and distribution of GRIP protein. Ann. NY Acad. Sci. 868, 535–540 (1999).

    Article  CAS  Google Scholar 

  13. Wyszynski, M. et al. Association of AMPA receptors with a subset of glutamate receptor-interacting protein in vivo. J. Neurosci. 19, 6528–6537 (1999).

    Article  CAS  Google Scholar 

  14. Buchert, M. et al. The junction-associated protein AF-6 interacts and clusters with specific Eph receptor tyrosine kinases at specialized sites of cell-cell contact in the brain. J. Cell Biol. 144, 361–371 (1999).

    Article  CAS  Google Scholar 

  15. Wang, H.U., Chen, Z.F. & Anderson, D.J. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93, 741–753 (1998).

    Article  CAS  Google Scholar 

  16. Adams, R.H. et al. Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev. 13, 295–306 (1999).

    Article  CAS  Google Scholar 

  17. Minichiello, L. et al. Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24, 401–414 (1999).

    Article  CAS  Google Scholar 

  18. Ethell, I.M. et al. EphB/syndecan-2 signaling in dendritic spine morphogenesis. Neuron 31, 1001–1013 (2001).

    Article  CAS  Google Scholar 

  19. Murai, K.K., Nguyen, L.N., Irie, F., Yamaguchi, Y. & Pasquale, E.B. Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling. Nat. Neurosci. 6, 153–160 (2003).

    Article  CAS  Google Scholar 

  20. Penzes, P. et al. Rapid induction of dendritic spine morphogenesis by trans-synaptic ephrinB-EphB receptor activation of the Rho-GEF kalirin. Neuron 37, 263–274 (2003).

    Article  CAS  Google Scholar 

  21. Henkemeyer, M., Itkis, O.S., Ngo, M., Hickmott, P.W. & Ethell, E.M. Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus. J. Cell Biol. (in press).

  22. Bliss, T.V. & Collingridge, G.L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993).

    CAS  Google Scholar 

  23. Kullander, K. et al. Ephrin-B3 is the midline barrier that prevents corticospinal tract axons from recrossing, allowing for unilateral motor control. Genes Dev. 15, 877–888 (2001).

    Article  CAS  Google Scholar 

  24. Yokoyama, N. et al. Forward signaling mediated by ephrin-B3 prevents contralateral corticospinal axons from recrossing the spinal cord midline. Neuron 29, 85–97 (2001).

    Article  CAS  Google Scholar 

  25. Dudek, S.M. & Bear, M.F. Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade. Proc. Natl. Acad. Sci. USA 89, 4363–4367 (1992).

    Article  CAS  Google Scholar 

  26. Mulkey, R.M. & Malenka, R.C. Mechanisms underlying induction of homosynaptic long-term depression in area CA1 of the hippocampus. Neuron 9, 967–975 (1992).

    Article  CAS  Google Scholar 

  27. Tronche, F. et al. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nat. Genet. 23, 99–103 (1999).

    Article  CAS  Google Scholar 

  28. Mellitzer, G., Xu, Q. & Wilkinson, D.G. Eph receptors and ephrins restrict cell intermingling and communication. Nature 400, 77–81 (1999).

    Article  CAS  Google Scholar 

  29. Kullander, K. et al. Kinase-dependent and kinase-independent functions of EphA4 receptors in major axon tract formation in vivo. Neuron 29, 73–84 (2001).

    Article  CAS  Google Scholar 

  30. Dottori, M. et al. EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract. Proc. Natl. Acad. Sci. USA 95, 13248–13253 (1998).

    Article  CAS  Google Scholar 

  31. Kullander, K. et al. Role of EphA4 and EphrinB3 in local neuronal circuits that control walking. Science 299, 1889–1892 (2003).

    Article  CAS  Google Scholar 

  32. Ghosh, A. Neurobiology. Learning more about NMDA receptor regulation. Science 295, 449–451 (2002).

    Article  Google Scholar 

  33. Murai, K.K. & Pasquale, E.B. Can Eph receptors stimulate the mind? Neuron 33, 159–162 (2002).

    Article  CAS  Google Scholar 

  34. Henkemeyer, M. et al. Nuk controls pathfinding of commissural axons in the mammalian central nervous system. Cell 86, 35–46 (1996).

    Article  CAS  Google Scholar 

  35. Godenschwege, T.A., Hu, H., Shan-Crofts, X., Goodman, C.S. & Murphey, R.K. Bi-directional signaling by Semaphorin 1a during central synapse formation in Drosophila. Nat. Neurosci. 5, 1294–1301 (2002).

    Article  CAS  Google Scholar 

  36. Zimmer, M., Palmer, A., Kohler, J. & Klein, R. EphB-ephrinB bi-directional endocytosis terminates adhesion allowing contact mediated repulsion. Nat. Cell Biol. 5, 869–878 (2003).

    Article  CAS  Google Scholar 

  37. Marston, D.J., Dickinson, S. & Nobes, C.D. Rac-dependent trans-endocytosis of ephrinBs regulates Eph-ephrin contact repulsion. Nat. Cell Biol. 5, 879–888 (2003).

    Article  CAS  Google Scholar 

  38. Dymecki, S.M. A modular set of Flp, FRT and lacZ fusion vectors for manipulating genes by site-specific recombination. Gene 171, 197–201 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We wish to thank V. Staiger, K. Mews, A. Schneider, A. Porthin, F. Diella, F. Hampel, D. Büringer, M. Winter and M. Falkenberg for technical help. We are grateful to F. Helmbacher, T. Mrsic-Flögel and G.A. Wilkinson for critical comments on the manuscript, and to M. Zimmer, B. Berninger and U.V. Nägerl for scientific discussions and initial experiments. We thank M. Sheng and associates for providing protocols, and N. Gale and G.D. Yancopoulos for providing ephrinB3 mutant mice. This work was supported by the Max-Planck Society and additional grants from the Deutsche Forschungsgemeinschaft (SFB 391 to R.K. and T.B., and SFB 505 to M.F.).

Author information

Author notes

  1. Ilona C Grunwald, Martin Korte, Tobias Bonhoeffer and Rüdiger Klein: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Neurobiology, Max-Planck Institute of Neurobiology, Munich-Martinsried, 82152, Germany

    Ilona C Grunwald & Rüdiger Klein

  2. Department of Cellular and Systems Neurobiology, Max-Planck Institute of Neurobiology, Munich-Martinsried, 82152, Germany

    Martin Korte & Tobias Bonhoeffer

  3. Institute for Anatomy and Cell Biology, University of Freiburg, Freiburg, 79001, Germany

    Giselind Adelmann & Michael Frotscher

  4. Institute for Genetics, University of Cologne, Köln, 50931, Germany

    Anne Plueck

  5. Department of Medical Biochemistry, Gothenburg University, Gothenburg, 40530, Sweden

    Klas Kullander

  6. Cancer Research UK - London Research Institute, London, WC2A 3PX, UK

    Ralf H Adams

Authors
  1. Ilona C Grunwald
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martin Korte
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giselind Adelmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anne Plueck
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Klas Kullander
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ralf H Adams
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael Frotscher
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tobias Bonhoeffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rüdiger Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Tobias Bonhoeffer or Rüdiger Klein.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Normal synaptic ultrastructure in single mutants of ephrinBs and Eph receptors. Electronmicroscopy analysis of ephrinB and Eph receptor mutants. No obvious difference was found in structure of the PSD (see arrowheads) and the appearance of the presynaptic terminals. (a) ephrinB2-Nescre (n=3), (b) ephrinB2lx/lx (n=3), (c) ephrinB3-/- (n=3), (d) littermate control (n=3), (e) EphA4EGFP/EGFP (n=3), and (f) littermate control (n=3). Scalebar: 0.7μm (JPG 77 kb)

Supplementary Fig. 2

NMDA receptor dependent components of the basal fEPSP are normal in Eph and ephrinB mutants. Following baseline stimulation in normal ACSF, 10μM DNQX was added and fEPSPs were recorded for 15min (white bars). The remaining response was almost completely dimished after additional application of 50μM AP-5 (black bars). (a) ephrinB2-CamKcre (n=5) slices versus ephrinB2lx/lx controls (n=5, t-test, p>0.05). (b) ephrinB3-/- (n=5) slices versus controls (n=5, t-test, p>0.05). (c) ephA4-/- (n=8) slices versus controls (n=9, t-test, p>0.05). (PDF 66 kb)

Supplementary Fig. 3

Single LTP experiment of ephrinB2-CamKcre and ephrinB2lx/lx controls. EPSP slope is plotted against time. LTP was induced by TBS. Every trace is an average from four consecutive trials. (PDF 60 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grunwald, I., Korte, M., Adelmann, G. et al. Hippocampal plasticity requires postsynaptic ephrinBs. Nat Neurosci 7, 33–40 (2004). https://doi.org/10.1038/nn1164

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1164

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing