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Hippocampal plasticity requires postsynaptic ephrinBs


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.

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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.


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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.).

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Correspondence to Tobias Bonhoeffer or Rüdiger Klein.

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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)

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Grunwald, I., Korte, M., Adelmann, G. et al. Hippocampal plasticity requires postsynaptic ephrinBs. Nat Neurosci 7, 33–40 (2004).

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