Plasticity in the brain is essential for maintaining memory and learning and is associated with the dynamic membrane trafficking of AMPA receptors. EphrinB proteins, ligands for EphB receptor tyrosine kinases, are transmembrane molecules with signaling capabilities that are required for spine morphogenesis, synapse formation and synaptic plasticity. Here, we describe a molecular mechanism for ephrinB2 function in controlling synaptic transmission. EphrinB2 signaling is critical for the stabilization of AMPA receptors at the cellular membrane. Mouse hippocampal neurons from conditional ephrinB2 knockouts showed enhanced constitutive internalization of AMPA receptors and reduced synaptic transmission. Mechanistically, glutamate receptor interacting proteins bridge ephrinB ligands and AMPA receptors. Moreover, this function involved a regulatory aspect of ephrinB reverse signaling that involves the phosphorylation of a single serine residue in their cytoplasmic tails. In summary, our findings uncover a model of cooperative AMPA receptor and ephrinB reverse signaling at the synapse.
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We would like to thank A.Yamasaki for technical help, J. Lauterbach and G. Wilkinson for valuable reagents, I. Kadow for helpful discussions, and A.Yamasaki, E. Fellows, I. Kadow, T. Acker and S. Sigrist for critically reading the manuscript. This work was supported by grants from the Deutsche Forschungsgemeinschaft (AC180/2-1 and AC180/2-2 to A.A.-P.) and the Cluster of Excellence 'Macromolecular Complexes' at the Goethe University Frankfurt (EXC 115).
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Essmann, C., Martinez, E., Geiger, J. et al. Serine phosphorylation of ephrinB2 regulates trafficking of synaptic AMPA receptors. Nat Neurosci 11, 1035–1043 (2008) doi:10.1038/nn.2171
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