Ephs and Ephrins Changing Places

Abstract

The EphB receptor tyrosine kinases and their transmembrane ligands, the ephrinBs, make up the bidirectional signaling complexes implicated in the regulation of long-term changes in the efficacy of hippocampal glutamatergic synapses that may mediate such processes as learning and memory. EphB2 interacts directly with N -methyl-D-aspartate receptors (NMDARs) and, at mossy fiber synapses, acts postsynaptically to mediate non-NMDAR-dependent long-term potentiation (LTP). The localization of the ephrinBs has been presumed to be presynaptic. Grunwald et al. used in situ hybridization and immunoelectron microscopy to show that, in the mouse hippocampal CA3 to CA1 synapse, ephrinB2 and ephrinB3 mRNAs were chiefly localized postsynaptically. Moreover, sucrose gradient fractionation indicated that the ephrinBs were enriched in fractions that contained postsynaptic density proteins, whereas EphB2 and EphA4 were found in all fractions. In mice expressing a conditional mutant that removed ephrinB2 from the postnatal forebrain (or mice lacking ephrinB3), synaptic ultrastructure in CA1 appeared normal, whereas NMDAR-dependent LTP and long-term depression (LTD) at the CA3 to CA1 synapse were attenuated. Electrophysiological analysis of EphA4 knockout mice (or mice expressing a mutant form of EphA4 that lacked any cytoplasmic domain) suggested that EphA4 acts as a nonsignaling presynaptic partner for ephrinB2 and ephrinB3 in mediating LTP and LTD at this synapse. Thus, the pre- or postsynaptic location of components of Eph receptor-ephrin signaling complexes that mediate use-dependent changes in synaptic efficacy appears to vary in different synapses. I. C. Grunwald, M. Korte, G. Adelman, A. Plueck, K. Kullander, R. H. Adams, M. Frotscher, T. Bonhoeffer, R. Klein, Hippocampal plasticity requires postsynaptic ephrinBs. Nat. Neurosci . 7 , 33-40 (2004). [Online Journal]