Tyrosine phosphorylation sites in ephrinB2 are required for hippocampal long-term Potentiation but not long-term depression

Long-lasting changes in synaptic function are thought to be the cellular basis for learning and memory and for activity-dependent plasticity during development. Long-term potentiation (LTP) and long-term depression (LTD) are two opposing forms of synaptic plasticity that help fine tune neural connections and possibly serve to store information in the brain. Eph receptor tyrosine kinases and their transmembrane ligands, the ephrinBs, have essential roles in certain forms of synaptic plasticity. At the CA3-CA1 hippocampal synapse, EphB2 and EphA4 receptors are critically involved in long-term plasticity independent of their cytoplasmic domains, suggesting that ephrinBs are the active signaling partners. In cell-based assays, ephrinB reverse signaling was previously shown to involve phosphotyrosine-dependent and postsynaptic density-95/Discs large/zona occludens-1 (PDZ) domain interaction-dependent pathways. Which reverse signaling mode is required at hippocampal synapses is unknown. To address this question, we used knock-in mice expressing mutant isoforms of ephrinB2 that are deficient in specific aspects of reverse signaling. Our analysis revealed that tyrosine phosphorylation sites in ephrinB2 are required to mediate normal hippocampal LTP, but not for LTD. Conversely, ephrinB2 lacking the C-terminal PDZ interaction site, but competent to undergo tyrosine phosphorylation, cannot mediate either form of long-term plasticity. Our results provide the first evidence for phosphotyrosine-dependent ephrinB reverse signaling in a neuronal network and for differential ephrinB2 reverse signaling in two forms of synaptic plasticity.