Search

Synapses are specialized cell-cell junctions that underlie the function of neural circuits by mediating communication between neurons. Both the formation and function of synapses require tight coordination of signaling between pre- and post-synaptic neurons. Trans-synaptic organizing molecules are important mediators of such signaling. Here we discuss how the EphB and ephrin-B families of trans-synaptic organizing proteins direct synapse formation during early development and regulate synaptic function and plasticity at mature synapses. Finally, we highlight recent evidence linking the synaptic organizing role of EphBs and ephrin-Bs to diseases of maladaptive synaptic function and plasticity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Synapses enable the transmission of information within neural circuits and allow the brain to change in response to experience. During the last decade numerous proteins that can induce synapse formation have been identified. Many of these synaptic inducers rely on trans-synaptic cell-cell interactions to generate functional contacts. Moreover, evidence now suggests that the same proteins that function early in development to regulate synapse formation may help to maintain and/or regulate the function and plasticity of mature synapses. One set of receptors and ligands that appear to impact both the development and the mature function of synapses are Eph receptors (erythropoietin-producing human hepatocellular carcinoma cell line) and their surface associated ligands, ephrins (Eph family receptor interacting proteins). Ephs can initiate new synaptic contacts, recruit and stabilize glutamate receptors at nascent synapses and regulate dendritic spine morphology. Recent evidence demonstrates that ephrin ligands also play major roles at synapses. Activation of ephrins by Eph receptors can induce synapse formation and spine morphogenesis, whereas in the mature nervous system ephrin signaling modulates synaptic function and long-term changes in synaptic strength. In this review we will summarize the recent progress in understanding the role of ephrins in presynaptic and postsynaptic differentiation, and synapse development, function and plasticity., (Copyright © 2012 Elsevier Inc. All rights reserved.)

B-ephrin-EphB receptor signaling modulates NMDA receptors by inducing tyrosine phosphorylation of NR2 subunits. Ephrins and EphB RTKs are localized to postsynaptic compartments in the CA1, and therefore potentially interact in a non-canonical cis- configuration. However, it is not known whether cis- configured receptor-ligand signaling is utilized by this class of RTKs, and whether this might influence excitatory synapses. We found that ablation of ephrin-B3 results in an enhancement of the NMDA receptor component of synaptic transmission relative to the AMPA receptor component in CA1 synapses. Synaptic AMPA receptor expression is reduced in ephrin-B3 knockout mice, and there is a marked enhancement of tyrosine phosphorylation of the NR2B receptor subunit. In a reduced system co-expression of ephrin-B3 attenuated EphB2-mediated NR2B tyrosine phosphorylation. Moreover, phosphorylation of EphB2 was elevated in the hippocampus of ephrin-B3 knockout mice, suggesting that regulation of EphB2 activity is lost in these mice. Direct activation of EphB RTKs resulted in phosphorylation of NR2B and a potential signaling partner, the non-receptor tyrosine kinase Pyk2. Our data suggests that ephrin-B3 limits EphB RTK-mediated phosphorylation of the NR2B subunit through an inhibitory cis- interaction which is required for the correct function of glutamatergic CA1 synapses., (Copyright © 2010 Elsevier Inc. All rights reserved.)