Regulation of excitatory synapse development by EphB receptors

The appropriate localization and function of NMDA-type excitatory glutamate receptors is essential for the development of synapses, for mechanisms of plasticity in the mature organism, and in neurological disease and stroke. Despite the wealth of information that had emerged about the process of synapse formation and the components of the synapse, the molecular and cellular regulators of receptor localization and synapse function in the central nervous system were not clear. The findings presented in this thesis identify a novel role for the EphB family of receptor tyrosine kinases in regulating NMDA receptor clustering and excitatory synapse development, and in modulating NMDA receptor function.; EphrinB binding to EphB induces a direct interaction of EphB with NMDA-type glutamate receptors. This interaction is mediated by the extra-cellular domains of the two receptors and does not require kinase activity of EphB. However, the kinase activity of EphB receptors is required for later steps in synapse development, as changes in EphB tyrosine kinase activity affects the number of synaptic specializations that form in cultured cortical and hippocampal neurons. In addition to the role of EphBs in mediating structural changes at the glutamatergic synapse, ephrinB activation of EphB receptors elicits changes in NMDA receptor function. EphrinB activation of EphB in primary cortical neurons potentiates NMDA receptor-dependent influx of calcium. EphrinB treatment also leads to NMDA receptor tyrosine phosphorylation through activation of the Src family of tyrosine kinases. These ephrinB-dependent events result in enhanced NMDA receptor-dependent transcription and endogenous calcium-dependent gene expression. Taken together, the work presented in this thesis demonstrates that ephrinB/EphB modulate synaptic structure and function, and suggest a model whereby activity-independent and activity-dependent signals can converge to regulate the development and remodeling of synaptic connections.