Dynamic regulation of the localization and function of NMDA receptors (NMDARs) is critical for synaptic development and function. The composition and localization of NMDAR subunits at synapses are tightly regulated and can influence the ability of individual synapses to undergo long-lasting changes in response to stimuli. Here, we examine mechanisms by which EphB2, a receptor tyrosine kinase that binds and phosphorylates NMDA Rs, controls NMDAR subunit localization and function at synapses. We find that, in mature neurons, EphB2 expression levels regulate the amount of NMDAR sat synapses, and Eph B activation decreases Ca2+-dependent desensitization of NR2B-containing NMDA Rs. Eph Bs are required for enhanced localization of NR2B-containing NMDARs at synapses of mature neurons; triple Eph B knock-out mice lacking EphB1-3 exhibit homeostatic up regulation of NMDAR surface expression and loss of proper targeting to synaptic sites. These findings demonstrate that, in the mature nervous system, EphBs are key regulators of the synaptic localization of NMDA Rs.
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