EphB Controls NMDA Receptor Function and Synaptic Targeting in a Subunit-Specific Manner

Abstract

Dynamic regulation of the localization and function of N-methyl-D-aspartate 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 NMDARs, controls NMDAR subunit localization and function at synapses. We find that in mature neurons, EphB2 expression levels regulate the amount of NMDARs at synapses, and EphB activation decreases Ca2+-dependent desensitization of NR2B-containing NMDARs. EphBs are required for enhanced localization of NR2B-containing NMDARs at synapses of mature neurons; triple EphB knockout mice lacking EphB1-3 exhibit homeostatic upregulation 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 NMDARs.

Metabotropic NMDA receptor function is required for β-amyloid–induced synaptic depression

“…In line with this scenario, the Aβ-dependent endocytosis of NMDARs requires phosphatase activity, and tyrosine dephosphorylation of GluN2B correlates with GluN1/GluN2B endocytosis (46,47). Interestingly, EphB2, a receptor tyrosine kinase that selectively controls the synaptic localization and function of GluN2B-containing NMDARs in mature neurons (48), has been implicated in the synapto-toxic effects of Aβ oligomers (8,49,50). By binding EphB2 and inducing its degradation (49), oligomeric Aβ could deprive synapses of a process that stabilizes their GluN2B-containing NMDARs.…”

miR‐204 downregulates EphB2 in aging mouse hippocampal neurons

“…EphB2 is known to control the surface expression of the NMDAR NR1 subunit in hippocampal neurons (Cissé et al ., 2011; Nolt et al ., 2011), expression necessary for the induction of a robust form of long‐term hippocampal potentiation (Klein, 2008). In addition, EphB2 controlled the surface expression of NR1 in an AD mouse model, which could account for the reduced synaptic plasticity and learning deficits in these mice (Cissé et al ., 2011).…”

“…The decrease in NR1 surface expression induced by miR‐204 transfection was likely due, at least in part, to the repression of EphB2 as miR‐204 represses EphB2, and EphB2 controls the surface expression of NR1 (Cissé et al ., 2011; Nolt et al ., 2011). However, EphB2 is not known to regulate the total cellular expression of NR1.…”

“…Accordingly, the increased miR‐204 expression in the aged hippocampus could contribute to the approximately 50% reduction in NR1 compared with the 2‐month‐old hippocampus (Fig. 4B; Nolt et al ., 2011; Liu et al ., 2008). These different pathways are schematically summarized in Fig.…”

“…We demonstrate that (i) EphB2 is decreased in aged hippocampus concomitant with miR‐204 upregulation, (ii) EphB2 is a target of miR‐204 in hippocampal neurons and (iii) miR‐204 reduces both total NR1 expression and surface expression in hippocampal neurons. As EphB2 signaling is linked to surface expression (Cissé et al ., 2011; Nolt et al ., 2011) but not total NR1 expression, there may be two miR‐204‐dependent NR1 regulatory pathways, one mediated by reduced EphB2 expression and the other independent of EphB2 as indicated by the dotted line (Fig. 4C).…”