The site of induction of long-term potentiation (LTP) at mossy fiber-CA3 synapses in the hippocampus is unresolved, with data supporting both pre- and postsynaptic mechanisms. Here we report that mossy fiber LTP was reduced by perfusion of postsynaptic neurons with peptides and antibodies that interfere with binding of EphB receptor tyrosine kinases (EphRs) to the PDZ protein GRIP. Mossy fiber LTP was also reduced by extracellular application of soluble forms of B-ephrins, which are normally membrane-anchored presynaptic ligands for the EphB receptors. The application of soluble ligands for presynaptic ephrins increased basal excitatory transmission and occluded both tetanus and forskolin-induced synaptic potentiation. These findings suggest that PDZ interactions in the postsynaptic neuron and trans-synaptic interactions between postsynaptic EphB receptors and presynaptic B-ephrins are necessary for the induction of mossy fiber LTP.

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Activation of N-methyl-D-aspartate-selective ionotropic glutamate receptors (NMDA receptors) requires two agonists, glutamate and glycine. These ligands are thought to bind to the NR2 and NR1 subunits, respectively, apparently ruling out the formation of functional homomeric receptors. However, NMDAmediated currents are observed when the mammalian NR1 subunit is expressed alone in Xenopus laevis oocytes. These currents have been generally ascribed to a functional association between NR1 and the endogenous glutamate receptor subunit XenU1. To determine whether such a functional association does in fact occur, we have isolated cDNAs for both XenU1 and XenU1a, a presumed nonallelic counterpart. We investigated whether the coexpression of either XenU1 or XenU1a with NR1 in either X. laevis oocytes and human embryonic kidney (HEK) 293 cells had any effect on the observed NMDA receptor responses. In oocytes, coinjection of XenU1 with NR1 did not increase the observed currents compared with injection of NR1 alone; similarly, in HEK 293 cells, coexpression of XenU1 and NR1 did not result in the formation of functional channels. We also found no pharmacological or biochemical evidence for interaction between the two subunits. We conclude, therefore, that XenU1 does not associate with the NR1 subunit and that an alternative explanation must be sought for the channels observed when NR1 is expressed alone in oocytes.