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.

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The neurotoxic effects of chronic ethanol consumption were investigated in the rat hippocampus by electrophysiological analyses of synaptic function of entorhinal afferents to stratum moleculare of the dentate gyrus. Rats were maintained on ethanol- or sucrose-containing liquid diets for a period of 20 weeks and were withdrawn from the special diets for a period of 8 weeks prior to acute electrophysiological studies. Synaptic response strength (Input/Output (I/O) functions) and synaptic potentiation (paired-pulse, frequency and long-term) were evaluated in each rat. Chronic ethanol treatment failed to influence the response strength or potentiation of basic synaptic responses (EPSP). Rather, the ethanol effects were confined to the population spike (PS). Chronic ethanol treatment produced reductions in PS responses 1) in the asymptotic portions of the I/O curves, 2) in paired-pulse potentiation, 3) in response to 1 and 5 Hz low-frequency stimulation and 4) during the development of long-term potentiation. Expressing PS amplitude as a function of EPSP amplitude emphasized the independence of these actions from those of the synaptic potentials. Definitive evidence concerning the cellular alterations underlying these effects of chronic ethanol treatment are presently lacking. However, available evidence supports the hypothesis that the ethanol-induced decreases in PS responses result from a reduction in the "excitability" of granule cells in the dentate gyrus.