Novel expression mechanism for synaptic potentiation: Alignment of presynaptic release site and postsynaptic receptor [long-term potentiationydentate gyrusy(6)-a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptoryN-methyl-D-aspartic acid receptorysynaptic model]

A combination of experimental and modeling approaches was used to study cellular–molecular mechanisms underlying the expression of short-term potentiation (STP) and long-term potentiation (LTP) of glutamatergic synaptic transmission in the hippocampal slice. Electrophysiological recordings from dentate granule cells revealed that highfrequency stimulation of perforant path afferents induced a robust STP and LTP of both (6)-a-amino-3-hydroxy-5methylisoxazole-4-propionic acid (AMPA) and N-methyl-Daspartic acid (NMDA) receptor-mediated synaptic responses. However, the decay time constant for STP of the AMPA receptor-mediated excitatory postsynaptic potential was approximately 6 min, whereas the decay time constant for STP of the NMDA receptor-mediated excitatory postsynaptic potential was only 1 min. In addition, focal application of agonists during the expression of STP revealed that the magnitude of conductance change elicited by NMDA application was significantly enhanced, whereas the magnitude of conductance change elicited by application of AMPA remained constant. These findings are most consistent with a postsynaptic mechanism of STP and LTP. Different putative mechanisms were evaluated formally using a computational model that included diffusion of glutamate within the synaptic cleft, different kinetic properties of AMPA and NMDA receptorychannels, and geometric relations between presynaptic release sites and postsynaptic receptorychannels. Simulation results revealed that the only hypothesis consistent with experimental data is that STP and LTP ref lect a relocation of AMPA receptorychannels in the postsynaptic membrane such that they become more closely ‘‘aligned’’ with presynaptic release sites. The same mechanism cannot account for STP or LTP of NMDA receptor-mediated responses; instead, potentiation of the NMDA receptor subtype is most consistent with an increase in receptor sensitivity or number. Long-term potentiation (LTP) is a widely studied form of use-dependent synaptic plasticity expressed robustly by glutamatergic synapses of the hippocampus. The initial stage of LTP expression, typically identified as short-term potentiation (STP), is characterized by a rapid decay in the magnitude of potentiation to an asymptotic, steady-state level. Although there is a convergence of evidence concerning the cellulary molecular mechanisms mediating the induction of N-methylD-aspartic acid (NMDA) receptor-dependent STP and LTP (1), there remains substantial debate as to whether the expression of potentiation reflects change in presynaptic release mechanisms or postsynaptic receptor-channel function. Because of the synaptic coexistence of (6)-a-amino-3-hydroxy5-methylisoxazole-4-propionic acid (AMPA) and NMDA glutamatergic receptor subtypes (2), substantial differences in the magnitude of LTP expressed by AMPA and NMDA receptors would favor a mechanism that is postsynaptic in origin. Several studies have reported a more substantial induction of AMPA receptor-mediated LTP compared with NMDA receptormediated LTP (3–7), though in the presence of low concentrations of extracellular magnesium (8) or upon depolarization of the postsynaptic neuron (9), procedures that relieve blockade of the NMDA receptorychannel, equivalent magnitude increases in AMPA and NMDA receptor-mediated LTP consistently are observed. The possibility of an exclusively AMPA receptor-mediated postsynaptic expression of LTP also has been weakened by persistent difficulties in detecting an increased responsivity of AMPA receptors to exogenously applied glutamate or receptor agonist (10–13). In the studies reported here, we have investigated the potential differential expression of STP by AMPA and NMDA receptors and found that the decay time course of STP is markedly different for AMPA and NMDA receptor-mediated EPSPs. Furthermore, during both STP and LTP, we found evidence of a differential responsivity of AMPA and NMDA receptors to focal application of their respective agonists. With these results strongly supportive of a postsynaptic expression mechanism of STP and LTP, a computational model incorporating parameters for the synaptic space, the kinetic properties of AMPA and NMDA receptorychannels, and the relative locations of the two receptorychannel subtypes was used to investigate several more specific hypotheses. Results suggest a unique expression mechanism not previously proposed, namely, receptorychannel relocalization in the postsynaptic membrane. Our findings demonstrate that this hypothesis is sufficient to explain both STP and LTP of the AMPA receptorychannel, though not the NMDA receptorychannel, and moreover, can explain experimental observations that cannot be accounted for by previously hypothesized mechanisms.