Long-term potentiation (LTP) of synaptic transmission in the hippocampus have been a fruitful model for studying the neuronal processes believed to underlie learning and memory. The discovery of the NMDA receptor/Ca2+ - channel as part of the mechanism of LTP has provided a solid foundation for further studies into additional substrates of synaptic plasticity. In this proposal we wish to study a form of LTP that does not utilize NMDA receptors. Namely, LTP mediated by non-NMDA calcium channel activation. Hippocampal LTP can be induced by brief exposure to elevated calcium concentrations if extracellular potassium concentration is elevated (^[K+]e). This appears to reflect the involvement of a voltage-dependent mechanism which enhances postsynaptic calcium influx, because, in intracellular experiments, depolarizing current injection can substitute for elevated [K+]e. A small increase in [K+]e is sufficient to produce the required depolarization. Tetanic stimulation produces rapid and large increases in [K+]e in the synaptic layer of hippocampus. These results suggest that the post-synaptic depolarization required to activate NMDA receptor-gated ion channels in LTP might arise in part from release of potassium into the extracellular space. The voltage-dependent calcium influx appears to be unaffected by the NMDA antagonist APV, but is abolished by specific dihydropyridine calcium channel blockers. Thus, our preliminary results indicate that postsynaptic depolarization can promote a non-NMDA, voltage-dependent post-synaptic calcium influx, leading to a long-term Ca2+ -induced potentiation. Furthermore, we have new evidence that the non-NMDA receptor-mediated calcium influx can be activated during tetanus-induced LTP in normal media, as well. Thus, tetanus-induced LTP appears to have two calcium-dependent components - one mediated by Ca2+ influx through NMDA receptor-mediated channels, and another mediated by Ca2+ influx through voltage sensitive calcium channels. The two components of LTP appear to be induced by different patterns of afferent activity and appear to have somewhat different properties. We propose to study this phenomena. We wish to determine the magnitude, spatial distribution, clearance kinetics, and source of the ^[K+]e associated with tetanus-induced hippocampal LTP. We wish to confirm the identity and study the role of voltage-dependent calcium channels in LTP. We wish to confirm the identity and study the role of voltage-dependent calcium channels in LTP. Finally, since the effect of tetanus-induced ^[K+]e can be expected to depolarize adjacent membranes, we wish to investigate the role of this mechanism in associative LTP. These studies will be done on CA1 cells of hippocampal slices using intracellular and field potential recordings. Ion-sensing microelectrodes will be used to measure [K+]e. Pharmacological agents will be used to manipulate the two components of LTP.
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