Long-term potentiation (LTP) is an example of activity-dependent plasticity, which has been studied intensively in the hippocampal formation. In the dentate gyrus, beta-adrenergic agonist-induced long- lasting potentiation (BAALLP) bears strong similarities to LTP. In particular, both require activation of N-methyl-D-aspartate (NMDA) receptors. The objective of the proposed research is to test the hypothesis that, at the medial perforant path-granule cell synapse, (1) LTP requires activation of the NMDA and metabotropic (ACPD) excitatory amino acid (EAA) receptors, and (2) beta-adrenergic agonists activate the NMDA receptor and either activate or circumvent the ACPD receptor to initiate the same events as those underlying LTP. Experiments at the medial perforant path-granule cell synapse of rat hippocampal slice are planned to determine: 1. The role of NMDA and ACPD receptors in LTP and BAALLP. Patch clamp, intracellular, and extracellular recording will be used to determine the roles of beta-adrenergic receptors and GABA-mediated inhibition in LTP and BAALLP, the ability of NMDA and ACPD, alone and in combination, to induce an LLP, and whether LTP and/or BAALLP results from increased release of EAA transmitter or increased postsynaptic sensitivity to EAA. 2. The role of second messengers and protein kinases in production and maintenance of LTP and BAALLP. Granule cells will be perfused internally with patch or intracellular pipets containing calcium chelators, cAMP analogs, or IP3. Effects of PKC activators, such as phobol esters, and PKC antagonists will be evaluated by electrophysiological and biochemical methods. Internal perfusion of cAMP- dependent protein kinase or PKC may give some insight into possible final common pathways for these two kinases. 3. The role of G proteins in the production and maintenance of LTP and BAALLP. Internal perfusion of granule cells with patch of intracellular pipets containing GTPgammaS or GDPbetaS will indicate whether (a) postsynaptic G protein(s) are required for LTP and BAALLP. Injection of purified G proteins and subunits into granule cells will be attempted in order to determine which G protein(s) is/are involved in LTP and BAALLP. The long-term goal of this research is to clarify the relationship between LTP and BAALLP, and thereby increase understanding of mechanisms of synaptic plasticity and cellular information storage.
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