The objective is to elucidate mechanisms of long-term potentiation (LPT) and norepinephrine-induced long-lasting potentiation (NELLP) in the dentate gyrus of the hippocampal formation. Electrophysiological methods will be employed to record evoked potentials and membrane biophysical properties of neurons in the dentate gyrus of the in vitro rat hippocampal slice preparation. LTP will be evoked by a burst of high frequency, repetitive electrical stimulation to the monosynaptic perforant path input. NELLP will be induced by bath application of norepinephrine (NE). Previous experiments have demonstrated that (1) LTP and LLP in the dentate require activation of Beta-adrenergic receptors by NE; (2) adenylate cyclase, linked to Betarecptors increases cAMP levels; (3) inhibitors of protein synthesis can prevent the development of LTP and NELLP; and (4) a monoclonal antibody against a hippocampal cell surface antigen can prevent LTP. It is hypothesized that NE, released by high frequency electrical stimulation (LTP) or exogenously applied (NELLP), enhances synthesis of cAMP. Cyclic AMP increases phosphorylation of proteins which may initiate protein synthesis and modify activity of enzymes and structural proteins. A cell surface protein, possibly one of those whose synthesis or phosphorylation is regulated by NE, or possibly a molecule which regulates the action of NE, is intimately involved in LTP. This hypothesis will be tested by (1) comparing the electrophysiological effects of high frequency stimulation and NE and of Beta-adrenergic antagonists on LTP and NELLP, (2) comparing cAMP production and phosphorylation of specific protein fractions after repetitive stimulation or exposure to NE, in the presence and absence of Beta-antagonists, (3) determining the effect of inhibitors of mRNA synthesis or protein synthesis on production and maintenance of LTP, NELLP, and forskolin-induced LLP, and (4) determining the physiological effects and site of action of a monoclonal antibody that blocks LTP.
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