Impaired memory is a major feature of many psychiatric disorders. Long-term potentiation (LTP) in the hippocampus, a long-lasting increase in the strength of synaptic transmission produced by brief, repetitive activation of excitatory pathways, has provided the most compelling model in the mammalian brain for a neural mechanism related to learning and memory. It has been proposed that the induction of LTP in the CAl region of the hippocampus requires activation of postsynaptic N-methyl-D-aspartate (NMDA) receptors and concomitant postsynaptic membrane depolarization leading to the influx of calcium, the presumed critical trigger for LTP. Using intra- and extracellular electrophysiological recording techniques, the proposed experiments will test this hypothesis and further elucidate the extra- and intracellular factors involved in the induction and maintenance of LTP in the dentate gyrus and CA1 region of the rat hippocampal slice preparation. Preliminary evidence indicates that application of depolarizing doses of NMDA or glutamate causes only a decremental, short-lived enhancement of synaptic transmission suggesting that additional factors are. required to induce LTP. Following the further characterization of agonist-induced potentiation. a series of experiments involving the application of a variety of receptor agonists and antagonists will attempt to identify the extracellular, diffusable factor(s), in addition to synaptically released glutamate, required for the induction and maintenance of LTP. Intracellular biochemical pathways potentially involved in LTP and agonist-induced potentiation will be examined by; (1) determining the effects on LTP and agonist-induced potentiation of a variety of protein kinase antagonists, calmodulin inhibitors, inhibitors of arachidonic acid breakdown and inhibitors of GTP-binding proteins and (2) monitoring the effects on synaptic transmission of simultaneous application of NMDA with activators of either protein kinase C or cAMP-dependent protein kinase. The involvement of de novo protein synthesis or RNA synthesis in LTP and agonist-induced potentiation also will be determined by examining the effects of protein synthesis inhibitors and RNA synthesis inhibitors. Two final experiments will examine whether a postsynaptic modification of glutamate receptors underlies the expression of LTP or agonist-induced potentiation. First, the postsynaptic responsiveness to specific glutamate agonists will be compared before and after the induction of LTP or agonist-induced potentiation. Second, whether the NMDA component of the stimulus evoked EPSP is increased following LTP or agonist-induced potentiaton will be determined. It is hoped that a detailed understanding of LTP may yield important insights into the cellular and molecular properties underlying synaptic plasticity and thus human memory. This in turn may eventually lead to pharmacological interventions which either promote the ability to learn and remember or retard the deterioration of this ability.
