The long-range goal of the proposed research is to gain a detailed understanding of the cellular and molecular mechanisms underlying long- term potentiation (LTP) of synaptic transmission. Changes in the efficiency of transmission at synapses, such at LTP, are thought to be an important mechanism by which the function of the brain is modulated and by which memories might be stored. One of the most important and controversial issues surrounding LTP is whether its expression involves the presynaptic terminal. The proposed experiments provide critical specific and direct tests of the role of the presynaptic neuron in LTP, with an emphasis on determining the biochemical mechanisms involved. Some of the experiments are geared towards testing the role of the diffusible messenger nitric oxide (NO), which may act as a "retrograde messenger" from the postsynaptic neuron to the presynaptic neuron in LTP. LTP will be studied using electrophysiological recordings from pairs of synaptically coupled rat hippocampal neurons in organotypic culture. Pharmacological agents will be injected into presynaptic neurons so as to test their effects on LTP. The specific targets of the experiments include, but are not limited to, signal transduction pathways which might be activated by NO in presynaptic terminals.