This project concerns the mechanisms for regulating the strength of synaptic transmission. Various forms of synaptic plasticity will be studied, including facilitation, augmentation, post-tetanic potentiation, and long-term potentiation and depression. These processes are involved in synaptic information processing, shaping of motor responses and behaviors, and adaptations of neural circuits to previous experience, and are thought to be essential for higher cognitive functions such as associative learning. Experiments will focus on answering the following specific questions: 1) What is the Ca2+ dependence of short-term synaptic plasticity and spontaneous release of transmitter? Photochemical methods of controlling presynaptic intracellular calcium concentration ([Ca2+]i), and measuring {Ca2+]i with fluorescent dyes, will be used to determine the basic properties of the Ca2+ sensitivity of low levels of transmitter release, facilitation, and post-tetanic potentiation. 2) How do exogenous Ca2+ buffers affect facilitation and transmission? The injection of alien fluorescent Ca2+ buffers is a useful technique for probing the mechanisms underlying plasticity of synaptic transmission. 3) How can a rapidly equilibrating high affinity Ca2+ target induce accumulating facilitation without being fully saturated by each action potential? Theoretical simulation on a supercomputer of presynaptic Ca2+ movements and its binding to targets involved in synaptic transmission and facilitation will be used to resolve how Ca2+ can act at fast tightly binding molecular sites to trigger facilitation without always saturating those sites. Effects of a rise in presynaptic [Ca2+]i on facilitation and secretion will be simulated to test chemical models of these processes. 4) How does Na+/Ca2+ exchange regulate post-tetanic potentiation? Experiments will be done to distinguish mitochondrial from plasma membrane Na+/Ca2+ exchangers as targets of intracellular Na+ action in enhancing post-tetanic potentiation. 5) How do the magnitude and duration of a postsynaptic {Ca2+]i rise selectively activate long-term potentiation (LTP) and long-term depression (LTD) in the CA1 region of mammalian hippocampal cortex? The roles of cyclic adenosine monophosphate dependent protein kinase and Ca2+/calmodulin dependent protein kinase will be evaluated as determinants of the different sensitivities to [Ca2+]i in the induction of LTP and LTD. 6) How do targets of Ca2+ action differ for secretion of fast and slow transmitters? The Ca2+ sensitivity of fast cholinergic transmission will be compared to that of slow peptidergic transmission at synapses releasing both kinds of transmitter.
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