One of the major forms of communication between neurons in the brain is that which occurs at chemical synapses. The control of synaptic communication is a crucial means by which the nervous system directs information flow in the brain. Understanding the detailed physiology of synaptic terminals in the central nervous system (CNS) will thus be critical to determining the nature of this control in both normal and diseased states of brain function. The long term objectives are to determine the mechanisms of control of synaptic transmission in the CNS. Traditional electrophysiological characterization gives a complex picture of a mixture of presynaptic and postsynaptic properties from an indeterminate number of synapses. Individual synaptic terminal properties remain poorly characterized. The optical tracer dye FM 1-43 labels synaptic vesicles specifically during membrane recycling; this allows one to cleanly separate presynaptic contributions to synaptic function and to obtain detailed information of presynaptic physiological parameters at the single synapse level.
Three specific aims are proposed: Characterize the control of synaptic vesicle exocytosis by extracellular Ca2+ in individual synaptic terminals during action potential stimulation and determine the role of specific Ca2+ channels in determining this control. Determine the maximal amount of exocytosis per action potential at individual synapses and how it is controlled. Examine the role of synaptotagmin-1 in the control of Ca2+-mediated exocytosis by measuring unitary presynaptic properties in neurons derived from synaptotagmin deficient mice. This work should lead to a much better understanding of the functioning of synaptic machinery, the major target of most therapies of CNS disorders such as epilepsy, depression, and schizophrenia.
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