Glutamate release and uptake at cerebellar synapses

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DESCRIPTION (provided by applicant): A basic tenet in neuroscience is that the synapse is the functional unit in the brain, and therefore in mentation. Each synapse acts relatively independently of its neighbors in that it primarily responds to its own released transmitter and either not at all or much less so to that of its neighbors. Exocytosis of synaptic vesicles is generally assumed to occur only at ultrastructurally defined presynaptic active zones. If this is true, receptors not located within the synaptic cleft must be activated by transmitter that diffuses out of the cleft, or not be activated at all. However, AMPA receptor-mediated quantal events resulting from climbing fiber release are recorded in Bergmann glial cells in the cerebellar cortex. These quantal events are not coincident with quanta recorded in neighboring Purkinje cells which receive input from the same climbing fiber and therefore it appears that exocytosis can occur from ectopic climbing fiber release sites located directly across from Bergmann glial membranes. If ectopic release is a general phenomenon, heterosynaptic and neural-glial interactions are more likely to result from this form of cross-talk rather than from the low concentrations of transmitter achieved by spillover from release within synaptic clefts. Using electrophysiological, optical, and pharmacological approaches, we will determine the characteristics of ectopic release including its calcium dependency, which types of voltage dependent calcium channels provide the necessary calcium influx, release probability, and the sensitivity of ectopic release to presynaptic receptor activation, all in comparison to release at conventional active zones. In addition, we will determine the advantages of high concentration transients of transmitter in the extrasynaptic space including differential calcium permeability of AMPA receptors and effects on motility of Bergmann glial processes.