The aim of the proposed project is to provide a detailed understanding of the processes that determine the dynamics of the synaptic release of zinc ions at mossy fiber synapses in the hippocampal formation of the mature rodent brain. A subsidiary issue that will be examined, is the relationship between amyloid peptides, implicated in the pathogenesis of Alzheimer's diseases, and Zn2+ storage and release. Fluorescent imaging experiments will be performed on mature rodent hippocampal slices (rat, mouse & guinea pig) using recently synthesized Zn2+ sensitive probes, to image Zn2+ in synaptic terminals and in the extracellular space. Concurrent imaging and whole-cell voltage-clamp experiments will be performed to estimate the rate of passage of Zn2+ across the plasma membrane. Immunochemical techniques will be used to estimate the release of APP and ABeta. The long term objective of the project is to understand the factors that contribute to Zn2+ release at synapses and the mechanisms for restoring extracellular and intracellular levels of Zn2+. Malfunctions in Zn2+ regulation have been implicated in a number of diseases, most notably Alzheimer's disease and epilepsy. A detailed understanding of the factors involved in Zn2+ release and uptake should allow the development of specific pharamacological interventions to ameliorate such nervous disorders.
| Kay, Alan R (2003) Evidence for chelatable zinc in the extracellular space of the hippocampus, but little evidence for synaptic release of Zn. J Neurosci 23:6847-55 |
| Snitsarev, V; Budde, T; Stricker, T P et al. (2001) Fluorescent detection of Zn(2+)-rich vesicles with Zinquin: mechanism of action in lipid environments. Biophys J 80:1538-46 |
