The mouse mutant coloboma has recently been identified as a unique animal model of spontaneous hyperactivity. While the coloboma mutation has been defined as a deletion mutation encompassing several genes on chromosome two, the hyperactivity of these mice has been shown to result directly from the depletion of SNAP-25. This protein is associated with the plasma membrane of presynaptic terminals and plays a critical role in neurotransmitter release. In coloboma, mice, it is therefore reasonable to conclude that decreased levels of SNAP-25 gives rise to abnormalities in presynaptic function that ultimately leads to their hyperactivity. Central to understanding the role of SNAP-25 in coloboma hyperactivity is defining, on the single-cell level, the changes in neurotransmitter release that result from decreased levels of this protein. The overall goal of this proposal is to use electrochemical methods to define how decreased levels of SNAP-25 can alter the release and storage of neurotransmitters at the single-cell level. Ultimately, these experiments should allow us to better understand how the cellular changes that result from decreased levels of a single protein, SNAP-25, lead to the hyperactivity of coloboma mice.
