In this proposal, I investigate how the integrative properties of Ca release pathways - the inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) and the ryanodine receptors (RyRs) - regulate postsynaptic Ca signaling and synaptic function in cerebellar Purkinje neurons. My hypothesis is that during parallel fiber (PF) synaptic transmission, nitric oxide (NO) released from PFs enhances postsynaptic Ca release from stores and that coincidence detection of IP3, Ca, and NO by IP3Rs and RyRs is a key mechanism underlying associativity in the induction of LTD. To test this hypothesis, I propose to address the following specific questions: 1) The role of NO in PF-stimulated Ca signals in Purkinje cells. 2) Regulation of Ca signaling pathways in Purkinje cells by NO. 3) The role of the Ca release pathways in mediating the effects of NO on the induction of LTD. These studies should give insight into the mechanisms through which NO regulates synaptic plasticity and more generally, into how interactions among signaling pathways regulates neuronal function.
