The proposed studies will answer key questions about molecular and cellular mechanisms that regulate synaptic transmission in brain. The applicant will study the role of postsynaptic Ca2+, protein kinases and protein phosphatases in controlling synaptic transmission. To elucidate postsynaptic mechanisms that regulate synaptic transmission, the applicant will examine intracellular signaling mechanisms downstream of presynaptic transmitter release and postsynaptic receptor activation. He will use specific manipulations of postsynaptic signaling pathways to test the hypothesis that synaptic potentiation requires intracellular Ca2+ release, functional cross-talk among protein kinase and phosphatase pathways and the dynamic balance of spatial and temporal properties of postsynaptic mechanisms controlling synaptic strength by combining (a) visually guided patch-pipette recordings from neuronal cell bodies vs. Dendrites using infrared differential interference contrast microscopy (IR-DIC), and (b) whole-cell pipette-perfusion to control the temporal delivery of modulators of postsynaptic protein kinases and phosphatases and intracellular Ca2+ release. Using whole-cell recordings from dendrites, the applicant will determine if synaptic potentiation can be induced by perfusion of Ca2+/CaM, phosphatase inhibitors, or activators of intracellular Ca2+ release. The experiments will test the hypothesis that dendritic Ca2+ and Ca2+/CaM pathways are responsible for potentiation at central synapses. The applicant will continue examining postsynaptic mechanisms that modulate PPF, and will study mechanisms that modulate PPF at single synapses. Finally, he will analyze developmental changes in the biochemistry of postsynaptic signaling pathways that regulate synaptic potentiation. Experiments will focus on developmental changes in calcineurin properties and its role in postsynaptic mechanisms controlling synaptic plasticity.
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