Mechanisms of Ras Signaling in Single Synapses

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DESCRIPTION (provided by applicant): The small GTPase protein Ras is important for many neuronal processes essential to synaptic plasticity including long-term synaptic potentiation, formation of new synapses, and regulation of cell excitability. Ras is also important for protein synthesis and gene transcription required for long-term maintenance of synaptic plasticity. Consistent with essential roles of Ras signaling in synaptic plasticity, abnormal Ras signaling is associated with diseases causing cognitive impairments and learning deficits. Although the importance of Ras signaling in synaptic plasticity is well recognized, it is not clear how the spatiotemporal dynamics of Ras signaling regulate its diverse downstream effects in different subcellular compartments. Using 2-photon fluorescence lifetime imaging and 2-photon glutamate uncaging, the objective of this project is to elucidate mechanisms and roles of Ras activation in neurons during synaptic plasticity induced in a single dendritic spine. Our specific aims are 1) to elucidate the roles of Neurofibromin in shaping the spatiotemporal profile of Ras activation in single spines, 2) to determine the activation kinetics of kinases that controls Ras activation during spine structural plasticity, and 3) to elucidate the mechanisms of synapse to nucleus Ras-ERK signaling. This work will advance our understanding of how Ras couples calcium with synaptic plasticity, and ultimately with learning and memory.