Dendritic spines are mushroom-shaped postsynaptic compartments that host intracellular signaling cascades important for synaptic plasticity and, thereby, learning and memory. Signaling events in spines involve a network composed of hundreds of proteins interacting with each other extensively. Synaptic plasticity is typically induced by Ca2+ elevation in spines, which activates a variety of signaling pathways. This leads to changes in the actin cytoskeleton and membrane dynamics, which in turn causes structural and functional changes of the spine. Recent studies have demonstrated that the activities of these proteins have a variety of spatiotemporal patterns, which orchestrate signaling activity in different subcellular compartments at different time scales. To better understand the operational principles of this network and the mechanisms underlying plasticity, we will develop tools to optically measure and manipulate signaling activity in neurons in both brain slices and in awake, behaving animals during plasticity. In particular, we aim to develop innovative technology to image and measure endogenous proteins by combining advanced imaging techniques, new optogenetic tools and genome-editing technology. Using these tools, we will determine time windows of signaling activity mediated by endogenous proteins, and elucidate how intracellular signaling mediates synaptic, circuit and behavioral plasticity. This will thus lead to a better understanding of how information is processed at different time scales and provide new insights into the molecular mechanisms underlying learning and memory.
Relevance to Public Health Many mental diseases, including Alzheimer?s disease and Huntington?s disease, are thought to be caused by failures in neuronal intracellular signaling related to learning and memory. This project will improve our understanding of the operational principles of intracellular signaling in neurons and thus is expected to provide new insights into the mechanisms underlying these mental diseases and new therapeutic strategies for them.
