Arc and the molecular control of LTP consolidation in vivo

The brain extracts information about the world that shapes our behavior and ultimately influences who we are as individuals. The immense capacity and specificity of memory storage in the mammalian central nervous system is thought to depend on the plastic ity of synaptic connections. Recent breakthroughs have identified the immediate early gene, Arc, as a key regulator of protein synthesis-dependent synaptic plasticity, memory, and brain adaptation. Uniquely, Arc mRNA is transported to dendrites for local translation at synapses, and this local Arc synthesis is necessary for long-term synaptic change. Therefore, one of the most important goals in the field is to elucidate the cell biological mechanisms by which the Arc protein regulates synaptic connectivi ty. We will rigorously address this issue in a focused project consisting of three interlocking Aims. Aim 1 is to elucidate how synthesis of Arc during long-term potentiation (LTP) regulates actin cytoskeletal dynamics in dendritic spines. Aim 2 is to un derstand how the actin cytoskeleton regulates the translational machinery. Aim 3 is to determine the role of endogenous BDNF signaling in controlling actin dynamics and translation. Arc interacting proteins mediating these effects will be identified. This interdisciplinary project combines electrophysiological studies in live animals with genetic manipulations, cell signaling, imaging, and state-of-the-art proteomics. The project involves extensive collaboration and training of staff nationally and abroad . The results will be of fundamental importance for understanding how Arc regulates information storage in the brain as well perturbations of these mechanisms in Alzheimer's disease and Angelman mental retardation syndrome.