The Roles of Protein Expression in Synaptic Stability and Memory Consolidation

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It is widely believed that memory formation is based on changes in synapses - sites of cell-cell contactspecialized for transmitting signals between nerve cells. Synapses are composed of proteins, complexmolecules with finite lifetimes, and therefore, for synapses to persist and maintain their individualcharacteristics that are assumed to subserve stable memories; they need to be continuously and precisely replenished with freshly synthesized protein copies. Where it comes to persistent changes in synaptic function, the need for freshly synthesized proteins is even more pronounced: It is now well established that the conversion of experimentally induced changes in synaptic function (long term potentiation / depression or LTP/LTD) into relatively persistent ones is abolished if protein synthesis is disregulated within well defined temporal windows. Although relationships between these forms of synaptic plasticity and memory formation are far from clear, the sensitivity of memory consolidation processes to protein synthesis inhibition within similar temporal windows is enticing. Here a group of German and Israeli experts on the molecular organization of brain synapses (Gundelfinger),molecular mechanisms of synaptic plasticity and learning and memory (Rosenblum), imaging of synaptic protein dynamics (Ziv), synaptic plasticity and synapto-nuclear signaling (Kreutz) and in vivo detection of newly synthesized synaptic proteins (Dieterich) propose to join forces to examine how synapses maintain their characteristics for long durations, change these when necessary and then stabilize them, with an emphasis on the roles of protein synthesis and degradation in these processes. In order to answer these fundamental questions we will develop new tools for resolving the spatiotemporal dynamics of constitutive and plasticity-related protein synthesis, for studying synapse to nucleus communication, and for studying the trafficking of newly synthesized proteins to synapses. Most importantly, we will attempt to determine how these findings compare with behavioral measures of learning, consolidation and retrieval, under baseline conditions and following experimental perturbations of the very same processes examined at the synaptic level. We feel that this experimental program will provide a much better and more realistic understanding of the roles played by local and global protein synthesis, trafficking and degradation in emergent phenomena such as memory formation and retention.