The Roles of Protein Expression in Synaptic Stability and Memory Consolidation

人们普遍认为，记忆的形成是基于突触的变化--突触是细胞与细胞接触的地方，专门用于在神经细胞之间传递信号。突触是由蛋白质组成的，这是一种寿命有限的复杂分子，因此，为了让突触持续存在并保持其独特的特征，这些特征被认为有助于稳定的记忆；它们需要不断地、准确地补充新合成的蛋白质副本。在突触功能的持续变化方面，对新合成蛋白质的需求更加明显：现在公认的是，如果蛋白质合成在明确定义的时间窗口内失控，那么实验诱导的突触功能变化(长时程增强/抑制或LTP/LTD)到相对持久的变化的转换就会取消。尽管这些形式的突触可塑性和记忆形成之间的关系还远不清楚，但在类似的时间窗口内，记忆巩固过程对蛋白质合成抑制的敏感性是诱人的。在这里，一组德国和以色列的专家在大脑突触的分子组织(Gundelinger)、突触可塑性和学习和记忆的分子机制(Rosenblum)、突触蛋白动力学(ZIV)的成像(ZIV)、突触可塑性和突触核信号(Kreutz)以及新合成的突触蛋白的体内检测(Dieterich)建议联合起来研究突触如何在较长的时间内保持其特征，必要时改变这些特征，然后稳定它们，重点强调蛋白质合成和降解在这些过程中的作用。为了回答这些基本问题，我们将开发新的工具来解决结构性和可塑性相关的蛋白质合成的时空动力学，研究突触到核的通讯，以及研究新合成的蛋白质向突触的运输。最重要的是，我们将试图确定这些发现与学习、巩固和提取的行为测量相比，在基线条件下，以及在突触水平上考察的相同过程的实验扰动下，如何进行比较。我们认为，这一实验计划将对局部和全球蛋白质合成、运输和降解在记忆形成和保持等新现象中所起的作用提供更好和更现实的理解。

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.