Sosanya Natasha M, Cacheaux Luisa P, Workman Emily R, Niere Farr, Perrone-Bizzozero Nora I, Raab-Graham Kimberly F
From the Center for Learning and Memory, Department of Neuroscience, Institute for Cell Biology, and United States Army Institute of Surgical Research, Joint Base San Antonio-Fort Sam, Houston, Texas 78234, and.
From the Center for Learning and Memory, Department of Neuroscience.
J Biol Chem. 2015 Jun 26;290(26):16357-71. doi: 10.1074/jbc.M114.599399. Epub 2015 May 5.
The fate of a memory, whether stored or forgotten, is determined by the ability of an active or tagged synapse to undergo changes in synaptic efficacy requiring protein synthesis of plasticity-related proteins. A synapse can be tagged, but without the "capture" of plasticity-related proteins, it will not undergo long lasting forms of plasticity (synaptic tagging and capture hypothesis). What the "tag" is and how plasticity-related proteins are captured at tagged synapses are unknown. Ca(2+)/calmodulin-dependent protein kinase II α (CaMKIIα) is critical in learning and memory and is synthesized locally in neuronal dendrites. The mechanistic (mammalian) target of rapamycin (mTOR) is a protein kinase that increases CaMKIIα protein expression; however, the mechanism and site of dendritic expression are unknown. Herein, we show that mTOR activity mediates the branch-specific expression of CaMKIIα, favoring one secondary, daughter branch over the other in a single neuron. mTOR inhibition decreased the dendritic levels of CaMKIIα protein and mRNA by shortening its poly(A) tail. Overexpression of the RNA-stabilizing protein HuD increased CaMKIIα protein levels and preserved its selective expression in one daughter branch over the other when mTOR was inhibited. Unexpectedly, deleting the third RNA recognition motif of HuD, the domain that binds the poly(A) tail, eliminated the branch-specific expression of CaMKIIα when mTOR was active. These results provide a model for one molecular mechanism that may underlie the synaptic tagging and capture hypothesis where mTOR is the tag, preventing deadenylation of CaMKIIα mRNA, whereas HuD captures and promotes its expression in a branch-specific manner.
一段记忆的命运，无论被存储还是被遗忘，都取决于活跃或被标记的突触改变突触效能的能力，而这种改变需要合成与可塑性相关的蛋白质。一个突触可以被标记，但如果没有“捕获”与可塑性相关的蛋白质，它就不会经历长期的可塑性形式（突触标记和捕获假说）。“标记”是什么以及与可塑性相关的蛋白质如何在被标记的突触处被捕获尚不清楚。钙/钙调蛋白依赖性蛋白激酶IIα（CaMKIIα）在学习和记忆中起关键作用，且在神经元树突中局部合成。雷帕霉素的机制性（哺乳动物）靶点（mTOR）是一种蛋白激酶，可增加CaMKIIα蛋白的表达；然而，其树突表达的机制和位点尚不清楚。在此，我们表明mTOR活性介导CaMKIIα的分支特异性表达，在单个神经元中，一个二级子分支比另一个二级子分支更受青睐。mTOR抑制通过缩短其多聚腺苷酸尾降低了CaMKIIα蛋白和mRNA的树突水平。当mTOR被抑制时，RNA稳定蛋白HuD的过表达增加了CaMKIIα蛋白水平，并保留了其在一个子分支相对于另一个子分支的选择性表达。出乎意料的是，删除HuD的第三个RNA识别基序（即与多聚腺苷酸尾结合的结构域），在mTOR活跃时消除了CaMKIIα的分支特异性表达。这些结果提供了一个分子机制模型，该模型可能是突触标记和捕获假说的基础，其中mTOR是标记，可防止CaMKIIα mRNA的去腺苷酸化，而HuD以分支特异性方式捕获并促进其表达。
