Polyadenylation in dendritic targeting of mRNA

神经科学的一个主要问题是理解短暂的神经活动如何转化为突触效能的稳定变化。持久突触修饰的产生需要新的蛋白质合成。这些新合成的多肽的一个来源是定位于突触的mrna的翻译。我们实验室最近的工作提供了强有力的证据，证明通过细胞质聚腺苷酸化激活翻译休眠mrna是经验驱动的局部合成的重要机制。这种聚腺苷化是由一种名为CPEB（胞质聚腺苷化元件结合蛋白）的序列特异性RNA结合蛋白介导的，CPEB定位于突触，是突触后密度部分的一个组成部分。在这个子项目中，我们将使用一种综合的方法来确定CPEB蛋白和mRNA在发育中的成人大脑和培养的海马神经元中的定位和表达。我们将测试CPE（细胞质聚腺苷化元件）和CPEB在树突靶向α - camkii mRNA中的作用。我们将使用CPEB在CA1区靶向突变的小鼠（在Core B中产生）来研究CPEB的功能。这些研究的结果将为健康大脑形成长期突触修饰的方式提供重要的见解。这些基本机制的知识构成了发展诊断和治疗方法的基础，以治疗脑部疾病。

A major problem in neuroscience is understanding how ephemeral episodes of neural activity are transformed into stable changes in synaptic efficacy. The creation of long-lasting synaptic modifications requires new protein synthesis. One source of these newly synthesized polypeptides is the translation of mRNAs that are localized to synapses. Recent work from our laboratories has provided strong evidence that the activation of translationally dormant mRNAs by cytoplasmic polyadenylation is an important mechanism for experience-driven local synthesis. T his polyadenylation is mediated by a sequence-specific RNA binding protein called CPEB (cytoplasmic polyadenylation element binding protein) that is localized at synapses and is a component of postsynaptic density fractions. In this sub-project we will use an integrated approach to determine CPEB protein and mRNA localization and expression in the developing adult brain, and in cultured hippocampal neurons. We will test the role of the CPE (cytoplasmic polyadenylation element) and CPEB in the dendritic targeting of alpha-CaMKII mRNA. We will study the function of CPEB using mice (produced in Core B) with targeted mutations of CPEB in area CA1. The results of these studies will provide vital insights into the means by which long-term synaptic modifications are formed by the healthy brain. Knowledge of these fundamental mechanisms forms the basis for developing diagnostic and therapeutic approaches to the treatment of brain disorders.