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.
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