One of the most intriguing functions the brain performs is the transformation of experience into memory. Since information is conveyed through synaptic connections, the ability of neurons to stably modify synapses is considered a likely mechanism for the coding of memories in the brain. A shared requirement for both long-lasting synaptic changes and memory formation is the production of new proteins. Therefore, an examination of experience-induced protein synthesis in neurons should reveal the molecular foundation of memory formation. One potential source for newly generated proteins is via the translational activation of dormant mRNA in the neuronal cell cytoplasm. Indeed, recent evidence supports a role for dendritic protein synthesis in long-lasting synaptic plasticity. Our lab was part of a group that recently provided strong evidence that the activation of translationally dormant mRNAs by cytoplasmic polyadenylation is an important mechanism for experience-driven local protein synthesis. This polyadenylation is mediated by an mRNA specific cis-element in the 3'-untranslated region (3'- UTR) called the cytoplasmic polyadenylation element (CPE). The CPE binding protein (CPEB) is localized to synapses in the brain and is a component of the postsynaptic density fraction isolated from rat hippocampus, cerebral cortex and cerebellum. The current proposal is designed to determine the mechanisms by which CPE-mediated protein synthesis contributes to synaptic plasticity. Specifically, we will focus on synaptic plasticity occurring in the cerebellum; a region of the brain with well characterized neural circuitry and defined synaptic plasticity. We will answer 5 questions: 1) Where and when is CPEB expressed, 2) What are the cadre of proteins that can be translated in a CPE-dependent fashion, 3) Can the translation of CPE-containing mRNAs occur in dendrites, 4) How is CPE-mediated translation regulated, and 5) Does synaptic plasticity depend on CPE-mediated protein synthesis? Purkinje neurons in the cerebellum undergo experience-dependent synaptic plasticity that is well correlated with relatively simple forms of learning and memory and is thus particularly well suited for the cellular and molecular dissection of protein synthesis-dependent synaptic plasticity.
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| Jones, Kendrick J; Korb, Erica; Kundel, Mitchell A et al. (2008) CPEB1 regulates beta-catenin mRNA translation and cell migration in astrocytes. Glia 56:1401-13 |
| McEvoy, Michael; Cao, Guan; Montero Llopis, Paula et al. (2007) Cytoplasmic polyadenylation element binding protein 1-mediated mRNA translation in Purkinje neurons is required for cerebellar long-term depression and motor coordination. J Neurosci 27:6400-11 |
| Wells, David G (2006) RNA-binding proteins: a lesson in repression. J Neurosci 26:7135-8 |
