Localized mRNAs in Synaptic Plasticity

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DESCRIPTION (provided by applicant): The long-term goals of this project are to understand the mechanisms whereby long-lasting, transcription-dependent neuronal plasticity can be regulated in a synapse-specific manner. A number of studies have indicated that localization and regulated translation of mRNAs at synapses serves as an important mechanism of gene expression in neurons during learning-related synaptic plasticity. We will use two model systems of learning-related plasticity, cultured Aplysia sensory-motor synapses and cultured mouse hippocampal neurons, to identify the population of mRNAs that are localized to synapses, and to investigate the mechanisms underlying the localization and regulated translation of these mRNAs. The specific aims are as follows: 1) Identify synaptically localized mRNAs. This aim is directed toward identifying, in an unbiased manner, the population of mRNAs present in Aplysia sensory neurites and in mouse hippocampal dendrites, by cDNA library construction and microarray analysis. 2) Characterize the effect of synaptic stimulation on mRNA localization. These experiments will examine the effect of synaptic stimulation on mRNA localization in cultured Aplysia neurons, in cultured mouse hippocampal neurons, and in adult mouse hippocampus. 3) Characterize the effect of synapse formation on mRNA localization. The aim of these experiments is to study how synapse formation alters mRNA localization in cultured Aplysia neurons. 4) Investigate the translational regulation of synaptically localized mRNAs and the function of local protein synthesis during plasticity. The aim of these experiments is to determine how synaptic stimulation regulates translation of localized mRNAs and to use gene specific silencing (RNA interference) to examine the function of local translation in synaptic plasticity. These studies should elucidate mechanisms underlying activity-dependent regulation of gene expression in neurons. In addition, they should elucidate the function of local translation during synaptic plasticity. From a larger perspective, they are likely to advance our understanding of the many physiological and pathological phenomena in the brain involving neuronal plasticity, including learning and memory and diseases in which learning and memory is altered.