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 i s 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045324-07
Application #
7090671
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (01))
Program Officer
Riddle, Robert D
Project Start
1999-09-30
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
7
Fiscal Year
2006
Total Cost
$274,817
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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