Synaptic plasticity, changes in the strength of connections between neurons with experience, provides a mechanism for information storage in the brain. Long-lasting forms of plasticity have been shown to require RNA and protein synthesis, indicating that signals can be transported from the synapse, where they are generated, to the nucleus, where they are converted into changes in gene expression. The extreme polarity of neurons and the significant distances that can exist between distal synapses and cell soma present a unique set of challenges to nucleocytoplasmic trafficking.
The aim of this proposal is to delineate the role of the active nuclear import pathway in transporting signals from synapse to nucleus during long-lasting forms of learning-related synaptic plasticity. In this pathway, proteins bearing nuclear localization signals (NLSs) are recognized by a nuclear transport adaptor, called importin alpha, which then binds a nuclear transporter called importin betal. Importin betal docks the heterotrimeric complex at the nuclear pore and mediates its translocation into the nucleus. We plan to study importin-mediated nuclear transport, using both dissociated mouse hippocampal cultures and acute hippocampal slices to study various aspects of synaptic plasticity. In our first aim, we will determine whether importins are localized to the synapse and subsequently translocate following stimuli that lead to transcription-dependent plasticity. In the second aim, we propose to identify synaptically localized proteins that are transported to the nucleus following synaptic stimulation. In the final aim, we will determine how the importin-cargo complex is assembled at the synapse and what cell biological pathways are involved in the translocation of this complex to the nucleus. Relevance to public health: Understanding the mechanisms whereby synaptically generated signals trigger changes in gene expression in the nucleus during memory formation provides a means of identifying therapeutic targets for a variety of disorders including mental retardation, age-related memory loss, Alzheimer's disease, epilepsy, drug addiction as well as many neuropsychiatric diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH077022-04
Application #
7802314
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Asanuma, Chiiko
Project Start
2007-07-05
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$327,250
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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Ch'ng, Toh Hean; DeSalvo, Martina; Lin, Peter et al. (2015) Cell biological mechanisms of activity-dependent synapse to nucleus translocation of CRTC1 in neurons. Front Mol Neurosci 8:48
Ch'ng, Toh Hean; Uzgil, Besim; Lin, Peter et al. (2012) Activity-dependent transport of the transcriptional coactivator CRTC1 from synapse to nucleus. Cell 150:207-21
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Jeffrey, Rachel A; Ch'ng, Toh Hean; O'Dell, Thomas J et al. (2009) Activity-dependent anchoring of importin alpha at the synapse involves regulated binding to the cytoplasmic tail of the NR1-1a subunit of the NMDA receptor. J Neurosci 29:15613-20

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