Little is known about the molecular and cellular mechanisms underlying actin dynamic-mediated changes in synaptic strength and memory formation. Here we propose to test the hypothesis that the regulatory mammalian target of rapamycin complex 2 (mTORC2) is the link between synaptic activity and actin cytoskeleton restructuring involved in synaptic plasticity and memory formation. Since mTORC2 was only recently discovered, relatively little is known about its function, including how it is regulated ad the nature of its downstream targets in the brain. This proposal combines biochemical, transgenic, pharmacological, electrophysiological, imaging, and behavioral approaches to explore several crucial aspects of mTORC2 function in the brain including: a) its role in synaptic plasticity and memory, b) the up-stream synaptic events which activate mTORC2, and c) the downstream molecular mechanisms by which mTORC2 regulates long- term synaptic plasticity and long-term memory. This study will provide insight into the basic molecular and cellular mechanisms underlying learning and memory, possibly leading to new treatments for conditions associated with memory dysfunction such as aging, developmental and neurodegenerative disorders, all conditions in which mTORC2 activity is altered.

Public Health Relevance

The formation of long-term memories requires structural changes at brain synapses that are dependent on actin polymerization. The key signaling pathways that regulate these being unknown, we propose a multidisciplinary approach to test a new idea: that the recently discovered mTOR complex 2 directs structural aspects of memory by controlling actin cytoskeleton dynamics. This study, will significantly advance our understanding of fundamental brain processes, and may identify new targets for the treatment of several major cognitive disorders such as age-related memory loss, and various neurodevelopmental and neurodegenerative disorders where mTORC2 activity is altered.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH096816-02
Application #
8443811
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Asanuma, Chiiko
Project Start
2012-04-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$375,600
Indirect Cost
$135,600
Name
Baylor College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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