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.
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.
|Huang, Wei; Zhu, Ping Jun; Zhang, Shixing et al. (2013) mTORC2 controls actin polymerization required for consolidation of long-term memory. Nat Neurosci 16:441-8|
|Costa-Mattioli, Mauro; Monteggia, Lisa M (2013) mTOR complexes in neurodevelopmental and neuropsychiatric disorders. Nat Neurosci 16:1537-43|