Several laboratories, including my laboratory, have shown that the mTORC1 signaling pathway regulates cap-dependent translation during protein synthesis-dependent forms of long-lasting synaptic plasticity and long-term memory in rodents. These findings have generated much excitement because they were the first demonstration of the complex biochemical regulation of translation during synaptic plasticity and memory. We plan to address three critical questions to gain a more complete understanding of the translational control mechanisms operating during synaptic plasticity and memory. First, what are the precise mTORC1-dependent translational control mechanisms that are required for fear memory reconsolidation? Second, what are the precise mTORC1-dependent translational control mechanisms that are required for fear extinction learning and memory? Third, what proteins are synthesized during protein synthesis-dependent synaptic plasticity and which mTORC1 effectors are required for their synthesis? Are these plasticity-induced proteins also upregulated during memory formation? These questions will be addressed by utilizing the powerful multidisciplinary combination of electrophysiological recordings, Western blot analyses, immunocytochemistry, innovative methods to measure new protein synthesis and identify newly synthesized proteins, and novel genetically-modified mice to study synaptic plasticity, as well as behavioral studies to examine the role of mTORC1-dependent translation in memory function. The results of our experiments will provide important information concerning the signaling mechanisms that underlie synaptic plasticity and multiple forms of memory. Finally, these studies will generate critical information about the molecular basis of altered synaptic plasticity and behavior in brain disorders associated with dysregulated mTORC1-dependent translation.

Public Health Relevance

signaling pathway, one the major signaling pathways that regulates protein synthesis during long-lasting synaptic plasticity and long-term memory, is dysregulated in multiple brain disorders, including Alzheimer's disease and several autism spectrum disorders. We have proposed experiments to determine the specific mechanisms downstream of mTORC1 that regulate protein synthesis during multiple forms of plasticity and memory, and to identify newly synthesized proteins during these processes. Thus, our studies have the potential to provide insight into the role of mTORC1-dependent protein synthesis in synaptic plasticity and memory, and to identify new therapeutic targets for the treatment of brain disorders associated with dysregulated mTORC1 signaling.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS047384-08A1
Application #
8505834
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Mamounas, Laura
Project Start
2003-11-01
Project End
2018-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
8
Fiscal Year
2013
Total Cost
$336,875
Indirect Cost
$118,125
Name
New York University
Department
Neurology
Type
Schools of Arts and Sciences
DUNS #
041968306
City
New York
State
NY
Country
United States
Zip Code
10012
Sethna, Ferzin; Zhang, Ming; Kaphzan, Hanoch et al. (2016) Calmodulin activity regulates group I metabotropic glutamate receptor-mediated signal transduction and synaptic depression. J Neurosci Res 94:401-8
Bowling, Heather; Bhattacharya, Aditi; Zhang, Guoan et al. (2016) BONLAC: A combinatorial proteomic technique to measure stimulus-induced translational profiles in brain slices. Neuropharmacology 100:76-89
Bowling, Heather; Bhattacharya, Aditi; Klann, Eric et al. (2016) Deconstructing brain-derived neurotrophic factor actions in adult brain circuits to bridge an existing informational gap in neuro-cell biology. Neural Regen Res 11:363-7
Huber, Kimberly M; Klann, Eric; Costa-Mattioli, Mauro et al. (2015) Dysregulation of Mammalian Target of Rapamycin Signaling in Mouse Models of Autism. J Neurosci 35:13836-42
Gross, Christina; Chang, Chia-Wei; Kelly, Seth M et al. (2015) Increased expression of the PI3K enhancer PIKE mediates deficits in synaptic plasticity and behavior in fragile X syndrome. Cell Rep 11:727-36
Huynh, Thu N; Shah, Manan; Koo, So Yeon et al. (2015) eIF4E/Fmr1 double mutant mice display cognitive impairment in addition to ASD-like behaviors. Neurobiol Dis 83:67-74
Richter, Joel D; Bassell, Gary J; Klann, Eric (2015) Dysregulation and restoration of translational homeostasis in fragile X syndrome. Nat Rev Neurosci 16:595-605
Kumari, Daman; Bhattacharya, Aditi; Nadel, Jeffrey et al. (2014) Identification of fragile X syndrome specific molecular markers in human fibroblasts: a useful model to test the efficacy of therapeutic drugs. Hum Mutat 35:1485-94
Varga, Andrew W; Kang, Mihwa; Ramesh, Priyanka V et al. (2014) Effects of acute sleep deprivation on motor and reversal learning in mice. Neurobiol Learn Mem 114:217-22
Bowling, Heather; Klann, Eric (2014) Shaping dendritic spines in autism spectrum disorder: mTORC1-dependent macroautophagy. Neuron 83:994-6

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