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.
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.
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