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.
|Huynh, T N; Santini, E; Mojica, E et al. (2018) Activation of a novel p70 S6 kinase 1-dependent intracellular cascade in the basolateral nucleus of the amygdala is required for the acquisition of extinction memory. Mol Psychiatry 23:1394-1401|
|Santini, Emanuela; Huynh, Thu N; Longo, Francesco et al. (2017) Reducing eIF4E-eIF4G interactions restores the balance between protein synthesis and actin dynamics in fragile X syndrome model mice. Sci Signal 10:|
|Ostroff, Linnaea E; Botsford, Benjamin; Gindina, Sofya et al. (2017) Accumulation of Polyribosomes in Dendritic Spine Heads, But Not Bases and Necks, during Memory Consolidation Depends on Cap-Dependent Translation Initiation. J Neurosci 37:1862-1872|
|Oaks, Adam W; Zamarbide, Marta; Tambunan, Dimira E et al. (2017) Cc2d1a Loss of Function Disrupts Functional and Morphological Development in Forebrain Neurons Leading to Cognitive and Social Deficits. Cereb Cortex 27:1670-1685|
|Bhattacharya, Aditi; Mamcarz, Maggie; Mullins, Caitlin et al. (2016) Targeting Translation Control with p70 S6 Kinase 1 Inhibitors to Reverse Phenotypes in Fragile X Syndrome Mice. Neuropsychopharmacology 41:1991-2000|
|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|
|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; 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|
|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|
|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|
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