Over the last 15 years, several laboratories, including my laboratory, have identified multiple signaling pathways that regulate translation via the translation initiation factors eIF4E and eIF2? during protein synthesis-dependent forms of long-lasting synaptic plasticity and various memory processes in rodents, including the consolidation, reconsolidation, and extinction of auditory threat memory. These findings have generated much excitement because they demonstrate the complex biochemical regulation of translation during synaptic plasticity and memory. Despite this progress, a number of critical and unresolved questions regarding the requirement for de novo protein synthesis in memory consolidation remain unanswered. We plan to focus on auditory threat memory in the amygdala and address three new questions that are critical for a more complete understanding of the role of de novo protein synthesis in memory formation. First, which cell types in the lateral amygdala (LA) and centrolateral (CeL) amygdala require eIF4E-dependent translation for auditory threat memory? Second, which cell types in the LA and CeL require eIF2?-dependent translation for the consolidation and reconsolidation of auditory threat memory? Third, does auditory threat learning induce cell type-specific translation profiles in the LA and CeL? These questions will be addressed by utilizing the powerful multidisciplinary combination of new groundbreaking genetically-engineered mice, electrophysiological recordings, immunocytochemistry, innovative methods to measure de novo protein synthesis in vivo, and cell-type translational profiling. The results of these studies will provide fundamental insights into the molecular events in both excitatory and inhibitory neurons that support consolidation and reconsolidation of auditory threat memory. Moreover, these studies have the potential to provide cell type-specific therapeutic targets for multiple brain disorders that are associated with dysregulated translation.
Previous studies have identified the signaling pathways that couple receptors to the translation machinery to regulate protein synthesis during long-lasting synaptic plasticity and long-term memory formation, and several of these translational control pathways are dysregulated in brain disorders including Alzheimer's disease, fragile X syndrome, and autism spectrum disorder. Herein we propose studies using new mouse lines that we have developed to determine the specific cell types in the amygdala that require de novo protein synthesis for the consolidation of threat memory and to identify the mRNAs that are translationally regulated in these cells. Our studies should provide insight into the cell type-specific role of de novo protein synthesis in threat memory consolidation and have the potential to identify new therapeutic targets for disorders associated with dysregulated protein synthesis.
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