TY - JOUR T1 - Chemogenetic evidence that rapid neuronal <em>de novo</em> protein synthesis is required for consolidation of long-term memory JF - bioRxiv DO - 10.1101/704965 SP - 704965 AU - Prerana Shrestha AU - Pinar Ayata AU - Pedro Herrero-Vidal AU - Francesco Longo AU - Alexandra Gastone AU - Joseph E. Ledoux AU - Nathaniel Heintz AU - Eric Klann Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/07/17/704965.abstract N2 - Translational control of memory processes is a tightly regulated process where the coordinated interaction and modulation of translation factors provides a permissive environment for protein synthesis during memory formation. Existing methods used to block translation lack the spatiotemporal precision to investigate cell-specific contributions to consolidation of long-term memories. Here, we have developed a novel chemogenetic mouse resource for cell type-specific and drug-inducible protein synthesis inhibition (ciPSI) that utilizes an engineered version of the catalytic kinase domain of dsRNA-activated protein (PKR). ciPSI allows rapid and reversible phosphorylation of eIF2α causing a block on general translation by 50% in vivo. Using this resource, we discovered that temporally structured pan-neuronal protein synthesis is required for consolidation of long-term auditory threat memory. Targeted protein synthesis inhibition in CamK2α expressing glutamatergic neurons in lateral amygdala (LA) impaired long-term memory, which was recovered with artificial chemogenetic reactivation at the cost of stimulus generalization. Conversely, genetically reducing phosphorylation of eIF2α in CamK2α positive neurons in LA enhanced memory strength, but was accompanied with reduced memory fidelity and behavior inflexibility. Our findings provide evidence for a finely tuned translation program during consolidation of long-term threat memories. ER -