Cell type-specific drug-inducible protein synthesis inhibition demonstrates that memory consolidation requires rapid neuronal translation

New protein synthesis is known to be required for the consolidation of memories, yet existing methods to block translation lack spatiotemporal precision and cell-type specificity, preventing investigation of cell-specific contributions of protein synthesis. Here, we developed a combined knock-in mouse and chemogenetic approach for cell type-specific and drug-inducible protein synthesis inhibition (ciPSI) that enables rapid and reversible phosphorylation of eIF2α, leading to inhibition of general translation by 50% in vivo. We use ciPSI to show that targeted protein synthesis inhibition pan-neuronally and in excitatory neurons in lateral amygdala (LA) impaired long-term memory. This could be recovered with artificial chemogenetic activation of LA neurons, though at the cost of stimulus generalization. Conversely, genetically reducing phosphorylation of eIF2α in excitatory neurons in LA enhanced memory strength, but reduced memory fidelity and behavioral flexibility. Our findings provide evidence for a cell-specific translation program during consolidation of threat memories.