Neurons repurpose the integrated stress response effector GADD34 to enhance protein synthesis in response to neuronal activity

Neurons are highly plastic cells, altering the proteome to adapt to environmental cues. These changes are governed by fluctuations in protein synthesis pace and the nature of the mRNAs that are being translated. Although it is well established that de novo protein synthesis is fundamental to consolidate long-term memory, many details remain unknown, including the molecular mechanisms that trigger protein synthesis pace elevation that drive consolidation. Mounting evidence suggests that triggering long-term memory consolidation requires the release of the translation initiation brake, particularly via de-phosphorylation of the eIF2α. Here, we combined contextual threat conditioning and TRAP-sequencing to identify mRNAs that were differentially loaded onto neuronal ribosomes within 15 min following learning. This approach led us to conserved and specific mRNA pools that are activated in different neuronal types at early stages of consolidation. Dissecting translatome alterations evidenced enrichment of protein synthesis-related mRNAs in ribosomes from excitatory neurons, indicating priming for long-term sustained translation. Among these mRNAs, we identified PPP1R15A, which encodes GADD34, a potent modulator of translation initiation, as a candidate to mediate learning-induced increases in excitatory neuron protein synthesis. The knockout GADD34 in CamK2α+ neurons impaired long-term contextual memory. We found that GADD34 is rapidly synthesized following neuronal activity, controls eIF2α-dependent increases in neuronal translation, and that this affects the translation of plasticity-related mRNAs. Overall, our results identify GADD34 as an important player in the activity-driven increases in mRNA translation and demonstrate for the first time that neurons remap stress-related effectors to effectively respond to stimuli.