The Integrated Stress Response effector GADD34 is repurposed by neurons to promote stimulus-induced translation

Neuronal protein synthesis is required for long-lasting plasticity and long-term memory consolidation. Dephosphorylation of eukaryotic initiation factor 2a is one of the key translational control events that is required to increase de novo protein synthesis that underlies long-lasting plasticity and memory consolidation. Here, we interrogate the molecular pathways of translational control that are triggered by neuronal stimulation with brain-derived neurotrophic factor (BDNF), which results in eIF2a dephosphorylation and de novo protein synthesis. Primary rodent neurons exposed to BDNF displayed elevated translation, but not transcription, of GADD34, which facilitates eIF2a dephosphorylation and subsequent de novo protein synthesis. Furthermore, GADD34 requires G-actin generated by cofilin to dephosphorylate eIF2a and enhance protein synthesis. Finally, GADD34 is required for BDNF-induced translation of synaptic plasticity-related proteins. Overall, we provide evidence that neurons repurpose GADD34, an effector of the Integrated Stress Response, as an orchestrator of rapid increases in eIF2-dependent translation in response to plasticity-inducing stimuli. Overall design: Wild type or GADD34flfl primary neurons were transduced either with mock virus or Cre-carrying virus. They were also co-transduced with AAV5.Camk2a.TRAP virus. After 14 days, neurons were exposed for 1h to either vehicle or BDNF and ribosomes purified for sequencing of translatome.