Résumé
In neurons, many mRNAs are transported to synapses in a translationally repressed state, allowing for the spatial and temporal regulation of protein synthesis required for synaptic plasticity. It has been assumed that these mRNAs are repressed at the initiation step of translation. Here we provide evidence for a second mechanism whereby these mRNAs are instead repressed at elongation/termination awaiting translational reactivation upon appropriate synaptic signals. Our results establish that a form of translation-dependent synaptic plasticity, which is dysregulated in neurodevelopmental and psychiatric pathologies, occurs independently of translation initiation. Elucidating the upstream pathways that lead to repression and reactivation of elongation/termination on these mRNAs may provide new avenues for the design of therapies targeting neurodevelopmental disorders. Some forms of synaptic plasticity require rapid, local activation of protein synthesis. Although this is thought to reflect recruitment of mRNAs to free ribosomes, this would limit the speed and magnitude of translational activation. Here we provide compelling in situ evidence supporting an alternative model in which synaptic mRNAs are transported as stably paused polyribosomes. Remarkably, we show that metabotropic glutamate receptor activation allows the synthesis of proteins that lead to a functional long-term depression phenotype even when translation initiation has been greatly reduced. Thus, neurons evolved a unique mechanism to swiftly translate synaptic mRNAs into functional protein upon synaptic signaling using stalled polyribosomes to bypass the rate-limiting step of translation initiation. Because dysregulated plasticity is implicated in neurodevelopmental and psychiatric disorders such as fragile X syndrome, this work uncovers a unique translational target for therapies.