Activity-dependent synthesis of translational machinery through dynamic remodeling of ribonucleoprotein granules

Abstract

Neuronal stimulation drives gene-expression programs supporting long-lasting changes, yet how depolarization reshapes post-transcriptional regulation remains poorly understood. Here, we combined optogenetic stimulation with neuron-specific Ribo-seq and RNA-seq in the Drosophila brain to resolve activity-evoked translational dynamics. Stimulation triggered two temporally ordered programs: a rapid wave to translate synapse remodeling factors and neuropeptides, followed by a dominant delayed program that selectively upregulated translation of protein synthesis machinery, including nearly all cytosolic ribosomal proteins (RPs). Transcripts in the late program are marked by 5 terminal oligopyrimidine (TOP) motifs. TOP mRNAs accumulated in ribonucleoprotein granules at the basal state but are released upon stimulation. We identified La-related protein as a key regulator of the activity-dependent translation of TOP mRNA and memory consolidation. Comparative genomics indicated that TOP enrichment in RP mRNAs is specific to metazoans. These findings suggest that animals acquired activity-dependent TOP-mRNA control to couple neuronal stimulation with adaptation of translational capacity.