Nucleotide resolution analysis reveals extensive regulation of translation in response to neural depolarization.. Mus musculus

Studies on regulation of gene expression have contributed substantially to understanding mechanisms for long term alterations in neural connectivity in response to activity. Most of these, however, focused on the regulation of mRNA transcription. Here, we utilized high-throughput sequencing coupled with ribosomal footprinting to globally characterize the regulation of translation in neural cells in response to depolarization-mediated neural activity. We identify substantial and complex regulation of translation, with hundreds of transcripts demonstrating changes in ribosome occupancy independent of transcriptional changes. These changes are partially mediated by features in the sequence —notably uAUGs and secondary structure in the 5’UTR— both of which predict downregulation in response to activity. These transcripts are also disproportionately targets of Fmrp and include genes implicated in autism in humans. Our findings indicate that in neurons activity plays a critical role in regulating mRNA translation across the genome and suggest dysregulation of the process may contribute to disease. Overall design: 3 replicates were prepared for both Kcl-stimulated and unstimulated neuronal cultures from P0 FVB mouse cortices.