Targeted Intron Retention and Excision for Rapid Gene Regulation in Response to Neuronal Activity

Activity-dependent transcription has emerged as a major source of gene products that regulate neuronal excitability, connectivity, and synaptic properties. However, the elongation rate of RNA polymerases imposes a significant temporal constraint for transcript synthesis, in particular for long genes where new synthesis requires hours. Here we reveal a novel, transcription-independent mechanism that releases transcripts within minutes of neuronal stimulation. We found that, in the mouse neocortex, polyadenylated transcripts retain select introns and are stably accumulated in the cell nucleus. A subset of these intron retention transcripts undergoes activity-dependent splicing, cytoplasmic export, and ribosome loading, thus acutely releasing mRNAs in response to stimulation. This process requires NMDA receptor- and calmodulin-dependent kinase pathways, and it is particularly prevalent for long transcripts. We conclude that regulated intron retention in fully transcribed RNAs represents a mechanism to rapidly mobilize a pool of mRNAs in response to neuronal activity. •PolyA+ transcripts can stably retain select introns and be confined in the nucleus•Some of these intron-retaining RNAs rapidly undergo splicing upon neuronal activation•Spliced transcripts are exported to the cytosol and loaded onto ribosomes•The activity-dependent intron excision process requires NMDAR and CaMK pathways Mauger et al. reveal a novel, transcription-independent mechanism to rapidly modify the neuronal transcriptome in response to activity. Neuronal stimulation triggers splicing of transcripts stably retaining select introns, and, thereby, it mobilizes a pool of mRNAs for translation.