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.
Keywords: Ca2+/calmodulin-dependent protein kinase; CaMK; NMDA receptor; activity-dependent gene expression; immediate early gene; intron retention; plasticity; splicing; synapse.
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