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

Neuron. 2016 Dec 21;92(6):1266-1278. doi: 10.1016/j.neuron.2016.11.032.


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.

MeSH terms

  • Animals
  • Blotting, Western
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Gene Expression Regulation*
  • Hippocampus / metabolism
  • Introns*
  • Mice
  • Neocortex / metabolism*
  • Poly A / metabolism*
  • RNA Splicing
  • RNA Transport
  • RNA, Messenger / metabolism*
  • RNA, Ribosomal
  • Real-Time Polymerase Chain Reaction
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribosomes
  • Sequence Analysis, RNA
  • Signal Transduction
  • Transcriptome


  • RNA, Messenger
  • RNA, Ribosomal
  • Receptors, N-Methyl-D-Aspartate
  • Poly A
  • Calcium-Calmodulin-Dependent Protein Kinases