Activity-induced Histone Modifications Govern Neurexin-1 mRNA Splicing and Memory Preservation

Nat Neurosci. 2017 May;20(5):690-699. doi: 10.1038/nn.4536. Epub 2017 Mar 27.


Epigenetic mechanisms regulate the formation, consolidation and reconsolidation of memories. However, the signaling path from neuronal activation to epigenetic modifications within the memory-related brain circuit remains unknown. We report that learning induces long-lasting histone modifications in hippocampal memory-activated neurons to regulate memory stability. Neuronal activity triggers a late-onset shift in Nrxn1 splice isoform choice at splicing site 4 by accumulating a repressive histone marker, H3K9me3, to modulate the splicing process. Activity-dependent phosphorylation of p66α via AMP-activated protein kinase recruits HDAC2 and Suv39h1 to establish repressive histone markers and changes the connectivity of the activated neurons. Removal of Suv39h1 abolished the activity-dependent shift in Nrxn1 splice isoform choice and reduced the stability of established memories. We uncover a cell-autonomous process for memory preservation in which memory-related neurons initiate a late-onset reduction of their rewiring capacities through activity-induced histone modifications.

MeSH terms

  • Animals
  • Coculture Techniques
  • Conditioning, Psychological / physiology
  • Epigenesis, Genetic
  • Female
  • GATA Transcription Factors
  • Hippocampus / physiology
  • Histone Code / physiology*
  • Histone Deacetylase 2 / metabolism
  • Histones / metabolism
  • Histones / physiology*
  • Learning / physiology
  • Male
  • Memory / physiology*
  • Methyltransferases / metabolism
  • Mice
  • Mice, Knockout
  • Neural Cell Adhesion Molecules / genetics
  • Neural Cell Adhesion Molecules / metabolism
  • Neural Cell Adhesion Molecules / physiology
  • Neurons / metabolism
  • Primary Cell Culture
  • Protein Isoforms / metabolism
  • Repressor Proteins / metabolism


  • GATA Transcription Factors
  • Gatad2a protein, mouse
  • Histones
  • Neural Cell Adhesion Molecules
  • Nrxn1 protein, mouse
  • Protein Isoforms
  • Repressor Proteins
  • Suv39h1 protein, mouse
  • Methyltransferases
  • Hdac2 protein, mouse
  • Histone Deacetylase 2