Regulated Intron Removal Integrates Motivational State and Experience

Cell. 2017 May 18;169(5):836-848.e15. doi: 10.1016/j.cell.2017.05.006.


Myriad experiences produce transient memory, yet, contingent on the internal state of the organism and the saliency of the experience, only some memories persist over time. How experience and internal state influence the duration of memory at the molecular level remains unknown. A self-assembled aggregated state of Drosophila Orb2A protein is required specifically for long-lasting memory. We report that in the adult fly brain the mRNA encoding Orb2A protein exists in an unspliced non-protein-coding form. The convergence of experience and internal drive transiently increases the spliced protein-coding Orb2A mRNA. A screen identified pasilla, the fly ortholog of mammalian Nova-1/2, as a mediator of Orb2A mRNA processing. A single-nucleotide substitution in the intronic region that reduces Pasilla binding and intron removal selectively impairs long-term memory. We posit that pasilla-mediated processing of unspliced Orb2A mRNA integrates experience and internal state to control Orb2A protein abundance and long-term memory formation.

Keywords: Nova; amyloid; detained-intron; intron retention; long-term memory; motivation; pasilla; poised splicing; prion.

MeSH terms

  • Animals
  • Base Sequence
  • Behavior, Animal
  • Brain / metabolism
  • Conditioning, Psychological
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism*
  • Introns*
  • Learning
  • Memory, Long-Term*
  • Models, Animal
  • Motivation
  • Mutation
  • Protein Isoforms / metabolism
  • RNA Splicing
  • Ribonucleoproteins / metabolism*
  • Transcription Factors / chemistry
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • mRNA Cleavage and Polyadenylation Factors / chemistry
  • mRNA Cleavage and Polyadenylation Factors / genetics*
  • mRNA Cleavage and Polyadenylation Factors / metabolism


  • Drosophila Proteins
  • Orb2 protein, Drosophila
  • Protein Isoforms
  • Ribonucleoproteins
  • Transcription Factors
  • mRNA Cleavage and Polyadenylation Factors
  • ps protein, Drosophila