AP-1 functions upstream of CREB to control synaptic plasticity in Drosophila

Nature. 2002 Apr 25;416(6883):870-4. doi: 10.1038/416870a.


Activity-regulated gene expression mediates many aspects of neural plasticity, including long-term memory. In the prevailing view, patterned synaptic activity causes kinase-mediated activation of the transcription factor cyclic AMP response-element-binding protein, CREB. Together with appropriate cofactors, CREB then transcriptionally induces a group of 'immediate early' transcription factors and, eventually, effector proteins that establish or consolidate synaptic change. Here, using a Drosophila model synapse, we analyse cellular functions and regulation of the best known immediate early transcription factor, AP-1; a heterodimer of the basic leucine zipper proteins Fos and Jun. We observe that AP-1 positively regulates both synaptic strength and synapse number, thus showing a greater range of influence than CREB. Observations from genetic epistasis and RNA quantification experiments indicate that AP-1 acts upstream of CREB, regulates levels of CREB messenger RNA, and functions at the top of the hierarchy of transcription factors known to regulate long-term plasticity. A Jun-kinase signalling module provides a CREB-independent route for neuronal AP-1 activation; thus, CREB regulation of AP-1 expression may, in some neurons, constitute a positive feedback loop rather than the primary step in AP-1 activation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Count
  • Cyclic AMP / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Dimerization
  • Drosophila melanogaster / genetics*
  • Drosophila melanogaster / growth & development
  • Drosophila melanogaster / metabolism*
  • Electrophysiology
  • Epistasis, Genetic
  • Gene Expression Regulation, Developmental*
  • JNK Mitogen-Activated Protein Kinases
  • Larva / genetics
  • Larva / growth & development
  • Larva / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Neuromuscular Junction / cytology
  • Neuromuscular Junction / enzymology
  • Neuromuscular Junction / growth & development
  • Neuromuscular Junction / metabolism
  • Neuronal Plasticity*
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • Proto-Oncogene Proteins c-jun / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Synapses / enzymology
  • Synapses / metabolism*
  • Transcription Factor AP-1 / metabolism*


  • Cyclic AMP Response Element-Binding Protein
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Transcription Factor AP-1
  • Cyclic AMP
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases