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

• DOI: 10.1038/416870a
• Publication Date: 2002-07-26T08:56:51Z
• Authors: Subhabrata Sanyal; David J. Sandstrom; Charles A. Hoeffer; Mani Ramaswami
• Keywords: 0301 basic medicine; Neuronal Plasticity; Proto-Oncogene Proteins c-jun; JNK Mitogen-Activated Protein Kinases; Neuromuscular Junction; Gene Expression Regulation, Developmental; Cell Count; Epistasis, Genetic; Electrophysiology; 03 medical and health sciences; Drosophila melanogaster; Larva; Synapses; Cyclic AMP; Animals; RNA, Messenger; Mitogen-Activated Protein Kinases; Cyclic AMP Response Element-Binding Protein; Promoter Regions, Genetic; Dimerization; Proto-Oncogene Proteins c-fos; Signal Transduction

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.