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

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Abstract
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 change1. 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 Jun2. We observe that AP-1 positively regulates both synaptic strength and synapse number, thus showing a greater range of influence than CREB3. 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 expression4 may, in some neurons, constitute a positive feedback loop rather than the primary step in AP-1 activation.