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

Nature volume 416, pages 870–874 (2002)Cite this article

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.

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Figure 1: Neuronal AP-1 controls bouton number and synaptic strength.
Figure 2: Both CREB and a cAMP-sensitive activity are required downstream of AP-1 to regulate synapse strength but not bouton number.
Figure 3: JNK signalling regulates AP-1-dependent synaptic plasticity.
Figure 4: A model for plasticity regulation at the Drosophila larval neuromuscular synapse.

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Acknowledgements

We thank D. Bohmann and E. Hafen for strains, and T. Littleton and H. Bellen for anti-Syt antibodies. We also thank H. Keshishian and T. Osterwalder for sharing elavGS-GLA4 strains before publication; P. Etter for early assistance; D. Stimson for advice on electrophysiology; and P. Jansma for help with confocal microscopy. We thank P. Etter, R. Narayanan and members of the Ramaswami laboratory for useful discussions and/or comments on the manuscript. The work was funded by grants from the National Institute on Drug Abuse (primarily), the National Institute for Neurological Disorders and Stroke, the Human Frontiers Science Program Organization, McKnight and Alfred P. Sloan Foundations to M.R., and NSF and NIH predoctoral fellowships to C.A.H.

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  1. David J. Sandstrom

    Present address: Laboratory of Molecular Biology, NIMH Building 36, Room 1B10, National Institutes of Health, Bethesda, Maryland, 20892, USA

  2. Subhabrata Sanyal and David J. Sandstrom: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Molecular and Cellular Biology, and Arizona Research Laboratories, Division of Neurobiology, University of Arizona, Tucson, Arizona, 85721, USA

    Subhabrata Sanyal, David J. Sandstrom, Charles A. Hoeffer & Mani Ramaswami

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Correspondence to Mani Ramaswami.

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Sanyal, S., Sandstrom, D., Hoeffer, C. et al. AP-1 functions upstream of CREB to control synaptic plasticity in Drosophila. Nature 416, 870–874 (2002). https://doi.org/10.1038/416870a

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