Letter | Published:

Retrograde semaphorin–plexin signalling drives homeostatic synaptic plasticity

Nature volume 550, pages 109113 (05 October 2017) | Download Citation

Abstract

Homeostatic signalling systems ensure stable but flexible neural activity and animal behaviour1,2,3,4. Presynaptic homeostatic plasticity is a conserved form of neuronal homeostatic signalling that is observed in organisms ranging from Drosophila to human1,5. Defining the underlying molecular mechanisms of neuronal homeostatic signalling will be essential in order to establish clear connections to the causes and progression of neurological disease. During neural development, semaphorin–plexin signalling instructs axon guidance and neuronal morphogenesis6,7,8,9,10. However, semaphorins and plexins are also expressed in the adult brain11,12,13,14,15,16. Here we show that semaphorin 2b (Sema2b) is a target-derived signal that acts upon presynaptic plexin B (PlexB) receptors to mediate the retrograde, homeostatic control of presynaptic neurotransmitter release at the neuromuscular junction in Drosophila. Further, we show that Sema2b–PlexB signalling regulates presynaptic homeostatic plasticity through the cytoplasmic protein Mical and the oxoreductase-dependent control of presynaptic actin. We propose that semaphorin–plexin signalling is an essential platform for the stabilization of synaptic transmission throughout the developing and mature nervous system. These findings may be relevant to the aetiology and treatment of diverse neurological and psychiatric diseases that are characterized by altered or inappropriate neural function and behaviour.

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Acknowledgements

We thank S. Meltzer for consultation throughout and members of the Davis laboratory for comments on an earlier version of this manuscript. Supported by NIH Grant number R01NS39313 and R35NS097212 to G.W.D.

Author information

Affiliations

  1. Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California 94158, USA

    • Brian O. Orr
    • , Richard D. Fetter
    •  & Graeme W. Davis

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Contributions

B.O.O. conducted all experiments and analyses, including genetics, electrophysiology and light microscopy experiments and wrote the text. R.D.F. performed electron microscopy. G.W.D. helped to analyse electron micrographs and wrote the text.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Graeme W. Davis.

Reviewer Information Nature thanks H. J. Bellen, A. Chedotal and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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    Supplementary Information

    This file contains figure 1 which shows a silver stain gel shown in full, referring to Figure 2e-h and extended data figure 3b. It also contains table 1 which shows primary data inclusive of genotypes, experimental conditions, and figure/panel to which the data refer.

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https://doi.org/10.1038/nature24017

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