Letter | Published:

Neuromodulators signal through astrocytes to alter neural circuit activity and behaviour

Nature volume 539, pages 428432 (17 November 2016) | Download Citation

Abstract

Astrocytes associate with synapses throughout the brain and express receptors for neurotransmitters that can increase intracellular calcium (Ca2+)1,2,3. Astrocytic Ca2+ signalling has been proposed to modulate neural circuit activity4, but the pathways that regulate these events are poorly defined and in vivo evidence linking changes in astrocyte Ca2+ levels to alterations in neurotransmission or behaviour is limited. Here we show that Drosophila astrocytes exhibit activity-regulated Ca2+ signalling in vivo. Tyramine and octopamine released from neurons expressing tyrosine decarboxylase 2 (Tdc2) signal directly to astrocytes to stimulate Ca2+ increases through the octopamine/tyramine receptor (Oct-TyrR) and the transient receptor potential (TRP) channel Water witch (Wtrw), and astrocytes in turn modulate downstream dopaminergic neurons. Application of tyramine or octopamine to live preparations silenced dopaminergic neurons and this inhibition required astrocytic Oct-TyrR and Wtrw. Increasing astrocyte Ca2+ signalling was sufficient to silence dopaminergic neuron activity, which was mediated by astrocyte endocytic function and adenosine receptors. Selective disruption of Oct-TyrR or Wtrw expression in astrocytes blocked astrocytic Ca2+ signalling and profoundly altered olfactory-driven chemotaxis and touch-induced startle responses. Our work identifies Oct-TyrR and Wtrw as key components of the astrocytic Ca2+ signalling machinery, provides direct evidence that octopamine- and tyramine-based neuromodulation can be mediated by astrocytes, and demonstrates that astrocytes are essential for multiple sensory-driven behaviours in Drosophila.

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Acknowledgements

We thank our colleagues, the Vienna Drosophila RNAi Center and the Bloomington Stock Center for providing fly stocks, members of the Freeman laboratory for comments on the manuscript and A. Sheehan for generating the wtrw::gfp construct. This work was supported by NINDS grant R01 NS053538 (to M.R.F.). During the period of this study M.R.F. was an Investigator with the Howard Hughes Medical Institute.

Author information

Author notes

    • Marc R. Freeman

    Present address: Vollum Institute, Oregon Health and Sciences University, Portland, Oregon 97239, USA.

Affiliations

  1. Department of Neurobiology and Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA

    • Zhiguo Ma
    • , Tobias Stork
    •  & Marc R. Freeman
  2. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • Dwight E. Bergles

Authors

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Contributions

Z.M. and M.R.F. designed experiments. Z.M. performed all experiments. T.S. provided alrm-LexA::GAD transgenic flies. D.E.B. provided unpublished data on norepinephrine-mediated activation of mammalian astrocytes and input that helped guide the course of the study. Z.M. and M.R.F. wrote the manuscript with editing by T.S.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Marc R. Freeman.

Reviewer Information

Nature thanks L. Luo, B. MacVicar, L. Vosshall and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data

Supplementary information

Videos

  1. 1.

    Synchronous somatic calcium transients in Drosophila astrocytes

    Top left: mCherry. Top right: GCaMP6s. Bottom left: merge. Video was sped up X100.

  2. 2.

    Concomitant activity of Tdc2+ neurons and astrocytes

    Top left: GCaMP6s labeled astrocytes. Top right: R-GECO1 labeled Tdc2+ neurites. Bottom left: merge. Video was sped up X50.

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DOI

https://doi.org/10.1038/nature20145

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