A circuit-dependent ROS feedback loop mediates glutamate excitotoxicity to sculpt the Drosophila motor system

Abstract

Overproduction of reactive oxygen species (ROS) is known to mediate glutamate excitotoxicity in neurological diseases. However, how ROS burdens can influence neural circuit integrity remains unclear. Here, we investigate the impact of excitotoxicity induced by depletion of Drosophila Eaat1, an astrocytic glutamate transporter, on locomotor central pattern generator (CPG) activity, neuromuscular junction architecture, and motor function. We show that glutamate excitotoxicity triggers a circuit-dependent ROS feedback loop to sculpt the motor system. Excitotoxicity initially elevates ROS to inactivate cholinergic interneurons, consequently changing CPG output activity to overexcite motor neurons and muscles. Remarkably, tonic motor neuron stimulation boosts muscular ROS, gradually dampening muscle contractility to feedback-enhance ROS accumulation in the CPG circuit and subsequently exacerbate circuit dysfunction. Ultimately, excess premotor excitation of motor neurons promotes ROS-activated stress signaling to alter neuromuscular junction architecture. Collectively, our results reveal that excitotoxicity-induced ROS can perturb motor system integrity by a circuit-dependent mechanism.

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Author details

  1. Jhan-Jie Peng

    Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, Republic of China
    Competing interests
    The authors declare that no competing interests exist.
  2. Shih-Han Lin

    Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, Republic of China
    Competing interests
    The authors declare that no competing interests exist.
  3. Yu-Tzu Liu

    Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, Republic of China
    Competing interests
    The authors declare that no competing interests exist.
  4. Hsin-Chieh Lin

    Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, Republic of China
    Competing interests
    The authors declare that no competing interests exist.
  5. Tsai-Ning Li

    Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, Republic of China
    Competing interests
    The authors declare that no competing interests exist.
  6. Chi-Kuang Yao

    Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, Republic of China
    For correspondence
    ckyao@gate.sinica.edu.tw
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0977-4347

Funding

Academia Sinica (AS-103-TP-B05)

  • Chi-Kuang Yao

Ministry of Science and Technology, Taiwan (101-2311-B-001-015-MY3)

  • Chi-Kuang Yao

Ministry of Science and Technology, Taiwan (105-2311-B-001-076)

  • Chi-Kuang Yao

Ministry of Science and Technology, Taiwan (107-2311-B-001-003-MY3)

  • Chi-Kuang Yao

Ministry of Science and Technology, Taiwan (106-0210-01-15-02)

  • Chi-Kuang Yao

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2019, Peng et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Jhan-Jie Peng
  2. Shih-Han Lin
  3. Yu-Tzu Liu
  4. Hsin-Chieh Lin
  5. Tsai-Ning Li
  6. Chi-Kuang Yao
(2019)
A circuit-dependent ROS feedback loop mediates glutamate excitotoxicity to sculpt the Drosophila motor system
eLife 8:e47372.
https://doi.org/10.7554/eLife.47372

Share this article

https://doi.org/10.7554/eLife.47372

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