A circuit-dependent ROS feedback loop mediates glutamate excitotoxicity to sculpt the Drosophila motor system
- Academia Sinica, Taiwan, Republic of China
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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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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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
