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

• Published in: eLife 2019-07, Vol.8
• Main Authors: Peng, Jhan-Jie, Lin, Shih-Han, Liu, Yu-Tzu, Lin, Hsin-Chieh, Li, Tsai-Ning, Yao, Chi-Kuang
• Format: Article
• Language: English
• Subjects: Amino acids; Animals; Astrocytes - drug effects; Astrocytes - metabolism; Central pattern generator; Cholinergic Neurons - drug effects; Cholinergic Neurons - metabolism; circuit dysfunction; Drosophila; Drosophila melanogaster - drug effects; Drosophila melanogaster - physiology; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; EAAT transporter; Electrodes; Excitotoxicity; Feedback; Feedback, Physiological; Glutamate; glutamate excitotoxicity; Glutamic Acid - toxicity; Glutamic acid transporter; Insects; Interneurons; Interneurons - drug effects; Interneurons - metabolism; MAP Kinase Signaling System - drug effects; motor circuit; Motor neurons; Motor Neurons - drug effects; Motor Neurons - physiology; Muscle contraction; Muscles; Mutation; Mutation - genetics; Nervous system; Nervous system diseases; Neural circuitry; Neurodegeneration; Neuroglia - drug effects; Neuroglia - metabolism; Neurological diseases; Neuromuscular Junction - drug effects; Neuromuscular Junction - metabolism; Neurons; Neuroscience; Neurotoxins - toxicity; Observations; Oxidative Stress - drug effects; Physiological aspects; Reactive oxygen species; Reactive Oxygen Species - metabolism; Software
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.47372

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 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, thereby inactivating cholinergic interneurons and 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 that alters neuromuscular junction architecture. Collectively, our results reveal that excitotoxicity-induced ROS can perturb motor system integrity through a circuit-dependent mechanism.