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

eLife

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[1] Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, Republic of China;Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, Republic of China;Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan, Republic of China;

关键词: glutamate excitotoxicity;    EAAT transporter;    reactive oxygen species;    circuit dysfunction;    motor circuit;    D. melanogaster;   

DOI  :  10.7554/eLife.47372

来源: publisher

【 摘 要 】

10.7554/eLife.47372.001Overproduction 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, 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.

【 授权许可】

CC BY