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

Overproduction of reactive oxygen species is known to mediate glutamate excitotoxicity in neurological diseases. However, how 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 duanyu1670 feedback loop to sculpt the motor system. Excitotoxicity initially elevates thereby inactivating cholinergic interneurons and consequently changing CPG output activity to overexcite motor neurons and muscles. Remarkably, tonic motor neuron stimulation boosts muscular duanyu1670, gradually dampening muscle contractility to feedback-enhance duanyu1670 accumulation in the CPG circuit and subsequently exacerbate circuit dysfunction. Ultimately, excess premotor excitation of motor neurons promotes stress signaling that alters neuromuscular junction architecture. Collectively, our results reveal that excitotoxicity-induced duanyu1670 can perturb motor system integrity through a circuit-dependent mechanism.

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