Objective:To observe the effect of early electroacupuncture intervention on the expression of TARDNA bind-ing protein 43(TDP-43)and HMGB1/RhoA signaling pathway in the cerebral cortex of amyotrophic lateral sclerosis(ALS)mice,and to explore the potential mechanism of early electroacupuncture intervention in im-proving motor function in ALS mice. Method:SOD1G93A gene phenotype mice were randomly divided into model group(SOD1G93A),acupuncture in-tervention group(EA),riluzole group(Riluzole),and SOD1G93A negative mice in the same litter were blank control group(Control),with 15 mice in each group.The electroacupuncture group was given acupuncture of Baihui point,bilateral Tianzhu point,bilateral Tianshu point,5 times/7 days,7 days for a course of treat-ment,a total of 4 courses of treatment.The riluzole group was treated with riluzole 30 mg/(kg·d)by gavage,once a day,five times a week for two weeks.The motor function of mice in each group was evaluated by hind limb functional neurological score and rotarod fatigue test,and the rate of TDP-43 positive cells in cere-bral cortex was observed by immunofluorescence.The relative expression of Iba-1,HMGB1 or RhoA protein in cerebral cortex was detected by Western Blot.The levels of serum TNF-α and MCP-1 were detected by Elisa.The morphological changes of cerebral cortical neurons were observed by transmission electron microscopy. Result:Compared with the control group,the rotarod latency time was decreased and the neurological score was increased in the model group(P＜0.01).The contents of serum MCP-1 and TNF-α,the expression of Iba-1,HMGB1 and RhoA protein in cerebral cortex and the rate of TDP-43 positive cells were increased in the model group(P＜0.01).Compared with the model group,the rotarod latency time of the electroacupuncture group and the riluzole group increased and the neurological score decreased(P＜0.01,P＜0.05),the serum MCP-1,TNF-α content and the cerebral cortex Iba-1,HMGB1,RhoA protein expression and TDP-43 positive cell rate decreased(P＜0.01,P＜0.05).The results of electron microscopy showed that the structure of cortical neurons in the control group was normal,and the nerve cells in the model group exhibited obvious pathologi-cal changes.The damage of nerve cells in the electroacupuncture group and the riluzole group was reduced,the structure was relatively complete,and some normal organelles were detected. Conclusion:Electroacupuncture intervention can improve the motor function of ALS model mice.The mecha-nism may be related to the inhibition of HMGBl/RhoA signaling pathway and the reduction of microglia-in-duced neuroinflammation,and it is speculated that it has a positive effect on the reduction of ALS pathologi-cal substrate TDP-43 deposition.