Depression is a chronic and recurrent disease without satisfactory treatment strategies. The therapeutic effect of acupuncture is well known in Traditional Chinese medicine (TCM) due to its unique non-pharmacological nature. Electroacupuncture (EA) for antidepressant therapy has been widely recognized and used in clinic. In this study, the lipopolysaccharide (LPS)-induced depression mice model was used to evaluate the anti-depressant effects of EA treatment. Open Field Test (OFT), Force Swimming Test (FST), and Sucrose Preference Test (SPT) were utilized to detect the ethological alterations in mice. The transcriptology technique was used to evaluate the changes in the hippocampal transcriptome in different groups. We measured protein levels using Western blot and immunohistochemistry. Our data showed that LPS induced ethological alterations in mice and enhanced the gene expression related to gene ontology such as the banded collagen fibril, fibrillar collagen trimer, and collagen fibril organization, pathways such as collagen chain trimerization, collagen biosynthesis and modifying enzymes, and collagen formation. EA could reverse the ECM deposition by inhibiting collagen type Ⅳ trimer, extracellular matrix organization, and collagen formation. EA could enhance the MMP1 and MMP9 expression and promote synaptic plasticity. These data indicated that EA possesses an antidepressant effect, this may achieve by increasing MMPs expression and then remodeling the ECM surrounding the neurons, ultimately repairing neural circuits and promoting synaptic plasticity.Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.