In this study, we intend to explore the antidepressant mechanism underlying acupuncture based on the neuroplasticity and its neural plasticity-related proteins BDNF/PSD95/SYN/PKMZ in the prefrontal cortex of chronic unpredicted mild stress- (CUMS-) induced depressed rats, providing prospective insights for the treatment of depression in the clinic. This evidence concerns the gene DLG4 and major depressive disorder.