Objective: To investigate the effects of chronic unpredictable mild stress (CUMS) on perineuronal nets (PNNs) and γ-aminobutyric acid (GABA)-ergic neurons in the medial prefrontal cortex (mPFC) of adult rats. Methods: 28 rats were randomly divided into two groups. The model group adopted CUMS to establish a depression model, and the control group did not give any treatment. The density of PNNs and the percentage of PNNs positive (PNNs+) and parvalbumin positive (PV+) neurons in total PV+ neurons in the mPFC were detected by immunofluorescence. The protein expression of main components of PNNs, Aggrecan and Brevican, and GABA main synthase glutamic acid decarboxylase 67 (GAD67) in the mPFC were detected by Western blot. Results: The density of PNNs and the percentage of PNNs+ and PV+ neurons in total PV+ neurons in the mPFC in the model group were decreased compared with the control group (P<0.05); The expression levels of PNNs component proteins Aggrecan and Brevican, and GABA main synthase GAD67 were also decreased in the model group (P<0.01). Conclusion: The levels of PNNs and GABA synthase GAD67 in the mPFC of rats were decreased after chronic unpredictable mild stress.