BACKGROUND: Depression is a prevalent affective disorder, but its pathophysiology remains unclear. Dysfunction in the gamma-aminobutyric acid (GABA)-ergic system may contribute to its onset. Recently, antidepressants ( AIM: To explore the relationship between GABAergic neurons in the ZI and depression-like behaviors in mice. METHODS: A chronic restraint stress (CRS) model was utilized to induce depression in mice. Whole-cell patch-clamp recordings assessed the excitability changes of GABAergic neurons in the ZI. Additionally, chemogenetic techniques were employed to modulate ZI GABAergic neurons. The performance of the mice in behavioral tests for depression and anxiety was observed. RESULTS: The findings indicated that GABAergic neurons in the ZI were closely associated with depression-like behaviors in mice. Twenty-eight days after the CRS model was established, depression-like and anxiety-like behaviors were observed in the mice. The excitability of GABAergic neurons in the ZI was reduced. Chemogenetic activation of these neurons alleviated CRS-induced depression-like and anxiety-like behaviors. Conversely, inhibition of GABAergic neurons in the ZI led to changes in emotion-related behavioral outcomes in mice. CONCLUSION: Activity of GABAergic neurons in the ZI was closely associated with depression-like phenotypes in mice, suggesting that these neurons could be a potential therapeutic target for treating depression.