Depression, regulated by central nervous system (CNS), is a significant inflammatory disorder. Neuro-ligin3 (NLGN3) has been implicated in brain functions. In the study, a chronic unpredictable mild stress (CUMS) model in wild type (WT) or NLGN3-knockout (KO) mice was established to explore the role of NLGN3 in regulating depression and to reveal the underlying molecular mechanism. The results indicated that NLGN3-knockout markedly reversed the loss of body weight, the reduction of sucrose consumption, the decrease of immobile time in the forced swimming tests (FST) and tail suspension tests (TST) induced by CUMS paradigm. CUMS up-regulated corticosterone (CORT) in serum, and down regulated serotonin (5-HT), norepinephrine (NE) and brain-derived neurotrophic factor (BDNF) in hippocampus of mice, which were significantly reversed by NLGN3 deficiency. The results further demonstrated that NLGN3-knockout improved the degenerative neurons in cortex and hippocampus of CUMS-treated mice, accompanied with a significant decrease of ionized calciumbinding adapter molecule 1 (lba-1) and glial fibrillary acidic protein (GFAP) expressions. Additionally, NLGN3-KO mice challenged with CUMS showed a significant reduction of pro-inflammatory cytokines and chemokine, including tumor necrosis factor-alpha (TNF-alpha), interleukin-18 (IL-18), interleukin-1 beta (IL-1 beta), interleukin-4 (IL-4), CC-chemokine ligand-1 (CCL-1) and CXC-chemokine ligand-1 (CXCL-1), in cortex, hippocampus and amygdala tissue samples. Western blot analysis suggested that NLGN3-knockout inhibited the activation of nod-like receptor protein 3 (NLRP3) inflammasome and its adaptor of apoptosis-associated speck like protein (ASC), and reduced the expression of Caspase-1, along with the inactivation of nuclear factor-kappa B (NF-kappa B) in CUMS-challenged mice. The role of NLGN3 in regulating depression in mice was confirmed in vitro using astrocytes stimulated by LPS that NLGN3 knockdown reduced LPS-induced inflammation. Importantly, the suppressive effects of NLGN3-knockdown on inflammatory response were reversed by NLRP3 or ASC over-expression in AST exposed to LPS. In sum, our findings indicated that suppressing NLGN3 played a potential antidepressant role in CUMS animal model by inactivating NLRP3 inflammasome, providing a new therapeutic avenue for depression. (C) 2018 Published by Elsevier Inc.