Splenic γδ T cells mediate antidepressant and prophylactic actions of arketamine in lipopolysaccharide-induced depression in mice

Arketamine, the (R)-enantiomer of ketamine, exhibits both therapeutic and sustained prophylactic effects in an inflammation-driven model of depression, although the precise mechanisms remain elusive. Given the involvement of γδ T cells in inflammatory processes, this study explored their role in the effects of arketamine. To assess therapeutic outcomes, mice received lipopolysaccharide (LPS:1.0 mg/kg), followed by either arketamine (10 mg/kg) or saline. For prophylactic assessment, arketamine or saline was administered six days prior to LPS exposure. A single dose of LPS (1.0 mg/kg) reduced the proportion of γδ T cells in the spleen but did not affect their levels in the blood, prefrontal cortex, or small intestine. Arketamine mitigated LPS-induced splenomegaly, counteracted the elevation of plasma interleukin-6 levels and the reduction in the proportion of splenic γδ T cells, and alleviated depression-like behavior as assessed by the forced swimming test. Notably, negative correlations were observed between the proportion of splenic γδ T cells and indicators of inflammation and depression. Furthermore, pretreatment with a γδ TCR antibody significantly countered the therapeutic and prophylactic effects of arketamine on LPS-induced changes. These findings highlight a novel role for splenic γδ T cells in inflammation-associated depression and suggest the potential of arketamine as a treatment option. Consequently, γδ T cells may represent a novel therapeutic target for inflammation-related depression. Further studies on the role of γδ T cells in depressed patients with inflammation are warranted.