Splenic γδ T cells mediate antidepressant and prophylactic actions of arketamine in lipopolysaccharide-induced depression in mice.
Guilin Liu, Li Ma, Akemi Sakamoto, Lisa Fujimura, Dan Xu, Mingming Zhao, Xiayun Wan, Rumi Murayama, Naohiko Anzai, Kenji Hashimoto
Pharmacology, biochemistry, and behavior December 1, 2024 DOI: 10.1016/j.pbb.2024.173906
Summary
A promising antidepressant compound, arketamine, works through an unexpected pathway: immune cells in the spleen. The compound shows both immediate and preventive effects against inflammation-induced depression by maintaining healthy levels of specific immune cells. When inflammation triggers depression-like symptoms in mice, arketamine helps restore balance by protecting crucial immune cells in the spleen, reducing inflammatory markers, and improving mood-related behaviors.
Abstract
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.