Ketamine reduces microglial activation and brain monocyte infiltration and promotes peripheral regulatory immune cells, relieving lipopolysaccharide (LPS)-induced depressive-like behavior in mice

Abstract

Ketamine has emerged as a rapid and sustained treatment for Major Depressive Disorder (MDD) and an alternative for patients who have not responded to traditional therapies. Its effects have been partly attributed to the noncompetitive antagonism of the Nmethyl-D-aspartate receptor (NMDAR) in the central nervous system, which enhances neuroplasticity. However, the etiopathology of MDD is complex, and substantial evidence suggests that inflammation may significantly contribute to the initiation and maintenance of MDD. Furthermore, the rapid and sustained antidepressant effect of ketamine may be attributed to its antiinflammatory and immunomodulatory actions. To investigate the antidepressant and anti-inflammatory effect of ketamine, we used a lipopolysaccharide (LPS)-induced depressive-like murine model. The Tail Suspension Test (TST) and Sucrose Preference Test (SPT) were conducted to assess depressive-like behaviors. Additionally, cellular immunophenotyping of blood, spleen, and brain was performed by flow cytometry. Ketamine administration (10–20 mg/kg) alleviated despair and anhedonia in LPS-depressive-like mice, as evidenced by the TST and SPT tests. Behavioral changes were accompanied by the reduction of Ly6G+ neutrophils and an increment of anti-inflammatory Ly6Clow/neg monocytes in the blood. Ketamine treatment also reduced CD45highLy6GnegLy6Chigh monocyte infiltration into the brain and dampened microglial activation (CD45lowCD11bhigh). In the spleen, ketamine decreased the expansion of acute T lymphocyte response (CD3+ CD4negCD8neg) induced by LPS, while increasing the percentage of CD4+ CD69+ TIM-3+ lymphocytes, known for their regulatory function. Splenic macrophages were also polarized towards an antiinflammatory CD206+ M2-phenotype with ketamine. Finally, we showed that the anti-inflammatory and antidepressant effects are linked, perhaps as convergent outcomes, by using another NMDA receptor antagonist, MK-801, and the mTOR signaling inhibitor, rapamycin. These findings highlight ketamine’s multifaceted mechanisms of action, underscoring its potential as a treatment for MDD, particularly in patients with significant inflammation.