Essential role of microglial transforming growth factor-β1 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-β1

<jats:title>Abstract</jats:title><jats:p>In rodent models of depression, (<jats:italic>R</jats:italic>)-ketamine has greater potency and longer-lasting antidepressant effects than (<jats:italic>S</jats:italic>)-ketamine; however, the precise molecular mechanisms underlying the antidepressant actions of (<jats:italic>R</jats:italic>)-ketamine remain unknown. Using RNA-sequencing analysis, we identified novel molecular targets that contribute to the different antidepressant effects of the two enantiomers. Either (<jats:italic>R</jats:italic>)-ketamine (10 mg/kg) or (<jats:italic>S</jats:italic>)-ketamine (10 mg/kg) was administered to susceptible mice after chronic social defeat stress (CSDS). RNA-sequencing analysis of prefrontal cortex (PFC) and subsequent GSEA (gene set enrichment analysis) revealed that transforming growth factor (TGF)-β signaling might contribute to the different antidepressant effects of the two enantiomers. (<jats:italic>R</jats:italic>)-ketamine, but not (<jats:italic>S</jats:italic>)-ketamine, ameliorated the reduced expressions of <jats:italic>Tgfb1</jats:italic> and its receptors (<jats:italic>Tgfbr1</jats:italic> and <jats:italic>Tgfbr2</jats:italic>) in the PFC and hippocampus of CSDS susceptible mice. Either pharmacological inhibitors (i.e., RepSox and SB431542) or neutralizing antibody of TGF-β1 blocked the antidepressant effects of (<jats:italic>R</jats:italic>)-ketamine in CSDS susceptible mice. Moreover, depletion of microglia by the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX3397 blocked the antidepressant effects of (<jats:italic>R</jats:italic>)-ketamine in CSDS susceptible mice. Similar to (<jats:italic>R</jats:italic>)-ketamine, the recombinant TGF-β1 elicited rapid and long-lasting antidepressant effects in animal models of depression. Our data implicate a novel microglial TGF-β1-dependent mechanism underlying the antidepressant effects of (<jats:italic>R</jats:italic>)-ketamine in rodents with depression-like phenotype. Moreover, TGF-β1 and its receptor agonists would likely constitute a novel rapid-acting and sustained antidepressant in humans.</jats:p>