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

Kai Zhang, Chun Yang, Lijia Chang, Akemi Sakamoto, Toru Suzuki, Yuko Fujita, Youge Qu, Siming Wang, Yaoyu Pu, Yunfei Tan, Xingming Wang, Tamaki Ishima, Yukihiko Shirayama, Masahiko Hatano, Kenji F. Tanaka, Kenji Hashimoto

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5 Citations (Scopus)

Abstract

In rodent models of depression, (R)-ketamine has greater potency and longer-lasting antidepressant effects than (S)-ketamine; however, the precise molecular mechanisms underlying the antidepressant actions of (R)-ketamine remain unknown. Using RNA-sequencing analysis, we identified novel molecular targets that contribute to the different antidepressant effects of the two enantiomers. Either (R)-ketamine (10 mg/kg) or (S)-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. (R)-ketamine, but not (S)-ketamine, ameliorated the reduced expressions of Tgfb1 and its receptors (Tgfbr1 and Tgfbr2) 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 (R)-ketamine in CSDS susceptible mice. Moreover, depletion of microglia by the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX3397 blocked the antidepressant effects of (R)-ketamine in CSDS susceptible mice. Similar to (R)-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 (R)-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.

Original languageEnglish
Article number32
JournalTranslational psychiatry
Volume10
Issue number1
DOIs
Publication statusPublished - 2020 Dec 1

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry

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    Zhang, K., Yang, C., Chang, L., Sakamoto, A., Suzuki, T., Fujita, Y., Qu, Y., Wang, S., Pu, Y., Tan, Y., Wang, X., Ishima, T., Shirayama, Y., Hatano, M., Tanaka, K. F., & Hashimoto, K. (2020). Essential role of microglial transforming growth factor-β1 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-β1. Translational psychiatry, 10(1), [32]. https://doi.org/10.1038/s41398-020-0733-x