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Essential role of microglial transforming growth factor-β1 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-β1
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 t...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026089/ https://www.ncbi.nlm.nih.gov/pubmed/32066676 http://dx.doi.org/10.1038/s41398-020-0733-x |
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author | Zhang, Kai Yang, Chun Chang, Lijia Sakamoto, Akemi Suzuki, Toru Fujita, Yuko Qu, Youge Wang, Siming Pu, Yaoyu Tan, Yunfei Wang, Xingming Ishima, Tamaki Shirayama, Yukihiko Hatano, Masahiko Tanaka, Kenji F. Hashimoto, Kenji |
author_facet | Zhang, Kai Yang, Chun Chang, Lijia Sakamoto, Akemi Suzuki, Toru Fujita, Yuko Qu, Youge Wang, Siming Pu, Yaoyu Tan, Yunfei Wang, Xingming Ishima, Tamaki Shirayama, Yukihiko Hatano, Masahiko Tanaka, Kenji F. Hashimoto, Kenji |
author_sort | Zhang, Kai |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7026089 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-70260892020-03-03 Essential role of microglial transforming growth factor-β1 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-β1 Zhang, Kai Yang, Chun Chang, Lijia Sakamoto, Akemi Suzuki, Toru Fujita, Yuko Qu, Youge Wang, Siming Pu, Yaoyu Tan, Yunfei Wang, Xingming Ishima, Tamaki Shirayama, Yukihiko Hatano, Masahiko Tanaka, Kenji F. Hashimoto, Kenji Transl Psychiatry Article 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. Nature Publishing Group UK 2020-01-27 /pmc/articles/PMC7026089/ /pubmed/32066676 http://dx.doi.org/10.1038/s41398-020-0733-x Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Zhang, Kai Yang, Chun Chang, Lijia Sakamoto, Akemi Suzuki, Toru Fujita, Yuko Qu, Youge Wang, Siming Pu, Yaoyu Tan, Yunfei Wang, Xingming Ishima, Tamaki Shirayama, Yukihiko Hatano, Masahiko Tanaka, Kenji F. Hashimoto, Kenji Essential role of microglial transforming growth factor-β1 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-β1 |
title | Essential role of microglial transforming growth factor-β1 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-β1 |
title_full | Essential role of microglial transforming growth factor-β1 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-β1 |
title_fullStr | Essential role of microglial transforming growth factor-β1 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-β1 |
title_full_unstemmed | Essential role of microglial transforming growth factor-β1 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-β1 |
title_short | Essential role of microglial transforming growth factor-β1 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-β1 |
title_sort | essential role of microglial transforming growth factor-β1 in antidepressant actions of (r)-ketamine and the novel antidepressant tgf-β1 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026089/ https://www.ncbi.nlm.nih.gov/pubmed/32066676 http://dx.doi.org/10.1038/s41398-020-0733-x |
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