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Essential Role of Microglial Transforming Growth Factor-Β1 Zhang et al. Translational Psychiatry (2020)10:32 https://doi.org/10.1038/s41398-020-0733-x Translational Psychiatry ARTICLE Open Access Essential role of microglial transforming growth factor-β1 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-β1 Kai Zhang1,5, Chun Yang1,6, Lijia Chang1, Akemi Sakamoto2,ToruSuzuki3, Yuko Fujita1, Youge Qu1, Siming Wang1, Yaoyu Pu1,YunfeiTan 1, Xingming Wang1, Tamaki Ishima1, Yukihiko Shirayama1,4, Masahiko Hatano2, Kenji F. Tanaka 3 and Kenji Hashimoto 1 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 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; 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. Introduction depressive disorder (MDD). Subsequently, several groups In 1990, Trullas and Skolnick1 demonstrated that N- replicated the robust antidepressant effects of ketamine in methyl-D-aspartate receptor (NMDAR) antagonists such treatment-resistant patients with either MDD or bipolar – as (+)-MK-801 showed antidepressant-like effects in disorder3 10. Interestingly, ketamine rapidly reduced sui- rodents. In 2000, Berman et al.2 demonstrated the rapid- cidal thoughts in depressed patients with suicidal ideation acting and sustained antidepressant effects of the within 1 day and for up to 1 week11,12. In addition, it is NMDAR antagonist ketamine in patients with major suggested that suicidal thoughts may be related to symptoms of anhedonia independent of other depressive symptoms13. Meta-analyses revealed that ketamine has Correspondence: Kenji Hashimoto ([email protected]) rapid-acting and sustained antidepressant effects and anti- 1Division of Clinical Neuroscience, Chiba University Center for Forensic Mental suicidal ideation effects in treatment-resistant patients – Health, Chiba 260-8670, Japan with depression14 16. Importantly, meta-analyses showed 2Department of Biomedical Science, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan that the effect sizes of ketamine are larger than those of Full list of author information is available at the end of the article. © 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/. -174- Zhang et al. Translational Psychiatry (2020)10:32 Page 2 of 12 other NMDAR antagonists14,15, suggesting that NMDAR whether the novel molecule (i.e., TGF-β) has rapid-acting blockade is not a sole mechanism of antidepressant action and sustained antidepressant effects in rodent models of for ketamine. The collective rapid-acting and sustained depression. antidepressant actions of ketamine in depressed patients – are serendipitous in the field of psychiatry;17 19 however, Materials and methods the precise molecular and cellular mechanisms underlying Animals antidepressant effects of ketamine remain to be eluci- Male adult C57BL/6 mice, aged 8 weeks (body weight – dated20 25. Off-label use of ketamine is popular in the 20–25 g, Japan SLC, Inc., Hamamatsu, Japan), male CD1 United States (US), although the adverse side-effects (i.e., mice, aged 14 weeks (body weight 40–45 g, Japan SLC, psychotomimetic effects, dissociation, and abuse liability) Inc., Hamamatsu, Japan) were used in the experiments. of ketamine remain to be resolved26,27. Male Sprague-Dawley rats, aged 7 weeks (body weight Ketamine (Ki = 0.53 μM for NMDAR), also known as (R, 200–230 g, Charles-River Japan, Co., Tokyo, Japan) were S)-ketamine, is a racemic mixture that contains equal used for learned helplessness (LH) model. No blinding for amounts of (R)-ketamine (or arketamine) (Ki = 1.4 μMfor animal experiments was done. Animals were housed NMDAR) and (S)-ketamine (or esketamine) (Ki = 0.30 μM under controlled temperature and 12 h light/dark cycles for NMDAR)24. Preclinical data have shown that (R)-keta- (lights on between 07:00–19:00), with ad libitum food and mine displays greater potency and longer -lasting anti- water. The study was approved by the Chiba University depressant effects than (S)-ketamine in rodent models of Institutional Animal Care and Use Committee. – depression28 34, suggesting that NMDARs do not play a major role in the robust antidepressant effects of keta- Compounds and treatment mine24. Importantly, in both rodents and monkey, the side- (R)-ketamine hydrochloride and (S)-ketamine hydro- effects of (R)-ketamine were lower than were those of (R,S)- chloride were prepared by recrystallization of (R,S)-keta- – ® ketamine and (S)-ketamine29,35 38. In addition, in humans, mine (Ketalar , ketamine hydrochloride, Daiichi Sankyo the incidence of psychotomimetic side-effects of (S)-keta- Pharmaceutical Ltd., Tokyo, Japan) and D-(-)-tartaric acid mine (0.45 mg/kg) was higher than that of (R)-ketamine (or L− (+)-tartaric acid), respectively28. The purity of (1.8 mg/kg), although the dose of (S)-ketamine was lower these enantiomers was determined by a high-performance ® than was that of (R)-ketamine39.Though(S)-ketamine liquid chromatography (CHIRALPAK IA, Column size: produced psychotic reactions, including depersonalization 250 × 4.6 mm, Mobile phase: n-hexane/dichloromethane/ and hallucinations, the same dosage of (R)-ketamine did not diethylamine (75/25/0.1), Daicel Corporation, Tokyo, induce psychotic symptoms in the healthy subjects, and Japan)28. The dose (10 mg/kg as hydrochloride salt) of most of them experienced a state of relaxation40.These (R)-ketamine and (S)-ketamine was selected as reported – results indicate that (S)-ketamine contributes to the acute previously28,29,32 35. RepSox (10 mg/kg, i.p., a TGF-β1 side-effects of ketamine, whereas (R)-ketamine may not be receptor inhibitor; Selleck Chemicals, Co., Ltd, Houston, associated with these side-effects22,24. On 5 March 2019, the TX, USA), SB431542 (10 μM, 2 μl, i.c.v., a TGF-β1 US Food & Drug Administration approved (S)-ketamine receptor inhibitor; Tocris Bioscience, Ltd., Bristol, UK), nasal spray for treatment-resistant depressed patients. Due neutralized TGF-β antibody (Catalog #: MAB1835–500; to the risk of serious adverse effects, (S)-ketamine nasal R&D System, Inc. Minneapolis, MN), and mouse IgG1 spray can be obtained only through a restricted distribution control antibody (Catalog #: MAB002; R&D System, Inc. system under the Risk Evaluation and Mitigation Strategy. Minneapolis, MN) were used. Recombinant mouse TGF- A clinical trial of (R)-ketamine in humans is underway24. β1 (Catalog #: 7666-MB-005; R&D System, Inc. Minnea- Meanwhile, little is known about the precise molecular polis, MN) and recombinant mouse TGF-β2 (Catalog #: mechanisms underlying the different antidepressant effects 302-B2; R&D System, Inc. Minneapolis, MN) were used as of the two enantiomers24,25,41,42. previously reported45,46. PLX3397 [Pexidartinib: a colony- The aim of this study was to identify the novel mole- stimulating factor 1 receptor (CSF1R) inhibitor, Med- cular mechanisms underlying the antidepressant effects of ChemExpress Co., Ltd., Monmouth Junction, NJ] was (R)-ketamine in animal models of depression. First, we used to decrease microglia in the brain. LPS (Catalog #: L- conducted RNA-sequencing analysis of the prefrontal 4130, serotype 0111:B4, Sigma-Aldrich, St
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