Essential role of microglial transforming growth factor-β1 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-β1
Essential role of microglial transforming growth factor-β1 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-β1
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DOI：
10.1038/s41398-020-0733-x
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发表时间：
2020-01-27
影响因子：
6.8
通讯作者：
Hashimoto, Kenji
中科院分区：
文献类型：
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作者：
Zhang, Kai;Yang, Chun;Hashimoto, Kenji
在抑郁症啮齿动物模型中，(R)-氯胺酮比 (S)-氯胺酮具有更强的效力和更持久的抗抑郁作用；然而，(R)-氯胺酮抗抑郁作用的确切分子机制仍然未知。通过 RNA 测序分析，我们确定了有助于两种对映体产生不同抗抑郁作用的新分子靶点。在慢性社交挫败压力（CSDS）后，对易感小鼠施用（R）-氯胺酮（10 mg/kg）或（S）-氯胺酮（10 mg/kg）。前额皮质 (PFC) 的 RNA 测序分析和随后的 GSEA（基因集富集分析）表明，转化生长因子 (TGF)-β 信号传导可能导致两种对映体具有不同的抗抑郁作用。 (R)-氯胺酮，而非 (S)-氯胺酮，可改善 CSDS 易感小鼠 PFC 和海马中 Tgfb1 及其受体（Tgfbr1 和 Tgfbr2）表达的减少。在 CSDS 易感小鼠中，药物抑制剂（即 RepSox 和 SB431542）或 TGF-β1 中和抗体可阻断 (R)-氯胺酮的抗抑郁作用。此外，在 CSDS 易感小鼠中，集落刺激因子 1 受体 (CSF1R) 抑制剂 PLX3397 消除小胶质细胞可阻断 (R)-氯胺酮的抗抑郁作用。与 (R)-氯胺酮类似，重组 TGF-β1 在抑郁症动物模型中引发快速且持久的抗抑郁作用。我们的数据暗示了一种新的小胶质细胞 TGF-β1 依赖性机制，该机制是 (R)-氯胺酮对具有抑郁样表型的啮齿类动物的抗抑郁作用的基础。此外，TGF-β1 及其受体激动剂可能会构成一种新型的快速作用且持续的人类抗抑郁药。
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)-beta 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-beta 1 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-beta 1 elicited rapid and long-lasting antidepressant effects in animal models of depression. Our data implicate a novel microglial TGF-beta 1-dependent mechanism underlying the antidepressant effects of (R)-ketamine in rodents with depression-like phenotype. Moreover, TGF-beta 1 and its receptor agonists would likely constitute a novel rapid-acting and sustained antidepressant in humans.