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Essential role of microglial transforming growth factor-?1 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-?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)-? 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-?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-?1 elicited rapid and long-lasting antidepressant effects in animal models of depression. Our data implicate a novel microglial TGF-?1-dependent mechanism underlying the antidepressant effects of (R)-ketamine in rodents with depression-like phenotype. Moreover, TGF-?1 and its receptor agonists would likely constitute a novel rapid-acting and sustained antidepressant in humans.

SUBMITTER: Zhang K

PROVIDER: S-EPMC7026089 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Zhang Kai K Yang Chun C Chang Lijia L Sakamoto Akemi A Suzuki Toru T Fujita Yuko Y Qu Youge Y Wang Siming S Pu Yaoyu Y Tan Yunfei Y Wang Xingming X Ishima Tamaki T Shirayama Yukihiko Y Hatano Masahiko M Tanaka Kenji F KF Hashimoto Kenji K

Translational psychiatry 20200127 1

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 soci ...[more]

PMID: 32066676

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Project description:(R,S)-ketamine elicits rapid-acting and sustained antidepressant actions in treatment-resistant patients with depression. (R)-ketamine produces longer-lasting antidepressant effects than (S)-ketamine in rodents; however, the precise molecular mechanisms underlying antidepressant actions of (R)-ketamine remain unknown. Using isobaric Tag for Relative and Absolute Quantification, we identified nuclear receptor-binding protein 1 (NRBP1) that could contribute to different antidepressant-like effects of the two enantiomers in chronic social defeat stress (CSDS) model. NRBP1 was localized in the microglia and neuron, not astrocyte, of mouse medial prefrontal cortex (mPFC). (R)-ketamine increased the expression of NRBP1, brain-derived neurotrophic factor (BDNF), and phosphorylated cAMP response element binding protein (p-CREB)/CREB ratio in primary microglia cultures thorough the extracellular signal-regulated kinase (ERK) activation. Furthermore, (R)-ketamine could activate BDNF transcription through activation of CREB as well as MeCP2 (methyl-CpG binding protein 2) suppression in microglia. Single intracerebroventricular (i.c.v.) injection of CREB-DNA/RNA heteroduplex oligonucleotides (CREB-HDO) or BDNF exon IV-HDO blocked the antidepressant-like effects of (R)-ketamine in CSDS susceptible mice. Moreover, microglial depletion by colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX3397 blocked the antidepressant-like effects of (R)-ketamine in CSDS susceptible mice. In addition, inhibition of microglia by single i.c.v. injection of mannosylated clodronate liposomes (MCLs) significantly blocked the antidepressant-like effects of (R)-ketamine in CSDS susceptible mice. Finally, single i.c.v. injection of CREB-HDO, BDNF exon IV-HDO or MCLs blocked the beneficial effects of (R)-ketamine on the reduced dendritic spine density in the mPFC of CSDS susceptible mice. These data suggest a novel ERK-NRBP1-CREB-BDNF pathways in microglia underlying antidepressant-like effects of (R)-ketamine.

Project description:(R,S)-Ketamine has rapid and sustained antidepressant effects in depressed patients. Although the metabolism of (R,S)-ketamine to (2 R,6 R)-hydroxynorketamine (HNK), a metabolite of (R)-ketamine, has been reported to be essential for its antidepressant effects, recent evidence suggests otherwise. The present study investigated the role of the metabolism of (R)-ketamine to (2 R,6 R)-HNK in the antidepressant actions of (R)-ketamine. Antidepressant effects were evaluated using the forced swimming test in the lipopolysaccharide (LPS)-induced inflammation model of mice and the tail suspension test in naive mice. To prevent the metabolism of (R)-ketamine to (2 R,6 R)-HNK, mice were pretreated with cytochrome P450 (CYP) inhibitors. The concentrations of (R)-ketamine, (R)-norketamine, and (2 R,6 R)-HNK in plasma, brain, and cerebrospinal fluid (CSF) samples were determined using enantioselective liquid chromatography-tandem mass spectrometry. The concentrations of (R)-norketamine and (2 R,6 R)-HNK in plasma, brain, and CSF samples after administration of (R)-norketamine (10 mg/kg) and (2 R,6 R)-HNK (10 mg/kg), respectively, were higher than those generated after administration of (R)-ketamine (10 mg/kg). Nonetheless, while (R)-ketamine attenuated, neither (R)-norketamine nor (2 R,6 R)-HNK significantly altered immobility times of LPS-treated mice. Treatment with CYP inhibitors prior to administration of (R)-ketamine increased the plasma levels of (R)-ketamine, while generation of (2 R,6 R)-HNK was almost completely blocked. (R)-Ketamine exerted the antidepressant effects at a lower dose in the presence of CYP inhibitors than in their absence, which is consistent with exposure levels of (R)-ketamine but not (2 R,6 R)-HNK. These results indicate that metabolism to (2 R,6 R)-HNK is not necessary for the antidepressant effects of (R)-ketamine and that unmetabolized (R)-ketamine itself may be responsible for its antidepressant actions.

Dataset Information

Essential role of microglial transforming growth factor-?1 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-?1.

Publications

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

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