Journal
MOLECULAR PSYCHIATRY
Volume 27, Issue 3, Pages 1618-1629Publisher
SPRINGERNATURE
DOI: 10.1038/s41380-021-01377-7
Keywords
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Funding
- National Natural Science Foundation of China [81973341, 81630104, 81973748]
- Fundamental Research Funds for the Central Universities [11620425, 21620426]
- Science and Technology Program of Guangzhou [202002030010]
- Huang Zhendong Research Fund for Traditional Chinese Medicine of Jinan University [201911]
- Japan Society for the Promotion of Science [24116006, 21H02846]
- Grants-in-Aid for Scientific Research [21H02846] Funding Source: KAKEN
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The study revealed that (R)-ketamine exerts its antidepressant-like effects through activation of the ERK-NRBP1-CREB-BDNF pathway in microglia. By increasing the expression of NRBP1, BDNF, and p-CREB/CREB ratio, as well as promoting BDNF transcription and suppressing MeCP2 in microglia, (R)-ketamine demonstrates prolonged antidepressant effects compared to (S)-ketamine. Additionally, microglial depletion or inhibition using specific inhibitors blocked the antidepressant-like effects of (R)-ketamine in susceptible mice, indicating the importance of microglia in mediating the antidepressant actions of (R)-ketamine.
(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.
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