Microglial ERK-NRBP1-CREB-BDNF signaling in sustained antidepressant actions of (R)-ketamine
W. Yao, Qianqian Cao, Shilin Luo, Lujuan He, Chun Yang, Jiaxu Chen, Q. Qi, Kenji Hashimoto, Ji-Chun Zhang
Molecular Psychiatry November 24, 2021 DOI: 10.1038/s41380-021-01377-7 (opens in new tab)
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Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice (chronic social defeat stress model) |
| Interventions | (R)-ketamine (S)-ketamine CREB-HDO BDNF exon IV-HDO PLX3397 mannosylated clodronate liposomes |
| Topics | Esketamine Ketamine |
| Citations | 208 |
| Key findings | (R)-ketamine's antidepressant-like effects in mice depend on the ERK-NRBP1-CREB-BDNF signaling pathway in microglia of the medial prefrontal cortex. |
Abstract
(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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 73
- Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms Neuropsychopharmacology July 24, 2023
- The Antidepressant Actions of Ketamine and its Enantiomers Pharmacology & Therapeutics May 1, 2023
- Arketamine, a new rapid-acting antidepressant: A historical review and future directions Neuropharmacology August 14, 2022
- Ketamine and its metabolites: Potential as novel treatments for depression. Neuropharmacology October 1, 2022
- Inflammation, stress and depression: an exploration of ketamine’s therapeutic profile Drug Discovery Today February 1, 2023
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Cites 39
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
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