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.
Highlights
Depression is the most common psychiatric disorder in the world
We investigated the role of nuclear receptor-binding protein 1 (NRBP1), upstream and downstream signaling such as the extracellular signal-regulated kinase (ERK), cAMP response element binding protein (CREB), and brain-derived neurotrophic factor (BDNF) in the antidepressant-like effects of (R)-ketamine
These results suggest that activation of BDNF via activation of CREB in microglia might play a role in the antidepressant-like effects of (R)-ketamine
Summary
Depression is the most common psychiatric disorder in the world. The currently available antidepressants have important limitations such as delayed onset from weeks to months and low rates of efficacy. The serendipitous discovery of the robust antidepressant actions of the N-methyl-D-aspartate receptor (NMDAR) antagonist (R,S)-ketamine in depressed patients has led to new avenues in mood disorders [1,2,3,4]. In 2000, Berman et al [5] reported rapid-acting and sustained antidepressant effects of (R,S)-ketamine in patients with depression. Several groups replicated the robust antidepressant effects of (R,S)-ketamine in treatment-resistant patients with major depression or bipolar disorder [6,7,8,9,10,11,12]. Meta-analyses revealed that (R,S)ketamine has rapid-acting and sustained antidepressant effects, and anti-suicidal ideation effects in treatment-resistant patients with depression [15,16,17,18]. The precise molecular and cellular mechanisms underlying antidepressant effects of (R,S)-ketamine remain poorly understood [19,20,21,22,23,24]
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