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7-Chlorokynurenic acid (7-CTKA) produces rapid antidepressant-like effects: through regulating hippocampal microRNA expressions involved in TrkB-ERK/Akt signaling pathways in mice exposed to chronic unpredictable mild stress

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Abstract

Rationale

7-Chlorokynurenic acid (7-CTKA), a NMDA receptor antagonist, has been reported as a potential rapid antidepressant with poor understanding about the molecular mechanism of its therapeutic action. MicroRNAs (miRNAs) are emerging as critical regulators of central nervous system plasticity and may play an important role in depression.

Objective

The objective of this study was to investigate the molecular mechanism of antidepressant action of 7-CTKA in chronic unpredictable mild stress (CUMS) animal model.

Methods

K252a (tropomyosin-related kinase receptor B (TrkB) antagonist), U0126 (extracellular signal-regulated kinase (ERK) phosphorylation inhibitor), LY294002 (serine-threonine kinase (Akt) phosphorylation inhibitor), or vehicle was given intracerebroventricularly to mice in each group 30 min before 7-CTKA or vehicle intraperitoneal injection. Behavioral changes were observed by sucrose preference test and miRNA microarray was performed to examine hippocampal miRNAs levels in mice. Quantitative RT-PCR was conducted to further confirm results in microarray study.

Results

7-CTKA not only reversed the decrease in sucrose preference and multiple hippocampal miRNAs changes induced by CUMS but also mediated 15 common miRNAs via TrkB-ERK/Akt pathways. Among them, the expression levels of four miRNAs (miR-34a-5p, miR-200a-3p, miR-144-3p, miR-1894-5p) were validated by quantitative real-time PCR (qRT-PCR). The findings from qRT-PCR study support results from microarray analysis except for the non-significance of miR-1894-5p expression.

Conclusions

This demonstrated that the 15 miRNA targets shared by TrkB-ERK/Akt pathways might participate in rapid-acting molecular mechanism of antidepressant 7-CTKA.

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References

  • Angelucci F, Brene S, Mathe AA (2005) BDNF in schizophrenia, depression and corresponding animal models. Mol Psychiatry 10:345–352

    Article  CAS  PubMed  Google Scholar 

  • Cao MQ, Chen DH, Zhang CH, Wu ZZ (2013) Screening of specific microRNA in hippocampus of depression model rats and intervention effect of Chaihu Shugan San. Zhongguo Zhong Yao Za Zhi 38:1585–1589

    PubMed  Google Scholar 

  • Castren E, Rantamaki T (2010) The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity. Dev Neurobiol 70:289–297

    Article  CAS  PubMed  Google Scholar 

  • Chen J, Graham S, Moroni F, Simon R (1993) A study of the dose dependency of a glycine receptor antagonist in focal ischemia. J Pharmacol Exp Ther 267:937–941

    CAS  PubMed  Google Scholar 

  • Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, Seeley RJ (2006) Hypothalamic mTOR signaling regulates food intake. Science 312:927–930

    Article  CAS  PubMed  Google Scholar 

  • Duman RS, Voleti B (2012) Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents. Trends Neurosci 35:47–56

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Dwivedi Y, Rizavi HS, Roberts RC, Conley RC, Tamminga CA, Pandey GN (2001) Reduced activation and expression of ERK1/2 MAP kinase in the post-mortem brain of depressed suicide subjects. J Neurochem 77:916–928

    Article  CAS  PubMed  Google Scholar 

  • Dwivedi Y, Rizavi HS, Conley RR, Pandey GN (2006) ERK MAP kinase signaling in post-mortem brain of suicide subjects: differential regulation of upstream Raf kinases Raf-1 and B-Raf. Mol Psychiatry 11:86–98

    Article  CAS  PubMed  Google Scholar 

  • Dwivedi Y (2011) Evidence demonstrating role of microRNAs in the etiopathology of major depression. J Chem Neuroanat 42:142–156

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ge JF, Qi CC, Zhou JN (2013) Imbalance of leptin pathway and hypothalamus synaptic plasticity markers are associated with stress-induced depression in rats. Behav Brain Res 249:38–43

    Article  CAS  PubMed  Google Scholar 

  • Guo W, Ji Y, Wang S, Sun Y, Lu B (2014) Neuronal activity alters BDNF-TrkB signaling kinetics and downstream functions. J Cell Sci 127:2249–2260

    Article  CAS  PubMed  Google Scholar 

  • Kenney JW, Gould TJ (2008) Modulation of hippocampus-dependent learning and synaptic plasticity by nicotine. Mol Neurobiol 38:101–121

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen HU, Kendler KS (1994) Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 51:8–19

    Article  CAS  PubMed  Google Scholar 

  • Krishnan V, Han MH, Mazei-Robison M et al (2008) AKT signaling within the ventral tegmental area regulates cellular and behavioral responses to stressful stimuli. Biol Psychiatry 64:691–700

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Krol J, Loedige I, Filipowicz W (2010) The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 11:597–610

    CAS  PubMed  Google Scholar 

  • Launay JM, Mouillet-Richard S, Baudry A, Pietri M, Kellermann O (2011) Raphe-mediated signals control the hippocampal response to SRI antidepressants via miR-16. Transl Psychiatry 1:e56

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329:959–964

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, Li XY, Aghajanian G, Duman RS (2011) Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 69:754–761

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lugli G, Torvik VI, Larson J, Smalheiser NR (2008) Expression of microRNAs and their precursors in synaptic fractions of adult mouse forebrain. J Neurochem 106:650–661

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Machado-Vieira R, Salvadore G, DiazGranados N, Ibrahim L, Latov D, Wheeler-Castillo C, Baumann J, Henter ID, Zarate CA Jr (2010) New therapeutic targets for mood disorders. ScientificWorldJournal 10:713–726

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Manji HK, Quiroz JA, Sporn J, Payne JL, Denicoff K, Gray NA, Zarate CA Jr, Charney DS (2003) Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol Psychiatry 53:707–742

    Article  CAS  PubMed  Google Scholar 

  • Mann JJ (1998) The neurobiology of suicide. Nat Med 4:25–30

    Article  CAS  PubMed  Google Scholar 

  • Mannironi C, Camon J, De Vito F et al (2013) Acute stress alters amygdala microRNA miR-135a and miR-124 expression: inferences for corticosteroid dependent stress response. PLoS One 8:e73385

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mao QQ, Ip SP, Ko KM, Tsai SH, Che CT (2009) Peony glycosides produce antidepressant-like action in mice exposed to chronic unpredictable mild stress: effects on hypothalamic-pituitary-adrenal function and brain-derived neurotrophic factor. Prog Neuropsychopharmacol Biol Psychiatry 33:1211–1216

    Article  CAS  PubMed  Google Scholar 

  • McEwen BS (1999) Stress and hippocampal plasticity. Annu Rev Neurosci 22:105–122

    Article  CAS  PubMed  Google Scholar 

  • Numakawa T, Adachi N, Richards M, Chiba S, Kunugi H (2013) Brain-derived neurotrophic factor and glucocorticoids: reciprocal influence on the central nervous system. Neuroscience 239:157–172

    Article  CAS  PubMed  Google Scholar 

  • O’Connor RM, Dinan TG, Cryan JF (2012) Little things on which happiness depends: microRNAs as novel therapeutic targets for the treatment of anxiety and depression. Mol Psychiatry 17:359–376

    Article  PubMed  Google Scholar 

  • O’Connor RM, Grenham S, Dinan TG, Cryan JF (2013) microRNAs as novel antidepressant targets: converging effects of ketamine and electroconvulsive shock therapy in the rat hippocampus. Int J Neuropsychopharmacol 16:1885–1892

    Article  PubMed  Google Scholar 

  • Schweizer MC, Henniger MS, Sillaber I (2009) Chronic mild stress (CMS) in mice: of anhedonia, ‘anomalous anxiolysis’ and activity. PLoS One 4:e4326

    Article  PubMed Central  PubMed  Google Scholar 

  • Soloff PH, Lynch KG, Kelly TM, Malone KM, Mann JJ (2000) Characteristics of suicide attempts of patients with major depressive episode and borderline personality disorder: a comparative study. Am J Psychiatry 157:601–608

    Article  CAS  PubMed  Google Scholar 

  • Sui L, Wang J, Li BM (2008) Role of the phosphoinositide 3-kinase-Akt-mammalian target of the rapamycin signaling pathway in long-term potentiation and trace fear conditioning memory in rat medial prefrontal cortex. Learn Mem 15:762–776

    Article  CAS  PubMed  Google Scholar 

  • Wu SY, Wang TF, Yu L, Jen CJ, Chuang JI, Wu FS, Wu CW, Kuo YM (2011) Running exercise protects the substantia nigra dopaminergic neurons against inflammation-induced degeneration via the activation of BDNF signaling pathway. Brain Behav Immun 25:135–146

    Article  CAS  PubMed  Google Scholar 

  • Yuan P, Zhou R, Wang Y, Li X, Li J, Chen G, Guitart X, Manji HK (2010) Altered levels of extracellular signal-regulated kinase signaling proteins in postmortem frontal cortex of individuals with mood disorders and schizophrenia. J Affect Disord 124:164–169

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhou R, Yuan P, Wang Y, Hunsberger JG, Elkahloun A et al (2009) Evidence for selective microRNAs and their effectors as common long-term targets for the actions of mood stabilizers. Neuropsychopharmacology 34:1395–1405

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhu WL, Wang SJ, Liu MM, Shi HS, Zhang RX, Liu JF, Ding ZB, Lu L (2013) Glycine site N-methyl-D-aspartate receptor antagonist 7-CTKA produces rapid antidepressant-like effects in male rats. J Psychiatry Neurosci 38:306–316

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The project was supported by grants from the National Natural Science Foundation of China (No. 81202940), the Science Research Foundation of ministry of Health & United Fujian Provincial Health and Education Project for Tacking the Key Research (WKJ-FJ-31) and the Promotion Program for Young and Middle-aged Teacher in Science and Technology Research of Huaqiao University (ZQN-PY218).

Conflict of interest

The authors declare that they have no financial or commercial conflicts of interest.

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Authors and Affiliations

  1. Department of Chemical and Pharmaceutical Engineering, College of Chemical Engineering, Huaqiao University, Xiamen, 361021, Fujian Province, People’s Republic of China

    Bin-Bin Liu, Liu Luo, Xiao-Long Liu, Di Geng, Qing Liu & Li-Tao Yi

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  1. Bin-Bin Liu
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  2. Liu Luo
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  3. Xiao-Long Liu
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  4. Di Geng
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  5. Qing Liu
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  6. Li-Tao Yi
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Correspondence to Li-Tao Yi.

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Liu, BB., Luo, L., Liu, XL. et al. 7-Chlorokynurenic acid (7-CTKA) produces rapid antidepressant-like effects: through regulating hippocampal microRNA expressions involved in TrkB-ERK/Akt signaling pathways in mice exposed to chronic unpredictable mild stress. Psychopharmacology 232, 541–550 (2015). https://doi.org/10.1007/s00213-014-3690-3

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  • DOI: https://doi.org/10.1007/s00213-014-3690-3

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