Neurochemical Research

, Volume 43, Issue 5, pp 985–994 | Cite as

Microglia Polarization and Endoplasmic Reticulum Stress in Chronic Social Defeat Stress Induced Depression Mouse

  • Jie Tang
  • Wenbo Yu
  • Sheng Chen
  • Zidan Gao
  • Baoguo Xiao
Original Paper


Inflammation recently has been considered to be participated in the pathogenesis of major depressive disorder (MDD). However, the detailed mechanism of inflammation in depression has not been completely understood yet. In the present study, depression mice model was established by chronic social defeat stress (CSDS) method and confirmed by behavior examinations including forced swimming test and sucrose preference test. The decrease of spine density and postsynaptic density protein 95 (PSD95) in hippocampus further verified the depression model. Then, the microglia polarization state and endoplasmic reticulum (ER) stress were investigated. At transcriptional level, M1 marker (inducible nitric oxide synthase (iNOS), CD16, CD86, CXCL10) in CSDS mice was higher than that in control group while there was no difference in M2 marker (Arginase and CD206) between two groups. And it was observed in the hippocampus of CSDS induced depression mice that increased activated microglia was merged with iNOS instead of arginase by immunofluorescence staining. Furthermore, the M1 marker Interleukin (IL)-1β and tumor necrosis factor (TNF)-α were increased in depression mice while the M1 marker IL-6 and M2 marker IL-10 remained unchanged. The expression of ER stress signaling factors, including protein kinase RNA-like ER kinase (PERK), Phosphorylated α-subunit of eukaryotic translation initiation factor 2(p-eIF2α), C/EBP homologous protein (CHOP), and X-box binding protein 1(XBP1) were significantly higher in CSDS-induced depression mice than in control mice. In all, our results suggest that M1 polarization and ER stress play a vital role in MDD pathogenesis.


Depression Inflammation Microglia Endoplasmic reticulum stress 



This study was supported by Grants from the National Natural Science Foundation of China (No. 81671151; No. 81371414).

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interests.


  1. 1.
    Ferrari AJ, Somerville AJ, Baxter AJ et al (2013) Global variation in the prevalence and incidence of major depressive disorder: a systematic review of the epidemiological literature. Psychol Med 43(3):471–481. CrossRefPubMedGoogle Scholar
  2. 2.
    Li N, Lee B, Liu RJ et al (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329(5994):959–964. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Kang HJ, Voleti B, Hajszan T et al (2012) Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med 18(9):1413–1417. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Duman RS, Aghajanian GK (2012) Synaptic dysfunction in depression: potential therapeutic targets. Science 338(6103):68–72. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Hodes GE, Kana V, Menard C et al (2015) Neuroimmune mechanisms of depression. Nat Neurosci 18(10):1386–1393. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Yirmiya R, Rimmerman N, Reshef R (2015) Depression as a microglial disease. Trends Neurosci 38(10):637–658. CrossRefPubMedGoogle Scholar
  7. 7.
    Wohleb ES, Franklin T, Iwata M et al (2016) Integrating neuroimmune systems in the neurobiology of depression. Nat Rev Neurosci 17(8):497–511. CrossRefPubMedGoogle Scholar
  8. 8.
    Kohler CA, Freitas TH, Maes M et al (2017) Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr Scand 135(5):373–387. CrossRefPubMedGoogle Scholar
  9. 9.
    Iwata M, Ota KT, Duman RS (2013) The inflammasome: pathways linking psychological stress, depression, and systemic illnesses. Brain Behav Immun 31:105–114. CrossRefPubMedGoogle Scholar
  10. 10.
    Kohler O, Benros ME, Nordentoft M et al (2014) Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry 71(12):1381–1391. CrossRefPubMedGoogle Scholar
  11. 11.
    De Kock M, Loix S, Lavand’homme P (2013) Ketamine and peripheral inflammation. CNS Neurosci Ther 19(6):403–410. CrossRefPubMedGoogle Scholar
  12. 12.
    Bayer TA, Buslei R, Havas L et al (1999) Evidence for activation of microglia in patients with psychiatric illnesses. Neurosci Lett 271(2):126–128CrossRefPubMedGoogle Scholar
  13. 13.
    Pan Y, Chen XY, Zhang QY et al (2014) Microglial NLRP3 inflammasome activation mediates IL-1beta-related inflammation in prefrontal cortex of depressive rats. Brain Behav Immun 41:90–100. CrossRefPubMedGoogle Scholar
  14. 14.
    de Pablos RM, Herrera AJ, Espinosa-Oliva AM et al (2014) Chronic stress enhances microglia activation and exacerbates death of nigral dopaminergic neurons under conditions of inflammation. J Neuroinflammation 11:34. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Franco R, Fernandez-Suarez D (2015) Alternatively activated microglia and macrophages in the central nervous system. Prog Neurobiol 131:65–86. CrossRefPubMedGoogle Scholar
  16. 16.
    Tang Y, Le W (2016) Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol 53(2):1181–1194. CrossRefPubMedGoogle Scholar
  17. 17.
    Golden SA, Covington HE 3rd, Berton O et al (2011) A standardized protocol for repeated social defeat stress in mice. Nat Protoc 6(8):1183–1191. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Shen J, Sheng X, Chang Z et al (2014) Iron metabolism regulates p53 signaling through direct heme-p53 interaction and modulation of p53 localization, stability, and function. Cell Rep 7(1):180–193. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Li C, Hu J, Li W et al (2016) Combined bortezomib-based chemotherapy and p53 gene therapy using hollow mesoporous silica nanospheres for p53 mutant non-small cell lung cancer treatment. Biomater Sci 5(1):77–88. CrossRefPubMedGoogle Scholar
  20. 20.
    Duman RS, Aghajanian GK, Sanacora G et al (2016) Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med 22(3):238–249. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Grootjans J, Kaser A, Kaufman RJ et al (2016) The unfolded protein response in immunity and inflammation. Nat Rev Immunol 16(8):469–484. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Qu Y, Yang C, Ren Q et al (2017) Regional differences in dendritic spine density confer resilience to chronic social defeat stress. Acta Neuropsychiatr. PubMedGoogle Scholar
  23. 23.
    Yang C, Shirayama Y, Zhang JC et al (2015) Regional differences in brain-derived neurotrophic factor levels and dendritic spine density confer resilience to inescapable stress. Int J Neuropsychopharmacol. Google Scholar
  24. 24.
    Xu W (2011) PSD-95-like membrane associated guanylate kinases (PSD-MAGUKs) and synaptic plasticity. Curr Opin Neurobiol 21(2):306–312. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Beumer W, Gibney SM, Drexhage RC et al (2012) The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes. J Leukoc Biol 92(5):959–975. CrossRefPubMedGoogle Scholar
  26. 26.
    Ramirez K, Niraula A, Sheridan JF (2016) GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations. Brain Behav Immun 51:154–168. CrossRefPubMedGoogle Scholar
  27. 27.
    Ramirez K, Shea DT, McKim DB et al (2015) Imipramine attenuates neuroinflammatory signaling and reverses stress-induced social avoidance. Brain Behav Immun 46:212–220. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Nakagawa Y, Chiba K (2014) Role of microglial m1/m2 polarization in relapse and remission of psychiatric disorders and diseases. Pharmaceuticals 7(12):1028–1048. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Steiner J, Walter M, Gos T et al (2011) Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission? J Neuroinflammation 8:94. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Xie W, Cai L, Yu Y et al (2014) Activation of brain indoleamine 2,3-dioxygenase contributes to epilepsy-associated depressive-like behavior in rats with chronic temporal lobe epilepsy. J Neuroinflammation 11:41. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Muller N, Schwarz MJ, Dehning S et al (2006) The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry 11(7):680–684. CrossRefPubMedGoogle Scholar
  32. 32.
    Abbasi SH, Hosseini F, Modabbernia A et al (2012) Effect of celecoxib add-on treatment on symptoms and serum IL-6 concentrations in patients with major depressive disorder: randomized double-blind placebo-controlled study. J Affect Disord 141(2–3):308–314. CrossRefPubMedGoogle Scholar
  33. 33.
    Wiley JC, Meabon JS, Frankowski H et al (2010) Phenylbutyric acid rescues endoplasmic reticulum stress-induced suppression of APP proteolysis and prevents apoptosis in neuronal cells. PLoS ONE 5(2):e9135. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Colla E, Coune P, Liu Y et al (2012) Endoplasmic reticulum stress is important for the manifestations of alpha-synucleinopathy in vivo. J Neurosci 32(10):3306–3320. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Nevell L, Zhang K, Aiello AE et al (2014) Elevated systemic expression of ER stress related genes is associated with stress-related mental disorders in the Detroit Neighborhood Health Study. Psychoneuroendocrinology 43:62–70. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Zhang HY, Wang ZG, Lu XH et al (2015) Endoplasmic reticulum stress: relevance and therapeutics in central nervous system diseases. Mol Neurobiol 51(3):1343–1352. CrossRefPubMedGoogle Scholar
  37. 37.
    Martinez G, Vidal RL, Mardones P et al (2016) Regulation of memory formation by the transcription factor XBP1. Cell Rep 14(6):1382–1394. CrossRefPubMedGoogle Scholar
  38. 38.
    Abelaira HM, Reus GZ, Ignacio ZM et al (2017) Effects of ketamine administration on mTOR and reticulum stress signaling pathways in the brain after the infusion of rapamycin into prefrontal cortex. J Psychiatr Res 87:81–87. CrossRefPubMedGoogle Scholar
  39. 39.
    Timberlake MA 2nd, Dwivedi Y (2015) Altered expression of endoplasmic reticulum stress associated genes in hippocampus of learned helpless rats: relevance to depression pathophysiology. Front Pharmacol 6:319. PubMedGoogle Scholar
  40. 40.
    Kreisel T, Frank MG, Licht T et al (2014) Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis. Mol Psychiatry 19(6):699–709. CrossRefPubMedGoogle Scholar
  41. 41.
    Meares GP, Liu Y, Rajbhandari R et al (2014) PERK-dependent activation of JAK1 and STAT3 contributes to endoplasmic reticulum stress-induced inflammation. Mol Cell Biol 34(20):3911–3925. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Li Y, Schwabe RF, DeVries-Seimon T et al (2005) Free cholesterol-loaded macrophages are an abundant source of tumor necrosis factor-alpha and interleukin-6: model of NF-kappaB- and map kinase-dependent inflammation in advanced atherosclerosis. J Biol Chem 280(23):21763–21772. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Jie Tang
    • 1
  • Wenbo Yu
    • 1
  • Sheng Chen
    • 1
  • Zidan Gao
    • 1
  • Baoguo Xiao
    • 1
  1. 1.Department of Neurology, Huashan HospitalFudan UniversityShanghaiChina

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