Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression

Molecular Psychiatry volume 16, pages 751–762 (2011)Cite this article

Subjects

Abstract

The etiology of major depression (MDD), a common and complex disorder, remains obscure. Gene expression profiling was conducted on post-mortem brain tissue samples from Brodmann Area 10 (BA10) in the prefrontal cortex from psychotropic drug-free persons with a history of MDD and age, gender, and post-mortem interval-matched normal controls (n=14 pairs of subjects). Microarray analysis was conducted using the Affymetrix Exon 1.0 ST arrays. A set of differential expression changes was determined by dual-fold change-probability criteria (∣average log ratios∣>0.585 [equivalent to a 1.5-fold difference in either direction], P<0.01), whereas molecular pathways of interest were evaluated using Gene Set Enrichment Analysis software. The results strongly implicate increased apoptotic stress in the samples from the MDD group. Three anti-apoptotic factors, Y-box-binding protein 1, caspase-1 dominant-negative inhibitor pseudo-ICE, and the putative apoptosis inhibitor FKGS2, were over-expressed. Gene set analysis suggested up-regulation of a variety of pro- and anti-inflammatory cytokines, including interleukin 1α (IL-1α), IL-2, IL-3, IL-5, IL-8, IL-9, IL-10, IL-12A, IL-13, IL-15, IL-18, interferon gamma (IFNγ), and lymphotoxin α (TNF superfamily member 1). The genes showing reduced expression included metallothionein 1M (MT1M), a zinc-binding protein with a significant function in the modulation of oxidative stress. The results of this study indicate that post-mortem brain tissue samples from BA10, a region that is involved in reward-related behavior, show evidence of local inflammatory, apoptotic, and oxidative stress in MDD.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Drevets WC, Price JL, Furey ML . Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct Funct 2008; 213: 93–118.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Sibille E, Arango V, Galfalvy HC, Pavlidis P, Erraji-Benchekroun L, Ellis SP et al. Gene expression profiling of depression and suicide in human prefrontal cortex. Neuropsychopharmacology 2004; 29: 351–361.

    Article  CAS  PubMed  Google Scholar 

  3. Evans SJ, Choudary PV, Neal CR, Li JZ, Vawter MP, Tomita H et al. Dysregulation of the fibroblast growth factor system in major depression. Proc Natl Acad Sci USA 2004; 101: 15506–15511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sequeira A, Gwadry FG, French-Mullen JM, Canetti L, Gingras Y, Casero Jr RA et al. Implication of SSAT by gene expression and genetic variation in suicide and major depression. Arch Gen Psychiatry 2006; 63: 35–48.

    Article  CAS  PubMed  Google Scholar 

  5. Klempan TA, Sequeira A, Canetti L, Lalovic A, Ernst C, French-Mullen J et al. Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression. Mol Psychiatry 2007; 14: 175–189.

    Article  PubMed  Google Scholar 

  6. Choudary PV, Molnar M, Evans SJ, Tomita H, Li JZ, Vawter MP et al. Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci USA 2005; 102: 15653–15658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Aston C, Jiang L, Sokolov BP . Transcriptional profiling reveals evidence for signaling and oligodendroglial abnormalities in the temporal cortex from patients with major depressive disorder. Mol Psychiatry 2005; 10: 309–322.

    Article  CAS  PubMed  Google Scholar 

  8. Kang HJ, Adams DH, Simen A, Simen BB, Rajkowska G, Stockmeier CA et al. Gene expression profiling in postmortem prefrontal cortex of major depressive disorder. J Neurosci 2007; 27: 13329–13340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tochigi M, Iwamoto K, Bundo M, Sasaki T, Kato N, Kato T . Gene expression profiling of major depression and suicide in the prefrontal cortex of postmortem brains. Neurosci Res 2008; 60: 184–191.

    Article  CAS  PubMed  Google Scholar 

  10. Lewis DA . The human brain revisited: opportunities and challenges in postmortem studies of psychiatric disorders. Neuropsychopharmacology 2002; 26: 143–154.

    Article  PubMed  Google Scholar 

  11. Mirnics K, Levitt P, Lewis DA . DNA microarray analysis of postmortem brain tissue. Int Rev Neurobiol 2004; 60: 153–181.

    Article  CAS  PubMed  Google Scholar 

  12. Rogers RD, Owen AM, Middleton HC, Williams EJ, Pickard JD, Sahakian BJ et al. Choosing between small, likely rewards and large, unlikely rewards activates inferior and orbital prefrontal cortex. J Neurosci 1999; 19: 9029–9038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kufahl PR, Li Z, Risinger RC, Rainey CJ, Wu G, Bloom AS et al. Neural responses to acute cocaine administration in the human brain detected by fMRI. NeuroImage 2005; 28: 904–914.

    Article  PubMed  Google Scholar 

  14. Devous MD, Trivedi MH, Rush AJ . Regional cerebral blood flow response to oral amphetamine challenge in healthy volunteers. J Nuclear Med 2001; 42: 535–542.

    CAS  Google Scholar 

  15. Pizzagalli DA, Iosifescu D, Hallett LA, Ratner KG, Fava M . Reduced hedonic capacity in major depressive disorder: evidence from a probabilistic reward task. J Psychiatr Res 2008; 43: 76–87.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Pizzagalli DA, Jahn AL, O’Shea JP . Toward an objective characterization of an anhedonic phenotype: a signal-detection approach. Biol Psychiatry 2005; 57: 319–327.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Tochigi M, Iwamoto K, Bundo M, Sasaki T, Kato N, Kato T . Gene expression profiling of major depression and suicide in the prefrontal cortex of postmortem brains. Neurosci Res 2008; 60: 184–191.

    Article  CAS  PubMed  Google Scholar 

  18. Gaughran F, Payne J, Sedgwick PM, Cotter D, Berry M . Hippocampal FGF-2 and FGFR1 mRNA expression in major depression, schizophrenia and bipolar disorder. Brain Res Bull 2006; 70: 221–227.

    Article  CAS  PubMed  Google Scholar 

  19. Carroll BJ, Cassidy F, Naftolowitz D, Tatham NE, Wilson WH, Iranmanesh A et al. Pathophysiology of hypercortisolism in depression. Acta Psychiatrica Scandinavica, Supplementum 2007; 433: 90–103.

    Article  CAS  Google Scholar 

  20. Pintor L, Torres X, Navarro V, Martinez de Osaba MA, Matrai S, Gasto C . Corticotropin-releasing factor test in melancholic patients in depressed state versus recovery: a comparative study. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 1027–1033.

    Article  CAS  PubMed  Google Scholar 

  21. Garbett K, Ebert PJ, Mitchell A, Lintas C, Manzi B, Mirnics K et al. Immune transcriptome alterations in the temporal cortex of subjects with autism. Neurobiol Dis 2008; 30: 303–311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hashimoto T, Arion D, Unger T, Maldonado-Aviles JG, Morris HM, Volk DW et al. Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry 2007; 13: 147–161.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Lazarov O, Robinson J, Tang YP, Hairston IS, Korade-Mirnics Z, Lee VM et al. Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell 2005; 120: 701–713.

    Article  CAS  PubMed  Google Scholar 

  24. Mirnics K, Pevsner J . Progress in the use of microarray technology to study the neurobiology of disease. Nat Neurosci 2004; 7: 434–439.

    Article  CAS  PubMed  Google Scholar 

  25. Reich M, Liefeld T, Gould J, Lerner J, Tamayo P, Mesirov JP . GenePattern 2.0. Nat Genet 2006; 38: 500–501.

    Article  CAS  PubMed  Google Scholar 

  26. Campbell DB, D’Oronzio R, Garbett K, Ebert PJ, Mirnics K, Levitt P et al. Disruption of cerebral cortex MET signaling in autism spectrum disorder. Ann Neurol 2007; 62: 243–250.

    Article  PubMed  Google Scholar 

  27. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al. From the cover: gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005; 102: 15545–15550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Storey JD, Tibshirani R . Statistical significance for genomewide studies. Proc Natl Acad Sci USA 2003; 100: 9440–9445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang X, Narayanan M, Bruey JM, Rigamonti D, Cattaneo E, Reed JC et al. Protective role of Cop in Rip2/caspase-1/caspase-4-mediated HeLa cell death. Biochim Biophys Acta 2006; 1762: 742–754.

    Article  CAS  PubMed  Google Scholar 

  30. Martinon F, Tschopp J . Inflammatory caspases and inflammasomes: master switches of inflammation. Cell Death Differ 2007; 14: 10–22.

    Article  CAS  PubMed  Google Scholar 

  31. Wang X, Wang H, Figueroa BE, Zhang WH, Huo C, Guan Y et al. Dysregulation of receptor interacting protein-2 and caspase recruitment domain only protein mediates aberrant caspase-1 activation in Huntington's disease. J Neurosci 2005; 25: 11645–11654.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Uzonyi B, Lotzer K, Jahn S, Kramer C, Hildner M, Bretschneider E et al. Cysteinyl leukotriene 2 receptor and protease-activated receptor 1 activate strongly correlated early genes in human endothelial cells. Proc Natl Acad Sci USA 2006; 103: 6326–6331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kohno K, Izumi H, Uchiumi T, Ashizuka M, Kuwano M . The pleiotropic functions of the Y-box-binding protein, YB-1. Bioessays 2003; 25: 691–698.

    Article  CAS  PubMed  Google Scholar 

  34. McKernan DP, Dinan TG, Cryan JF . Killing the blues. A role for cellular suicide (apoptosis) in depression and the antidepressant response? Progress Neurobiol 2009; 88: 246–263.

    Article  CAS  Google Scholar 

  35. Dwivedi Y . Brain-derived neurotrophic factor: role in depression and suicide. Neuropsychiatr Dis Treat 2009; 5: 433–449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Monti S, Savage KJ, Kutok JL, Feuerhake F, Kurtin P, Mihm M et al. Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Blood 2005; 105: 1851–1861.

    Article  CAS  PubMed  Google Scholar 

  37. Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 2004; 10: 594–601.

    Article  CAS  PubMed  Google Scholar 

  38. Raison CL, Capuron L, Miller AH . Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 2006; 27: 24–31.

    Article  CAS  PubMed  Google Scholar 

  39. Maes M . The cytokine hypothesis of depression: inflammation, oxidative & nitrosative stress (IO&NS) and leaky gut as new targets for adjunctive treatments in depression. Minireview. Neuro Endocrinol Lett 2008; 29: 287–291.

    CAS  PubMed  Google Scholar 

  40. Capuron L, Miller AH . Cytokines and psychopathology: lessons from interferon-alpha. Biol Psychiatry 2004; 56: 819–824.

    Article  CAS  PubMed  Google Scholar 

  41. Capuron L, Gumnick JF, Musselman DL, Lawson DH, Reemsnyder A, Nemeroff CB et al. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology 2002; 26: 643–652.

    Article  CAS  PubMed  Google Scholar 

  42. Raison CL, Woolwine BJ, Demetrashvili MF, Borisov AS, Weinreib R, Staab JP et al. Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C. Aliment Pharmacol Ther 2007; 25: 1163–1174.

    Article  CAS  PubMed  Google Scholar 

  43. Maes M, Song C, Lin AH, Bonaccorso S, Kenis G, De Jongh R et al. Negative immunoregulatory effects of antidepressants: inhibition of interferon-gamma and stimulation of interleukin-10 secretion. Neuropsychopharmacology 1999; 20: 370–379.

    Article  CAS  PubMed  Google Scholar 

  44. Leonard BE . The immune system, depression and the action of antidepressants. Prog Neuropsychopharmacol Biol Psychiatry 2001; 25: 767–780.

    Article  CAS  PubMed  Google Scholar 

  45. Kubera M, Lin AH, Kenis G, Bosmans E, van Bockstaele D, Maes M . Anti-inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio. J Clin Psychopharmacol 2001; 21: 199–206.

    Article  CAS  PubMed  Google Scholar 

  46. Kenis G, Maes M . Effects of antidepressants on the production of cytokines. Int J Neuropsychopharmacol 2002; 5: 401–412.

    Article  CAS  PubMed  Google Scholar 

  47. O’Brien SM, Scott LV, Dinan TG . Cytokines: abnormalities in major depression and implications for pharmacological treatment. Hum Psychopharmacol 2004; 19: 397–403.

    Article  PubMed  Google Scholar 

  48. Dantzer R . Cytokine, sickness behavior, and depression. Neurol Clin 2006; 24: 441–460.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Garcia-Bueno B, Caso JR, Leza JC . Stress as a neuroinflammatory condition in brain: damaging and protective mechanisms. Neurosci Biobehav Rev 2008; 32: 1136–1151.

    Article  CAS  PubMed  Google Scholar 

  50. Miller AH, Maletic V, Raison CL . Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009; 65: 732–741.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Griffiths M, Neal JW, Gasque P . Innate immunity and protective neuroinflammation: new emphasis on the role of neuroimmune regulatory proteins. In: Giacinto Bagetta MTCa (ed). International Review of Neurobiology Neuroinflammation in Neuronal Death and Repair, Vol. 82 ed Academic Press: Amsterdam, NL, 2007, pp 29–55.

    Chapter  Google Scholar 

  52. Ekdahl CT, Kokaia Z, Lindvall O . Brain inflammation and adult neurogenesis: the dual role of microglia. Neuroscience 2009; 158: 1021–1029.

    Article  CAS  PubMed  Google Scholar 

  53. Hayley S, Poulter MO, Merali Z, Anisman H . The pathogenesis of clinical depression: stressor- and cytokine-induced alterations of neuroplasticity. Neuroscience 2005; 135: 659–678.

    Article  CAS  PubMed  Google Scholar 

  54. Bartolomucci A, Palanza P, Parmigiani S, Pederzani T, Merlot E, Neveu PJ et al. Chronic psychosocial stress down-regulates central cytokines mRNA. Brain Res Bull 2003; 62: 173–178.

    Article  CAS  PubMed  Google Scholar 

  55. Ekdahl CT, Kokaia Z, Lindvall O . Brain inflammation and adult neurogenesis: the dual role of microglia. Neuroscience 2009; 158: 1021–1029.

    Article  CAS  PubMed  Google Scholar 

  56. Zhu CB, Carneiro AM, Dostmann WR, Hewlett WA, Blakely RD . p38 MAPK activation elevates serotonin transport activity via a trafficking-independent, protein phosphatase 2A-dependent process. J Biol Chem 2005; 280: 15649–15658.

    Article  CAS  PubMed  Google Scholar 

  57. Ip WK, Wong CK, Wang CB, Tian YP, Lam CW . Interleukin-3, -5, and granulocyte macrophage colony-stimulating factor induce adhesion and chemotaxis of human eosinophils via p38 mitogen-activated protein kinase and nuclear factor kappaB. Immunopharmacol Immunotoxicol 2005; 27: 371–393.

    Article  CAS  PubMed  Google Scholar 

  58. Zhu CB, Blakely RD, Hewlett WA . The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology 2006; 31: 2121–2131.

    Article  CAS  PubMed  Google Scholar 

  59. Delgado PL, Charney DS, Price LH, Aghajanian GK, Landis H, Heninger GR . Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry 1990; 47: 411–418.

    Article  CAS  PubMed  Google Scholar 

  60. Chung RS, Leung YK, Butler CW, Chen Y, Eaton ED, Pankhurst MW et al. Metallothionein treatment attenuates microglial activation and expression of neurotoxic quinolinic acid following traumatic brain injury. Neurotox Res 2009; 15: 381–389.

    Article  CAS  PubMed  Google Scholar 

  61. Formigari A, Irato P, Santon A . Zinc, antioxidant systems and metallothionein in metal mediated-apoptosis: biochemical and cytochemical aspects. Comp Biochem Physiol C Toxicol Pharmacol 2007; 146: 443–459.

    Article  PubMed  Google Scholar 

  62. Krezel A, Hao Q, Maret W . The zinc/thiolate redox biochemistry of metallothionein and the control of zinc ion fluctuations in cell signaling. Arch Biochem Biophys 2007; 463: 188–200.

    Article  CAS  PubMed  Google Scholar 

  63. Kumari MVR, Hiramatsu M, Ebadi M . Free radical scavenging actions of metallothionein isoforms I and II. Free Radic Res 1998; 29: 93–101.

    Article  CAS  PubMed  Google Scholar 

  64. Sequeira A, Klempan T, Canetti L, ffrench-Mullen J, Benkelfat C, Rouleau GA et al. Patterns of gene expression in the limbic system of suicides with and without major depression. Mol Psychiatry 2007; 12: 640–655.

    Article  CAS  PubMed  Google Scholar 

  65. Leventhal AM, Rehm LP . The empirical status of melancholia: implications for psychology. Clin Psychol Rev 2005; 25: 25–44.

    Article  PubMed  Google Scholar 

  66. Parker G, Hadzi-Pavlovic D, Austin MP, Mitchell P, Wilhelm K, Hickie I et al. Sub-typing depression, I. Is psychomotor disturbance necessary and sufficient to the definition of melancholia? Psychol Med 1995; 25: 815–823.

    Article  CAS  PubMed  Google Scholar 

  67. Rothermundt M, Arolt V, Fenker J, Gutbrodt H, Peters M, Kirchner H . Different immune patterns in melancholic and non-melancholic major depression. Eur Arch Psychiatry Clin Neurosci 2001; 251: 90–97.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Phil Ebert (currently with Eli Lilly) for help with data analysis and Dr Christine Konradi for advising the microarray experiments. The project described was supported by grant Award Numbers MH073630 (RCS), MH079299 (KM), MH070786 (KM), and MH084053 (DAL) from the National Institute of Mental Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIMH or the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA

    R C Shelton, J Claiborne & R Reddy

  2. Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA

    M Sidoryk-Wegrzynowicz & M Aschner

  3. Departments of Psychiatry and Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA

    D A Lewis

  4. Department of Psychiatry and the John F. Kennedy Center for Human Development, Vanderbilt University, Nashville, TN, USA

    K Mirnics

Authors
  1. R C Shelton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Claiborne
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Sidoryk-Wegrzynowicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R Reddy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Aschner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D A Lewis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K Mirnics
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R C Shelton.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shelton, R., Claiborne, J., Sidoryk-Wegrzynowicz, M. et al. Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression. Mol Psychiatry 16, 751–762 (2011). https://doi.org/10.1038/mp.2010.52

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2010.52

Keywords

This article is cited by

Search

Advanced search

Quick links