Advertisement

Russian Journal of Genetics: Applied Research

, Volume 5, Issue 6, pp 582–588 | Cite as

Expression of genes in the brain associated with depression

  • N. N. Dygalo
  • M. Yu. Stepanichev
  • N. V. Gulyaeva
  • G. T. Shishkina
Article

Abstract

Meta-analysis of genome-wide studies involving thousands of patients and healthy subjects did not reveal significant genetic associations with major depressive disorder (Ripke et al., 2013), which may be due to the heterogeneity of this pathology. To identify the genetic base of depression, it is obviously necessary to assess the contributions of not only the alleles of individual genes but also of the gene complex altering activity of molecular pathways, which are important in the disease manifestation. The range of genes in which variability contributes to a genetic predisposition to depression includes genes inducing activity in neurotransmission systems, stress and immune response, and neurotrophic and apoptotic processes. Impairments of the functions of glutamate, norepinephrine, GABA, serotonin (5-HT), and other neurotransmitters in the brain contribute to the pathology. While the contribution of individual genes of neurotransmitter systems in the pathology can be smallish, the summation of effects of alleles of several genes that contribute to the disease and those of adverse life circumstances may predispose one to develop depression. Stress converts the genetic predisposition into psychopathology via epigenetic regulation of gene activity. Neuroplasticity and inflammatory processes in the brain that depend on the functions of neurotrophins and interleukins contribute significantly to psychopathology. The resistance of brain structure and its cells to damaging genetic and/or environmental factors is an important component for predisposition of an individual to depression state. Neurotrophins activate the expression of proteins, such as anti-apoptotic proteins Bcl-2 and Bcl-xL, which protect cells from death and counteract the effects of pathogenic processes damaging brain structure. Obviously, the interaction of different sets of alleles that predispose or counteract the development of pathology with environmental factors, such as stress, determines individual differences in resistance to the manifestation of depression.

Keywords

depression gene expression serotonergic system stress system neurotrophins immune system factors cell viability proteins 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Anisman, H., Du, L., Palkovits, M., Faludi, G., et al., Serotonin receptor subtype and p11 mRNA expression in stress-relevant brain regions of suicide and control subjects, J. Psychiatry Neurosci., 2008, vol. 33, pp. 131–141.PubMedCentralPubMedGoogle Scholar
  2. Arango, V., Underwood, M.D., Boldrini, M., et al., Serotonin 1a receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims, Neuropsychopharmacology, 2001, vol. 25, pp. 892–903.CrossRefPubMedGoogle Scholar
  3. Van der Auwera, S., Janowitz, D., Schulz, A., et al., Interaction among childhood trauma and functional polymorphisms in the serotonin pathway moderate the risk of depressive disorders, Eur. Arch. Psychiatry. Clin. Neurosci., 2014, suppl. 1, pp. 45–54.CrossRefGoogle Scholar
  4. Bach-Mizrachi, H., Underwood, M.D., Tin, A., et al., Elevated expression of tryptophan hydroxylase-2 mRNA at the neuronal level in the dorsal and median raphe nuclei of depressed suicides, Mol. Psychiatry, 2008, vol. 13, no. 5, pp. 507–513.PubMedCentralCrossRefPubMedGoogle Scholar
  5. Bethea, C.L., Phu, K., Reddy, A.P., and Cameron, J.L., The effect of short-term stress on serotonin gene expression in high and low resilient macaques, Prog. Neuropsychopharmacol. Biol. Psychiatry, 2013, vol. 44, pp. 143–153.PubMedCentralCrossRefPubMedGoogle Scholar
  6. Bufalino, C., Hepgul, N., Aguglia, E., and Pariante, C.M., The role of immune genes in the association between depression and inflammation: a review of recent clinical studies, Brain Behav. Immun., 2013, vol. 31, pp. 31–47.CrossRefPubMedGoogle Scholar
  7. Chandley, M.J., Szebeni, A., Szebeni, K., et al., Elevated gene expression of glutamate receptors in noradrenergic neurons from the locus coeruleus in major depression, Int. J. Neuropsychopharmacol., 2014, vol. 17, no. 10, pp. 1569–1578.CrossRefPubMedGoogle Scholar
  8. Choudary, P.V., Molnar, M., Evans, S.J., et al., Altered cortical glutamatergic and gabaergic signal transmission with glial involvement in depression, Proc. Natl. Acad. Sci. USA, 2005, vol. 102, no. 43, pp. 15653–15658.PubMedCentralCrossRefPubMedGoogle Scholar
  9. Curry, J., Silva, S., Rohde, P., Ginsburg, G., Kratochvil, C., Si-mons, A., Kirchner, J., May, D., Kennard, B., Mayes, T., Feeny, N., Albano, A.M., Lavanier, S., Reinecke, M., Jacobs, R., Becker-Weidman, E., Weller, E., Emslie, G., Walkup, J., Kastelic, E., Burns, B., Wells, K., and March, J., Recovery and recurrence following treatment for adolescent major depression, Arch. Gen. Psychiatry, 2011, vol. 68, no. 3, pp. 263–269.PubMedCentralCrossRefPubMedGoogle Scholar
  10. Diz-Chaves, Y., Pernia, O., Carrero, P., and Garcia-Segura, L.M., Prenatal stress causes alterations in the morphology of microglia and the inflammatory response of the hippocampus of adult female mice, J. Neuroinflammation., 2012, vol. 9, article 71.PubMedCentralCrossRefPubMedGoogle Scholar
  11. Dwivedi, Y., Rizavi, H.S., Conley, R.R., et al., Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects, Arch. Gen. Psychiatry, 2003, vol. 60, pp. 804–815.CrossRefPubMedGoogle Scholar
  12. Dygalo, N.N., Shishkina, G.T., Kalinina, T.S., et al., Effect of repeated treatment with fluoxetine on tryptophan hydroxylase-2 gene expression in the rat brainstem, Pharmacol. Biochem. Behav., 2006, vol. 85, no. 1, pp. 220–227.CrossRefPubMedGoogle Scholar
  13. Dygalo, N.N., Kalinina, T.S., Bulygina, V.V., and Shishkina, G.T., Increased expression of the anti-apoptotic protein bcl-xl in the brain is associated with resilience to stress-induced depression-like behavior, Cell. Mol. Neurobiol., 2012, vol. 32, no. 5, pp. 767–776.CrossRefPubMedGoogle Scholar
  14. Enhancing Neuro Imaging Genetics through Meta-Analysis Consortium. Identification of common variants associated with human hippocampal and intracranial volumes, Nat. Genet., 2012, vol. 44, no. 5, pp. 552–561.CrossRefGoogle Scholar
  15. Fabbri, C., Porcelli, S., and Serretti, A., From pharmacogenetics to pharmacogenomics: the way toward the personalization of antidepressant treatment, Can. J. Psychiatry, 2014, vol. 59, no. 2, pp. 62–75.PubMedCentralPubMedGoogle Scholar
  16. Fitzgerald, K.T. and Bronstein, A.C., Selective serotonin reuptake inhibitor exposure, Top Companion Anim. Med., 2013, vol. 28, no. 1, pp. 13–17.CrossRefPubMedGoogle Scholar
  17. Flint, J. and Kendler, K.S., The genetics of major depression, Neuron, 2014, vol. 81, no. 3, pp. 484–503.PubMedCentralCrossRefPubMedGoogle Scholar
  18. Frazier, T.W., Youngstrom, E.A., Frankel, B.A., et al., Candidate gene associations with mood disorder, cognitive vulnerability, and fronto-limbic volumes, Brain Behav., 2014, vol. 4, no. 3, pp. 418–430.PubMedCentralCrossRefPubMedGoogle Scholar
  19. Frodl, T., Reinhold, E., Koutsouleris, N., et al., Interaction of childhood stress with hippocampus and prefrontal cortex volume reduction in major depression, J. Psychiatr. Res., 2010, vol. 44, no. 13, pp. 799–807.CrossRefPubMedGoogle Scholar
  20. Goswami, D.B., May, W.L., Stockmeier, C.A., and Austin, M.C., Transcriptional expression of serotonergic regulators in laser-captured microdissected dorsal raphe neurons of subjects with major depressive disorder: sex-specific differences, J. Neurochem., 2010, vol. 112, no. 2, pp. 397–409.PubMedCentralCrossRefPubMedGoogle Scholar
  21. Holsboer, F., The corticosteroid receptor hypothesis of depression, Neuropsychopharmacology, 2000, vol. 23, no. 5, pp. 477–501.CrossRefPubMedGoogle Scholar
  22. Karg, K., Burmeister, M., Shedden, K., and Sen, S., The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation, Arch. Gen. Psychiatry, 2011, vol. 68, no. 5, pp. 444–454.PubMedCentralCrossRefPubMedGoogle Scholar
  23. Kessler, R.C., The costs of depression, Psychiatr. Clin. North. Am., 2012, vol. 35, no. 1, pp. 1–14.PubMedCentralCrossRefPubMedGoogle Scholar
  24. Kishi, T., Yoshimura, R., Fukuo, Y., et al., The serotonin 1A receptor gene confer susceptibility to mood disorders: results from an extended meta-analysis of patients with major depression and bipolar disorder, Eur. Arch. Psychiatry. Clin. Neurosci., 2013, vol. 263, no. 2, pp. 105–118.CrossRefPubMedGoogle Scholar
  25. Klengel, T., Mehta, D., Anacker, C., et al., Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat. Neurosci., 2013, vol. 16, no. 1, pp. 33–41.PubMedCentralCrossRefPubMedGoogle Scholar
  26. Krishnan, V. and Nestler, E.J., The molecular neurobiology of depression, Nature, 2008, vol. 455, no. 7215, pp. 894–902.PubMedCentralCrossRefPubMedGoogle Scholar
  27. Lekman, M., Laje, G., Charney, D., et al., The FKBP5gene in depression and treatment response—an association study in the sequenced treatment alternatives to relieve depression (STAR*D) cohort, Biol. Psychiatry, 2008, vol. 63, no. 12, pp. 1103–1110.PubMedCentralCrossRefPubMedGoogle Scholar
  28. Mandelli, L., Antypa, N., Nearchou, F.A., et al., The role of serotonergic genes and environmental stress on the development of depressive symptoms and neuroticism, J. Affect. Disord., 2012, vol. 142, nos. 1/3, pp. 82–89.CrossRefPubMedGoogle Scholar
  29. Menke, A., Klengel, T., Rubel, J., et al., Genetic variation in FKBP5 associated with the extent of stress hormone dysregulation in major depression, Genes Brain Behav., 2013, vol. 12, no. 3, pp. 289–296.CrossRefPubMedGoogle Scholar
  30. Merali, Z., Kent, P., Du, L., et al., Corticotropin-releasing hormone, arginine vasopressin, gastrin-releasing peptide, and neuromedin B alterations in stress-relevant brain regions of suicides and control subjects, Biol. Psychiatry, 2006, vol. 59, no. 7, pp. 594–602.CrossRefPubMedGoogle Scholar
  31. Muguruza, C., Miranda-Azpiazu, P., Diez-Alarcia, R., et al., Evaluation of 5-HT2A and mGlu2/3 receptors in postmortem prefrontal cortex of subjects with major depressive disorder: effect of antidepressant treatment, Neuropharmacology, 2014, vol. 86, pp. 311–318.CrossRefPubMedGoogle Scholar
  32. Nurnberger, J.I.Jr., Koller, D.L., Jung, J., et al., Psychiatric genomics consortium bipolar group. Identification of pathways for bipolar disorder: a meta-analysis, JAMA Psychiatry, 2014, vol. 71, no. 6, pp. 657–664.PubMedCentralCrossRefPubMedGoogle Scholar
  33. Qi, X.R., Kamphuis, W., Wang, S., et al., Aberrant stress hormone receptor balance in the human prefrontal cortex and hypothalamic paraventricular nucleus of depressed patients, Psychoneuroendocrinology, 2013, vol. 38, no. 6, pp. 863–870.CrossRefPubMedGoogle Scholar
  34. Raadsheer, F.C., van Heerikhuize, J.J., Lucassen, P.J., et al., Corticotropin-releasing hormone mRNA levels in the paraventricular nucleus of patients with Alzheimer’s disease and depression, Am. J. Psychiatry, 1995, vol. 152, pp. 1372–1376.CrossRefPubMedGoogle Scholar
  35. Richardson-Jones, J.W., Craige, C.P., Guiard, B.P., et al., 5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants, Neuron, 2010, vol. 65, no. 1, pp. 40–52.PubMedCentralCrossRefPubMedGoogle Scholar
  36. Ripke, S., Wray, N.R., Lewis, C.M., et al., A mega-analysis of genome-wide association studies for major depressive disorder. major depressive disorder working group of the psychiatric GWAS consortium, Mol. Psychiatry, 2013, vol. 18, no. 4, pp. 497–511.CrossRefPubMedGoogle Scholar
  37. Risch, N., Herrell, R., Lehner, T., et al., Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis, J. Am. Med. Assoc., 2009, vol. 301, no. 23, pp. 2462–2471.CrossRefGoogle Scholar
  38. Rotberg, B., Kronenberg, S., Carmel, M., et al., Additive effects of 5-HTTLPR (serotonin transporter) and tryptophan hydroxylase 2 G-703T gene polymorphisms on the clinical response to citalopram among children and adolescents with depression and anxiety disorders, J. Child. Adolesc. Psychopharmacol., 2013, vol. 23, no. 2, pp. 117–122.CrossRefPubMedGoogle Scholar
  39. Samuels, B.A., Leonardo, E.D., Gadient, R., et al., Modeling treatment-resistant depression, Neuropharmacology, 2011, vol. 3, pp. 408–413.CrossRefGoogle Scholar
  40. Sanacora, G., Treccani, G., and Popoli, M., Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders, Neuropharmacology, 2012, vol. 62, no. 1, pp. 63–77.PubMedCentralCrossRefPubMedGoogle Scholar
  41. Sharp, T. and Cowen, P.J., 5-ht and depression: is the glass half-full?, Curr. Opin. Pharmacol., 2011, vol. 11, no. 1, pp. 45–51.CrossRefPubMedGoogle Scholar
  42. Shelton, R.C., Claiborne, J., Sidoryk-Wegrzynowicz, M., et al., Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression, Mol. Psychiatry, 2011, vol. 16, no. 7, pp. 751–762.PubMedCentralCrossRefPubMedGoogle Scholar
  43. Shishkina, G.T., Kalinina, T.S., and Dygalo, N.N., Upregulation of tryptophan hydroxylase-2 mRNA in the rat brain by chronic fluoxetine treatment correlates with its antidepressant effect, Neuroscience, 2007, vol. 150, no. 2, pp. 404–412.CrossRefPubMedGoogle Scholar
  44. Shishkina, G.T., Kalinina, T.S., and Dygalo, N.N., Serotonergic changes produced by repeated exposure to forced swimming: correlation with behavior, Ann. N. Y. Acad. Sci., 2008, vol. 1148, pp. 148–153.CrossRefPubMedGoogle Scholar
  45. Shishkina, G.T. and Dygalo, N.N., Neurobiological mechanisms of depression and antidepressant therapy, Zh. Vyssh. Nerv. Deyat., 2010, vol. 60, pp. 138–152.Google Scholar
  46. Shishkina, G.T., Kalinina, T.S., Berezova, I.V., et al., Resistance to the development of stress-induced behavioral despair in the forced swim test associated with elevated hippocampal Bcl-xl expression, Behav. Brain Res., 2010, vol. 213, no. 2, pp. 218–224.CrossRefPubMedGoogle Scholar
  47. Shishkina, G.T., Kalinina, T.S., and Dygalo, N.N., Effects of swim stress and fluoxetine on 5-HT1A receptor gene expression and monoamine metabolism in the rat brain regions, Cell Mol. Neurobiol., 2012a, vol. 32, no. 5, pp. 787–794.CrossRefPubMedGoogle Scholar
  48. Shishkina, G.T., Kalinina, T.S., Berezova, I.V., and Dygalo, N.N., Stress-induced activation of the brainstem Bcl-xl gene expression in rats treated with fluoxetine: correlations with serotonin metabolism and depressive-like behavior, Neuropharmacology, 2012b, vol. 62, no. 1, pp. 177–183.CrossRefPubMedGoogle Scholar
  49. Stein, D.J., Daniels, W.M., Savitz, J., and Harvey, B.H., Brain-derived neurotrophic factor: the neurotrophin hypothesis of psychopathology, CNS Spectr., 2008, vol. 13, no. 11, pp. 945–949.PubMedGoogle Scholar
  50. Stepanichev, M., Dygalo, N.N., Grigoryan, G., et al., Rodent models of depression: neurotrophic and neuroinflammatory biomarkers, Biomed. Res. Int., 2014, vol. 2014, p. 932757.PubMedCentralCrossRefPubMedGoogle Scholar
  51. Uemura, T., Green, M., Corson, T.W., et al., Bcl-2 SNP rs956572 associates with disrupted intracellular calcium homeostasis in bipolar I disorder, Bipolar. Disord., 2011, vol. 13, pp. 41–51.CrossRefPubMedGoogle Scholar
  52. Uher, R., Gene-environment interactions in severe mental illness, Front. Psychiatry, 2014, vol. 5, Article 48.Google Scholar
  53. Wang, S.S., Kamphuis, W., Huitinga, I., et al., Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR: the presence of multiple receptor imbalances, Mol. Psychiatry, 2008, vol. 13, no. 8, pp. 786–799.CrossRefPubMedGoogle Scholar
  54. Wann, B.P., Bah, T.M., Kaloustian, S., et al., Behavioural signs of depression and apoptosis in the limbic system following myocardial infarction: effects of sertraline, J. Psychopharmacol., 2009, vol. 23, no. 4, pp. 451–459.CrossRefPubMedGoogle Scholar
  55. You, Z., Luo, C., Zhang, W., et al., Proand anti-inflammatory cytokines expression in rat’s brain and spleen exposed to chronic mild stress: involvement in depression, Behavioural Brain Res., 2011, vol. 225, no. 1, pp. 135–141.CrossRefGoogle Scholar
  56. Zhang, C., Wu, Z., Hong, W., et al., Influence of BCL2 gene in major depression susceptibility and antidepressant treatment outcome, J. Affect. Disord., 2014, vol. 155, pp. 288–294.CrossRefPubMedGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2015

Authors and Affiliations

  • N. N. Dygalo
    • 1
    • 2
  • M. Yu. Stepanichev
    • 3
  • N. V. Gulyaeva
    • 3
  • G. T. Shishkina
    • 1
  1. 1.Institute of Cytology and Genetics, Siberian BranchRussian Academy of SciencesNovosibirskRussia
  2. 2.Novosibirsk State UniversityNovosibirskRussia
  3. 3.Institute of Higher Nervous Activity and NeurophysiologyRussian Academy of SciencesMoscowRussia

Personalised recommendations