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Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression

Molecular Psychiatry volume 14, pages 175–189 (2009)Cite this article

Abstract

The prefrontal cortex is believed to play a major role in depression and suicidal behavior through regulation of cognition, memory, recognition of emotion, and anxiety-like states, with numerous post-mortem studies documenting a prefrontal serotonergic dysregulation considered to be characteristic of depressive psychopathology. This study was carried out to detect changes in gene expression associated with both suicide and major depression using oligonucleotide microarrays (Affymetrix HG-U133 chip set) summarizing expression patterns in primarily ventral regions of the prefrontal cortex (BA44, 45, 46 and 47). A total of 37 male subjects were included in this study, of which 24 were suicides (depressed suicides=16, nondepressed suicides=8) and 13 were matched controls. All subjects were clinically characterized by means of psychological autopsies using structured interviews. Unique patterns of differential expression were validated in each of the cortical regions evaluated, with group-specific changes highlighting the involvement of several key neurobiological pathways that have been implicated in both suicide and depression. An overrepresentation of factors involved in cell cycle control and cell division (BA44), transcription (BA44 and 47) and myelination (BA46) was seen in gene ontology analysis of differentially expressed genes, which also highlights changes in the expression of genes involved in ATP biosynthesis and utilization across all areas. Gene misexpression in BA46 was most pronounced between the two suicide groups, with many significant genes involved in GABAergic neurotransmission. The pronounced misexpression of genes central to GABAergic signaling and astrocyte/oligodendrocyte function provides further support for a central glial pathology in depression and suicidal behavior.

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References

  1. Brent DA, Oquendo M, Birmaher B, Greenhill L, Kolko D, Stanley B et al. Familial pathways to early-onset suicide attempt: risk for suicidal behavior in offspring of mood-disordered suicide attempters. Arch Gen Psychiatry 2002; 59: 801–807.

    Article  PubMed  Google Scholar 

  2. Mann JJ, Brent DA, Arango V . The neurobiology and genetics of suicide and attempted suicide: a focus on the serotonergic system. Neuropsychopharmacology 2001; 24: 467–477.

    Article  CAS  PubMed  Google Scholar 

  3. Turecki G . Suicidal behavior: is there a genetic predisposition? Bipolar Disord 2001; 3: 335–349.

    Article  CAS  PubMed  Google Scholar 

  4. Davidson RJ, Pizzagalli D, Nitschke JB, Putnam K . Depression: perspectives from affective neuroscience. Annu Rev Psychol 2002; 53: 545–574.

    Article  PubMed  Google Scholar 

  5. Rajkowska G, Miguel-Hidalgo JJ, Dubey P, Stockmeier CA, Krishnan KR . Prominent reduction in pyramidal neurons density in the orbitofrontal cortex of elderly depressed patients. Biol Psychiatry 2005; 58: 297–306.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Mann JJ, Henteleff RA, Lagattuta TF, Perper JA, Li S, Arango V . Lower 3H-paroxetine binding in cerebral cortex of suicide victims is partly due to fewer high affinity, non-transporter sites. J Neural Transm 1996; 103: 1337–1350.

    Article  CAS  PubMed  Google Scholar 

  7. Arango V, Underwood MD, Gubbi AV, Mann JJ . Localized alterations in pre- and postsynaptic serotonin binding sites in the ventrolateral prefrontal cortex of suicide victims. Brain Res 1995; 688: 121–133.

    Article  CAS  PubMed  Google Scholar 

  8. Yanagi M, Shirakawa O, Kitamura N, Okamura K, Sakurai K, Nishiguchi N et al. Association of 14-3-3 epsilon gene haplotype with completed suicide in Japanese. J Hum Genet 2005; 50: 210–216.

    Article  PubMed  Google Scholar 

  9. Sequeira A, Gwadry FG, Ffrench-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 

  10. 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 

  11. Klempan T, Turecki G . Suicide: a neurobiological point of view. Rev Bras Psiquiatr 2005; 27: 172–173.

    Article  PubMed  Google Scholar 

  12. Labuda M, Labuda D, Korab-Laskowska M, Cole DE, Zietkiewicz E, Weissenbach J et al. Linkage disequilibrium analysis in young populations: pseudo-vitamin D-deficiency rickets and the founder effect in French Canadians. Am J Hum Genet 1996; 59: 633–643.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. DeArmond SJ, Fusco MM, Dewey MM . Structure of the Human Brain: A Photographic Atlas,3rd edn. Oxford University Press: New York, 1989.

    Google Scholar 

  14. von Economo C, Koskinas GN . Die Cytoarchitektonik der Grosshirnrinde der envachsenen Menschen. Springer: Wien-Berlin, 1925.

    Google Scholar 

  15. Dumais A, Lesage A, Dumont M, Chawky N, Benkelfat C, Turecki G . Risk factors for suicide completion in major depression: a case–control study of impulsive and aggressive behaviors in males. Am J Psychiatry 2005; 162: 2116–2124.

    Article  CAS  PubMed  Google Scholar 

  16. Comings DE, Gade-Andavolu R, Gonzalez N, Blake H, Wu S, MacMurray JP . Additive effect of three noradrenergic genes (ADRA2a, ADRA2C, DBH) on attention-deficit hyperactivity disorder and learning disabilities in Tourette syndrome subjects. Clin Genet 1999; 55: 160–172.

    Article  CAS  PubMed  Google Scholar 

  17. Bustin SA, Nolan T . Pitfalls of quantitative real-time reverse-transcription polymerase chain reaction. J Biomol Tech 2004; 15: 155–166.

    PubMed  PubMed Central  Google Scholar 

  18. Gerlach R, Demel G, Konig HG, Gross U, Prehn JH, Raabe A et al. Active secretion of S100B from astrocytes during metabolic stress. Neuroscience 2006; 141: 1697–1701.

    Article  CAS  PubMed  Google Scholar 

  19. Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M et al. Alterations in 5-HT1B receptor function by p11 in depression-like states. Science 2006; 311: 77–80.

    Article  CAS  PubMed  Google Scholar 

  20. Tramontina F, Leite MC, Goncalves D, Tramontina AC, Souza DF, Frizzo JK et al. High glutamate decreases S100B secretion by a mechanism dependent on the glutamate transporter. Neurochem Res 2006; 31: 815–820.

    Article  CAS  PubMed  Google Scholar 

  21. 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 

  22. Brambilla P, Perez J, Barale F, Schettini G, Soares JC . GABAergic dysfunction in mood disorders. Mol Psychiatry 2003; 8: 721–737,15.

    Article  CAS  PubMed  Google Scholar 

  23. Sanacora G, Gueorguieva R, Epperson CN, Wu YT, Appel M, Rothman DL et al. Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 2004; 61: 705–713.

    Article  CAS  PubMed  Google Scholar 

  24. Middleton FA, Mirnics K, Pierri JN, Lewis DA, Levitt P . Gene expression profiling reveals alterations of specific metabolic pathways in schizophrenia. J Neurosci 2002; 22: 2718–2729.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pellegrini-Giampietro DE . An activity-dependent spermine-mediated mechanism that modulates glutamate transmission. Trends Neurosci 2003; 26: 9–11.

    Article  CAS  PubMed  Google Scholar 

  26. Williams K . Modulation and block of ion channels: a new biology of polyamines. Cell Signal 1997; 9: 1–13.

    Article  CAS  PubMed  Google Scholar 

  27. Petroff OA . GABA and glutamate in the human brain. Neuroscientist 2002; 8: 562–573.

    Article  CAS  PubMed  Google Scholar 

  28. Strehl S, Glatt K, Liu QM, Glatt H, Lalande M . Characterization of two novel protocadherins (PCDH8 and PCDH9) localized on human chromosome 13 and mouse chromosome 14. Genomics 1998; 53: 81–89.

    Article  CAS  PubMed  Google Scholar 

  29. Bray NJ, Kirov G, Owen RJ, Jacobsen NJ, Georgieva L, Williams HJ et al. Screening the human protocadherin 8 (PCDH8) gene in schizophrenia. Genes Brain Behav 2002; 1: 187–191.

    Article  CAS  PubMed  Google Scholar 

  30. Laifenfeld D, Karry R, Klein E, Ben-Shachar D . Alterations in cell adhesion molecule L1 and functionally related genes in major depression: a postmortem study. Biol Psychiatry 2005; 57: 716–725.

    Article  CAS  PubMed  Google Scholar 

  31. Thomas AJ, Ferrier IN, Kalaria RN, Davis S, O'Brien JT . Cell adhesion molecule expression in the dorsolateral prefrontal cortex and anterior cingulate cortex in major depression in the elderly. Br J Psychiatry 2002; 181: 129–134.

    Article  PubMed  Google Scholar 

  32. McMahon HT, Ushkaryov YA, Edelmann L, Link E, Binz T, Niemann H et al. Cellubrevin is a ubiquitous tetanus-toxin substrate homologous to a putative synaptic vesicle fusion protein. Nature 1993; 364: 346–349.

    Article  CAS  PubMed  Google Scholar 

  33. Mirnics K, Middleton FA, Marquez A, Lewis DA, Levitt P . Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron 2000; 28: 53–67.

    Article  CAS  PubMed  Google Scholar 

  34. Bezzi P, Gundersen V, Galbete JL, Seifert G, Steinhauser C, Pilati E et al. Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate. Nat Neurosci 2004; 7: 613–620.

    Article  CAS  PubMed  Google Scholar 

  35. Fan HP, Fan FJ, Bao L, Pei G . SNAP-25/syntaxin 1A complex functionally modulates neurotransmitter GABA reuptake. J Biol Chem 2006; 281: 28174–28184.

    Article  CAS  PubMed  Google Scholar 

  36. Vawter MP, Thatcher L, Usen N, Hyde TM, Kleinman JE, Freed WJ . Reduction of synapsin in the hippocampus of patients with bipolar disorder and schizophrenia. Mol Psychiatry 2002; 7: 571–578.

    Article  CAS  PubMed  Google Scholar 

  37. Li ZZ, Kondo T, Murata T, Ebersole TA, Nishi T, Tada K et al. Expression of Hqk encoding a KH RNA binding protein is altered in human glioma. Jpn J Cancer Res 2002; 93: 167–177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wu JI, Reed RB, Grabowski PJ, Artzt K . Function of quaking in myelination: regulation of alternative splicing. Proc Natl Acad Sci USA 2002; 99: 4233–4238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Aberg K, Saetre P, Lindholm E, Ekholm B, Pettersson U, Adolfsson R et al. Human QKI, a new candidate gene for schizophrenia involved in myelination. Am J Med Genet B Neuropsychiatr Genet 2006; 141: 84–90.

    Article  Google Scholar 

  40. Aberg K, Saetre P, Jareborg N, Jazin E . Human QKI, a potential regulator of mRNA expression of human oligodendrocyte-related genes involved in schizophrenia. Proc Natl Acad Sci USA 2006; 103: 7482–7487.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Haroutunian V, Katsel P, Dracheva S, Davis KL . The human homolog of the QKI gene affected in the severe dysmyelination ‘quaking’ mouse phenotype: downregulated in multiple brain regions in schizophrenia. Am J Psychiatry 2006; 163: 1834–1837.

    Article  PubMed  Google Scholar 

  42. 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 

  43. Rajkowska G . Cell pathology in mood disorders. Semin Clin Neuropsychiatry 2002; 7: 281–292.

    Article  PubMed  Google Scholar 

  44. Rajkowska G . Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol Psychiatry 2000; 48: 766–777.

    Article  CAS  PubMed  Google Scholar 

  45. Cotter D, Mackay D, Landau S, Kerwin R, Everall I . Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Arch Gen Psychiatry 2001; 58: 545–553.

    Article  CAS  PubMed  Google Scholar 

  46. Cotter D, Mackay D, Chana G, Beasley C, Landau S, Everall IP . Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Cereb Cortex 2002; 12: 386–394.

    Article  PubMed  Google Scholar 

  47. Merali Z, Du L, Hrdina P, Palkovits M, Faludi G, Poulter MO et al. Dysregulation in the suicide brain: mRNA expression of corticotropin-releasing hormone receptors and GABA(A) receptor subunits in frontal cortical brain region. J Neurosci 2004; 24: 1478–1485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Krystal JH, Sanacora G, Blumberg H, Anand A, Charney DS, Marek G et al. Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments. Mol Psychiatry 2002; 7(Suppl 1): S71–S80.

    Article  CAS  PubMed  Google Scholar 

  49. Kendell SF, Krystal JH, Sanacora G . GABA and glutamate systems as therapeutic targets in depression and mood disorders. Expert Opin Ther Targets 2005; 9: 153–168.

    Article  CAS  PubMed  Google Scholar 

  50. Hashimoto T, Volk DW, Eggan SM, Mirnics K, Pierri JN, Sun Z et al. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci 2003; 23: 6315–6326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Guidotti A, Auta J, Davis JM, Dong E, Grayson DR, Veldic M et al. GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon. Psychopharmacology (Berl) 2005; 180: 191–205.

    Article  CAS  Google Scholar 

  52. Erraji-Benchekroun L, Underwood MD, Arango V, Galfalvy H, Pavlidis P, Smyrniotopoulos P et al. Molecular aging in human prefrontal cortex is selective and continuous throughout adult life. Biol Psychiatry 2005; 57: 549–558.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. McGill Group for Suicide Studies, Douglas Hospital, McGill University, Montreal, QC, Canada

    T A Klempan, A Sequeira, L Canetti, A Lalovic, C Ernst & G Turecki

  2. Gene Logic Inc., Gaithersburg, MD, USA

    J ffrench-Mullen

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  1. T A Klempan
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  4. A Lalovic
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  7. G Turecki
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Correspondence to G Turecki.

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Klempan, T., Sequeira, A., Canetti, L. 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 14, 175–189 (2009). https://doi.org/10.1038/sj.mp.4002110

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