Altered Gene Expression of Brain-Derived Neurotrophic Factor and Receptor Tyrosine Kinase B in Postmortem Brain of Suicide Subjects | Law and Medicine | JAMA Psychiatry | JAMA Network
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1.
Mann  JJ The neurobiology of suicide.  Nat Med. 1998;425- 30PubMedGoogle ScholarCrossref
2.
Malone  KMHaas  GLSweeney  JAMann  JJ Major depression and the risk of attempted suicide.  J Affect Disord. 1995;34173- 185PubMedGoogle ScholarCrossref
3.
Pykel  ES Life stress, depression and attempted suicide.  J Human Stress. 1976;23- 12Google ScholarCrossref
4.
Westrin  A Stress system alterations and mood disorders in suicidal patients.  Biomed Pharmacother. 2000;54142- 145PubMedGoogle ScholarCrossref
5.
Bradvik  LBerglund  M Suicidal ideation in severe depression.  Eur Arch Psychiatry Clin Neurosci. 2000;250139- 143PubMedGoogle ScholarCrossref
6.
Rajkowska  G Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells.  Biol Psychiatry. 2000;48766- 777PubMedGoogle ScholarCrossref
7.
Benes  FMVincent  SLTodtenkopf  M The density of pyramidal and nonpyramidal neurons in anterior cingulate cortex of schizophrenic and bipolar subjects.  Biol Psychiatry. 2001;50395- 406PubMedGoogle ScholarCrossref
8.
Miguel-Hidalgo  JJRajkowska  G Morphological brain changes in depression: can antidepressants reverse them? [review].  CNS Drugs. 2002;16361- 372PubMedGoogle ScholarCrossref
9.
Sapolsky  RM Stress, glucocorticoids and damage to the nervous system: the current state of confusion.  Stress. 1996;11- 11PubMedGoogle ScholarCrossref
10.
Brown  ESRush  AJMcEwen  BS Hippocampal remodeling and damage by corticosteroids: implications for mood disorders.  Neuropsychopharmacology. 1999;21474- 484PubMedGoogle ScholarCrossref
11.
McEwen  BS Stress and hippocampal plasticity.  Annu Rev Neurosci. 1999;22105- 122PubMedGoogle ScholarCrossref
12.
Woolley  CSGould  EMcEwen  BS Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons.  Brain Res. 1990;531225- 231PubMedGoogle ScholarCrossref
13.
Sapolsky  RM The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death.  Biol Psychiatry. 2000;48755- 765PubMedGoogle ScholarCrossref
14.
Altshuler  LLCasanova  MFGoldberg  TEKleinman  JE The hippocampus and parahippocampus in schizophrenia, suicide, and control brains.  Arch Gen Psychiatry. 1990;471029- 1034PubMedGoogle ScholarCrossref
15.
Rajkowska  G Morphometric methods for studying the prefrontal cortex in suicide victims and psychiatric patients.  Ann N Y Acad Sci. 1997;836253- 268PubMedGoogle ScholarCrossref
16.
Huang  EReichardt  LF Neurotrophins: roles in neuronal development and function.  Annu Rev Neurosci. 2001;24677- 736PubMedGoogle ScholarCrossref
17.
Thoenen  H Neurotrophins and neuronal plasticity.  Science. 1995;270593- 598PubMedGoogle ScholarCrossref
18.
Altar  CACai  NBliven  TJuhasz  MConner  JMAcheson  ALLindsay  RMWiegand  SJ Anterograde transport of brain-derived neurotrophic factor and its role in the brain.  Nature. 1997;389856- 860PubMedGoogle ScholarCrossref
19.
Bartrup  JTMoorman  JMNewberry  NR BDNF enhances neuronal growth and synaptic activity in hippocampal cell cultures.  Neuroreport. 1997;83791- 3794Google ScholarCrossref
20.
Smith  MAMakino  SKvetnansky  RPost  RM Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus.  J Neurosci. 1995;151768- 1777PubMedGoogle Scholar
21.
Ueyama  TKawai  YNemoto  KSekimoto  MTone  SSenba  E Immobilization stress reduced the expression of neurotrophins and their receptors in the rat brain.  Neurosci Res. 1997;28103- 110PubMedGoogle ScholarCrossref
22.
Vaidya  VATerwilliger  RMDuman  RS Role of 5HT2A receptors in the stress-induced downregulation of brain-derived neurotrophic factor expression in the rat hippocampus.  Neurosci Lett. 1999;2621- 4PubMedGoogle ScholarCrossref
23.
Chen  BDowlatshahi  DMacQueen  GMWang  JFYoung  LT Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication.  Biol Psychiatry. 2001;50260- 265PubMedGoogle ScholarCrossref
24.
Nibuya  MMorinobu  SDuman  RS Regulation of BDNF and TrkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments.  J Neurosci. 1995;157539- 7547PubMedGoogle Scholar
25.
Duman  RSVaidya  VA Molecular and cellular actions of chronic electroconvulsive seizures.  J ECT. 1998;14181- 193PubMedGoogle ScholarCrossref
26.
Siuciak  JALewis  DRWiegand  SJLindsay  RM Antidepressant-like effect of brain-derived neurotrophic factor (BDNF).  Pharmacol Biochem Behav. 1997;56131- 137PubMedGoogle ScholarCrossref
27.
Shirayama  YChen  ACNakagawa  SRussell  DSDuman  RS Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression.  J Neurosci. 2002;223251- 3261PubMedGoogle Scholar
28.
Karege  FPerret  GBondolfi  GSchwald  MBertschy  GAubry  JM Decreased serum brain-derived neurotrophic factor levels in major depressed patients.  Psychiatry Res. 2002;109143- 148PubMedGoogle ScholarCrossref
29.
Dwivedi  YRao  JSRizavi  HSKotowski  JConley  RRRoberts  RCTamminga  CAPandey  GN Abnormal expression and functional characteristics of cyclic adenosine monophosphate response element binding protein in postmortem brain of suicide subjects.  Arch Gen Psychiatry. 2003;60273- 282PubMedGoogle ScholarCrossref
30.
Barbacid  M The Trk family of neurotrophin receptors.  J Neurobiol. 1994;251386- 1403PubMedGoogle ScholarCrossref
31.
Dechant  GRodriguez-Tebar  ABarde  Y-A Neurotrophin receptors.  Prog Neurobiol. 1994;42347- 352PubMedGoogle ScholarCrossref
32.
Middlemas  DSLindberg  RAHunter  T trkB, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors.  Mol Cell Biol. 1991;11143- 153PubMedGoogle Scholar
33.
Salzman  SEndicott  JClayton  PWinokur  G Diagnostic Evaluation After Death (DEAD).  Rockville, Md National Institute of Mental Health, Neuroscience Research Branch1983;
34.
Spitzer  RLWilliams  JBWGibbon  MFirst  MB Structured Clinical Interview for DSM-IV (SCID).  New York, NY New York State Psychiatric Institute, Biometrics Research1995;
35.
Ferrer  IMarin  CRey  MJRibalta  TGoutan  EBlanco  RTolosa  EMarti  E BDNF and full-length and truncated TrkB expression in Alzheimer disease: implications in therapeutic strategies.  J Neuropathol Exp Neurol. 1999;58729- 739PubMedGoogle ScholarCrossref
36.
Dwivedi  YPandey  GN Quantitation of 5HT2A receptor mRNA in human postmortem brain using competitive RT-PCR.  Neuroreport. 1998;93761- 3765PubMedGoogle ScholarCrossref
37.
Grayson  DRIkonomovic  S Competitive RT-PCR to quantitate steady-state mRNA levels. Boulton  AABaker  GBBateson  ANeds. In Vitro Neurochemical Techniques. Totowa, NJ Humana Press1998;127- 151Neuromethods;No. 34Google Scholar
38.
Barbany  GPersson  H Regulation of neurotrophin mRNA expression in the rat brain by glucocorticoids.  Eur J Neurosci. 1992;4396- 403PubMedGoogle ScholarCrossref
39.
Schaaf  MJHoetelmans  RWde Kloet  ERVreugdenhil  E Corticosterone regulates expression of BDNF and trk B but not NT-3 and trkC mRNA in the rat hippocampus.  J Neurosci Res. 1997;48334- 341PubMedGoogle ScholarCrossref
40.
Schlessinger  JUllrich  A Growth factor signaling by receptor tyrosine kinases.  Neuron. 1992;9383- 391PubMedGoogle ScholarCrossref
41.
Allendoerfer  KLCabelli  RJEscandon  EKaplan  DRNikolics  KShatz  CJ Regulation of neurotropin receptors during the maturation of the mammalian visual system.  J Neurosci. 1994;14 (3 pt 2) 1795- 1811PubMedGoogle Scholar
42.
Armanini  MPMcMahon  SBSutherland  JShelton  DLPhillips  HS Truncated and catalytic isoforms of trk B are co-expressed in neurons of rat and mouse CNS.  Eur J Neurosci. 1995;71403- 1409PubMedGoogle ScholarCrossref
43.
Eide  FFVining  EREide  BLZang  KWang  X-YReichardt  LF Naturally occurring truncated trk B receptors have dominant inhibitory effects on brain-derived neurotrophic factor signaling.  J Neurosci. 1996;163123- 3129PubMedGoogle Scholar
44.
Fryer  RHKaplan  DRFeinstein  SCRadeke  MJGrayson  DRKromer  LF Developmental and mature expression of full-length and truncated TrkB receptors in the rat forebrain.  J Comp Neurol. 1996;37421- 40PubMedGoogle ScholarCrossref
45.
Uno  HTarara  RElse  JGSuleman  MASapolsky  RM Hippocampal damage associated with prolonged and fatal stress in primates.  J Neurosci. 1989;91705- 1711PubMedGoogle Scholar
46.
Bremner  JDNarayan  MAnderson  ERStalb  LHMiller  HLCharney  DS Hippocampal volume reduction in major depression.  Am J Psychiatry. 2000;157115- 118PubMedGoogle ScholarCrossref
47.
Sheline  YIWang  PWGado  MHCsernansky  JGVannier  MW Hippocampal atrophy in recurrent major depression.  Proc Natl Acad Sci U S A. 1996;933908- 3913PubMedGoogle ScholarCrossref
48.
Murer  MGYan  QRaisman-Vozari  R Brain-derived neurotrophic factor in the control human brain, and in Alzheimer's disease and Parkinson's disease.  Prog Neurobiol. 2001;6371- 124PubMedGoogle ScholarCrossref
49.
Nakayama  MGahara  YKitamura  TOhara  O Distinctive four promoters collectively direct expression of brain-derived neurotrophic factor gene.  Brain Res Mol Brain Res. 1994;21206- 218PubMedGoogle ScholarCrossref
50.
Finkbeiner  S Calcium regulation of the brain-derived neurotrophic factor gene.  Cell Mol Life Sci. 2000;57394- 401PubMedGoogle ScholarCrossref
51.
Dwivedi  YConley  RRRoberts  RCTamminga  CAPandey  GN [3H]cAMP binding sites and protein kinase A activity in the prefrontal cortex of suicide victims.  Am J Psychiatry. 2002;15966- 73 PubMedGoogle ScholarCrossref
52.
Lauterborn  JCPoulsen  FRStinis  CTIsackson  PJGall  CM Transcript-specific effects of adrenalectomy on seizure-induced BDNF expression in rat hippocampus.  Brain Res Mol Brain Res. 1998;5581- 91PubMedGoogle ScholarCrossref
53.
Zetterstrom  TSPei  QMadhav  TRCoppell  ALLewis  LGraham-Smith  DG Manipulations of brain 5HT levels affect gene expression for BDNF in rat brain.  Neuropharmacology. 1999;381063- 1073PubMedGoogle ScholarCrossref
54.
Mann  JJStanley  MMcBride  PAMcEwen  BS Increased serotonin2 and beta-adrenergic receptor binding in the frontal cortices of suicide victims.  Arch Gen Psychiatry. 1986;43954- 959PubMedGoogle ScholarCrossref
55.
Arango  VErnsberger  PMarzuk  PMChen  JSTierney  HStanley  MRice  DJMann  JJ Autoradiographic demonstration of increased serotonin 5-HT2 and beta-adrenergic receptor binding sites in the brain of suicide victims.  Arch Gen Psychiatry. 1990;471038- 1047PubMedGoogle ScholarCrossref
56.
Pandey  GNDwivedi  YRizavi  HRen  XPandey  SCRoberts  RCConley  RRTamminga  CA Higher expression of serotonin (5HT)2A in the postmortem brain of teenage suicide victims.  Am J Psychiatry. 2002;159419- 429PubMedGoogle ScholarCrossref
57.
Nemeroff  CBOwens  MJBissette  GAndorn  ACStanley  M Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims.  Arch Gen Psychiatry. 1988;45577- 579PubMedGoogle ScholarCrossref
58.
Arató  MBanki  CMBissette  GNemeroff  CB Elevated CSF CRF in suicide victims.  Biol Psychiatry. 1989;25355- 359PubMedGoogle ScholarCrossref
59.
Lopez  JFChalmers  DTLittle  KYWatson  SJ Regulation of serotonin1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for the neurobiology of depression.  Biol Psychiatry. 1998;43547- 573PubMedGoogle ScholarCrossref
60.
Kang  HSchuman  EM Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus.  Science. 1995;2671658- 1662PubMedGoogle ScholarCrossref
61.
Korte  MCarroll  PWolf  EBrem  GThoenen  HBonhoeffer  T Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor.  Proc Natl Acad Sci U S A. 1995;928856- 8860Google ScholarCrossref
62.
Mesulam  MM Neuroplasticity failure in Alzheimer's disease: bridging the gap between plaques and tangles.  Neuron. 1999;24521- 529PubMedGoogle ScholarCrossref
63.
Duman  RSMalberg  JNakagawa  SD'Sa  C Neuronal plasticity and survival in mood disorders.  Biol Psychiatry. 2000;48732- 739PubMedGoogle ScholarCrossref
64.
Altar  CABoylan  CBFritsche  MJackson  CHyman  CLindsay  RM The neurotrophins NT-4/5 and BDNF augment serotonin, dopamine, and GABAergic systems during behaviorally effective infusions to the substantia nigra.  Exp Neurol. 1994;13031- 40PubMedGoogle ScholarCrossref
65.
Siuciak  JABoylan  CFritsche  MAltar  CALindsay  RM BDNF increases monoaminergic activity in rat brain following intracerebroventricular or intraparenchymal administration.  Brain Res. 1996;71011- 20PubMedGoogle ScholarCrossref
66.
Mamounas  LABlue  MESiuciak  JAAltar  CA Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain.  J Neurosci. 1995;157929- 7939PubMedGoogle Scholar
Original Article
August 2003

Altered Gene Expression of Brain-Derived Neurotrophic Factor and Receptor Tyrosine Kinase B in Postmortem Brain of Suicide Subjects

Author Affiliations

From the Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago (Drs Dwivedi and Pandey and Ms Rizavi); and the Maryland Psychiatric Research Center, University of Maryland, Baltimore (Drs Conley, Roberts, and Tamminga).

Arch Gen Psychiatry. 2003;60(8):804-815. doi:10.1001/archpsyc.60.8.804
Abstract

Background  Suicide is a major public health concern. Although authors of many studies have examined the neurobiological aspects of suicide, the molecular mechanisms associated with suicidal behavior remain unclear. Brain-derived neurotrophic factor (BDNF), one of the most important neurotrophins, after binding with and activating receptor tyrosine kinase B (trk B), is directly involved in many physiological functions in the brain, including cell survival and synaptic plasticity. The present study was performed to examine whether the expression of BDNF and/or trk B isoforms was altered in postmortem brain in subjects who commit suicide (hereafter referred to as suicide subjects) and whether these alterations were associated with specific psychopathologic conditions.

Methods  These studies were performed in prefrontal cortex in Brodmann area 9 and hippocampus obtained in 27 suicide subjects and 21 nonpsychiatric control subjects. Levels of messenger RNA and protein levels of BDNF and trk B were determined with competitive reverse transcriptase–polymerase chain reaction and Western blot technique, respectively. The level of neuron-specific enolase messenger RNA as a neuronal marker was also determined in these brain areas.

Results  Messenger RNA levels of BDNF and trk B were significantly reduced, independently and as a ratio to neuron-specific enolase, in both prefrontal cortex and hippocampus in suicide subjects, as compared with those in control subjects. These reductions were associated with significant decreases in the protein levels of BDNF and of full-length trk B but not trk B's truncated isoform. These changes were present in all suicide subjects regardless of psychiatric diagnosis and were unrelated to postmortem interval, age, sex, or pH of the brain.

Conclusions  Given the importance of BDNF in mediating physiological functions, including cell survival and synaptic plasticity, our findings of reduced expression of BDNF and trk B in postmortem brain in suicide subjects suggest that these molecules may play an important role in the pathophysiological aspects of suicidal behavior.

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