Skip to main content
×
Home
    • Aa
    • Aa
  • The International Journal of Neuropsychopharmacology, Volume 11, Issue 8
  • December 2008, pp. 1047-1061

Brain-derived neurotrophic factor and tyrosine kinase B receptor signalling in post-mortem brain of teenage suicide victims

  • Ghanshyam N. Pandey (a1), Xinguo Ren (a1), Hooriyah S. Rizavi (a1), Robert R. Conley (a2), Rosalinda C. Roberts (a2) and Yogesh Dwivedi (a1)
  • DOI: http://dx.doi.org/10.1017/S1461145708009000
  • Published online: 09 July 2008
Abstract
Abstract

Teenage suicide is a major public health concern, but its neurobiology is not very well understood. Stress and major mental disorders are major risk factors for suicidal behaviour, and it has been shown that brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (TrkB) are not only regulated by stress but are also altered in these illnesses. We therefore examined if BDNF/TrkB signalling is altered in the post-mortem brain of teenage suicide victims. Protein and mRNA expression of BDNF and of TrkB receptors were determined in the prefrontal cortex (PFC), Brodmann's Area 9 (BA 9), and hippocampus obtained from 29 teenage suicide victims and 25 matched normal control subjects. Protein expression was determined using the Western blot technique; mRNA levels by a quantitative RT–PCR technique. The protein expression of BDNF was significantly decreased in the PFC of teenage suicide victims compared with normal control subjects, whereas no change was observed in the hippocampus. Protein expression of TrkB full-length receptors was significantly decreased in both PFC and hippocampus of teenage suicide victims without any significant changes in the truncated form of TrkB receptors. mRNA expression of both BDNF and TrkB was significantly decreased in the PFC and hippocampus of teenage suicide victims compared with normal control subjects. These studies indicate a down-regulation of both BDNF and its receptor TrkB in the PFC and hippocampus of teenage suicide victims, which suggests that stress and altered BDNF may represent a major vulnerability factor in teenage suicidal behaviour.

Copyright
Corresponding author
Address for correspondence: G. N. Pandey, Ph.D., The Psychiatric Institute, University of Illinois at Chicago, 1601 West Taylor Street, Chicago, IL 60612, USA. Tel.: (312) 413-4540Fax: (312) 413-4547E-mail: Gnpandey@psych.uic.edu
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

CA Altar , CB Boylan , M Fritsche , C Jackson , C Hyman , RM Lindsay (1994). The neurotrophins NT-4/5 and BDNF augment serotonin, dopamine, and GABAergic systems during behaviorally effective infusions to the substantia nigra. Experimental Neurology 130, 3140.

CA Altar , N Cai , T Bliven , M Juhasz , JM Conner , AL Acheson , RM Lindsay , SJ Wiegand (1997). Anterograde transport of brain-derived neurotrophic factor and its role in the brain. Nature 389, 856860.

CA Altar , RE Whitehead , R Chen , G Wortwein , TM Madsen (2003). Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain. Biological Psychiatry 54, 703709.

A Apter , D Gothelf , I Orbach , R Weizman , G Ratzoni , D Har-Even , S Tyano (1995). Correlation of suicidal and violent behavior in different diagnostic categories in hospitalized adolescent patients. Journal of the American Academy of Child and Adolescent Psychiatry 34, 912918.

MP Armanini , SB McMahon , J Sutherland , DL Shelton , HS Phillips (1995). Truncated and catalytic isoforms of trkB are co-expressed in neurons of rat and mouse CNS. European Journal of Neuroscience 7, 14031409.

M Barbacid (1994). The Trk family of neurotrophin receptors. Journal of Neurobiology 25, 13861403.

JT Bartrup , JM Moorman , NR Newberry (1997). BDNF enhances neuronal growth and synaptic activity in hippocampal cell cultures. Neuroreport 8, 37913794.

DA Brent , DJ Kolko , ME Wartella , MB Boylan , G Moritz , M Baugher , JP Zelenak (1993). Adolescent psychiatric inpatients' risk of suicide attempt at 6-month follow-up. Journal of the American Academy of Child and Adolescent Psychiatry 32, 95105.

PF Buckley , S Mahadik , A Pillai , A Terry Jr. (2007a). Neurotrophins and schizophrenia. Schizophrenia Research 94, 111.

PF Buckley , A Pillai , D Evans , E Stirewalt , S Mahadik (2007b). Brain derived neurotropic factor in first-episode psychosis. Schizophrenia Research 91, 15.

B Chen , D Dowlatshahi , GM MacQueen , JF Wang , LT Young (2001). Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biological Psychiatry 50, 260265.

AB Cunha , BN Frey , AC Andreazza , JD Goi , AR Rosa , CA Goncalves , A Santin , F Kapczinski (2006). Serum brain-derived neurotrophic factor is decreased in bipolar disorder during depressive and manic episodes. Neuroscience Letters 398, 215219.

G Dechant , A Rodriguez-Tebar , YA Barde (1994). Neurotrophin receptors. Progress in Neurobiology 42, 347352.

RS Duman , VA Vaidya (1998). Molecular and cellular actions of chronic electroconvulsive seizures. Journal of ECT 14, 181193.

Y Dwivedi , AC Mondal , HS Rizavi , RR Conley (2005). Suicide brain is associated with decreased expression of neurotrophins. Biological Psychiatry 58, 315324.

Y Dwivedi , JS Rao , HS Rizavi , J Kotowski , RR Conley , RC Roberts , CA Tamminga , GN Pandey (2003a). Abnormal expression and functional characteristics of cyclic adenosine monophosphate response element binding protein in postmortem brain of suicide subjects. Archives of General Psychiatry 60, 273282.

Y Dwivedi , HS Rizavi , RR Conley , RC Roberts , CA Tamminga , GN Pandey (2003b). Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. Archives of General Psychiatry 60, 804815.

Y Dwivedi , HS Rizavi , PK Shukla , J Lyons , G Faludi , M Palkovits , A Sarosi , RR Conley , RC Roberts , CA Tamminga , (2004). Protein kinase A in postmortem brain of depressed suicide victims: altered expression of specific regulatory and catalytic subunits. Biological Psychiatry 55, 234243.

T Fukumoto , S Morinobu , Y Okamoto , A Kagaya , S Yamawaki (2001). Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain. Psychopharmacology (Berlin) 158, 100106.

R Hashimoto , N Takei , K Shimazu , L Christ , B Lu , DM Chuang (2002). Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: an essential step for neuroprotection against glutamate excitotoxicity. Neuropharmacology 43, 11731179.

EJ Huang , LF Reichardt (2001). Neurotrophins: roles in neuronal development and function. Annual Review of Neuroscience 24, 677736.

H Kang , EM Schuman (1995). Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science 267, 16581662.

F Karege , G Bondolfi , N Gervasoni , M Schwald , JM Aubry , G Bertschy (2005a). Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity. Biological Psychiatry 57, 10681072.

F Karege , G Perret , G Bondolfi , M Schwald , G Bertschy , JM Aubry (2002). Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Research 109, 143148.

F Karege , G Vaudan , M Schwald , N Perroud , R La Harpe (2005b). Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs. Brain Research Molecular Brain Research 136, 2937.

J Kaufman , A Martin , RA King , D Charney (2001). Are child-, adolescent-, and adult-onset depression one and the same disorder? Biological Psychiatry 49, 9801001.

R Klein , V Nanduri , SA Jing , F Lamballe , P Tapley , S Bryant , C Cordon-Cardo , KR Jones , LF Reichardt , M Barbacid (1991). The trkB tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3. Cell 66, 395403.

M Kovacs (1996). Presentation and course of major depressive disorder during childhood and later years of the life span. Journal of the American Academy of Child and Adolescent Psychiatry 35, 705715.

UE Lang , MC Jockers-Scherubl , R Hellweg (2004). State of the art of the neurotrophin hypothesis in psychiatric disorders: implications and limitations. Journal of Neural Transmission 111, 387411.

RM Lindsay , SJ Wiegand , CA Altar , PS DiStefano (1994). Neurotrophic factors: from molecule to man. Trends in Neuroscience 17, 182190.

R Machado-Vieira , MO Dietrich , R Leke , VH Cereser , V Zanatto , F Kapczinski , DO Souza , LV Portela , V Gentil (2007). Decreased plasma brain derived neurotrophic factor levels in unmedicated bipolar patients during manic episode. Biological Psychiatry 61, 142144.

KM Malone , GL Haas , JA Sweeney , JJ Mann (1995). Major depression and the risk of attempted suicide. Journal of Affective Disorders 34, 173185.

AK McAllister , LC Katz , DC Lo (1999). Neurotrophins and synaptic plasticity. Annual Review of Neuroscience 22, 295318.

DS Middlemas , RA Lindberg , T Hunter (1991). trkB, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors. Molecular Cell Biology 11, 143153.

M Mizuno , K Yamada , N Takei , MH Tran , J He , A Nakajima , H Nawa , T Nabeshima (2003). Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation. Molecular Psychiatry 8, 217224.

GN Pandey , Y Dwivedi , X Ren , HS Rizavi , AC Mondal , PK Shukla , RR Conley (2005). Brain region specific alterations in the protein and mRNA levels of protein kinase A subunits in the post-mortem brain of teenage suicide victims. Neuropsychopharmacology 30, 15481556.

GN Pandey , Y Dwivedi , X Ren , HS Rizavi , RC Roberts , RR Conley (2007). Cyclic AMP response element-binding protein in post-mortem brain of teenage suicide victims: specific decrease in the prefrontal cortex but not the hippocampus. International Journal of Neuropsychopharmacology 10, 621629.

GN Pandey , Y Dwivedi , HS Rizavi , X Ren , SC Pandey , C Pesold , RC Roberts , RR Conley , CA Tamminga (2002). Higher expression of serotonin 5-HT(2A) receptors in the postmortem brains of teenage suicide victims. American Journal of Psychiatry 159, 419429.

ES Paykel (1976). Life stress, depression and attempted suicide. Journal of Human Stress 2, 312.

G Rajkowska (1997). Morphometric methods for studying the prefrontal cortex in suicide victims and psychiatric patients. Annals of the New York Academy of Sciences 836, 253268.

G Rajkowska (2000). Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biological Psychiatry 48, 766777.

M Ramirez Basco , JQ Bostic , D Davies , AJ Rush , B Witte , W Hendrickse , V Barnett (2000). Methods to improve diagnostic accuracy in a community mental health setting. American Journal of Psychiatry 157, 15991605.

MJ Schaaf , RW Hoetelmans , ER de Kloet , E Vreugdenhil (1997). Corticosterone regulates expression of BDNF and trkB but not NT-3 and trkC mRNA in the rat hippocampus. Journal of Neuroscience Research 48, 334341.

AF Schinder , M Poo (2000). The neurotrophin hypothesis for synaptic plasticity. Trends in Neurosciences 23, 639645.

RA Segal (2003). Selectivity in neurotrophin signaling: theme and variations. Annual Review of Neuroscience 26, 299330.

E Shimizu , K Hashimoto , N Okamura , K Koike , N Komatsu , C Kumakiri , M Nakazato , H Watanabe , N Shinoda , S Okada , (2003). Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biological Psychiatry 54, 7075.

G Shoval , A Weizman (2005). The possible role of neurotrophins in the pathogenesis and therapy of schizophrenia. European Neuropsychopharmacology 15, 319329.

H Thoenen (1995). Neurotrophins and neuronal plasticity. Science 270, 593598.

K Toyooka , K Asama , Y Watanabe , T Muratake , M Takahashi , T Someya , H Nawa (2002). Decreased levels of brain-derived neurotrophic factor in serum of chronic schizophrenic patients. Psychiatry Research 110, 249257.

T Ueyama , Y Kawai , K Nemoto , M Sekimoto , S Tone , E Senba (1997). Immobilization stress reduced the expression of neurotrophins and their receptors in the rat brain. Neuroscience Research 28, 103110.

VA Vaidya , RM Terwilliger , RS Duman (1999). Role of 5-HT2A receptors in the stress-induced down-regulation of brain-derived neurotrophic factor expression in rat hippocampus. Neuroscience Letters 262, 14.

A Westrin (2000). Stress system alterations and mood disorders in suicidal patients. A review. Biomedicine & Pharmacotherapy 54, 142145.

TS Zetterstrom , Q Pei , TR Madhav , AL Coppell , L Lewis , DG Grahame-Smith (1999). Manipulations of brain 5-HT levels affect gene expression for BDNF in rat brain. Neuropharmacology 38, 10631073.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

The International Journal of Neuropsychopharmacology
  • ISSN: 1461-1457
  • EISSN: 1469-5111
  • URL: /core/journals/the-international-journal-of-neuropsychopharmacology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords: