Top

European Archives of Psychiatry and Clinical Neuroscience

Published in:

Open Access 01-02-2012 | Original Paper

Association of the brain-derived neurotrophic factor val66met polymorphism with magnetic resonance spectroscopic markers in the human hippocampus: in vivo evidence for effects on the glutamate system

Authors: Oliver Gruber, Alkomiet Hasan, Harald Scherk, Thomas Wobrock, Thomas Schneider-Axmann, Savira Ekawardhani, Andrea Schmitt, Martin Backens, Wolfgang Reith, Jobst Meyer, Peter Falkai

Published in: European Archives of Psychiatry and Clinical Neuroscience | Issue 1/2012

Abstract

The brain-derived neurotrophic factor (BDNF) is a key regulator of synaptic plasticity and has been suggested to be involved in the pathophysiology and pathogenesis of psychotic disorders, with particular emphasis on dysfunctions of the hippocampus. The aim of the present study was to replicate and to extend prior findings of BDNF val66met genotype effects on hippocampal volume and N-acetyl aspartate (NAA) levels. Hundred and fifty-eight caucasians (66 schizophrenic, 45 bipolar, and 47 healthy subjects; 105 subjects underwent MRI and 103 MRS scanning) participated in the study and were genotyped with regard to the val66met polymorphism (rs6265) of the BDNF gene. Hippocampal volumes were determined using structural magnetic resonance imaging (MRI), and measures of biochemical markers were taken using proton magnetic resonance spectroscopy (¹H-MRS) in the hippocampus and other brain regions. Verbal memory was assessed as a behavioral index of hippocampal function. BDNF genotype did not impact hippocampal volumes. Significant genotype effects were found on metabolic markers specifically in the left hippocampus. In particular, homozygous carriers of the met-allele exhibited significantly lower NAA/Cre and (Glu + Gln)/Cre metabolic ratios compared with val/val homozygotes, independently of psychiatric diagnoses. BDNF genotype had a numerical, but nonsignificant effect on verbal memory performance. These findings provide first in vivo evidence for an effect of the functional BDNF val66met polymorphism on the glutamate system in human hippocampus.

Aicardi G, Argilli E, Cappello S, Santi S, Riccio M, Thoenen H, Canossa M (2004) Induction of long-term potentiation and depression is reflected by corresponding changes in secretion of endogenous brain-derived neurotrophic factor. Proc Natl Acad Sci USA 101:15788–15792PubMedCrossRef

Ashburner J, Friston K (1997) Multimodal image coregistration and partitioning—a unified framework. Neuroimage 6:209–217PubMedCrossRef

Bekinschtein P, Cammarota M, Izquierdo I, Medina JH (2008) BDNF and memory formation and storage. Neuroscientist 14:147–156PubMedCrossRef

Bertolino A, Callicott JH, Mattay VS, Weidenhammer KM, Rakow R, Egan MF, Weinberger DR (2001) The effect of treatment with antipsychotic drugs on brain N-acetylaspartate measures in patients with schizophrenia. Biol Psychiatry 49:39–46PubMedCrossRef

Bueller JA, Aftab M, Sen S, Gomez-Hassan D, Burmeister M, Zubieta JK (2006) BDNF Val66 Met allele is associated with reduced hippocampal volume in healthy subjects. Biol Psychiatry 59:812–815PubMedCrossRef

Carvalho AL, Caldeira MV, Santos SD, Duarte CB (2008) Role of the brain-derived neurotrophic factor at glutamatergic synapses. Br J Pharmacol 153(Suppl 1):S310–S324PubMed

Cheng CY, Hong CJ, Yu YW, Chen TJ, Wu HC, Tsai SJ (2005) Brain-derived neurotrophic factor (Val66Met) genetic polymorphism is associated with substance abuse in males. Brain Res Mol Brain Res 140:86–90PubMedCrossRef

Chepenik LG, Fredericks C, Papademetris X, Spencer L, Lacadie C, Wang F, Pittman B, Duncan JS, Staib LH, Duman RS, Gelernter J, Blumberg HP (2009) Effects of the brain-derived neurotrophic growth factor val66met variation on hippocampus morphology in bipolar disorder. Neuropsychopharmacology 34:944–951PubMedCrossRef

Cumming AG, Matthews NL, Park S (2010) Olfactory identification and preference in bipolar disorder and schizophrenia. Eur Arch Psychiatry Clin Neurosci [Epub ahead of print]

10.

Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112:257–269PubMedCrossRef

11.

Fannon D, Simmons A, Tennakoon L, O’Ceallaigh S, Sumich A, Doku V, Shew C, Sharma T (2003) Selective deficit of hippocampal N-acetylaspartate in antipsychotic-naive patients with schizophrenia. Biol Psychiatry 54:587–598PubMedCrossRef

12.

Frodl T, Schule C, Schmitt G, Born C, Baghai T, Zill P, Bottlender R, Rupprecht R, Bondy B, Reiser M, Moller HJ, Meisenzahl EM (2007) Association of the brain-derived neurotrophic factor Val66Met polymorphism with reduced hippocampal volumes in major depression. Arch Gen Psychiatry 64:410–416PubMedCrossRef

13.

Gallinat J, Schubert F, Bruhl R, Hellweg R, Klar AA, Kehrer C, Wirth C, Sander T, Lang UE (2010) Met carriers of BDNF Val66Met genotype show increased N-acetylaspartate concentration in the anterior cingulate cortex. Neuroimage 49:767–771PubMedCrossRef

14.

Gruber O, Falkai P, Schneider-Axmann T, Schwab SG, Wagner M, Maier W (2008) Neuregulin-1 haplotype HAP(ICE) is associated with lower hippocampal volumes in schizophrenic patients and in non-affected family members. J Psychiatr Res 43:1–6PubMedCrossRef

15.

Gruber O, Melcher T, Diekhof EK, Karch S, Falkai P, Goschke T (2009) Brain mechanisms associated with background monitoring of the environment for potentially significant sensory events. Brain Cogn 69:559–564PubMedCrossRef

16.

Hansell NK, James MR, Duffy DL, Birley AJ, Luciano M, Geffen GM, Wright MJ, Montgomery GW, Martin NG (2007) Effect of the BDNF V166M polymorphism on working memory in healthy adolescents. Genes Brain Behav 6:260–268PubMedCrossRef

17.

Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF, Weinberger DR (2003) Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci 23:6690–6694PubMed

18.

Harte MK, Bachus SB, Reynolds GP (2005) Increased N-acetylaspartate in rat striatum following long-term administration of haloperidol. Schizophr Res 75:303–308PubMedCrossRef

19.

Hashimoto R, Moriguchi Y, Yamashita F, Mori T, Nemoto K, Okada T, Hori H, Noguchi H, Kunugi H, Ohnishi T (2008) Dose-dependent effect of the Val66Met polymorphism of the brain-derived neurotrophic factor gene on memory-related hippocampal activity. Neurosci Res 61:360–367PubMedCrossRef

20.

Hasler G, Neumeister A, van der Veen JW, Tumonis T, Bain EE, Shen J, Drevets WC, Charney DS (2005) Normal prefrontal gamma-aminobutyric acid levels in remitted depressed subjects determined by proton magnetic resonance spectroscopy. Biol Psychiatry 58:969–973PubMedCrossRef

21.

Ho BC, Andreasen NC, Dawson JD, Wassink TH (2007) Association between brain-derived neurotrophic factor Val66Met gene polymorphism and progressive brain volume changes in schizophrenia. Am J Psychiatry 164:1890–1899PubMedCrossRef

22.

Ho BC, Milev P, O’Leary DS, Librant A, Andreasen NC, Wassink TH (2006) Cognitive and magnetic resonance imaging brain morphometric correlates of brain-derived neurotrophic factor Val66Met gene polymorphism in patients with schizophrenia and healthy volunteers. Arch Gen Psychiatry 63:731–740PubMedCrossRef

23.

Hoerst M, Weber-Fahr W, Tunc-Skarka N, Ruf M, Bohus M, Schmahl C, Ende G (2010) Correlation of glutamate levels in the anterior cingulate cortex with self-reported impulsivity in patients with borderline personality disorder and healthy controls. Arch Gen Psychiatry 67:946–954PubMedCrossRef

24.

Jamrozinski K, Gruber O, Kemmer C, Falkai P, Scherk H (2009) Neurocognitive functions in euthymic bipolar patients. Acta Psychiatry Scand 119:365–374CrossRef

25.

Kaymaz N, van Os J (2009) Heritability of structural brain traits an endophenotype approach to deconstruct schizophrenia. Int Rev Neurobiol 89:85–130PubMedCrossRef

26.

Klar AA, Ballmaier M, Leopold K, Hake I, Schaefer M, Bruhl R, Schubert F, Gallinat J (2010) Interaction of hippocampal volume and N-acetylaspartate concentration deficits in schizophrenia: a combined MRI and 1H-MRS study. Neuroimage 53:51–57PubMedCrossRef

27.

Krebs MO, Guillin O, Bourdell MC, Schwartz JC, Olie JP, Poirier MF, Sokoloff P (2000) Brain derived neurotrophic factor (BDNF) gene variants association with age at onset and therapeutic response in schizophrenia. Mol Psychiatry 5:558–562PubMedCrossRef

28.

Maisonpierre PC, Le Beau MM, Espinosa R 3rd, Ip NY, Belluscio L, de la Monte SM, Squinto S, Furth ME, Yancopoulos GD (1991) Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations. Genomics 10:558–568PubMedCrossRef

29.

Manahan-Vaughan D, Kulla A (2003) Regulation of depotentiation and long-term potentiation in the dentate gyrus of freely moving rats by dopamine D2-like receptors. Cereb Cortex 13:123–135PubMedCrossRef

30.

Marenco S, Radulescu E (2010) Imaging genetics of structural brain connectivity and neural integrity markers. Neuroimage 53:848–856PubMedCrossRef

31.

McIntosh AM, Moorhead TW, McKirdy J, Sussmann JE, Hall J, Johnstone EC, Lawrie SM (2007) Temporal grey matter reductions in bipolar disorder are associated with the BDNF Val66Met polymorphism. Mol Psychiatry 12:902–903PubMedCrossRef

32.

Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215PubMedCrossRef

33.

Miyajima F, Ollier W, Mayes A, Jackson A, Thacker N, Rabbitt P, Pendleton N, Horan M, Payton A (2008) Brain-derived neurotrophic factor polymorphism Val66Met influences cognitive abilities in the elderly. Genes Brain Behav 7:411–417PubMedCrossRef

34.

Molina V, Galindo G, Cortes B, de Herrera AG, Ledo A, Sanz J, Montes C, Hernandez-Tamames JA (2010) Different gray matter patterns in chronic schizophrenia and chronic bipolar disorder patients identified using voxel-based morphometry. Eur Arch Psychiatry Clin Neurosci

35.

Muller H, Hasse-Sander I, Horn R, Helmstaedter C, Elger CE (1997) Rey auditory-verbal learning test: structure of a modified German version. J Clin Psychol 53:663–671PubMedCrossRef

36.

Patterson SL, Abel T, Deuel TA, Martin KC, Rose JC, Kandel ER (1996) Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron 16:1137–1145PubMedCrossRef

37.

Pezawas L, Verchinski BA, Mattay VS, Callicott JH, Kolachana BS, Straub RE, Egan MF, Meyer-Lindenberg A, Weinberger DR (2004) The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci 24:10099–10102PubMedCrossRef

38.

Poo MM (2001) Neurotrophins as synaptic modulators. Nat Rev Neurosci 2:24–32PubMedCrossRef

39.

Scherk H, Backens M, Zill P, Schneider-Axmann T, Wobrock T, Usher J, Reith W, Falkai P, Moller HJ, Bondy B, Gruber O (2008) SNAP-25 genotype influences NAA/Cho in left hippocampus. J Neural Transm 115:1513–1518PubMedCrossRef

40.

Sklar P, Gabriel SB, McInnis MG, Bennett P, Lim YM, Tsan G, Schaffner S, Kirov G, Jones I, Owen M, Craddock N, DePaulo JR, Lander ES (2002) Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neutrophic factor. Mol Psychiatry 7:579–593PubMedCrossRef

41.

Stern AJ, Savostyanova AA, Goldman A, Barnett AS, van der Veen JW, Callicott JH, Mattay VS, Weinberger DR, Marenco S (2008) Impact of the brain-derived neurotrophic factor Val66Met polymorphism on levels of hippocampal N-acetyl-aspartate assessed by magnetic resonance spectroscopic imaging at 3 Tesla. Biol Psychiatry 64:856–862PubMedCrossRef

42.

Tamminga CA, Stan AD, Wagner AD (2010) The Hippocampal Formation in Schizophrenia. Am J Psychiatry 167(10):1178–1193

43.

Tan YL, Zhou DF, Cao LY, Zou YZ, Wu GY, Zhang XY (2005) Effect of the BDNF Val66Met genotype on episodic memory in schizophrenia. Schizophr Res 77:355–356PubMedCrossRef

44.

Wittchen HU, Wunderlich U, Gruschwitz S, Zaudig M (1997) Strukturiertes Klinisches Interview für DSM-IV. Achse I: Psychische Störungen. A German, advanced adaptation of the original SCID version by RL Spitzer. JB Williams, M Gibbon and MB First. Hogrefe-Verlag, Göttingen

Title: Association of the brain-derived neurotrophic factor val66met polymorphism with magnetic resonance spectroscopic markers in the human hippocampus: in vivo evidence for effects on the glutamate system
Authors: Oliver Gruber
Alkomiet Hasan
Harald Scherk
Thomas Wobrock
Thomas Schneider-Axmann
Savira Ekawardhani
Andrea Schmitt
Martin Backens
Wolfgang Reith
Jobst Meyer
Peter Falkai
Publication date: 01-02-2012
Publisher: Springer-Verlag
Published in: European Archives of Psychiatry and Clinical Neuroscience / Issue 1/2012
Print ISSN: 0940-1334
Electronic ISSN: 1433-8491
DOI: https://doi.org/10.1007/s00406-011-0214-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Association of the brain-derived neurotrophic factor val66met polymorphism with magnetic resonance spectroscopic markers in the human hippocampus: in vivo evidence for effects on the glutamate system

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2012

Subjective emotional over-arousal to neutral social scenes in paranoid schizophrenia

Psychobiological responses to unpleasant emotions in cannabis users

Perfusion abnormalities in mild cognitive impairment and mild dementia in Alzheimer’s disease measured by pulsed arterial spin labeling MRI

Repetitive magnetic stimulation of human-derived neuron-like cells activates cAMP-CREB pathway

Executive summary of the report by the WPA section on pharmacopsychiatry on general and comparative efficacy and effectiveness of antidepressants in the acute treatment of depressive disorders

The estimated prevalence and correlates of adult ADHD in a German community sample