Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism differentially predicts hippocampal function in medication-free patients with schizophrenia

Molecular Psychiatry volume 18, pages 713–720 (2013)Cite this article

Subjects

Abstract

A Val66Met single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene impairs activity-dependent BDNF release in cultured hippocampal neurons and predicts impaired memory and exaggerated basal hippocampal activity in healthy humans. Several clinical genetic association studies along with multi-modal evidence for hippocampal dysfunction in schizophrenia indirectly suggest a relationship between schizophrenia and genetically determined BDNF function in the hippocampus. To directly test this hypothesized relationship, we studied 47 medication-free patients with schizophrenia or schizoaffective disorder and 74 healthy comparison individuals with genotyping for the Val66Met SNP and [15O]H2O positron emission tomography (PET) to measure resting and working memory-related hippocampal regional cerebral blood flow (rCBF). In patients, harboring a Met allele was associated with significantly less hippocampal rCBF. This finding was opposite to the genotype effect seen in healthy participants, resulting in a significant diagnosis-by-genotype interaction. Exploratory analyses of interregional resting rCBF covariation revealed a specific and significant diagnosis-by-genotype interaction effect on hippocampal-prefrontal coupling. A diagnosis-by-genotype interaction was also found for working memory-related hippocampal rCBF change, which was uniquely attenuated in Met allele-carrying patients. Thus, both task-independent and task-dependent hippocampal neurophysiology accommodates a Met allelic background differently in patients with schizophrenia than in control subjects. Potentially consistent with the hypothesis that cellular sequelae of the BDNF Val66Met SNP interface with aspects of schizophrenic hippocampal and frontotemporal dysfunction, these results warrant future investigation to understand the contributions of unique patient trait or state variables to these robust interactions.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Cohen-Cory S, Kidane AH, Shirkey NJ, Marshak S . Brain-derived neurotrophic factor and the development of structural neuronal connectivity. Dev Neurobiol 2010; 70: 271–288.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Lu B, Gottschalk W . Modulation of hippocampal synaptic transmission and plasticity by neurotrophins. Prog Brain Res 2000; 128: 231–241.

    Article  CAS  PubMed  Google Scholar 

  4. Lu B . BDNF and activity-dependent synaptic modulation. Learn Mem 2003; 10: 86–98.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Tartaglia N, Du J, Tyler WJ, Neale E, Pozzo-Miller L, Lu B . Protein synthesis-dependent and -independent regulation of hippocampal synapses by brain-derived neurotrophic factor. J Biol Chem 2001; 276: 37585–37593.

    Article  CAS  PubMed  Google Scholar 

  6. Barnabe-Heider F, Miller FD . Endogenously produced neurotrophins regulate survival and differentiation of cortical progenitors via distinct signaling pathways. J Neurosci 2003; 23: 5149–5160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kang H, Schuman E . Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science 1995; 267: 1658–1662.

    Article  CAS  PubMed  Google Scholar 

  8. Sairanen M, Lucas G, Ernfors P, Castren M, Castren E . Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J Neurosci 2005; 25: 1089–1094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lipska BK, Khaing ZZ, Weickert CS, Weinberger DR . BDNF mRNA expression in rat hippocampus and prefrontal cortex: effects of neonatal ventral hippocampal damage and antipsychotic drugs. Eur J Neurosci 2001; 14: 135–144.

    Article  CAS  PubMed  Google Scholar 

  10. Owens SF, Picchioni MM, Rijsdijk FV, Stahl D, Vassos E, Rodger AK et al. Genetic overlap between episodic memory deficits and schizophrenia: results from The Maudsley Twin Study. Psychol Med 2011; 41: 521–532.

    Article  CAS  PubMed  Google Scholar 

  11. Tamminga CA, Thaker GK, Buchanan R, Kirkpatrick B, Alphs LD, Chase TN et al. Limbic system abnormalities identified in schizophrenia using positron emission tomography with fluorodeoxyglucose and neocortical alterations with deficit syndrome. Arch Gen Psychiatry 1992; 49: 522–530.

    Article  CAS  PubMed  Google Scholar 

  12. Nordahl TE, Kusubov N, Carter C, Salamat S, Cummings AM, O’Shora-Celaya L et al. Temporal lobe metabolic differences in medication-free outpatients with schizophrenia via the PET-600. Neuropsychopharmacology 1996; 15: 541–554.

    Article  CAS  PubMed  Google Scholar 

  13. Andreasen NC, O’Leary DS, Flaum M, Nopoulos P, Watkins GL, Ponto LLB et al. Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic-naïve patients. Lancet 1997; 349: 1730–1734.

    Article  CAS  PubMed  Google Scholar 

  14. Heckers S, Rauch S, Goff D, Savage C, Schacter D, Fischman A et al. Impaired recruitment of the hippocampus during conscious recollection in schizophrenia. Nat Neurosci 1998; 1: 318–323.

    Article  CAS  PubMed  Google Scholar 

  15. Ragland JD, Gur RC, Valdez JN, Loughead J, Elliott M, Kohler C et al. Levels-of-processing effect on frontotemporal function in schizophrenia during word encoding and recognition. Am J Psychiatry 2005; 162: 1840–1848.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Meyer-Lindenberg A, Poline J-B, Kohn PD, Holt JL, Egan MF, Weinberger DR et al. Evidence for abnormal cortical functional connectivity during working memory in schizophrenia. Am J Psychiatry 2001; 158: 1809–1817.

    Article  CAS  PubMed  Google Scholar 

  17. Buckley PF, Mahadik S, Pillai A, Terry A . Neurotrophins and schizophrenia. Schizophr Res 2007; 94: 1–11.

    Article  PubMed  Google Scholar 

  18. Shoval G, Weizman A . The possible role of neurotrophins in the pathogenesis and therapy of schizophrenia. Eur Neuropsychopharmacol 2005; 15: 319–329.

    Article  CAS  PubMed  Google Scholar 

  19. Angelucci F, Brene S, Mathe AA . BDNF in schizophrenia, depression and corresponding animal models. Mol Psychiatry 2005; 10: 345–352.

    Article  CAS  PubMed  Google Scholar 

  20. Durany N, Michel T, Zöchling R, Boissl KW, Cruz-Sánchez FF, Riederer P et al. Brain-derived neurotrophic factor and neurotrophin 3 in schizophrenic psychoses. Schizophr Res 2001; 52: 79–86.

    Article  CAS  PubMed  Google Scholar 

  21. Takahashi M, Shirakawa O, Toyooka K, Kitamura N, Hashimoto T, Maeda K et al. Abnormal expression of brain-derived neurotrophic factor and its receptor in the corticolimbic system of schizophrenic patients. Mol Psychiatry 2000; 5: 293–300.

    Article  CAS  PubMed  Google Scholar 

  22. Wong J, Hyde TM, Cassano HL, Deep-Soboslay A, Kleinman JE, Weickert CS . Promoter specific alterations of brain-derived neurotrophic factor mRNA in schizophrenia. Neuroscience 2010; 169: 1071–1084.

    Article  CAS  PubMed  Google Scholar 

  23. Hashimoto T, Bergen SE, Nguyen QL, Xu B, Monteggia LM, Pierri JN et al. Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia. J Neurosci 2005; 25: 372–383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Weickert CS, Hyde TM, Lipska BK, Herman MM, Weinberger DR, Kleinman JE . Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol Psychiatry 2003; 8: 592–610.

    Article  CAS  PubMed  Google Scholar 

  25. Green MJ, Matheson SL, Shepherd A, Weickert CS, Carr VJ . Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis. Mol Psychiatry 2010; 16: 960–972.

    Article  PubMed  Google Scholar 

  26. Chen D, Wang J, Wang B, Yang S, Zhang C, Zheng Y et al. Decreased levels of serum brain-derived neurotrophic factor in drug-naive first-episode schizophrenia: relationship to clinical phenotypes. Psychopharmacology (Berl) 2009; 207: 375–380.

    Article  CAS  Google Scholar 

  27. Vinogradov S, Fisher M, Holland C, Shelly W, Wolkowitz O, Mellon SH . Is serum brain-derived neurotrophic factor a biomarker for cognitive enhancement in schizophrenia? Biol Psychiatry 2009; 66: 549–553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chao HM, Kao HT, Porton B . BDNF Val66Met variant and age of onset in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 505–506.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Neves-Pereira M, Cheung JK, Pasdar A, Zhang F, Breen G, Yates P et al. BDNF gene is a risk factor for schizophrenia in a Scottish population. Mol Psychiatry 2005; 10: 208–212.

    Article  CAS  PubMed  Google Scholar 

  30. Muglia P, Vicente AM, Verga M, King N, Macciardi F, Kennedy JL . Association between the BDNF gene and schizophrenia. Mol Psychiatry 2003; 8: 146–147.

    Article  CAS  PubMed  Google Scholar 

  31. Zai GCM, Zai CCH, Chowdhury NI, Tiwari AK, Souza RP, Lieberman JA et al. The role of brain-derived neurotrophic factor (BDNF) gene variants in antipsychotic response and antipsychotic-induced weight gain. Prog Neuropsychopharmacol Biol Psychiatry 2012; 39: 96–101.

    Article  CAS  PubMed  Google Scholar 

  32. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003; 112: 257–269.

    CAS  PubMed  Google Scholar 

  33. Lahti AC, Holcomb HH, Weiler MA, Medoff DR, Tamminga CA . Functional effects of antipsychotic drugs: comparing clozapine with haloperidol. Biol Psychiatry 2003; 53: 601–608.

    Article  CAS  PubMed  Google Scholar 

  34. First MB, Spitzer RL, Miriam G, Williams JBW . User’s Guide for the Structured Clinical Interview for DSM-IV Axis I Disorders: SCID-I, Research Version. Biometrics Research, New York State Psychiatric Institute: New York, NY, 2001.

    Google Scholar 

  35. Kay SR, Fiszbein A, Opler LA . The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261–276.

    Article  CAS  PubMed  Google Scholar 

  36. Wei SM, Eisenberg DP, Kohn PD, Kippenhan JS, Kolachana BS, Weinberger DR et al. Brain-derived neurotrophic factor Val66Met polymorphism affects resting regional cerebral blood flow and functional connectivity differentially in women versus men. J Neurosci 2012; 32: 7074–7081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Eisenberg DP, Sarpal D, Kohn PD, Meyer-Lindenberg A, Wint D, Kolachana B et al. Catechol-o-methyltransferase valine(158)methionine genotype and resting regional cerebral blood flow in medication-free patients with schizophrenia. Biol Psychiatry 2010; 67: 287–290.

    Article  CAS  PubMed  Google Scholar 

  38. Wigginton JE, Cutler DJ, Abecasis GaR. A . Note on exact tests of Hardy-Weinberg equilibrium. Am J Hum Genet 2005; 76: 887–893.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Meyer-Lindenberg AS, Olsen RK, Kohn PD, Brown T, Egan MF, Weinberger DR et al. Regionally specific disturbance of dorsolateral prefrontal-hippocampal functional connectivity in schizophrenia. Arch Gen Psychiatry 2005; 62: 379–386.

    Article  PubMed  Google Scholar 

  40. Forman SD, Cohen JD, Fitzgerald M, Eddy WF, Mintun MA, Noll DC . Improved assessment of significant activation in functional magnetic resonance imaging (fMRI): use of a cluster-size threshold. Magn Reson Med 1995; 33: 636–647.

    Article  CAS  PubMed  Google Scholar 

  41. Kovalchuk Y, Hanse E, Kafitz KW, Konnerth A . Postsynaptic induction of BDNF-mediated long-term potentiation. Science 2002; 295: 1729–1734.

    Article  CAS  PubMed  Google Scholar 

  42. Lohof AM, Ip NY, Poo MM . Potentiation of developing neuromuscular synapses by the neurotrophins NT-3 and BDNF. Nature 1993; 363: 350–353.

    Article  CAS  PubMed  Google Scholar 

  43. Binder DK, Croll SD, Gall CM, Scharfman HE . BDNF and epilepsy: too much of a good thing? Trends Neurosci 2001; 24: 47–53.

    Article  CAS  PubMed  Google Scholar 

  44. Rex CS, Lin C-Y, Kramar EA, Chen LY, Gall CM, Lynch G . Brain-derived neurotrophic factor promotes long-term potentiation-related cytoskeletal changes in adult hippocampus. J Neurosci 2007; 27: 3017–3029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Messaoudi E, BÃ¥rdsen K, Srebro B, Bramham CR . Acute intrahippocampal infusion of BDNF induces lasting potentiation of synaptic transmission in the rat dentate gyrus. J Neurophysiol 1998; 79: 496–499.

    Article  CAS  PubMed  Google Scholar 

  46. Sherwood NT, Lo DC . Long-term enhancement of central synaptic transmission by chronic brain-derived neurotrophic factor treatment. J Neurosci 1999; 19: 7025–7036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Medoff DR, Holcomb HH, Lahti AC, Tamminga CA . Probing the human hippocampus using rCBF: contrasts in schizophrenia. Hippocampus 2001; 11: 543–550.

    Article  CAS  PubMed  Google Scholar 

  48. Erkwoh R, Sabri O, Steinmeyer EM, Büll U, Saß H . Psychopathological and SPECT findings in never-treated schizophrenia. Acta Psychiatr Scand 1997; 96: 51–57.

    Article  CAS  PubMed  Google Scholar 

  49. Malaspina D, Harkavy-Friedman J, Corcoran C, Mujica-Parodi L, Printz D, Gorman JM et al. Resting neural activity distinguishes subgroups of schizophrenia patients. Biol Psychiatry 2004; 56: 931–937.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Molina V, Sanz J, Sarramea F, Benito C, Palomo T . Prefrontal atrophy in first episodes of schizophrenia associated with limbic metabolic hyperactivity. J Psychiatr Res 2005; 39: 117–127.

    Article  PubMed  Google Scholar 

  51. al-Mousawi AH, Evans N, Ebmeier KP, Roeda D, Chaloner F, Ashcroft GW . Limbic dysfunction in schizophrenia and mania. A study using 18F-labelled fluorodeoxyglucose and positron emission tomography. Br J Psychiatry 1996; 169: 509–516.

    Article  CAS  PubMed  Google Scholar 

  52. Schobel SA, Lewandowski NM, Corcoran CM, Moore H, Brown T, Malaspina D et al. Differential targeting of the CA1 subfield of the hippocampal formation by schizophrenia and related psychotic disorders. Arch Gen Psychiatry 2009; 66: 938–946.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Whitfield-Gabrieli S, Thermenos HW, Milanovic S, Tsuang MT, Faraone SV, McCarley RW et al. Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia. Proc Natl Acad Sci USA 2009; 106: 1279–1284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Lahti AC, Weiler MA, Holcomb HH, Tamminga CA, Carpenter WT, McMahon R . Correlations between rCBF and symptoms in two independent cohorts of drug-free patients with schizophrenia. Neuropsychopharmacology 2005; 31: 221–230.

    Article  Google Scholar 

  55. Ninan I, Bath KG, Dagar K, Perez-Castro R, Plummer MR, Lee FS et al. The BDNF Val66Met polymorphism impairs NMDA receptor-dependent synaptic plasticity in the hippocampus. J Neurosci 2010; 30: 8866–8870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Liu R-J, Lee FS, Li X-Y, Bambico F, Duman RS, Aghajanian GK . Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry 2012; 71: 996–1005.

    Article  CAS  PubMed  Google Scholar 

  57. Thomason ME, Yoo DJ, Glover GH, Gotlib IH . BDNF genotype modulates resting functional connectivity in children. Front Hum Neurosci 2009; 3: 55.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Veltman DJ, Friston KJ, Sanders G, Price CJ . Regionally specific sensitivity differences in fMRI and PET: where do they come from? NeuroImage 2000; 11: 575–588.

    Article  CAS  PubMed  Google Scholar 

  59. Wolf RC, Vasic N, Sambataro F, Höse A, Frasch K, Schmid M et al. Temporally anticorrelated brain networks during working memory performance reveal aberrant prefrontal and hippocampal connectivity in patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33: 1464–1473.

    Article  PubMed  Google Scholar 

  60. Goldman-Rakic PS, Selemon LD, Schwartz ML . Dual pathways connecting the dorsolateral prefrontal cortex with the hippocampal formation and parahippocampal cortex in the rhesus monkey. Neuroscience 1984; 12: 719–743.

    Article  CAS  PubMed  Google Scholar 

  61. Freyberg Z, Ferrando SJ, Javitch JA . Roles of the Akt/GSK-3 and Wnt signaling pathways in schizophrenia and antipsychotic drug action. Am J Psychiatry 2009; 167: 388–396.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Nicodemus KK, Marenco S, Batten AJ, Vakkalanka R, Egan MF, Straub RE et al. Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk. Mol Psychiatry 2008; 13: 873–877.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by the Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892. We would like to thank the staff of the NIH PET Center and the NIMH GCAP Inpatient Program for their assistance in data acquisition.

Author information

Authors and Affiliations

  1. Section on Integrative Neuroimaging, National Institute of Mental Health, NIH, DHHS, Bethesda, MD, USA

    D P Eisenberg, A M Ianni, S-M Wei, P D Kohn & K F Berman

  2. Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, NIH, DHHS, Bethesda, MD, USA

    D P Eisenberg, A M Ianni, S-M Wei, P D Kohn, B Kolachana, J Apud & K F Berman

  3. The Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA

    D R Weinberger

Authors
  1. D P Eisenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A M Ianni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S-M Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P D Kohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B Kolachana
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Apud
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D R Weinberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. K F Berman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K F Berman.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Eisenberg, D., Ianni, A., Wei, SM. et al. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism differentially predicts hippocampal function in medication-free patients with schizophrenia. Mol Psychiatry 18, 713–720 (2013). https://doi.org/10.1038/mp.2012.187

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2012.187

Keywords

This article is cited by

Search

Advanced search

Quick links