Hostname: page-component-6766d58669-vgfm9 Total loading time: 0 Render date: 2026-05-15T20:15:12.943Z Has data issue: false hasContentIssue false
  • English
  • Français

Brain-Derived Neurotrophic Factor: The Neurotrophin Hypothesis of Psychopathology

Published online by Cambridge University Press:  07 November 2014

Dan J. Stein ,
Willie M.U. Daniels ,
Jonathan Savitz  and
Brian H. Harvey
Get access Rights & Permissions [Opens in a new window]

Abstract

While monoaminergic hypotheses of psychopathology remain popular, there has been growing interest in the role of neurotrophins in neuropsychiatric disorders. Basic laboratory work has documented the importance of neurotrophins in neuronal survival and synaptic plasticity, and a range of clinical studies has provided analogous evidence of their role in neuropathology. Work on gene variants in brain-derived neurotrophic factor, and associated changes in structural and function brain imaging, have further contributed to our understanding of this area. Much remains to be done to delineate fully the relevant mechanisms by which brain-derived neurotrophic factor and other neurotrophins contribute to psychopathology, and to develop targeted therapeutic interventions. Nevertheless, the neurotrophin hypothesis has already given impetus to a range of valuable research.

Information

Type
Pearls in Clinical Neuroscience
Information
CNS Spectrums , Volume 13 , Issue 11 , November 2008 , pp. 945 - 949
Copyright
Copyright © Cambridge University Press 2008

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

REFERENCES

1.Levi-Montalcini, R. The nerve growth factor: thirty-five yeras later. EMBO J. 1987;6:1145–1154.CrossRefGoogle Scholar
2.Tongiorgi, E. Activity-dependent expression of brain-derived neurotrophic factor in dendrites: facts and open questions. Neurosci Res. 2008;61:335–346.CrossRefGoogle ScholarPubMed
3.Hu, Y, Russek, SJ. BDNF and the diseased nervous system: a delicate balance between adaptive and pathological processes of gene regulation. J Neurochem. 2008;105:1–17.CrossRefGoogle ScholarPubMed
4.Lu, B, Pang, PT, Woo, NH. The yin and yang of neurotrophin action. Nat Rev Neurosci. 2005;6:603–614.CrossRefGoogle ScholarPubMed
5.Bekinschtein, P, Cammarota, M, Izquierdo, I, Medina, JH. BDNF and memory formation and storage. Neuroscientist. 2008;14:147–156.CrossRefGoogle ScholarPubMed
6.Carvalho, AL, Caldeira, MV, Santos, SO, Duarte, CB. Role of the brain-derived neurotrophic factor at glutamatergic synapses. Br J Pharmacol. 2008;153(suppl 1):S310–S324.CrossRefGoogle ScholarPubMed
7.Berton, O, McClung, CA, DiLeone, RJ, et al.Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science. 2006;311:864–868.CrossRefGoogle ScholarPubMed
8.Takahashi, T, Suzuki, M, Tsunoda, M, et al.The association of genotypic combination of the DRD3 and BDNF polymorphisms on the adhesio interthalamica and medial temporal lobe structures. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:1236–1242.CrossRefGoogle ScholarPubMed
9.Pezawas, L, Meyer-Lindenberg, A, Goldman, AL, et al.Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression. Mol Psychiatry. 2008;13:709–716.CrossRefGoogle ScholarPubMed
10.Martinowich, K, Lu, B. Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology. 2008;33:73–83.CrossRefGoogle ScholarPubMed
11.Galloway, EM, Woo, NH, Lu, B. Persistent neural activity in the prefrontal cortex: a mechanism by which BDNF regulates working memory? Prog Brain Res. 2008;169:251–266.CrossRefGoogle ScholarPubMed
12.Kerschensteiner, M, Stadelmann, C, Deohant, G, Wekerle, H, Hohlfeld, R. Neurotrophic cross-talk between the nervous and immune systems: Implications for neurological diseases. Ann Neurol. 2003;53:292–304.CrossRefGoogle ScholarPubMed
13.Santarelli, L, Saxe, M, Gross, C, et al.Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301:805–809.CrossRefGoogle ScholarPubMed
14.Schmidt, HD, Duman, RS. The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior. Behav Pharmacol. 2007;18:391–418.CrossRefGoogle ScholarPubMed
15.Brunoni, AR, Lopes, M, Fregni, F. A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. Int J Neuropsychopharmacol. 2008 Aug 28:1–12. [Epub ahead of print].Google ScholarPubMed
16.Post, RM. Role of BDNF in bipolar and unipolar disorder: clinical and theoretical implications. J Psychiatr Res. 2007;41:979–990.CrossRefGoogle ScholarPubMed
17.Groves, JO. Is it time to reassess the BDNF hypothesis of depression? Mol Psychiatry. 2007;12:1079–1088.CrossRefGoogle ScholarPubMed
18.Kozisek, ME, Middlemas, D, Bylund, DB. Brain-derived neurotrophic factor and its receptor tropomyosin-related kinase B in the mechanism of action of antidepressant therapies. Pharmacol Ther. 2008;117:30–51.CrossRefGoogle ScholarPubMed
19.Castrén, E, Võikar, V, Rantamäki, T. Role of neurotrophic factors in depression. Curr Opin Pharmacol. 2007;7:18–21.CrossRefGoogle ScholarPubMed
20.Martinowich, K, Manji, H, Lu, B. New insights into BDNF function in depression and anxiety. Nature Neuroscience. 2007;10:1089–1093.CrossRefGoogle ScholarPubMed
21.Egan, MF, Kojima, M, Callicott, JH, et al.The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003;112:257–269.CrossRefGoogle ScholarPubMed
22.Chen, ZY, Patel, PD, Sant, G, et al.Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci. 2004;24:4401–4411.CrossRefGoogle ScholarPubMed
23.Chen, ZY, Ieraci, A, Teng, H, et al.Sortilin controls intracellular sorting of brain-derived neurotrophic factor to the regulated secretory pathway. J Neurosci. 2005;25:6156–6166.CrossRefGoogle Scholar
24.Chen, ZY, Jing, DQ, Bath, KG, et al.Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science. 2006;314:140–143.CrossRefGoogle ScholarPubMed
25.Dempster, E, Toulopoulou, T, McDonald, C, et al.Association between BDNF Val(66)Met genotype and episodic memory. Am J Med Genet B Neuropsychiatr Genet. 2005;134B:73–75.CrossRefGoogle Scholar
26.Miyajima, F, Ollier, W, Mayes, A, et al.Brain-derived neurotrophic factor polymorphism Val66Met influences cognitive abilities in the elderly. Genes Brain Behav. 2008;7:411–417.CrossRefGoogle ScholarPubMed
27.Goldberg, TE, Iudicello, J, Russo, C, et al.BDNF Val66Met polymorphism significantly affects d' in verbal recognition memory at short and long delays. Biol Psychol. 2008;77:20–24.CrossRefGoogle Scholar
28.Ho, BC, Milev, P, O'Leary, DS, Librant, A, Andreasen, NC, Wassink, TH. 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. 2006;63:731–740.CrossRefGoogle ScholarPubMed
29.Pezawas, L, Verchinski, BA, Mattay, VS, et al.The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci. 2004;24:10099–10102.CrossRefGoogle ScholarPubMed
30.Szeszko, PR, Lipsky, R, Mentschel, C, et al.Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation. Mol Psychiatry. 2005;10:631–636.CrossRefGoogle ScholarPubMed
31.Bueller, JA, Aftab, M, Sen, S, et al.BDNF val(66) met allele is associated with reduced hippocampal volume in healthy subjects. Biol Psychiatry. 2006;59:812–815.CrossRefGoogle ScholarPubMed
32.Sublette, ME, Baca-Garcia, E, Parsey, RV, et al.Effect of BDNF val66met polymorphism on age-related amygdala volume changes in healthy subjects. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:1652–1655.CrossRefGoogle ScholarPubMed
33.Takahashi, T, Suzuki, M, Tsunoda, M, et al.Association between the brain-derived neurotrophic factor Val66Met polymorphism and brain morphology in a Japanese sample of schizophrenia and healthy comparisons. Neurosci Lett. 2008;435:34–39.CrossRefGoogle Scholar
34.Chepenik, LG, Fredericks, C, Papademetris, X, et al.Effects of the brain-derived neurotrophic growth factor val66met variation on hippocampus morphology in bipolar disorder. Neuropsychopharmacology. 2008 Aug 13. [Epub ahead of print].Google ScholarPubMed
35.Hariri, AR, Goldberg, TE, Mattay, VS, et al.Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci. 2003;23:6690–6694.CrossRefGoogle ScholarPubMed
36.Montag, C, Reuter, M, Newport, B, et al.The BDNF Val66Met polymorphism affects amygdala activity in response to emotional stimuli: evidence from a genetic imaging study. Neuroimage. 2008;42:1554–1559.CrossRefGoogle ScholarPubMed
37.Stern, AH, Savostyanova, AA, Goldman, A, et al.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. In press.Google Scholar
38.Taylor, WD, Züchner, S, McQuoid, DR, et al.The brain-derived neurotrophic factor VAL66MET polymorphism and cerebral white matter hyperintensities in late-life depression. Am J Geriatr Psychiatry. 2008;16:263–271.CrossRefGoogle ScholarPubMed
39.Frodl, T, Schuele, C, Schmitt, G, et al.Association of the brain-derived neurotrophic factor Val66Met polymorphism with reduced hippocampal volumes in major depression. Arch Gen Psychiatry. 2007;64:410–416.CrossRefGoogle ScholarPubMed
40.Frey, BN, Walss-Bass, C, Stanley, JA, et al.Brain-derived neurotrophic factor val66met polymorphism affects prefrontal energy metabolism in bipolar disorder. Neuroreport. 2007;18:1567–1570.CrossRefGoogle ScholarPubMed
41.Agartz, I, Sedvall, GC, Terenius, L, et al.BDNF gene variants and brain morphology in schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:513–523.CrossRefGoogle ScholarPubMed
42.Ho, BC, Andreasen, NC, Dawson, JD, et al.Association between brain-derived neurotrophic factor val66met gene polymorphism and progressive brain volume changes in schizophrenia. Am J Psychiatry. 2007;164:1890–1899.CrossRefGoogle ScholarPubMed
43.Nemoto, K, Ohnishi, T, Mori, T, et al.The Val66Met polymorphism of the brain-derived neurotrophic factor gene affects age-related brain morphology. Neurosci Lett. 2006;397:25–29.CrossRefGoogle ScholarPubMed
44.Hemmings, SM, Kinnear, CJ, Van der merwe, L, et al.Investigating the role of the brain-derived neurotrophic factor (BDNF) val66met variant in obsessive-compulsive disorder (OCD). World J Biol Psychiatry. 2008;9:126–134.CrossRefGoogle ScholarPubMed
45.Fan, J, Sklar, P. Genetics of bipolar disorder: focus on BDNF Val66Met polymorphism. Novartis Found Symp. 2008;289:60–72.CrossRefGoogle ScholarPubMed
46.Chen, L, Lawlor, DA, Lewis, SJ, et al.Genetic association study of BDNF in depression: finding from two cohort studies and a meta-analysis. Am J Med Genet B Neuropsychiatr Genet. 2008;147B:814–821.CrossRefGoogle ScholarPubMed
47.Joffe, RT, Gatt, JM, Kemp, AH, et al.Brain derived neurotrophic factor Val66Met polymorphism, the five factor model of personality and hippocampal volume: Implications for depressive illness. Hum Brain Mapp. 2008 Jun 11. [Epub ahead of print].Google Scholar
48.Cirulli, F, Francia, N, Berry, A, Aloe, L, Alleva, E, Suomi, SJ. Early life stress as a risk factor for mental health: Role of neurotrophins from rodents to non-human primates. Neurosci Biobehav Rev. 2008 Sep 4. [Epub ahead of print].Google Scholar
49.Uys, JDK, Marais, L, Faure, J, et al.Developmental trauma is associated with behavioral hyperarousal, altered HPA axis activity, and decreased hippocampal neurotrophin expression in the adult rat. In: Yehuda, R, ed. Psychobiology of Posttraumatic Stress Disorder: A Decade of Progress (Annals of the New York Academy of Sciences). 2006;1071:542–546.Google Scholar
50.Faure, J, Uys, JD, Marais, L, Stein, DJ, Daniels, WM. Early maternal separation alters the response to traumatization: resulting in increased levels of hippocampal neurotrophic factors. Metab Brain Dis. 2007;22:183–195.CrossRefGoogle ScholarPubMed
51.Lu, B, Martinowich, K. Cell biology of BDNF and its relevance to schizophrenia. Novartis Found Symp. 2008;289:119–129.CrossRefGoogle ScholarPubMed
52.Savitz, J, van der Merwe, L, Stein, DJ, Solms, M, Ramesar, R. Genotype and childhood sexual trauma moderate neurocognitive performance: a possible role for brain-derived neurotrophic factor and apolipoprotein E variants. Biol Psychiatry. 2007;62:391–399.CrossRefGoogle ScholarPubMed
53.McClung, CA, Nestler, EJ. Neuroplasticity mediated by altered gene expression. Neuropsychopharmacology. 2008;33:3–17.CrossRefGoogle ScholarPubMed
54.Citri, A, Malenka, RC. Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacology. 2008;33:18–41.CrossRefGoogle ScholarPubMed
55.Mössner, R, Mikova, O, Koutsilieri, E, et al.Consensus paper of the WFSBP Task Force on Biological Markers: biological markers in depression. World J Biol Psychiatry. 2007;8:141–174.CrossRefGoogle ScholarPubMed
56.Schulte-Herbrüggen, O, Braun, A, Rochlitzer, S, Jockers-Scherübl, MC, Hellweg, R. Neurotrophic factors—a tool for therapeutic strategies in neurological, neuropsychiatric and neuroimmunological diseases? Current Medicinal Chemistry. 2007;14:2318–2329.CrossRefGoogle ScholarPubMed
57.Mocchetti, I, Brown, M. Targeting neurotrophin receptors in the central nervous system. CNS Neurol Disord Drug Targets. 2008;7:71–82.CrossRefGoogle ScholarPubMed
58.Rantamäki, T, Castrén, E. Targeting TrkB neurotrophin receptor to treat depression. Expert Opin Ther Targets. 2008;12:705–715.CrossRefGoogle ScholarPubMed
59.Kalra, S, Genge, A, Arnold, DL. A prospective, randomized, placebo-controlled evaluation of corticoneuronal response to intrathecal BDNF therapy in ALS using magnetic resonance spectroscopy: feasibility and results. Amyotroph Lateral Scler Other Motor Neuron Disord. 2003;4:22–26.CrossRefGoogle ScholarPubMed
60.Scharfman, HE, Hen, R. Is more neurogenesis always better? Science. 2007;315:336–338.CrossRefGoogle ScholarPubMed