Skip to main content
SpringerLink
Log in

The Hippocampus, Neurotrophic Factors and Depression

Possible Implications for the Pharmacotherapy of Depression

  • Leading Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Depression is a prevalent, highly debilitating mental disorder affecting up to 15% of the population at least once in their lifetime, with huge costs for society. Neurobiological mechanisms of depression are still not well known, although there is consensus about interplay between genetic and environmental factors. Antidepressant medications are frequently used in depression, but at least 50% of patients are poor responders, even to more recently discovered medications. Furthermore, clinical response only occurs following weeks to months of treatment and only chronic treatment is effective, suggesting that actions beyond the rapidly occurring effect of enhancing monoaminergic systems, such as adaptation of these systems, are responsible for the effects of antidepressants.

Recent studies indicate that an impairment of synaptic plasticity (neurogenesis, axon branching, dendritogenesis and synaptogenesis) in specific areas of the CNS, particularly the hippocampus, may be a core factor in the pathophysiology of depression. The abnormal neural plasticity may be related to alterations in the levels of neurotrophic factors, namely brain-derived neurotrophic factor (BDNF), which play a central role in plasticity. As BDNF is repressed by stress, epigenetic regulation of the BDNF gene may play an important role in depression. The hippocampus is smaller in depressed patients, although it is unclear whether smaller size is a consequence of depression or a pre-existing, vulnerability marker for depression. Environmental stressors triggering activation of the hypothalamic-pituitary-adrenal axis cause the brain to be exposed to corticosteroids, affecting neurobehavioural functions with a strong downregulation of hippocampal neurogenesis, and are a major risk factor for depression. Antidepressant treatment increases BDNF levels, stimulates neurogenesis and reverses the inhibitory effects of stress, but this effect is evident only after 3–4 weeks of administration, the time course for maturation of new neurons. The ablation of hippocampal neurogenesis blocks the behavioural effects of antidepressants in animal models.

The above findings suggest new possible targets for the pharmacotherapy of depression such as neurotrophic factors, their receptors and related intracellular signalling cascades; agents counteracting the effects of stress on hippocampal neurogenesis (including antagonists of corticosteroids, inflammatory cytokines and their receptors); and agents facilitating the activation of gene expression and increasing the transcription of neurotrophins in the brain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003; 289(23): 3095–105

    PubMed  Google Scholar 

  2. Kessler RC, Avenevoli S, Ries Merikangas K. Mood disorders in children and adolescents: an epidemiologic perspective. Biol Psychiatry 2001; 49: 1002–14

    PubMed  CAS  Google Scholar 

  3. Evans E, Hawton K, Rodham K, et al. The prevalence of suicidal phenomena in adolescents: a systematic review of population-based studies. Suicide Life Threat Behav 2005; 35: 239–50

    PubMed  Google Scholar 

  4. Lee S, Jeong J, Kwak Y, et al. Depression research: where are we now? Mol Brain 2010; 3: 8

    PubMed  Google Scholar 

  5. Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression. Nat Med 2000; 7: 541–7

    Google Scholar 

  6. Mill J, Petronis A. Molecular studies of major depressive disorder: the epigenetic perspective. Mol Psychiatry 2007; 12: 799–814

    PubMed  CAS  Google Scholar 

  7. Berton O, Nestler EJ. New approaches to antidepressant drug discoveries: beyond monoamines. Nat Rev Neurosci 2006; 7: 137–51

    PubMed  CAS  Google Scholar 

  8. Ressler KJ, Mayberg KS. Targeting abnormal circuits in mood and anxiety disorders from the laboratory to the clinic. Nat Neurosci 2007; 10: 1116–24

    PubMed  CAS  Google Scholar 

  9. Dwivedi Y. Brain derived neurotrophic factor: a role in depression and suicide. Neuropsychiatr Dis Treat 2009; 5: 433–49

    PubMed  CAS  Google Scholar 

  10. Gross CG. Neurogenesis in the adult brain: death of a dogma. Nature Rev Neurosci 2000; 1: 67–73

    CAS  Google Scholar 

  11. Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comparative Neurol 1965; 124: 319–35

    CAS  Google Scholar 

  12. Paizanis E, Hamon M, Lanfumey L. Hippocampal neurogenesis, depressive disorders, and antidepressant therapy. Neural Plasticity 2007; 2007: 73754

    PubMed  Google Scholar 

  13. Eriksson PS, Perfilieva S, Bjork-Eriksson T, et al. Neurogenesis in the adult human hippocampus. Nature Med 1998; 4: 1313–7

    PubMed  CAS  Google Scholar 

  14. Hastings NB, Seth MI, Tanapat P, et al. Granule neurons generated during development extend divergent axon collaterals to hippocampal area CA 3. J Comparative Neurol 2002; 452: 324–33

    Google Scholar 

  15. Kempermann G, Kuhn HG, Gage FH. Experience-induced neurogenesis in the senescent dentate gyrus. J Neuroscience 1998; 18: 3206–12

    CAS  Google Scholar 

  16. Cameron HA, McKay RDG. Adult neurogenesis produces a large pool of granule cells in the dentate gyrus. J Comparative Neurol 2001; 435: 406–17

    CAS  Google Scholar 

  17. Erickson KI, Voss MW, Prakash RS, et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A 2011; 108(7): 3017–22

    PubMed  CAS  Google Scholar 

  18. Dranovsky A, Hen R. Hippocampal neurogenesis: regulation by stress and antidepressants. Biol Psychiatry 2006; 59: 1136–43

    PubMed  CAS  Google Scholar 

  19. Anderson ML, Sisti HM, Curlik 2nd DM, et al. Associative learning increases adult neurogenesis during a critical period. Eur J Neurosci 2011; 33: 175–81

    PubMed  Google Scholar 

  20. Duman RS, Malberg J, Thome J. Neural plasticity to stress and antidepressant treatment. Biol Psychiatry 1999; 46: 1181–91

    PubMed  CAS  Google Scholar 

  21. Vythilingham M, Vermetten E, Andreson GM, et al. Hippocampal volume, memory, and cortisol status in major depressive disorder: effects of treatment. Biol Psychiatry 2004; 56: 101–12

    Google Scholar 

  22. Colla M, Kronenberg G, Deuschle M, et al. Hippocampal volume reduction and HPA-system activity in major depression. J Psychiatry Res 2007; 41: 553–60

    Google Scholar 

  23. Duman RS, Nakagawa S, Malberg J. Regulation of adult neurogenesis by antidepressant treatment. Neuropsycho-pharmacology 2001; 25: 836–84

    CAS  Google Scholar 

  24. Sheline YI, Wang PW, Gado MH, et al. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A 1996; 93: 3908–13

    PubMed  CAS  Google Scholar 

  25. Sapolsky RM. Depression, antidepressants and the shrinking hippocampus. Proc Natl Acad Sci U S A 2001; 98: 12320–2

    PubMed  CAS  Google Scholar 

  26. MacQueen GM, Campbell S, McEwen BS, et al. Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci U S A 2003; 100: 1387–92

    PubMed  CAS  Google Scholar 

  27. Frodl TS, Koutsouleris N, Bottlender R, et al. Depression-related variation in brain morphology over 3 years: effects of stress? Arch Gen Psychiatry 2008; 65: 1156–65

    PubMed  Google Scholar 

  28. McKinnon MC, Yucel K, Nazarov A, et al. A meta-analysis examining clinical predictors of hippocampal volume in patients with major depressive disorder. J Psychiatry Neurosci 2009; 34: 41–54

    PubMed  Google Scholar 

  29. Banasr M, Hery M, Printemps R, et al. Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone. Neuropsychopharmacol 2004; 29: 450–60

    CAS  Google Scholar 

  30. Pham K, Nacher J, Hof PR, et al. Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in adult rat dentate gyrus. Eur J Neurosci 2003; 17: 879–86

    PubMed  Google Scholar 

  31. MacMaster FP, Mirza Y, Szeszko PR, et al. Amygdala and hippocampal volume loss in familial early-onset major depressive disorder. Biol Psychiatry 2008; 63: 385–90

    PubMed  Google Scholar 

  32. Rao U, Chen LA, Bidesi AS, et al. Hippocampal changes associated with early-life adversity and vulnerability to depression. Biol Psychiatry 2010; 67: 357–64

    PubMed  Google Scholar 

  33. Chen MC, Hamilton JP, Gotlib IH. Decreased hippocampus volume in healthy girls at risk for depression. Arch Gen Psychiatry 2010; 67: 270–6

    PubMed  Google Scholar 

  34. Frodl T, Reinhold E, Koutsouleris N, et al. Childhood stress, serotonin transporter gene and brain structures in major depression. Neuropsychopharmacology 2010; 35: 1383–90

    PubMed  CAS  Google Scholar 

  35. Koolschijn PC, van Haren NE, Cahn W, et al. Hippocampal volume changes in schizophrenia. J Clin Psychiatry 2010; 71: 737–44

    PubMed  Google Scholar 

  36. Javadapour A, Mahli GS, Ivanowski B, et al. Hippocampal volume in adults with bipolar disorder. J Neuropsychiatry Clin Neurosci 2010; 22: 55–62

    PubMed  Google Scholar 

  37. Malberg JE, Duman RS. Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology 2003; 28: 1562–71

    PubMed  CAS  Google Scholar 

  38. Wang JW, David DJ, Monckton JE, et al. Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells. J Neurosci 2008; 28(6): 1374–84

    PubMed  CAS  Google Scholar 

  39. Jacobs BL, van Praag H, Gage FH. Adult brain neurogenesis and psychiatry: a novel theory of depression. Mol Psychiatry 2000; 5: 262–9

    PubMed  CAS  Google Scholar 

  40. Santarelli L, Saxe M, Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 2003; 301: 805–9

    PubMed  CAS  Google Scholar 

  41. Czéh B, Michaelis T, Watanabe T, et al. Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci U S A 2001; 98: 12796–801

    PubMed  Google Scholar 

  42. Hanson ND, Nemeroff CB, Owe MJ. Lithium, but not fluoxetine or the corticotrophin-releasing factor receptor 1 receptor antagonist r121919 increases cell proliferation in the adult dentate gyrus. J Pharm Exp Ther 2011; 337: 180–6

    CAS  Google Scholar 

  43. Linthorst AC, Reul JM. Stress and the brain: solving the puzzle using microdialysis. Pharmacol Biochem Behav 2008; 90: 163–73

    PubMed  CAS  Google Scholar 

  44. Figlewicz DP. Endocrine regulation of neurotransmitter transport. Epilepsy Res 1999; 37: 203–10

    PubMed  CAS  Google Scholar 

  45. Huang GJ, Herbert J. The role of 5-HT1A receptors in the proliferation and survival of progenitor cells in the dentate gyrus of the adult hippocampus and their regulation by corticoids. Neuroscience 2005; 135: 803–13

    PubMed  CAS  Google Scholar 

  46. Gotlieb IH, Joormann J, Minor KL, et al. HPA axis reactivity: a mechanism underlying the associations among 5-HTTLPR, stress, and depression. Biol Psychiatry 2007; 63: 847–51

    Google Scholar 

  47. Jabbi M, Korf J, Kema IP, et al. Convergent genetic modulation of the endocrine stress response involves polymorphic variations of 5-HT, COMPY and MAOA. Mol Psychiatry 2007; 12: 483–90

    PubMed  CAS  Google Scholar 

  48. Karl A, Schaefer M, Malta LS, et al. A meta-analysis of structural brain abnormalities in PTSD. Neurosci Biobehav Rev 2006; 30: 1004–31

    PubMed  Google Scholar 

  49. Bahtnagar S, Lee TM, Vining C. Prenatal stress differentially affects habituation of corticosterone responses to repeated stress in adult male and female rats. Horm Behav 2005; 47: 430–8

    Google Scholar 

  50. Coe CL, Kramer M, Czéh B, et al. Prenatal stress diminishes neurogenesis in the dentate gyrus of juvenile Rhesus monkeys. Biol Psychiatry 2003; 54: 1025–34

    PubMed  CAS  Google Scholar 

  51. Schoenfeld TJ, Gould E. Stress, stress hormones, and adult neurogenesis. Exp Neurol. Epub 2011 Jan 31

  52. McEwen B. Effects of adverse experiences for brain structure and function. Biol Psychiatry 2000; 48: 721–31

    PubMed  CAS  Google Scholar 

  53. Hajszan T, Dow A, Warner-Schmidt JL, et al. Remodeling of hippocampal spine synapses in the rat learned helplessness model of depression. Biol Psychiatry 2009; 65: 392–400

    PubMed  Google Scholar 

  54. Law AJ, Weickert CS, Hyde TM, et al. Reduced spino-phillin but not microtubule-associated protein 2 expression in the hippocampal formation in schizophrenia and mood disorders: molecular evidence for a pathology of dendritic spines. Am J Psychiatry 2004; 161: 1848–55

    PubMed  Google Scholar 

  55. Stockmeyer CA, Mahajan GJ, Konick LC, et al. Cellular changes in the post-mortem hippocampus in major depression. Biol Psychiatry 2004; 56: 640–50

    Google Scholar 

  56. Kobayashi K, Ikeda Y, Sakai A, et al. Reversal of hippocampal neuronal maturation by serotonergic antidepressants. Proc Natl Acad Sci U S A 2010; 107: 8434–9

    PubMed  CAS  Google Scholar 

  57. Cushing BS, Kramer KM. Mechanism underlying epigenetic effects of early social experience: the role of neuropeptides and steroids. Neurosci Behav Rev 2005; 29: 1089–105

    CAS  Google Scholar 

  58. Goodyer I. Early onset depressions: meanings, mechanisms and processes. J Child Psychol Psychiatry 2008; 49: 1239–56

    PubMed  Google Scholar 

  59. Blakemore SJ. Development of social brain during adolescence. Quart J Exp Psychol 2008; 61: 40–9

    Google Scholar 

  60. Heim C, Nemeroff CB. The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol Psychiatry 2001; 49: 1023–39

    PubMed  CAS  Google Scholar 

  61. Kendler KS, Karkowki LM, Prescott CA. Causal relationship between stressful life events and the onset of major depression. Am J Psychiatry 1999; 156: 837–41

    PubMed  CAS  Google Scholar 

  62. Jokinen J, Nordstrom P. HPA axis hyperactivity and attempted suicide in young adult mood disorder inpatients. J Affect Disord 2009; 116: 117–20

    PubMed  CAS  Google Scholar 

  63. Ehlert U, Gaab J, Heinrichs M. Psychoneuroendocrinological contributions to the etiology of depression, post-traumatic stress disorder, and stress-related bodily disorders: the role of the hypothalamic-pituitary-adrenal axis. Biol Psychol 2001; 57: 141–52

    PubMed  CAS  Google Scholar 

  64. Nestler EJ, Gould E, Manji H, et al. Preclinical models: the status of basic research in depression. Biol Psychiatry 2002; 52: 503–28

    PubMed  Google Scholar 

  65. Lopez-Duran NL, Kovacs M, George CJ. Hypothalamic-pituitary-adrenal axis depression in children and adolescents: a meta-analysis. Psychoneuroendocrinology 2009; 34: 1272–83

    PubMed  CAS  Google Scholar 

  66. Kaufman J, Martin A, King RA, et al. Are child-, adolescent-, and adult-onset depression the same disorder? Biol Psychiatry 2001; 49: 980–1001

    PubMed  CAS  Google Scholar 

  67. Parker KJ, Schatzberg AF, Lyons DM. Neuroendocrine aspects of hypercortisolism in major depression. Horm Behav 2003; 43: 60–6

    PubMed  CAS  Google Scholar 

  68. Mannie ZN, Harmer CJ, Cohen PJ. Increased waking salivary cortisol levels in young people at familial risk of depression. Am J Psychiatry 2007; 164: 617–21

    PubMed  Google Scholar 

  69. Koo JW, Duman RS. IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci U S A 2008; 105: 751–6

    PubMed  CAS  Google Scholar 

  70. Miller AH, Maletic V, Raion CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009; 65: 732–41

    PubMed  CAS  Google Scholar 

  71. Pace TW, Mletzko TC, Alagbe O, et al. Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry 2006; 163: 1630–3

    PubMed  Google Scholar 

  72. Koo JW, Russo SJ, Ferguson D, et al. Nuclear factor-κB is a critical mediator of stress-impaired neurogenesis and depressive behaviour. Proc Natl Acad Sci U S A 2010; 107: 2669–74

    PubMed  CAS  Google Scholar 

  73. Chao MV. Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 2006; 4: 299–309

    Google Scholar 

  74. Sairanen M, Lucas G, Ernfors P et al. Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turn-over, proliferation, and survival in the adult dentate gyrus. J Neurosci 2005; 25(5): 1089–94

    PubMed  CAS  Google Scholar 

  75. Castrén E, Rantamaki T. Role of brain-derived neurotrophic factor in the etiology of depression: implications for pharmacological treatment. CNS Drugs 2010; 24: 1–7

    PubMed  Google Scholar 

  76. Greenberg ME, Xu B, Lu B, et al. New insights in the biology of BDNF synthesis and release: implications in CNS function. J Neurosci 2009; 29: 12764–7

    PubMed  CAS  Google Scholar 

  77. Lommatzsch M, Quarcoo D, Schulte-Herbruggen O, et al. Neurotrophins in murine viscera: a dynamic pattern from birth to adulthood. Int J Dev Neurosci 2005; 23: 495–500

    PubMed  CAS  Google Scholar 

  78. Pandey GN, Dwivedi Y, Rizavi HS, et al. Brain-derived neurotrophic factor gene in pediatric and adult depressed subjects. Prog Neuro-Psychopharmacol Biol Psychiatry 2010; 34: 645–51

    CAS  Google Scholar 

  79. Sen S, Duman RS, Sanacora G. Serum brain derived neurotrophic factor, depression and antidepressant medications: meta-analyses and implications. Biol Psychiatry 2008; 64: 527–32

    PubMed  CAS  Google Scholar 

  80. Trejo JL, Carro E, Torres-Aleman I. Circulating insulin-like growth factor I mediates exercise-induced increases of the number of new neurons in the adult hippocampus. J Neurosci 2001; 21: 1628–34

    PubMed  CAS  Google Scholar 

  81. Schmidt HD, Banasr M, Duman RS. Future antidepressant targets: neurotrophic factors and related signaling cascades. Drug Discov Today Ther Strat 2008; 5(3): 151–6

    Google Scholar 

  82. Warner-Schmidt JL, Duman RS. VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants. Proc Natl Acad Sci U S A 2007; 104(11): 4647–52

    PubMed  CAS  Google Scholar 

  83. Heine VM, Zareno J, Maslam S, et al. Chronic stress in the adult dentate gyrus reduces cell proliferation near the vasculature and VEGF and Flk-1 protein expression. Eur J Neurosci 2005; 21(5): 1304–14

    PubMed  Google Scholar 

  84. Warner-Schmidt JL, Duman RS. VEGF as a potential target for therapeutic intervention in depression. Curr Opin Pharmacol 2008; 8: 14–19

    PubMed  CAS  Google Scholar 

  85. Anderson MF, Aberg MA, Nilsson M, et al. Insulin-like growth factor-I and neurogenesis in the adult mammalian brain. Brain Res Dev Brain Res 2002; 134: 115–22

    PubMed  CAS  Google Scholar 

  86. Turner CA, Gula EL, Taylor LP, et al. Antidepressant-like effects of intra-cerebro-ventricular FGF2 in rats. Brain Res 2008; 1224: 63–8

    PubMed  CAS  Google Scholar 

  87. Michel M, Frangou TS, Camara S, et al. Altered glial cell-line derived neurotrophic factor (GDNF) concentrations in the brain of patients with depressive disorder: a comparative post-mortem study. Eur Psychiatry 2008; 23: 413–20

    PubMed  Google Scholar 

  88. Otsuki K, Uchida S, Watanuki T, et al. Altered expression of neurotrophic factors in patients with major depression. J Psychiatr Res 2008; 42: 1145–53

    PubMed  Google Scholar 

  89. Lu B, Pang PT, Woo NH. The yin and yang of neurotrophin action. Nat Rev Neurosci 2005; 6: 603–14

    PubMed  CAS  Google Scholar 

  90. Middlemans DS, Lindberg RA, Hunter T. TrkB, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors. Mol Cell Biol 1991; 11: 143–53

    Google Scholar 

  91. Luberg K, Wong J, Weickert CS, et al. Human TrkB gene: novel alternative transcripts, protein isomorfs, and expression pattern in the prefrontal cerebral cortex during postnatal development. J Neurochem 2010; 113: 952–64

    PubMed  CAS  Google Scholar 

  92. Eide EF, Vioning ER, Eide BL, et al. Naturally occurring truncated TrkB receptors have dominant inhibitory effects on brain derived neurotrophic factor signaling. J Neurosci 1996; 16: 3123–9

    PubMed  CAS  Google Scholar 

  93. Esposito D, Patel P, Stephens RM, et al. The cytoplasmic and transmembrane domain of P75 and Trk A receptors regulate high affinity binding to nerve growth factor. J Biol Chemistry 2001; 276: 32687–95

    CAS  Google Scholar 

  94. Friedman W. Neurotrophins induce death of hippocampal neurons via the p75 receptor. J Neurosci 2000; 28: 6340–6

    Google Scholar 

  95. Dwivedi Y, Rizavi HS, Conley RR, et al. Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in post-mortem brain of suicide subjects. Arch Gen Psychiatry 2003; 60: 804–15

    PubMed  CAS  Google Scholar 

  96. McGregor S, Strauss J, Bulgin N, et al. P75 (NTR) gene and suicide attempts in young adults with a history of childhood onset mood disorder. Am J Med Genet B Neuropsychiatr Genet 2007; 144B: 696–700

    PubMed  CAS  Google Scholar 

  97. Pittenger C, Duman RS. Stress, depression and neuro-plasticity: a convergence of mechanisms. Neuropsycho-pharmacology 2008; 33: 88–109

    CAS  Google Scholar 

  98. Dwivedi Y, Rizawi HS, Teppen T, et al. Aberrant extracellular signal regulated kinase (ERK) 5 signaling in hippocampus of suicide subjects. Neuropsychopharmacology 2007; 32: 2338–50

    PubMed  CAS  Google Scholar 

  99. Duman CH, Schlesinger L, Kodama M, et al. A role for MAP kinase signalling in behavioral models of depression and antidepressant treatment. Biol Psychiatry 2007; 61(5): 661–70

    PubMed  CAS  Google Scholar 

  100. Dowlatshahi D, MacQueen GM, Wang JF, et al. Increased temporal cortex CREB concentrations and antidepressant treatment. Lancet 1998; 352: 1754–5

    PubMed  CAS  Google Scholar 

  101. Nibuya M, Nestler EJ, Duman RS. Chronic antidepressant administration increases the expression of c-AMP response element binding protein (CREB) in rat hippocampus. J Neurosci 1996; 7: 2365–72

    Google Scholar 

  102. Roceri M, Hendriks W, Racagni G et al. Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus. Mol Psychiatry 2002; 7: 609–16

    PubMed  CAS  Google Scholar 

  103. Pizarro JM, Lumley LA, Medina W, et al. Acute social defeat reduces neurotrophin expression in brain cortical and subcortical areas in mice. Brain Res 2004; 1025: 10–20

    PubMed  CAS  Google Scholar 

  104. Fuchikami M, Morinobu S, Kurata A, et al. Single immobilization stress differentially alters the expression profile of transcripts of the brain-derived neurotrophic factor (BDNF) gene and histone acetylation at its promoters in the rat hippocampus. Int J Neuropsychopharmacol 2009; 12: 73–82

    PubMed  CAS  Google Scholar 

  105. Dwivedi Y, Rizawi HS, Pandey GN. Antidepressants reverse corticosterone-mediated decrease in BDNF expression: dissociation in regulation of specific exons by antidepressants and corticosterone. Neuroscience 2006; 139: 1017–29

    PubMed  CAS  Google Scholar 

  106. Shirayama Y, Chen AC, Nakagawa S, et al. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci 2002; 22: 3251–61

    PubMed  CAS  Google Scholar 

  107. Saarelainen T, Hendolin P, Lucas G, et al. Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for anti-depressant-induced behavioral effects. J Neurosci 2005; 25(5): 1089–94

    Google Scholar 

  108. Schmidt HD, Duman RS. Peripheral BDNF produces antidepressant-like effects in cellular and behavioral models. Neuropsychopharmacol 2010; 35: 2378–91

    CAS  Google Scholar 

  109. Groves JO. Is it time to reassess the BDNF hypothesis of depression? Mol Psychiatry 2007; 12: 1079–88

    PubMed  CAS  Google Scholar 

  110. Eisch AJ, Bolanos CA, de Wit J, et al. Brain derived neurotrophic factor in the ventral midbrain-nucleus accumbens pathway: a role in depression. Biol Psychiatry 2003; 54: 994–1005

    PubMed  CAS  Google Scholar 

  111. Berton O, McClung CA, Dileone RJ, et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 2006; 311: 864–8

    PubMed  CAS  Google Scholar 

  112. MacQueen GM, Ramakrishan K, Croll SD, et al. Performance of heterozygous brain-derived neurotrophic factor knockout mice on behavioral analogues of anxiety, nociception, and depression. Behav Neurosci 2001; 115: 1145–53

    PubMed  CAS  Google Scholar 

  113. Monteggia LM, Luikart B, Barrott M, et al. Brain derived neurotrophic factor conditional knockouts show gender differences in depression-related behaviors. Biol Psychiatry 2007; 61: 187–97

    PubMed  CAS  Google Scholar 

  114. Dias BG, Banerjee SB, Duman RS, et al. Differential regulation of brain derived neurotrophin factor transcripts by antidepressant treatments in the adult rat brain. Neuropharmacology 2003; 45: 553–63

    PubMed  CAS  Google Scholar 

  115. Rantamaki T, Hendolin P, Kankaanpaa A, et al. Pharmacologically diverse antidepressants rapidly activate brain-derived neurotrophic factor receptor TrkB and induce phospholipase-C gamma signaling pathways in mouse brain. Neuropsychopharmacology 2007; 32: 2152–62

    PubMed  CAS  Google Scholar 

  116. Brunoni AR, Lopes M, Fregni F. A systematic review and meta-analysis of clinical studies on depression and BDNF levels: implications for the role of neuroplasticity in depression. Int J Neuropsychopharmacol 2008; 11: 1169–80

    PubMed  CAS  Google Scholar 

  117. Karege F, Bondolfi G, Gervasoni N, et al. Low brain derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity. Biol Psychiatry 2005; 57: 1068–72

    PubMed  CAS  Google Scholar 

  118. Karege F, Vaudan G, Schwald M, et al. Neurotrophin levels in post-mortem brains of suicide victims and the effect of antemortem diagnosis and psychotropic drugs. Brain Res Mol Brain Res 2005; 136: 29–37

    PubMed  CAS  Google Scholar 

  119. Lee BH, Kim YK. Reduced platelet BDNF in patients with major depression. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33: 849–53

    PubMed  CAS  Google Scholar 

  120. Molendijk ML, Bus BA, Spinhoven B, et al. Serum levels of brain-derived neurotrophic factor in major depressive-disorder: state-trait issues, clinical features and pharmacological treatment. Mol Psychiatry. Epub 2010 Sep 21

  121. Aydemir O, Deveci A, Taneli F. The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed patients: a preliminary study. Prog Neuropsychopharmacol 2005; 29: 261–5

    CAS  Google Scholar 

  122. Gonul AS, Akdeniz F, Taneli F, et al. Effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients. Eur Arch Psychiatry Clin Neurosci 2005; 255: 381–6

    PubMed  Google Scholar 

  123. Shimizu E, Hashimoto K, Okamura N, et al. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 2003; 54: 70–5

    PubMed  CAS  Google Scholar 

  124. Chen ZY, Patel PD, Sant G, et al. Variant brain derived neurotrophic factor (BDNF) [Met66] alters the intracellular trafficking and activity secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci 2004; 24: 4401–11

    PubMed  CAS  Google Scholar 

  125. Frodl T, Schule C, Schmitt G, et al. Association of the brain derived neurotrophic factor Val66Met polymorphism with reduced hippocampal volumes in depression. Arch Gen Psychiatry 2007; 64: 410–6

    PubMed  CAS  Google Scholar 

  126. 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: 6690–4

    PubMed  CAS  Google Scholar 

  127. Kliem JA, Chan S, Pringle E, et al. BDNF val66met polymorphism is associated with modified experience-dependent plasticity in motor cortex. Nat Neurosci 2006; 9: 735–7

    Google Scholar 

  128. Tsai SJ, Chen CY, Yu YW, et al. Association study of a brain-derived neurotrophic-factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response. Am J Med Genet B Neuropsychiatr Genet 2003; 123B: 19–22

    PubMed  Google Scholar 

  129. Choi MJ, Kang RH, Lim SW, et al. Brain-derived neurotrophic-factor gene polymorphism (Val66Met) and citalopram response in major depressive disorder. Brain Res 2006; 1118: 176–82

    PubMed  CAS  Google Scholar 

  130. Sen S, Nesse RM, Stoltenberg SF, et al. A BDNF coding variant is associated with NEO personality inventory domain neuroticism, a risk factor for depression. Neuropsychopharmacol 2003; 28: 397–401

    CAS  Google Scholar 

  131. Strauss J, Barr CL, George CJ, et al. Brain-derived neurotrophic factor variants are associated with childhood-onset mood disorder: confirmation in an Hungarian sample. Mol Psychiatry 2005; 10: 861–7

    PubMed  CAS  Google Scholar 

  132. Hilt LM, Sander LC, Nolen-Hoeksema S, et al. The BDNF Val66Met polymorphism predicts rumination and depression differently in young adolescent girls and their mothers. Neurosci Lett 2007; 429: 12–6

    PubMed  CAS  Google Scholar 

  133. Kaufman J, Yang BZ, Douglas-Palumberi H, et al. Social supports and serotonin transporter gene moderate depression in maltreated children. Proc Natl Acad Sci U S A 2004; 101: 17316–21

    PubMed  CAS  Google Scholar 

  134. Kaufman J, Yang BZ, Douglas-Palumberi H, et al. Brain derived neurotrophic factor: 5-HTTLPR gene interactions and environmental modifiers of depression in children. Biol Psychiatry 2006; 59(8): 673–80

    PubMed  CAS  Google Scholar 

  135. Aguilera M, Arias B, Wichers M, et al. Early adversity and 5-HTT/BDNF genes: new evidence of gene environment interactions on depressive symptoms in general population. Psychol Med 2009; 39: 1425–32

    PubMed  CAS  Google Scholar 

  136. Licinio J, Dong C, Wong ML. Novel sequence variations in the brain derived neurotrophic factor gene and association with major depression and antidepressant treatment. Arch Gen Psychiatry 2009; 66: 488–97

    PubMed  CAS  Google Scholar 

  137. Hashimoto K. Brain-derived neurotrophic factor as a bio-marker for mood disorders: an historical overview and future directions. Psychiatry Clin Neurosci 2010; 64: 341–57

    PubMed  CAS  Google Scholar 

  138. Kim YK, Lee HP, Won SD, et al. Low plasma BDNF is associated with suicidal behaviour in depression. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 578–9

    Google Scholar 

  139. Pandey GN, Ren X, Rizavi HS, et al. Brain-derived neurotrophic factor and tyrosine kinase B receptor signalling in post-mortem brain of teenage suicide victims. Int J Neuropsychopharmacol 2008; 11: 1047–61

    PubMed  CAS  Google Scholar 

  140. Dwivedi Y, Rizavi H, Zhang H, et al. Neurotrophin receptor activation and expression in human postmortem brain: effect of suicide. Biol Psychiatry 2009; 65: 319–28

    PubMed  CAS  Google Scholar 

  141. Tanis KQ, Newton SS, Duman RS. Targeting neurotrophic/growth factor expression and signaling for antidepressant drug development. CNS Neurol Disord Drug Targets 2007; 6: 151–60

    PubMed  CAS  Google Scholar 

  142. Duman RS. Genetics of childhood disorders: XXXIX. Stem cell research, part 3: regulation of neurogenesis by stress and antidepressant treatment. J Am Acad Child Adolesc Psychiatry 2002; 41: 745–8

    Google Scholar 

  143. Griebel G, Simiand J, Serradeil-LeGal C, et al. Anxiolitic- and antidepressant-like effects of the non-peptide vasopressin V1B receptor antagonist, SSR1494415, suggest an innovative approach for the treatment of stress-related disorders. Proc Natl Acad Sci U S A 2002; 99: 6370–5

    PubMed  CAS  Google Scholar 

  144. Van West D, Del-Favero J, Aulchenko Y, et al. A major SNP aplotype of the arginine vasopressive 1B receptor protects against recurrent major depression. Mol Psychiatry 2004; 9: 287–92

    PubMed  Google Scholar 

  145. Gallagher P, Malik N, Newham J, et al. Antiglucocorticoid treatments for mood disorders. Cochrane Database Syst Rev 2008; (1): CD005168

  146. Seymour PA, Achmidt AW, Schulz DW. The pharmacology of CP-154526, a non-peptide antagonist of the CRH1 receptor: a review. CNS Drugs Rev 2003; 9: 57–96

    CAS  Google Scholar 

  147. Holsboer F, Ising M. Central CRH system in depression and anxiety: evidence from clinical studies with CRH1 receptor antagonists. Eur J Pharmacol 2008; 583: 350–7

    PubMed  CAS  Google Scholar 

  148. Tsankova NM, Berton O, Rental W, et al. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 2006; 9: 519–25

    PubMed  CAS  Google Scholar 

  149. Covington III HE, Maze I, LaPlant QC, et al. Antidepressant action of HDAC inhibitors. J Neurosci 2009; 29: 11451–60

    PubMed  CAS  Google Scholar 

  150. Schroeder FA, Lin CL, Crusio WE, et al. Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse. Biol Psychiatry 2007; 62: 55–64

    PubMed  CAS  Google Scholar 

  151. Grayson DR, Kundakovic M, Sharma RP. Is there a future for histone deacetylase inhibitors in the pharmacotherapy of psychiatric disorders? Mol Pharmacol 2010; 77: 126–35

    PubMed  CAS  Google Scholar 

  152. Jaholkowski P, Kiryk A, Jedynak P, et al. New hippo-campal neurons are not obligatory for memory formation; cyclin D2 knockout mice with no adult brain neurogenesis show learning. Learn Mem 2009; 16: 439–51

    PubMed  Google Scholar 

  153. Gould E. How widespread is adult neurogenesis in mammals? Nat Rev Neurosci 2007; 8: 481–8

    PubMed  CAS  Google Scholar 

  154. Boldrini M, Underwood MD, Hen R, et al. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology 2009; 34: 2376–89

    PubMed  CAS  Google Scholar 

  155. Gadian DG, Aicardi J, Watkins KE, et al. Developmental amnesia associated with early hypoxic-ischaemic injury. Brain 2000; 123: 499–507

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. IRCCS Stella Maris, Scientific Institute of Child Neurology and Psychiatry, Via dei Giacinti 2, 56018, Calambrone (Pisa), Italy

    Gabriele Masi & Paola Brovedani

Authors
  1. Gabriele Masi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paola Brovedani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gabriele Masi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Masi, G., Brovedani, P. The Hippocampus, Neurotrophic Factors and Depression. CNS Drugs 25, 913–931 (2011). https://doi.org/10.2165/11595900-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11595900-000000000-00000

Keywords

Search

Navigation