Cellular Plasticity and the Pathophysiology of Depression

  • Thérèse M. Jay


The precise etiology of depression and other mood disorders remains unknown, and causation is likely to be a multifactorial, involving psychological, genetic, social, and biochemical aspects. However, it is becoming increasingly apparent that neuroplastic changes are implicated in the neurobiological mechanisms that underlie depression. Advances in neuroimaging have allowed investigations into the gross anatomical changes in the brain of people with depression; in parallel with this, post-mortem studies of depressed patients and animal studies using models of depression have explored the molecular, chemical, and cellular phenomena that accompany these gross morphological changes.


These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Duman R S: Neural plasticity: consequences of stress and actions of antidepressant treatment. Dialogues Clin Neurosci 2004; 6:157–169.PubMedGoogle Scholar
  2. 2.
    McEwen BS, Chattarji S: Molecular mechanisms of neuroplasticity and pharmacological implications: the example of tianeptine. Eur Neuropsychopharmacol 2004; 14Suppl 4:S497–502.PubMedCrossRefGoogle Scholar
  3. 3.
    Sheline YI, Gado MH, Kraemer HC: Untreated depression and hippocampal volume loss. Am J Psychiatry 2003; 160:1516–1518.PubMedCrossRefGoogle Scholar
  4. 4.
    McEwen BS, Magariños AM: Stress effects on morphology and function of the hippocampus. Ann N Y Acad Sci 1997; 821:271–284.PubMedCrossRefGoogle Scholar
  5. 5.
    McEwen BS, Olié JP: Neurobiology of mood, anxiety, and emotions as revealed by studies of a unique antidepressant: tianeptine. Mol Psychiatry 2005; 10:525–537.PubMedCrossRefGoogle Scholar
  6. 6.
    Frodl T, Meisenzahl E, Zetzsche T, et al: Enlargement of the amygdala in patients with a first episode of major depression. Biol Psychiatry 2002; 51:708–714.PubMedCrossRefGoogle Scholar
  7. 7.
    Sheline YI, Gado MH, Price JL: Amygdala core nuclei volumes are decreased in recurrent major depression. Neuroreport 1998; 9:2023–2028.PubMedCrossRefGoogle Scholar
  8. 8.
    Hamidi M, Drevets WC, Price JL: Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes. Biol Psychiatry 2004; 55:563–598.PubMedCrossRefGoogle Scholar
  9. 9.
    Bremner JD, Narayan M, Anderson ER, et al.: Hippocampal volume reduction in major depression. Am J Psychiatry 2000; 157:15–18.CrossRefGoogle Scholar
  10. 10.
    Ongur D, Drevets WC, Price JL: Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci USA 1998; 95:13290–13295.PubMedCrossRefGoogle Scholar
  11. 11.
    Herrmann MJ, Ehlis AC, Fallgatter AJ: Bilaterally reduced frontal activation during a verbal fluency task in depressed patients as measured by near-infrared spectroscopy. J Neuropsychiatry Clin Neurosci 2004; 16:170–175.PubMedCrossRefGoogle Scholar
  12. 12.
    Duman RS, Monteggia LM: A neurotrophic model for stress-related mood disorders. Biol Psychiatry 2006; 59:1116–1127.PubMedCrossRefGoogle Scholar
  13. 13.
    Cahill L, McGaugh JL: Mechanisms of emotional arousal and lasting declarative memory. Trends Neurosci 1998; 285:294–299.CrossRefGoogle Scholar
  14. 14.
    LeDoux J: Emotion circuits in the brain. Annu Rev Neurosci 2000; 23:155–184.PubMedCrossRefGoogle Scholar
  15. 15.
    Kim JJ, Song EY, Kosten TA: Stress effects in the hippocampus: synaptic plasticity and memory. Stress 2006; 9:1–11.PubMedCrossRefGoogle Scholar
  16. 16.
    Kim J, Diamond DM: The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci 2002; 3:453–462.PubMedCrossRefGoogle Scholar
  17. 17.
    van der Flier WM, van Buchem MA, Weverling-Rijnsburger AW, et al.: Memory complaints in patients with normal cognition are associated with smaller hippocampal volumes. J Neurol 2004; 251:671–5.PubMedCrossRefGoogle Scholar
  18. 18.
    von Gunten A, Ron MA: Hippocampal volume and subjective memory impairment in depressed patients. Eur Psychiatry 2004; 19:438–440.CrossRefGoogle Scholar
  19. 19.
    Bremner JD, Vythilingam M, Vermetten E, et al.: Reduced volume of orbitofrontal cortex in major depression. Biol Psychiatry 2002; 5:273–9.CrossRefGoogle Scholar
  20. 20.
    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 USA 2001; 98:12796–12801.PubMedCrossRefGoogle Scholar
  21. 21.
    Duman RS, Nakagawa S, Malberg J: Regulation of adult neurogenesis by antidepressant treatment. Neuropsychopharmacology 2001; 25:836–844.PubMedCrossRefGoogle Scholar
  22. 22.
    Malberg JE, Duman RS: Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology 2003; 28:1562–1571.PubMedCrossRefGoogle Scholar
  23. 23.
    Du J, Quiroz JA, Gray NA, et al.: Regulation of cellular plasticity and resilience by mood stabilizers. Dialogues Clin Neurosci 2004; 6:143–155.PubMedGoogle Scholar
  24. 24.
    Paizanis E, Hamon M, Lanfumey L: Hippocampal neurogenesis, depressive disorders, and antidepressant therapy. Neural Plast 2007; ID number:73754.Google Scholar
  25. 25.
    Mayberg HS: Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci 1997; 9:471–481.PubMedGoogle Scholar
  26. 26.
    Liston C, McEwen BS, Casey BJ: Psychosocial stress reversibly disrupts prefrontal processing and attentional control. Proc Natl Acad Sci U S A 2009; 106:912–917.PubMedCrossRefGoogle Scholar
  27. 27.
    Rocher C, Spedding M, Munoz C, Jay TM: Acute stress-induced changes in hippocampal/prefrontal circuits in rats: effects of antidepressants. Cereb Cortex 2004; 14: 224–229.PubMedCrossRefGoogle Scholar
  28. 28.
    Cerqueira JJ, Mailliet F, Almeida OF, et al.: The prefrontal cortex as a key target of the maladaptive response to stress. J Neurosci 2007; 27:2781–2787.PubMedCrossRefGoogle Scholar
  29. 29.
    Wellman CL: Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration. J Neurobiol 2001; 49:245–253.PubMedCrossRefGoogle Scholar
  30. 30.
    Radley JJ, Sisti HM, Hao J, et al.: Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex. Neuroscience 2004; 125:1–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Brown SM. Henning S, Wellman CL: Mild, short-term stress alters dendritic morphology in rat medial prefrontal cortex. Cereb Cortex 2005; 15;1714–1722.PubMedCrossRefGoogle Scholar
  32. 32.
    Cerqueira JJ, Taipa R, Uylings HB, et al.: Specific configuration of dendritic degeneration in pyramidal neurons of the medial prefrontal cortex induced by differing corticosteroid regimens. Cereb Cortex 2007; 17:1998–2006.PubMedCrossRefGoogle Scholar
  33. 33.
    Spedding M, Jay T, Costa e Silva J, Perret L: A pathophysiological paradigm for the thereapy of psychiatric disease. Nat Rev Drug Discov 2005; 4:467–476.PubMedCrossRefGoogle Scholar
  34. 34.
    Fuchs E: Social stress in tree shrews as an animal model of depression: an example of a behavioral model of a CNS disorder. CNS Spectr 2005; 10:182–190.PubMedGoogle Scholar
  35. 35.
    Yamamoto BK, Reagan LP: The glutamatergic system in neuronal plasticity and vulnerability in mood disorders. Neuropsychiatr Dis Treat 2006; 2Suppl 2:7–13.Google Scholar
  36. 36.
    Magariños AM, McEwen BS, Flügge G, Fuches E: Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews. J Neurosci 1996; 16:3534–3540.PubMedGoogle Scholar
  37. 37.
    Blanchard DC, Blanchard RJ: Behavior correlates of chronic dominance-subordination relationships of adult male rats in a seminatural situation. Neurosci Biobehav Rev 1990; 14:455–462.PubMedCrossRefGoogle Scholar
  38. 38.
    van Kampen M, Kramer M, Hiemke C, et al.: The chronic psychosocial stress paradigm in male tree shrews: evaluation of a novel animal model for depressive disorders. Stress 2002; 5:37–46.PubMedCrossRefGoogle Scholar
  39. 39.
    Pacher P, Kecskemeti V: Trends in the development of new antidepressants. Is there a light at the end of the tunnel? Curr Med Chem 2004; 11:925–943.PubMedCrossRefGoogle Scholar
  40. 40.
    Mathew SJ, Keegan K, Smith L: Glutamate modulators as novel interventions for mood disorders. Rev Bras Psiquiatr 2005; 27:243–248.PubMedCrossRefGoogle Scholar
  41. 41.
    McEwen BS: Possible mechanisms for atrophy of the human hippocampus. Mol Psychiatry 1997; 2:255–262.PubMedCrossRefGoogle Scholar
  42. 42.
    Lowy MT, Wittenberg L, Yamamoto BK: Effects of acute stress on hippocampal glutamate levels and spectrin proteolysis in young and aged rats. J Neurochem 1995; 65:268–274.PubMedCrossRefGoogle Scholar
  43. 43.
    Faden AI, Demediuk P, Panter SS, Vink R: The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 1989; 244:798–800.PubMedCrossRefGoogle Scholar
  44. 44.
    Panter SS, Faden AI: Pretreatment with NMDA antagonists limits release of excitatory amino acids following traumatic brain injury. Neurosci Lett 1992; 136:165–168.PubMedCrossRefGoogle Scholar
  45. 45.
    Nugent AC, Wood S, Bain EE, et al.: High resolution MRI neuromorphometric assessment of the hippocampal subiculum in mood disorders. Presented at the International Society for Magnetic Resonance in Medicine, 12th Annual Meeting, Kyoto, Japan; 2004.Google Scholar
  46. 46.
    Rosoklija G, Toomayan G, Ellis SP, et al.: Structural abnormalities in subicular dendrites in subjects with schizophrenia and mood disorders. Arch Gen Psychiatry 2000; 57:349–356.PubMedCrossRefGoogle Scholar
  47. 47.
    McEwen BS: Structural plasticity of the adult brain: how animal models help us understand brain changes in depression and systemic disorders related to depression. Dialogues Clin Neurosci 2004; 6:119–133.PubMedGoogle Scholar
  48. 48.
    McEwen BS: Stress and hippocampal plasticity. Annu Rev Neurosci. 1999; 22:105–122.PubMedCrossRefGoogle Scholar
  49. 49.
    MacQueen GM, Campbell S, McEwen BS, et al.: Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci USA 2003; 100:1387–1392.PubMedCrossRefGoogle Scholar
  50. 50.
    Sheline YI, Wang PW, Gado MH, et al.: Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A 1996; 93:3908–3913.PubMedCrossRefGoogle Scholar
  51. 51.
    Vythilingam M, Heim C, Newport J, et al.: Childhood trauma associated with smaller hippocampal volume in women with major depression. Am J Psychiatry 2002; 159:2072.PubMedCrossRefGoogle Scholar
  52. 52.
    Rajkowska G, Miguel-Hidalgo JJ, Wei J, et al.: Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry 1999; 45:1085–1098.PubMedCrossRefGoogle Scholar
  53. 53.
    Malenka R, Nicoll RA: Long-term potentiation — a decade of progress? Science 1999; 285:1870–1874.PubMedCrossRefGoogle Scholar
  54. 54.
    Bliss TV, Collingridge GL: A synaptic model of memory: long-term potentiation in the hippocampus. Nature 1993; 361:31–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Pavlides C, Nivon LG, McEwen BS: Effects of chronic stress on hippocampal long-term potentiation. Hippocampus 2002; 12:245–257.PubMedCrossRefGoogle Scholar
  56. 56.
    Shors T, Seib TB, Levine S, Thompson RF: Inescapable versus escapable shock modulates long-term potentiation in the rat hippocampus. Science 1989; 244:224–226.PubMedCrossRefGoogle Scholar
  57. 57.
    Vouimba RM, Muñoz C, Diamond DM: Differential effects of predator stress and the antidepressant tianeptine on physiological plasticity in the hippocampus and basolateral amygdala. Stress 2006; 9:29–40.PubMedCrossRefGoogle Scholar
  58. 58.
    Watanabe Y, Gould E, Daniels DC, et al.: Tianeptine attenuates stress-induced morphological changes in the hippocampus. Eur J Pharmacol 1992; 222:157–162.PubMedCrossRefGoogle Scholar
  59. 59.
    Magariños AM, Deslandes A, McEwen BS: Effects of antidepressants and benzodiazepine treatments on the dendritic structure of CA3 pyramidal neurons after chronic stress. Eur J Pharmacol 1999; 371:113–122.PubMedCrossRefGoogle Scholar
  60. 60.
    Reagan LP, Rosell DR, Wood GE, et al.: Chronic restraint stress up-regulates GLT-1 mRNA and protein expression in the rat hippocampus: reversal by tianeptine. Proc Natl Acad Sci U S A 2004; 101:2179–2184.PubMedCrossRefGoogle Scholar
  61. 61.
    Paul IA, Skolnick P: Glutamate and depression: clinical and preclinical studies. Ann N Y Acad Sci 2003; 1003:250–272.PubMedCrossRefGoogle Scholar
  62. 62.
    Manji HK, Drevets WC, Charney DS: The cellular neurobiology of depression. Nat Med 2001; 7:541–547.PubMedCrossRefGoogle Scholar
  63. 63.
    Kasper S, Olié JP: A meta-analysis of randomized controlled trials of tianeptine versus SSRI in the short-term treatment of depression. Eur Psychiatry 2002; 17Suppl 3:331–340.PubMedCrossRefGoogle Scholar
  64. 64.
    Wagstaff AJ, Ormrod D, Spencer CM: Tianeptine: a review of its use in depressive disorders. CNS Drugs 2001; 15:231–259.PubMedCrossRefGoogle Scholar
  65. 65.
    Novotny V, Faltus F: Tianeptine and fluoxetine in major depression: a 6-week randomised double-blind study. Hum Psychopharmacol 2002; 17:299–303.PubMedCrossRefGoogle Scholar
  66. 66.
    Novotny V, Faltus F: First signs of improvement with tianeptine in the treatment of depression: an analysis of a double blind study versus fluoxetine. Eur Neuropsycopharmacol 2003; 13Suppl:S230.CrossRefGoogle Scholar
  67. 67.
    Montgomery SA, Åsberg M: A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134:382–389.PubMedCrossRefGoogle Scholar
  68. 68.
    Kasper S: Neuroplasticity and the treatment of depression. Neuropsychiatr Dis Treat 2006; 2suppl 2:15–20.Google Scholar
  69. 69.
    Kasper S, McEwen BS: Neurobiological and clinical effects of the antidepressant tianeptine. CNS Drugs 2008; 22:15–26.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Healthcare, a part of Springer Science+Business Media 2011

Authors and Affiliations

  • Thérèse M. Jay

There are no affiliations available

Personalised recommendations