Role of neurotrophic factors in depression
Introduction
Neurotrophic factors are critical regulators of the formation and plasticity of neuronal networks [1]. Of these neurotrophic factors, the neurotrophin family — comprising nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-3 and neurotrophin-4 — is the best characterized. However, other factors such as members of the insulin-like growth factor (IGF), fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) families also regulate neuronal plasticity.
Recently, the involvement of neurotrophic factors, particularly BDNF and its tyrosine kinase receptor TrkB, in the regulation of mood disorders and antidepressant effects has been under intense investigation. These studies, which are briefly reviewed below (for more comprehensive recent reviews, please see [2, 3, 4]), have led to the formulation of the neurotrophic hypothesis of depression, which proposes that reduced brain BDNF levels predispose to depression, whereas increases in brain BDNF levels produce an antidepressant action. However, several recent observations, together with information gained on the basic role of neurotrophins in the developing and adult brain, suggest a modified neurotrophic hypothesis which emphasises the role of BDNF as a tool of experience-dependent modifications in neural networks that regulate different aspects of mood.
Section snippets
BDNF in depression and stress
In humans, brain BDNF levels have been found to be reduced in postmortem samples from depressed patients, and antidepressant therapy restores brain BDNF levels to the normal range [2, 5]. BDNF is found in the blood, where it mostly accumulates in platelets. Interestingly, several studies have found decreased blood levels of BDNF in depressed patients and, again, antidepressant therapy appears to normalize this change [6, 7]; however, the relevance of these findings to the action of BDNF in the
BDNF and antidepressant drug action
Several studies have suggested that normal BDNF signaling is both necessary and sufficient for antidepressant drug action. We have recently found that antidepressants acting through different mechanisms rapidly increase TrkB activation and signaling within an hour of drug administration [11, 12] (Rantamäki and Castrén, unpublished). Antidepressant-induced tyrosine phosphorylation of TrkB does not induce activity of the extracellular signal-regulated kinase pathway, but does activate
Does BDNF control mood?
A straightforward interpretation of the data reviewed above is that mood is dependent upon and directly proportional to the levels of BDNF expression in the brain. However, several recent observations suggest that the relationship between neurotrophins and depression is more complex than originally thought. Although BDNF signaling is clearly involved in the antidepressant response, reduction of BDNF levels or BDNF signaling does not produce depression-like symptoms [4, 12]. We have found that
Other neurotrophic factors and depression
In addition to the above-mentioned neurotrophins, members of other neurotrophic factor families also play a role in mood disorders and antidepressant drug action [4]. Dysregulation of several members of the FGF family and their receptors has been found to occur in brains of patients with major depressive disorder [26], and FGFs are regulated by antidepressant drugs [27]. IGF-I is also increased in the hippocampus by antidepressants [28], and IGF-I infusion into the brain produces behavioral
Conclusions
A new view of the pathophysiology of mood disorders and antidepressant drug action is emerging from research performed during the past decade [3]. This view emphasizes defects in information processing within critical neural networks as the mechanisms underlying mood disorders, as well as the role of plasticity-induced network recovery in antidepressant treatment. Recent findings suggest that early childhood events and adult stress produce neurodegenerative changes in the brain that can
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We would like to thank Olivia O’Leary for her comments on the manuscript, as well as Sigrid Jusélius Foundation, Academy of Finland and Päivikki and Sakari Sohlberg Foundation for financial support.
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