Role of neurotrophic factors in depression

doi:10.1016/j.coph.2006.08.009

Current Opinion in Pharmacology

Volume 7, Issue 1, February 2007, Pages 18-21

https://doi.org/10.1016/j.coph.2006.08.009 Get rights and content

Major depression is associated with reduced volumes in the hippocampus and prefrontal cortex, whereas antidepressant treatments promote several forms of neuronal plasticity, including neurogenesis, synaptogenesis and neuronal maturation, in the hippocampus. Several neurotrophic factors are associated with depression or antidepressant action. Stress suppresses brain-derived neurotrophic factor (BDNF) synthesis in the hippocampus, at least partially through a sustained modification of chromatin structure. Essentially all antidepressant treatments increase BDNF synthesis and signaling in the hippocampus and prefrontal cortex. This signaling is required for the behavioral effects of antidepressant drugs in rodents, and increased BDNF levels in the hippocampus mimic the behavioral effects of antidepressants. However, injection of BDNF into the mesolimbic dopamine pathway produces an opposing depression-like response. One hypothesis emerging from these data proposes that mood disorders reflect failed function of critical neuronal networks, whereas a gradual network recovery through activity-dependent neuronal plasticity induces the antidepressant effect. Neurotrophic factors themselves do not control mood, but they act as necessary tools in the activity-dependent modulation of networks, the physiological function of which determines how a plastic change influences mood.

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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Role of neurotrophic factors in depression

Introduction

Section snippets

BDNF in depression and stress

BDNF and antidepressant drug action

Does BDNF control mood?

Other neurotrophic factors and depression

Conclusions

References and recommended reading

Acknowledgements

Curr Opin Pharmacol

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Eur Neuropsychopharmacol

J Neurosci

Eur J Neurosci

Biol Psychiatry

Proc Natl Acad Sci USA

Brain Res

Neuropsychopharmacology

Neurotrophins: roles in neuronal development and function

Annu Rev Neurosci

Is mood chemistry?

Nat Rev Neurosci

Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action

Nat Neurosci

Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment

Hippocampus