ReviewA Neurotrophic Model for Stress-Related Mood Disorders
Section snippets
Opposing Actions of Stress and Antidepressant Treatment on BDNF
The time delay for the therapeutic action of antidepressant treatment suggests that adaptations of receptor-coupled signal transduction proteins and their corresponding genes could contribute to the actions of antidepressants. In contrast, alterations in the expression of signaling proteins could also contribute to the effects of stress-related mood disorders. A role for BDNF in the effects of stress and the response to antidepressant treatment is supported by studies demonstrating opposing
BDNF Polymorphisms in Mood Disorders
Based on basic and clinical work on BDNF, recent studies have been undertaken to identify and evaluate BDNF polymorphisms in mood disorders. A functional variant of BDNF at codon 66 (val66met) has been identified with the met allele that results in abnormal intracellular packaging and secretion of BDNF (Egan et al 2003). Carriers of the met allele are reported to have poorer episodic memory and reduced hippocampal N-acetyl aspartate (Egan et al 2003). Studies of the val66met alleles in
Influence of BDNF in Cellular Models of Depression
The regulation of BDNF and other neurotrophic factors by stress and antidepressant treatment could result in alterations at the cellular and behavioral levels. At a cellular level, one of the most interesting areas of research is neurogenesis in the adult hippocampus and the opposing actions of stress and antidepressant treatment. The potential use of neurogenesis as a cellular model for studies of depression and antidepressant response is covered in more detail in another review in this issue.
Influence of BDNF in Behavioral Models of Depression
Studies of adult neurogenesis are useful for identifying cellular actions of antidepressants, but ultimately, it is essential that the behavioral actions of neurotrophic factors are also determined. In this context, the role of BDNF in several established models of depression has been determined. In addition to providing a review of these behavioral data, this section will provide a brief review of the current models of depression/antidepressant response, including the strengths and weaknesses
Limitations of the Neurotrophic Hypothesis
Although there is strong evidence from basic and clinical studies to support a neurotrophic hypothesis of depression, there are also several limitations. Some of the limitations or inconsistencies have been discussed. These include: 1) not all studies report an upregulation of BDNF by antidepressant treatments (Table 1); and 2) not all studies of mutant mice demonstrate a role for BDNF in models of depression. Some of these concerns can be explained by the experimental paradigm used (e.g., dose
Summary
The results of this review support the hypothesis that a reduction of BDNF could contribute to depression and that antidepressants mediate their therapeutic benefit, in part, by increasing levels of this factor in the hippocampus. In addition, the regulation of other neurotrophic/growth factors, including VEGF, IGF-I, and FGF2, may also play a role in the pathophysiology and/or treatment of depression. Two common actions of these different classes of factors are the activation of tyrosine
References (134)
- et al.
The timecourse of induction of brain-derived neurotrophic factor nRNA and protein in the rat hippocampus following voluntary exercise
Neurosci Lett
(2004) - et al.
Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain
Biol Psychiatry
(2003) - et al.
Insulin-like growth factor-I and neurogenesis in the adult mammalian brain
Brain Res Dev Brain Res
(2002) - et al.
Brain-derived neurotrophic factor mRNA downregulation induced by social isolation is blocked by intrahippocampal interleukin-1 receptor anatagonist
Neuroscience
(2003) - et al.
Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication
Biol Psychiatry
(2001) - et al.
Mice with reduced bran-derived neurotrophic factor expression show decreased choline acetyltransferade activity, but regular brain monoamine levels and unaltered emotional behavior
Brain Res Mol Brain Res
(2004) - et al.
Bi-phasic change in BDNF gene expression following antidepressant drug treatment
Neuropharmacology
(2003) - et al.
Assessing antidepressant activity in rodentsRecent developments and future needs
Trends Pharmacol Sci
(2002) - et al.
Fluoxetiine-induced change in rat brain expression of brain-derived neurotrophic factor varies depending on length of treatment
Neuroscience
(2004) - et al.
Differentiation regulation of brain derived neurotrophic factor transcripts by antidepressant treatments in the adult rat brain
Neuropharmacology
(2003)