Restraint stress increases the expression of brain derived neurotrophic factor in the hippocampus of a mouse model of depression

Statement of the study: Brain-Derived Neurotrophic Factor (BDNF) is a
member of the neurotrophin family which includes a group of molecules
important for the development and the maintenance of the nervous system.
Since BDNF is highly expressed in the hippocampus, the action and regulation
of BDNF in this particular area has become subject of intense study. Single or
repeated immobilization stress markedly reduces both BDNF mRNA and protein
levels in rat hippocampus. Consequently, BDNF is considered a stress-responsive
gene, and it has been recently suggested that alterations in the expression of this
growth factor may be important in regulating some of the physiological and
pathophysiological effects of stress on the hippocampus.
Stress-induced changes observed in the hippocampus of experimental animals
resulted in a novel hypothesis attributing a central role to neurotrophic factors
in both the etiology of depression and as well as in its treatment. However,
the effects of stress on neurotrophic factors in the hippocampus of depressed
patients remain unknown. In fact, the expression pattern of a large array of
genes affected by depression or antidepressant drugs, such as BDNF, may differ
between a normal and a pathological brain.
Methods: In these experiments, we used transgenic (TG) mice deficient in
glucocorticoid receptor (GR) functioning. This TG mouse was created as a model
to study the neuroendocrine changes occurring in stress-related disorders, such as
major depression. We evaluated the hypothesis that a single period of 30 minutes of restraint stress affects BDNF mRNA expression in the hippocampus of TG
mice differently than in WT mice.
Summary of results: BDNF mRNA was significantly increased by the stress
procedure only in the hippocampus of TG mice, the induction being specific for
the CA3 subregion as revealed by in situ hybridization.
Moreover, we found that stress down-regulated CREB phosphorylation in the
hippocampus of TG mice whereas it upregulated the level of phosphorylated
CREB Ser133 in WT mice.
Conclusion: These data suggest that, in the presence of emotional stress, lifelong
central glucocorticoid receptor dysfunction results in altered hippocampal
sensitivity, with respect to the level of neurotrophic gene expression.
The understanding of the mechanisms through which psychological stress
(such as restraint stress) induces BDNF mRNA in the hippocampus of TG
mice, may help to clarify the biological and molecular basis of the action of
neurotrophic factors and may contribute to the development of new strategies that
will ultimately reduce the vulnerability of neurons and prevent neuropathological
alterations in the hippocampus.