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.