It is now clear that the neurotrophic factor-ERKl/2-MAPK-Bcl-2 signaling cascade has a critical role in cell survival in the CNS and that a fine balance exists between the levels and activities of cell survival and cell death factors. BDNF-ERKl/2-CREB-Bcl-2 cascade dysregulation may be a key mechanism via which prolonged stress induces Inhibitors,research,lifescience,medical atrophy of select vulnerable neuronal subpopulations,

distal dendrites, or both. Although dysregulation of this cascade most likely results in decreased neuronal survival, the differential survival is likely modulated not only by region-specific expression of protective factors, but also by the network properties of vulnerable structures. Inhibitors,research,lifescience,medical Therefore, it is likely that the dynamics of the impairments

of cellular selleck chemicals plasticity and resilience are determined by intrinsic properties of the affected regions. There is emerging evidence – mainly from postmortem studies – supporting a role for abnormalities in neurotrophic signaling pathways in depression. Decreased levels of CREB, BDNF, and the TrkB receptor have been described in suicide victims.46-48 Depressed individuals may also have genetic abnormalities in CREB and BDNF. Sequence variations in the CREB1 gene have been observed in depressed women.6 A coding variant of BDNF may be associated with the personality trait of neuroticism, Inhibitors,research,lifescience,medical which is a risk factor for depression.49 Furthermore, two recent studies50,51 suggest that a polymorphism in the pro-BDNF molecule is associated with bipolar disorder (a condition in which depressive episodes are accompanied by manic episodes). This polymorphism is associated with alterations in BDNF trafficking and secretion in vitro, as well as with alterations Inhibitors,research,lifescience,medical in hippocampal working memory

Inhibitors,research,lifescience,medical in humans.52 Therefore, an opportunity exists to study the interaction of life stress, signal transduction-related genes, neuroimaging abnormalities consistent with deficient structural plasticity, and susceptibility to depression.15 Antidepressant mechanisms and neurotrophic signaling cascades An increasing amount of evidence suggests that antidepressants regulate neurotrophic signaling cascades. Antidepressant treatment increases CREB phosphorylation and CREB-mediated Capmatinib clinical trial gene expression in mice limbic brain regions.53 Various classes of chronic antidepressant treatments, as well as electroconvulsive treatment (ECT), upregulate CREB and BDNF expression, suggesting that the CREB cascade and BDNF are common post-receptor targets of antidepressants.54,55 This increase is exclusively seen after chronic use, thus corresponding to the onset clinical antidepressant effects with these therapies. Additional evidence that relates upregulation of these pathways and antidepressant treatment comes from antidepressant-like performance in behavioral models.