Decreased glial number has been one of the most consistent findings of postmortem studies.24,25 This includes decreased numbers of astrocytes and oligodendrocytes in PFC. Preclinical studies also demonstrate that stress decreases glial fibrillary

acidic protein (GFAP)-labeled astrocytes as well as the proliferation of oligodendrocytes.24 Conversely, chronic antidepressant administration increases the proliferation of oligodendrocytes in the PFC.24 Glial cells play an important role in providing metabolic support for neurons, and loss of glia could contribute to the atrophy and Inhibitors,research,lifescience,medical loss of neurons caused by stress and depression. This is an interesting, yet understudied, area of afatinib mechanism of action research that has important implications for elucidating the pathophysiology of stress and depression. Stress decreases brain-derived neurotrophic factor expression One of the mechanisms that has Inhibitors,research,lifescience,medical been studied for the atrophy and loss of neurons caused by stress and depression is disruption of neurotrophic/growth factor

support, most notably brain-derived neurotrophic factor (BDNF) (Figure 2). Neurotrophic factors were first identified and characterized for their role Inhibitors,research,lifescience,medical during development, including guidance, maturation, and survival of neurons, but it is now well-established that these factors continue to play an important role in the adult brain, including activity-dependent synaptic plasticity as well as survival.26 BDNF, a member of the nerve growth factor family, is one of the most highly expressed neurotrophic factors in the brain, and can be regulated at the level of gene expression as well as activity-stimulated release at synapses. Stress significantly impacts the expression of BDNF, decreasing Inhibitors,research,lifescience,medical levels of messenger RNA (mRNA) and protein in the hippocampus and PFC.3,4 A possible role

Inhibitors,research,lifescience,medical for BDNF in depression is supported by studies demonstrating that levels of this factor are decreased in postmortem cerebral cortex of depressed subjects.3 Surprisingly, blood levels of BDNF are also decreased in depressed Drug_discovery subjects.27 Studies of BDNF heterozygous deletion mutant mice have not revealed an outright depressive phenotype as might be expected, although BDNF deletion increases vulnerability to depressive behavior in rodents, measured in models of despair, anxiety, and anhedonia.28 The finding that the BDNF deletion mutants do not display depressive behavior could be due to region-specific effects of BDNF (ie, BDNF is prodepressant in the mesolimbic dopamine system, but antidepressant in the PFC and hippocampus).29 This possibility is supported by recent studies demonstrating that hippocampus-specific FTY720 clinical knockdown of BDNF produces depressive behavior.30 Figure 2. Stress and depression decrease, while rapid-acting antidepressants (eg, ketamine) increase, synaptic connections.