br Acknowledgements Supported by the
Acknowledgements Supported by the grant from National Natural Science Funds of China (81371262). I would like to express my heartfelt gratitude to Professor Yonghua Zhu, who help language editing.
Introduction Glucocorticoids are steroid hormones secreted from the adrenal glands in response to environmental and physical stress and are regulated by hormonal signaling pathways that form a negative feedback loop, known as the hypothalamic-pituitary-adrenal (HPA) axis (Holsboer and Barden, 1996; De Kloet, 2004). Increased blood concentration of glucocorticoids during transient stress later returns to basal levels via this system. An HPA axis dysfunction, therefore, results in a hyperglucocorticoid state, which in turn affects tissue/cellular functions, and is reported to be an important fosaprepitant dimeglumine in the pathogenesis of major depressive disorder (MDD) (De Kloet et al., 2005; Kunugi et al., 2006; Chrousos, 2009). Downregulation of GR in the central nervous system (CNS), caused by an excess amount of glucocorticoid levels after high stress, is considered a main factor of this dysregulation. While the exact mechanisms by which HPA axis dysfunction results in depressive symptoms are so far unclear, success in normalizing HPA axis function seems to be associated with an effective antidepressant treatment (Kunugi et al., 2006; O'Toole et al., 1997). Glucocorticoids exert their biological functions through glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs), both of which have ligand-binding and DNA-binding domains that regulate the transcription of several genes (Tsai and O'Malley, 1994). GRs are distributed throughout the brain, while MRs are expressed primarily in limbic areas. Given that GRs have lower affinity for endogenous glucocorticoids compared to MR (Spencer et al., 1990; De Kloet et al., 1998), GRs are considered the main signal transducers under strong and sustained stress that causes excess glucocorticoid levels in the blood (Holsboer, 2001). In addition, it has been reported that both in humans and animal models, reduced GR expression in forebrain regions may be associated with the pathogenesis of stress-related psychiatric disorders and behaviors. Decreased mRNA levels of GR in the cortex and hippocampus were shown in postmortem studies examining brain tissues obtained from suicide victims and patients with MDD (Webster et al., 2002; Calfa et al., 2003). The family of fibroblast growth factors (FGFs) regulates many aspects of brain development, including brain patterning and branching morphogenesis (Beenken and Mohammadi, 2009; Turner et al., 2012). Twenty-two FGF ligands have been identified thus far, which are further classified into several subfamilies based on structural and functional similarities (Itoh and Ornitz, 2011). Binding of these ligands to one of the four FGF membrane-bound receptors induces receptor dimerization and phosphorylation, subsequently activating downstream signaling pathways such as the RAS/mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/Akt, and phospholipase gamma (PLCγ) pathways (Itoh and Ornitz, 2011; Terwisscha et al., 2013). Basic FGF (bFGF), also known as FGF2, is one of the most characterized FGF ligands and plays important roles in the proliferation, differentiation, growth, and survival of many cell types (Turner et al., 2012). bFGF has also been studied with respect to MDD, and its antidepressant-like effects have also been reported. For example, reduction of bFGF mRNA expression was obsearved in the hippocampus and serum of MDD patients (Gaughran et al., 2006; He et al., 2014). In rodents, a bFGF injection into the lateral ventricle of the rat brain led to a decrease in depression-like behaviors (Turner et al., 2008). Moreover, a single administration of bFGF into the axillary space one day after birth significantly decreased anxiety-like behavior of rats in adulthood (Turner et al., 2011). In the preset study, we examined the possible functional interactions between GR and bFGF and demonstrate that bFGF increases GR expression in cortical neurons both in vitro and in vivo. Importantly, bFGF was found to compensate the reduction in GR expression caused by excess glucocorticoid levels through the MAPK pathway.