ABSTRACT
BACKGROUND: Despite strong evidence linking fibroblast growth factor 2 (FGF2) with anxiety and depression in both rodents and humans, the molecular mechanisms linking FGF2 with anxiety are not understood. METHODS: We compare 1) mice that lack a functional Fgf2 gene (Fgf2 knockout [KO]), 2) wild-type mice, and 3) Fgf2 KO with adult rescue by FGF2 administration on measures of anxiety, depression, and motor behavior, and further investigate the mechanisms of this behavior by cellular, molecular, and neuroendocrine studies. RESULTS: We demonstrate that Fgf2 KO mice have increased anxiety, decreased hippocampal glucocorticoid receptor (GR) expression, and increased hypothalamic-pituitary-adrenal axis activity. FGF2 administration in adulthood was sufficient to rescue the entire phenotype. Blockade of GR in adult mice treated with FGF2 precluded the therapeutic effects of FGF2 on anxiety behavior, suggesting that GR is necessary for FGF2 to regulate anxiety behavior. The level of Egr-1/NGFI-A was decreased in Fgf2 KO mice and was reestablished with FGF2 treatment. By chromatin immunoprecipitation studies, we found decreased binding of EGR-1 to the GR promoter region in Fgf2 KO mice. Finally, we examined anxiety behavior in FGF receptor (FGFR) KO mice; however, FGFR1, FGFR2, and FGFR3 KO mice did not mimic the phenotype of Fgf2 KO mice, suggesting a role for other receptor subtypes (i.e., FGFR5). CONCLUSIONS: These data suggest that FGF2 levels are critically related to anxiety behavior and hypothalamic-pituitary-adrenal axis activity, likely through modulation of hippocampal glucocorticoid receptor expression, an effect that is likely receptor mediated, albeit not by FGFR1, FGFR2, and FGFR3.
Subject(s)
Anxiety/metabolism , Anxiety/psychology , Fibroblast Growth Factor 2/pharmacology , Hypothalamo-Hypophyseal System/drug effects , Pituitary-Adrenal System/drug effects , Receptors, Glucocorticoid/physiology , Animals , Behavior, Animal/drug effects , Behavior, Animal/physiology , Early Growth Response Protein 1/metabolism , Fibroblast Growth Factor 2/genetics , Fibroblast Growth Factor 2/physiology , Fibroblast Growth Factor 2/therapeutic use , Hippocampus/metabolism , Mice , Mice, Knockout , Mifepristone/pharmacology , Receptors, Fibroblast Growth Factor/genetics , Receptors, Fibroblast Growth Factor/physiology , Receptors, Glucocorticoid/antagonists & inhibitors , Receptors, Glucocorticoid/biosynthesisABSTRACT
Three main cellular components have been described in the CNS: neurons, astrocytes, and oligodendrocytes. In the past 10 years, lineage studies first based on retroviruses in the embryonic CNS and then by genetic fate mapping in both the prenatal and postnatal CNS have proposed that astroglial cells can be progenitors for neurons and oligodendrocytes. Hence, the population of astroglial cells is increasingly recognized as heterogeneous and diverse, encompassing cell types performing widely different roles in development and plasticity. Astroglial cells populating the neurogenic niches increase their proliferation after perinatal injury and in young mice can differentiate into neurons and oligodendrocytes that migrate to the cerebral cortex, replacing the cells that are lost. Although much remains to be learned about this process, it appears that the up-regulation of the Fibroblast growth factor receptor is critical for mediating the injury-induced increase in cell division and perhaps for the neuronal differentiation of astroglial cells.
