Fibroblast Growth Factor 2 Modulates Hypothalamic Pituitary Axis Activity and Anxiety Behavior Through Glucocorticoid Receptors



      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.


      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.


      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).


      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.


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      Linked Article

      • Fibroblast Growth Factor 2 Sits at the Interface of Stress and Anxiety
        Biological PsychiatryVol. 80Issue 6
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          The role of growth factors in the control of mood and emotions has gained considerable interest. In particular, discoveries during the past decade have pointed to the involvement of the fibroblast growth factor (FGF) family in affect regulation and have underscored the ability of one member, FGF2, to decrease depression and anxiety behaviors in animal models (1). In the present report, Salmaso et al. (2) show that Fgf2 knockout (KO) mice exhibit increased anxiety behavior, and this phenotype is rescued by FGF2 administration in adulthood (2).
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