Research Article: Fibroblast growth factor 2 is necessary for the antidepressant effects of fluoxetine

Date Published: October 1, 2018

Publisher: Public Library of Science

Author(s): Stephanie Simard, Pragya Shail, Jessica MacGregor, Maha El Sayed, Ronald S. Duman, Flora. M. Vaccarino, Natalina Salmaso, Judith Homberg.

http://doi.org/10.1371/journal.pone.0204980

Abstract

Previous research has shown that fibroblast growth factor 2 protein (FGF2) can act as an anxiolytic and anti-depressive agent in rodents. Levels of hippocampal FGF2 and FGF2 receptors are decreased in post-mortem brains of individuals with mood disorders. No changes in FGF2 were noted in the post-mortem brains of individuals with mood disorders that were successfully treated with anti-depressant medication prior to death. Mutations in the FGF2 gene in humans have been shown to predict non-responsiveness to the therapeutic effects of selective serotonin reuptake inhibitors (SSRIs). These findings suggest that FGF2 may potentially be a target of and/or required for the therapeutic effects of antidepressant medications. To test this, we employed a rodent model of depressive behaviour, chronic variable stress (CVS) in conjunction with antidepressant treatment (fluoxetine) in wild-type (WT) and FGF2 knockout mice (FGF2KO) and examined depressive and anxiety behaviors. Results showed that fluoxetine reversed the effects of CVS on depressive and anxiety behaviours in wild-type mice only, suggesting that the FGF2 gene is indeed necessary for the therapeutic effects of fluoxetine. Interestingly, CVS decreased hippocampal FGF2 levels and fluoxetine partially reversed this effect. Because FGF2 has been previously shown to modify HPA activity through hippocampal glucocorticoid receptors (GR), we examined levels of glucocorticoid receptors and found a decrease in GR in response to CVS, with a further decrease in FGF2KO. No effect of fluoxetine on GR was observed in either WT or FGF2KO mice. This suggests that further changes in glucocorticoid receptors are not necessary for the anti-depressant effects of fluoxetine in WT mice, although decreased glucocorticoid receptors in response to FGF2 deletion may preclude the therapeutic actions of fluoxetine in FGF2KO. Whether astroglia, astroglial functions, or HPA changes are the downstream target of FGF2-mediated changes induced by fluoxetine remains to be determined, however, the current study reaffirms the potential of FGF2 as a novel therapeutic target in the treatment of depression and anxiety disorders.

Partial Text

Mood and anxiety disorders currently are the most prevalent mental illnesses diagnosed in North America and have far-reaching effects on family and community function, as well as gastrointestinal, respiratory and cardiovascular diseases [1, 2]. While distinct, depressive and anxiety disorders have several overlapping symptoms and are often co-morbid. As such, current treatments are often similar for both disorders and range from cognitive-behavioral psychotherapy to antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs). Unfortunately, these treatments are effective in just over half of diagnosed individuals, leaving a considerable population treatment-resistant. A great deal of research has therefore focused on understanding the neurobiological mechanisms that underlie the psychopathology of depression and anxiety to elucidate novel therapeutic targets. Despite important recent developments such as the use of ketamine for intractable depression, the molecular basis of the etiology and treatment of depression remains largely unknown.

The current study sought to ascertain whether there is a causal role for the FGF2 gene in mediating the therapeutic effects of the SSRI fluoxetine in mice exposed to CVS. No effects of fluoxetine were observed in naïve mice, however, fluoxetine predictably reversed many of the stress-induced depressive and anxiety behaviors in WT mice. Remarkably, FGF2KO mice did not show any reversal of stress-induced behaviors with fluoxetine, suggesting that FGF2 is necessary for the therapeutic effects of fluoxetine. These findings corroborate studies in humans with major depressive disorder that showed that variants of the FGF2 gene can predict efficacy of SSRI treatment and suggest an important role for FGF2 in the mechanisms of anti-depressant action [23]. While the anti-depressant and anxiolytic effects of FGF2 have been previously documented in several rodent models, the current study would suggest that FGF2 not only has antidepressant/anxiolytic properties, but that it is necessary for fluoxetine’s therapeutic effects.

 

Source:

http://doi.org/10.1371/journal.pone.0204980

 

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