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Antidepressant effects of fibroblast growth factor-2 in behavioral and cellular models of depression.

ABSTRACT: Basic and clinical studies report that the expression of fibroblast growth factor-2 (FGF-2) is decreased in the prefrontal cortex (PFC) of depressed subjects or rodents exposed to stress and increased following antidepressant treatment. Here, we aim to determine if 1) FGF-2/fibroblast growth factor receptor (FGFR) signaling is sufficient and required for mediating an antidepressant response behaviorally and cellularly; and 2) if the antidepressant actions of FGF-2 are mediated specifically by the PFC.The role of FGF-2 signaling in behavioral models of depression and anxiety was tested using chronic unpredictable stress (CUS)/sucrose consumption test (SCT), forced swim test (FST), and novelty suppressed feeding test (NSFT). We also assessed the number of bromodeoxyuridine labeled dividing glial cells in the PFC as a cellular index relevant to depression (i.e., decreased by stress and increased by antidepressant treatment).Chronic FGF-2 infusions (intracerebroventricular) blocked the deficit in SCT caused by CUS. Moreover, the response to antidepressant treatment in the CUS/SCT and FST was abolished upon administration of an inhibitor of FGFR activity, SU5402. These results are consistent with the regulation of proliferating cells in the PFC, a portion of which are of oligodendrocyte lineage. Lastly, subchronic infusions of FGF-2 into the PFC but not into the dorsal striatum produced antidepressant-like and anxiolytic-like effects on FST and NSFT respectively.These findings demonstrate that FGF-2/FGFR signaling is sufficient and necessary for the behavioral, as well as gliogenic, actions of antidepressants and highlight the PFC as a brain region sensitive to the antidepressant actions of FGF-2.

SUBMITTER: Elsayed M

PROVIDER: S-EPMC3401338 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Antidepressant effects of fibroblast growth factor-2 in behavioral and cellular models of depression.

Elsayed Maha M Banasr Mounira M Duric Vanja V Fournier Neil M NM Licznerski Pawel P Duman Ronald S RS

Biological psychiatry 20120417 4

<h4>Background</h4>Basic and clinical studies report that the expression of fibroblast growth factor-2 (FGF-2) is decreased in the prefrontal cortex (PFC) of depressed subjects or rodents exposed to stress and increased following antidepressant treatment. Here, we aim to determine if 1) FGF-2/fibroblast growth factor receptor (FGFR) signaling is sufficient and required for mediating an antidepressant response behaviorally and cellularly; and 2) if the antidepressant actions of FGF-2 are mediated ...[more]

PMID: 22513055

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Project description: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.

Project description:Microglial polarization and the subsequent neuroinflammatory response were identified as key contributors to the progress of Parkinson's disease (PD). Researchers have shown that fibroblast growth factor 21 (FGF21) plays multiple biological functions, including anti-inflammation and neuroprotection. However, the knowledge of FGF21 on microglial polarization in PD in vivo is far from completion. In this study, both in vivo and in vitro models were used to investigate whether FGF21 enhances the brain function by modulating microglial polarization in PD. The protective effects of FGF21 in vivo were conducted using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mice model alongside intraperitoneally received FGF21. A behavioral test battery and tyrosine hydroxylase (TH) immunohistochemistry were conducted to evaluate the neuronal function and nigrostriatal tract integrity. Immunofluorescence assay and Western blot were used to examine M1/M2 microglial polarization. Then, a microglia-neuron co-culture system was adopted in vitro to identify the underlying molecular mechanisms of FGF21. The results showed that FGF21 significantly alleviated motor and cognitive impairment in mice with PD. FGF21 also protected TH-positive neuron cells in the striatum and midbrain. Mechanistically, FGF21 suppressed M1 microglial polarization and the subsequent mRNA expression of pro-inflammatory factors while promoting M2 microglial polarization with increasing anti-inflammatory factors in mice with PD. Furthermore, sirtuin 1 (SIRT1) and the nuclear factor-kappa B (NF-κB) pathway were involved in the FGF21-induced M2 microglial polarization. Conversely, SIRT1 inhibitor EX527 significantly prevented both the FGF21-induced SIRT1 expression and M2 microglial polarization. Moreover, FGF21 pretreatment of microglia significantly prevented neuronal cell apoptosis in a microglia-neuron co-culture system. In conclusion, our data demonstrate that FGF21 exerted its protective effects in the pathology of PD through SIRT1/NF-κB pathway-mediated microglial polarization. Given the safety record of human clinical trials, FGF21 could be a promising therapy for clinical trials to ameliorate motor and nonmotor deficits in patients with PD.

Dataset Information

Antidepressant effects of fibroblast growth factor-2 in behavioral and cellular models of depression.

Publications

Antidepressant effects of fibroblast growth factor-2 in behavioral and cellular models of depression.

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