A Role for the Fibroblast Growth Factor Family in Depression and Circadian Rhythms.

Abstract

An unbiased microarray analysis of post-mortem tissue of individuals diagnosed with major depressive disorder (MDD) reported on the dysregulation of the fibroblast growth factor (FGF) family in cortical and limbic regions. This was the first study to implicate this system of growth factors in mood disorders. While FGF2 gene expression was consistently downregulated in a number of brain regions in MDD, FGF9 gene expression was consistently upregulated in MDD. While we have recently characterized the behavioral and molecular effects of the well-known FGF2 ligand in emotionality, the role of FGF9 in affective behavior had yet to be explored. Initial studies that paralleled FGF2 administration provided important information about method of administration, dosing, and time-sensitivity of testing. While chronic FGF2 had antidepressant-like and anxiolytic effects in animal models of depression, chronic FGF9 increased depression-like behavior and was anxiogenic. Chronic injections of FGF9 decreased expression of FGFR1 in the dentate gyrus in the hippocampus suggesting that FGF9 may alter the level of FGF2/FGFR1 signaling. In addition to the role of exogenous FGF9 in altering affective behaviors, endogenous FGF9 expression was increased by chronic social stress. These findings support the hypothesis that FGF9 mediates the long-term negative aspects of neurotrophic factor dysregulation in the hippocampus. As circadian disruptions are often implicatedin mechanisms underlying MDD, we also investigated the basal expression of FGF family members in the hippocampus over time. FGF2 and FGFR1 both displayed endogenous circadian gene expression in the hippocampus. Exogenous administration of FGF2 also altered circadian locomotor activity. These data support the hypothesis that dysregulation of fibroblast growth factor system gene expression may cause a disruption in circadian rhythms that underlie sleep/wake cycles. This series of studies increased our understanding of the role of the FGF family in affective behavior and circadian activity. Additionally, these studies suggest that dysregulation of FGF system gene expression in MDD may be a potential mechanism for alteration of circadian rhythms in individuals with this disorder. Taken together, these findings implicate FGF9 as a novel mediator of anxiety-like and depression-like behavior, endogenous antagonist of FGF2, and potential modulator of circadian rhythms.