Fibroblast growth factor 9 is a novel modulator of negative affect (depression)

This study used rats and postmortem human hippocampal tissue to show that there are two proteins in inverse relationships to each other that are involved in major depressive disorder (MDD). They are both fibroblast growth factors (FGF) specifically FGF2 and FGF9. FGF2 is decreased (http://www.ncbi.nlm.nih.gov/pubmed/25079902) in postmortem tissue of depressed individuals and FGF9 in increased. Also in rats, the same thing is seen. In rats if FGF9 levels are increased experimentally, they start showing symptoms of depression, and localized blockade of FGF9 reduces depression and anxiety symptoms. Also, “chronic social defeat stress” (an animal model recapitulating some aspects of MDD) in rats increases FGF9 levels.

What are FGF2 and 9? They are growth factors, produced by the cells of the body and the brain. They are involved in the proliferation and differentiation of somatic cells and neurons. They are important and key factors in the growth, differentiation and development of the brain. (The regulation of FGFs expression as well as of their receptors during development presumably plays a critical role in cell-cell signaling among neurons, astrocytes and microglia in the immature human brain: http://www.med.unibs.it/~airc/pdf/fgf%20human%20brain.pdf)

Important in the growth and development and differentiation of the brain, changed in depression, changed when depression is induced, and in normal controls, levels are different than in people with MDD. All good reasons to think of them as good targets for treatment and as markers for MDD.

Original Article: http://www.pnas.org/content/early/2015/09/02/1510456112

Fibroblast growth factor 9 is a novel modulator of negative affect

Molecular mechanisms mediating negative emotion and contributing to major depression remain elusive: here, we present evidence implicating fibroblast growth factor 9 (FGF9) as a key mediator. We use whole-transcriptome studies of postmortem human tissue to demonstrate that FGF9 is elevated in depression. Reverse translation animal studies demonstrate that both endogenous and exogenous FGF9 promotes anxiety- and depression-like behavior. Conversely, localized blockade of endogenous FGF9 expression decreases anxiety behavior. To our knowledge, this paper is the first description of hippocampal FGF9 function and the first evidence implicating FGF9 in negative affect. Thus, FGF9 represents a novel target for treating affective disorders. Moreover, our findings suggest that FGF2 and FGF9 work in functional opposition; we hypothesize that the balance between FGF factors may prove critical for optimal regulation of mood.

Abstract

Both gene expression profiling in postmortem human brain and studies using animal models have implicated the fibroblast growth factor (FGF) family in affect regulation and suggest a potential role in the pathophysiology of major depressive disorder (MDD). FGF2, the most widely characterized family member, is down-regulated in the depressed brain and plays a protective role in rodent models of affective disorders. By contrast, using three microarray analyses followed by quantitative RT-PCR confirmation, we show that FGF9 expression is up-regulated in the hippocampus of individuals with MDD, and that FGF9 expression is inversely related to the expression of FGF2. Because little is known about FGF9’s function in emotion regulation, we used animal models to shed light on its potential role in affective function. We found that chronic social defeat stress, an animal model recapitulating some aspects of MDD, leads to a significant increase in hippocampal FGF9 expression, paralleling the elevations seen in postmortem human brain tissue. Chronic intracerebroventricular administration of FGF9 increased both anxiety- and depression-like behaviors. In contrast, knocking down FGF9 expression in the dentate gyrus of the hippocampus using a lentiviral vector produced a decrease in FGF9 expression and ameliorated anxiety-like behavior. Collectively, these results suggest that high levels of hippocampal FGF9 play an important role in the development or expression of mood and anxiety disorders. We propose that the relative levels of FGF9 in relation to other members of the FGF family may prove key to understanding vulnerability or resilience in affective disorders.

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