Antidepressant Effects of Fibroblast Growth Factor-2 in Behavioral and Cellular Models of Depression

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.fibroblast growth factor 9 | major depression | anxiety | hippocampus | affect T he neurotrophic hypothesis of major depressive disorder (MDD) posits that the neurobiological basis for mood disorders may be due to the dysregulation of growth factors and their effects on brain circuitry (1, 2). This hypothesis is supported by gene expression profiling experiments in postmortem human brains that implicate the fibroblast growth factor (FGF) family and other neurotrophins in MDD (3, 4). To date, only a few growth factors involved in mood disorders, such as brain-derived neurotrophic factor (BDNF) and FGF2, have been studied extensively.Our laboratory and others have demonstrated that FGF2 is down-regulated in the frontal cortices (3), hippocampus (5), and locus coeruleus (4) in depressed individuals. This consistent decrease in FGF2 expression across regions is striking and underscores the likely importance of FGF2 in mediating affect.Follow-up studies from our laboratory and others have focused on the FGF family and have demonstrated a key role of FGF2 in the control of emotional behavior. Rats exposed to chronic social defeat stress, an animal model recapitulating some aspects of MDD, showed decreased hippocampal FGF2 expression relative to unstressed controls (6), whereas subchronic and chronic administration of FGF2 had antidepressant properties (7,8). Moreover, adminis...

Section: Fgf9 Expression Mediates Affect In An Animalmentioning

confidence: 94%

mentioning

confidence: 99%

Fibroblast growth factor 9 is a novel modulator of negative affect

Aurbach

Inui

Turner

et al. 2015

“…Also selective infusion of FGF-2 in the PFC, but not into dorsal striatum, shows antidepressant-like and anxiolytic-like effects following forced swim test and novelty suppressed feeding test (46). Moreover, knockdown of FGF2 using single microinjection in the hippocampus resulted in an anxiety-like effect in outbred animals (26).…”

Section: Role Of Fgf2 In Altering the Levels Of Repressive H3k9me3 Anmentioning

confidence: 99%

FGF2 is a target and a trigger of epigenetic mechanisms associated with differences in emotionality: Partnership with H3K9me3

Chaudhury

Aurbach

Sharma

et al. 2014

Posttranslational modifications of histone tails in chromatin template can result from environmental experiences such as stress and substance abuse. However, the role of epigenetic modifications as potential predisposing factors in affective behavior is less well established. To address this question, we used our selectively bred lines of high responder (bHR) and low responder (bLR) rats that show profound and stable differences in affective responses, with bLRs being prone to anxiety-and depression-like behavior and bHRs prone to addictive behavior. We first asked whether these phenotypes are associated with basal differences in epigenetic profiles. Our results reveal broad between-group differences in basal levels of trimethylated histone protein H3 at lysine 9 (H3K9me3) in hippocampus (HC), amygdala, and nucleus accumbens. Moreover, levels of association of H3K9me3 at Glucocorticoid Receptor (GR) and Fibroblast growth Factor 2 (FGF2) promoters differ reciprocally between bHRs and bLRs in these regions, consistent with these genes' opposing levels of expression and roles in modulating anxiety behavior. Importantly, this basal epigenetic pattern is modifiable by FGF2, a factor that modulates anxiety behavior. Thus, early-life FGF2, which decreases anxiety, altered the levels of H3K9me3 and its binding at FGF2 and GR promoters of bLRs rendering them more similar to bHRs. Conversely, knockdown of HC FGF2 altered both anxiety behavior and levels of H3K9me3 in bHRs, rendering them more bLR-like. These findings implicate FGF2 as a modifier of epigenetic mechanisms associated with emotional responsiveness, and point to H3K9me3 as a key player in the regulation of affective vulnerability.C hromatin remodeling is a mediator of lasting neural changes in response to experience, such as exposure to stress and drugs of abuse (1-7). Indeed, the interaction of certain modified histones with specific gene promoters has been shown to be an important mechanism of experience-dependent neuroplasticity (8-13). Although numerous studies have examined the impact of the environment on neural epigenetic profiles, relatively few studies have focused on preexisting differences in epigenetic profiles as potential predisposing factors in emotional reactivity. Such studies require the availability of an animal model where difference in "temperament" or propensity for specific affective responses can be reliably predicted and altered. Our laboratory has generated such an animal model that captures vulnerability for "internalizing disorders" vs. "externalizing disorders." Selectively bred high responder (bHR) rats exhibit greater responsiveness to novelty and to drug seeking behavior (externalizing behaviors), whereas selectively bred low responders (bLR) exhibit greater anxiety and depression-like responses (internalizing behaviors) (14, 15). These genetically bred phenotypes amplify behavioral traits observed in outbred animals (16)(17)(18)(19)(20).Several genes have been implicated in modifying these phenotypes, both in the bred and outbr...

“…CUS procedure. The CUS animals were subjected to exactly the same sequence of 12 stressors (2 per day for 35 d) described previously (32). FST.…”

Section: Methodsmentioning

confidence: 99%

Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats

Choi

Lee

Wang

et al. 2015

Self Cite

Ketamine produces rapid antidepressant-like effects in animal assays for depression, although the molecular mechanisms underlying these behavioral actions remain incomplete. Here, we demonstrate that ketamine rapidly stimulates histone deacetylase 5 (HDAC5) phosphorylation and nuclear export in rat hippocampal neurons through calcium/calmodulin kinase II-and protein kinase D-dependent pathways. Consequently, ketamine enhanced the transcriptional activity of myocyte enhancer factor 2 (MEF2), which leads to regulation of MEF2 target genes. Transfection of a HDAC5 phosphorylation-defective mutant (Ser259/Ser498 replaced by Ala259/Ala498, HDAC5-S/A), resulted in resistance to ketamineinduced nuclear export, suppression of ketamine-mediated MEF2 transcriptional activity, and decreased expression of MEF2 target genes. Behaviorally, viral-mediated hippocampal knockdown of HDAC5 blocked or occluded the antidepressant effects of ketamine both in unstressed and stressed animals. Taken together, our results reveal a novel role of HDAC5 in the actions of ketamine and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of ketamine.ketamine | HDAC | depression | hippocampus D epression is a multifaceted illness, characterized by somatic, cognitive, and behavioral changes. All currently available antidepressants primarily act via monoaminergic neurotransmitters, such as serotonin and/or noradrenaline (1). Currently available pharmacotherapies for depression provide some relief for patients, but these agents have significant limitations (1). In this context, new antidepressants with faster onset of action and greater efficacy are needed (2).The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown remarkable consistency in rapidly ameliorating depressive symptoms in major depressive disorder (MDD) (3). Preclinical studies have demonstrated that ketamine produces rapid antidepressant responses (within hours) (4, 5). Ketamine's antidepressant effects in rodents are associated with activation of several signaling systems including the mammalian target of rapamycin complex 1 (mTORC1) (4), brain derived neurotrophic factor (BDNF) and elongation factor 2 (EF2) kinase (5). Despite these remarkable effects, the widespread use of ketamine is limited by potential side effects and abuse. Thus, studies are necessary to further elucidate mechanistic actions of ketamine at cellular and network levels.Recent studies have generated evidence that epigenetic regulation is closely involved in the pathophysiology of depression and in the therapeutic mechanisms of typical antidepressants (6, 7). In addition, reports that sodium butyrate, a histone deacetylase (HDAC) inhibitor, has antidepressant effects indicate that HDAC inhibition is sufficient to produce an antidepressant response (8). HDACs are a family of enzymes capable of repressing gene expression by removing acetyl groups from histones to produce a less accessible chromatin structure (9).Previous studies demonstrate that the...