Expression and regulation of the Fkbp5 gene in the adult mouse brain

Scharf, SH; Liebl, C; Binder, E. B.; Schmidt, MV; Müller, M. B.

doi:10.1055/s-0031-1292538

Cited by 32 publications

(48 citation statements)

References 32 publications

(40 reference statements)

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“…Furthermore, Fkbp5 methylation levels have been correlated with anxiety-like behavior (Lee et al, 2011). Also, brain regions with low basal Fkbp5 expression such as the amygdala display higher increases in Fkbp5 mRNA expression following stress as compared with regions with high basal expression, supporting the hypothesis that GR sensitivity is mediated via Fkbp5 (Scharf et al, 2011).…”

Section: Introductionmentioning

confidence: 74%

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Sawamura

Klengel

Armario

et al. 2015

Neuropsychopharmacol

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Posttraumatic stress disorder (PTSD) is both a prevalent and debilitating trauma-related disorder associated with dysregulated fear learning at the core of many of its signs and symptoms. Improvements in the currently available psychological and pharmacological treatments are needed in order to improve PTSD treatment outcomes and to prevent symptom relapse. In the present study, we used a putative animal model of PTSD that included presentation of immobilization stress (IMO) followed by fear conditioning (FC) a week later. We then investigated the acute effects of GR receptor activation on the extinction (EXT) of conditioned freezing, using dexamethasone administered systemically which is known to result in suppression of the HPA axis. In our previous work, IMO followed by tone-shockmediated FC was associated with impaired fear EXT. In this study, we administered dexamethasone 4 h before EXT training and then examined EXT retention (RET) 24 h later to determine whether dexamethasone suppression rescued EXT deficits. Dexamethasone treatment produced dose-dependent enhancement of both EXT and RET. Dexamethasone was also associated with reduced amygdala Fkbp5 mRNA expression following EXT and after RET. Moreover, DNA methylation of the Fkbp5 gene occurred in a dose-dependent and time course-dependent manner within the amygdala. Additionally, we found dynamic changes in epigenetic regulation, including Dnmt and Tet gene pathways, as a function of both fear EXT and dexamethasone suppression of the HPA axis. Together, these data suggest that dexamethasone may serve to enhance EXT by altering Fkbp5-mediated glucocorticoid sensitivity via epigenetic regulation of Fkbp5 expression.

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Section: Introductionmentioning

confidence: 74%

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Sawamura

Klengel

Armario

et al. 2015

Neuropsychopharmacol

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“…A promising candidate gene is FKBP5, which codes for a protein FK506 binding protein 5-51, a co-chaperone of the hsp90, and regulates the affinity of the GR for cortisol (Binder 2009;Denny et al 2000;Wochnik et al 2005). Recently, a strong stressinduced increase of FKBP5 mRNA in the central amygdala has been demonstrated (Scharf et al 2011), supporting the significance of FKBP5 regulation during central GR activation. One of the most commonly investigated polymorphisms in this gene is rs1360780, a single nucleotide polymorphism (SNP) located in intron two at chromosome six (position 6p21.31) with a minor allele frequency of 42 % (Binder et al 2008).…”

Section: Introductionmentioning

confidence: 95%

“…No study, so far, has investigated the impact of FKBP5 on amygdala volume. However this issue may be crucial, given the facts that FKBP5 is expressed in the amygdala (Scharf et al 2011) and that amygdala volume is increased following stress (Buss et al 2012;Lupien et al 2011;Tottenham et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Role of FKBP5 in emotion processing: results on amygdala activity, connectivity and volume

et al. 2014

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Accumulating evidence suggests a role of FKBP5, a co-chaperone regulating the glucocorticoid receptor sensitivity, in the etiology of depression and anxiety disorders. Based on recent findings of altered amygdala activity following childhood adversity, the present study aimed at clarifying the impact of genetic variation in FKBP5 on threat-related neural activity and coupling as well as morphometric alterations in stress-sensitive brain systems. Functional magnetic resonance imaging during an emotional face-matching task was performed in 153 healthy young adults (66 males) from a high-risk community sample followed since birth. Voxel-based morphometry was applied to study structural alterations and DNA was genotyped for FKBP5 rs1360780. Childhood adversity was measured using retrospective selfreport (Childhood Trauma Questionnaire) and by a standardized parent interview assessing childhood family adversity. Depression was assessed by the Beck Depression Inventory. There was a main effect of FKBP5 on the left amygdala, with T homozygotes showing the highest activity, largest volume and increased coupling with the left hippocampus and the orbitofrontal cortex (OFC). Moreover, amygdala-OFC coupling proved to be associated with depression in this genotype. In addition, our results support previous evidence of a gene-environment interaction on right amygdala activity with respect to retrospective assessment of childhood adversity, but clarify that this does not generalize to the prospective assessment. These findings indicated that activity in T homozygotes increased with the level of adversity, whereas the opposite pattern emerged in C homozygotes, with CT individuals being intermediate. Abstract Accumulating evidence suggests a role of FKBP5, a co-chaperone regulating the glucocorticoid receptor sensitivity, in the etiology of depression and anxiety disorders. Based on recent findings of altered amygdala activity following childhood adversity, the present study aimed at clarifying the impact of genetic variation in FKBP5 on threat-related neural activity and coupling as well as morphometric alterations in stresssensitive brain systems. Functional magnetic resonance imaging during an emotional face-matching task was performed in 153 healthy young adults (66 males) from a high-risk community sample followed since birth. Voxelbased morphometry was applied to study structural alterations and DNA was genotyped for FKBP5 rs1360780. Childhood adversity was measured using retrospective selfreport (Childhood Trauma Questionnaire) and by a standardized parent interview assessing childhood family adversity. Depression was assessed by the Beck Depression Inventory. There was a main effect of FKBP5 on the left amygdala, with T homozygotes showing the highest activity, largest volume and increased coupling with the left hippocampus and the orbitofrontal cortex (OFC). Moreover, amygdala-OFC coupling proved to be associated with depression in this genotype. In addition, our results support previous evidence of a gene-env...

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“…We assessed Crhr1 and Crhr2 expression in three brain regions: amygdala, bed nucleus of stria terminalis (BNST), and lateral septum, which are areas of relatively high expression for at least one of these genes (Van Pett et al, 2000). We also assessed Fkbp51 in the hippocampus and neocortex, areas of moderate to high expression for these genes (Scharf et al, 2011). Briefly, male/female DOX-treated/untreated and handled/predator stressed double-mutant mice were killed 7 days after predator stress exposure, regions of interest were dissected on ice-cold platform immediately after brain extraction and were placed in 1.5 ml tubes containing 500 μl of RNA Later (Life Technologies, Carlsbad, CA).…”

Section: Quantitative Real-time Pcr (Qrt-pcr)mentioning

confidence: 99%

Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood

Tóth

Flandreau

Deslauriers

et al. 2015

Neuropsychopharmacol

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Although early-life stress is a significant risk factor for developing anxiety disorders, including posttraumatic stress disorder (PTSD), the underlying mechanisms are unclear. Corticotropin releasing hormone (CRH) is disrupted in individuals with PTSD and early-life stress and hence may mediate the effects of early-life stress on PTSD risk. We hypothesized that CRH hyper-signaling in the forebrain during early development is sufficient to increase response to trauma in adulthood. To test this hypothesis, we induced transient, forebrain-specific, CRH overexpression during early-life (pre-puberty, CRHOE dev ) in double-mutant mice (Camk2a-rtta2 × tetO-Crh) and tested their behavioral and gene expression responses to the predator stress model of PTSD in adulthood. In one cohort of CRHOE dev exposed and unexposed mice, avoidance and arousal behaviors were examined 7-15 days after exposure to predator stress. In another cohort, gene expression changes in Crhr1, Crhr2, and Fkbp51 in forebrain of CRHOE dev exposed and unexposed mice were examined 7 days after predator stress. CRHOE dev induced robust increases in startle reactivity and reductions in startle inhibition independently of predator stress in both male and female mice. Avoidance behaviors after predator stress were highly dependent on sex and CRHOE dev exposure. Whereas stressed females exhibited robust avoidance responses that were not altered by CRHOE dev , males developed significant avoidance only when exposed to both CRHOE dev and stress. Quantitative real-time-PCR analysis indicated that CRHOE dev unexposed males exhibit significant changes in Crhr2 expression in the amygdala and bed nucleus stria terminalis in response to stress, whereas males exposed to CRHOE dev did not. Similar to CRHOE dev males, females exhibited no significant Crhr2 gene expression changes in response to stress. Cortical Fkbp51 expression was also significantly reduced by stress and CRHOE dev exposure in males, but not in females. These findings indicate that forebrain CRH hyper-signaling in early-life is sufficient to increase enduring effects of adult trauma and attenuate Crhr2 expression changes in response to stress in males. These data support growing evidence for significant sex differences in response to trauma, and support further study of CRHR2 as a candidate mechanism for PTSD risk.

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Expression and regulation of the Fkbp5 gene in the adult mouse brain

Cited by 32 publications

References 32 publications

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Role of FKBP5 in emotion processing: results on amygdala activity, connectivity and volume

Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood

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