Florian Holsboer

Publications (323)1938.11 Total impact

• Article: Nectin-3 links CRHR1 signaling to stress-induced memory deficits and spine loss.

  Xiao-Dong Wang, Yun-Ai Su, Klaus V Wagner, Charilaos Avrabos, Sebastian H Scharf, Jakob Hartmann, Miriam Wolf, Claudia Liebl, Claudia Kühne, Wolfgang Wurst, Florian Holsboer, Matthias Eder, Jan M Deussing, Marianne B Müller, Mathias V Schmidt
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  ABSTRACT: Stress impairs cognition via corticotropin-releasing hormone receptor 1 (CRHR1), but the molecular link between abnormal CRHR1 signaling and stress-induced cognitive impairments remains unclear. We investigated whether the cell adhesion molecule nectin-3 is required for the effects of CRHR1 on cognition and structural remodeling after early-life stress exposure. Postnatally stressed adult mice had decreased hippocampal nectin-3 levels, which could be attenuated by CRHR1 inactivation and mimicked by corticotropin-releasing hormone (CRH) overexpression in forebrain neurons. Acute stress dynamically reduced hippocampal nectin-3 levels, which involved CRH-CRHR1, but not glucocorticoid receptor, signaling. Suppression of hippocampal nectin-3 caused spatial memory deficits and dendritic spine loss, whereas enhancing hippocampal nectin-3 expression rescued the detrimental effects of early-life stress on memory and spine density in adulthood. Our findings suggest that hippocampal nectin-3 is necessary for the effects of stress on memory and structural plasticity and indicate that the CRH-CRHR1 system interacts with the nectin-afadin complex to mediate such effects.
  Nature Neuroscience 05/2013; · 15.53 Impact Factor
• Article: RSUME enhances Glucocorticoid Receptor SUMOylation and transcriptional activity.

  Jimena Druker, Ana C Liberman, María Antunica-Noguerol, Juan Gerez, Marcelo Paez-Pereda, Theo Rein, Jorge A Iñiguez-Lluhí, Florian Holsboer, Eduardo Arzt
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  ABSTRACT: Glucocorticoid receptor (GR) activity is modulated by post-translational modifications including phosphorylation, ubiquitination and SUMOylation. The GR has three SUMOylation sites: lysine (K) 297 and K313 in the N-terminal domain (NTD) and K721 within the ligand binding domain. SUMOylation of the NTD sites mediate the negative effect of the synergy control motifs of GR on promoters with closely spaced GR binding sites. There is scarce evidence on the role of SUMO conjugation to K721 and its impact on GR transcriptional activity. We have previously shown that RSUME (RWD-containing SUMOylation Enhancer) increases protein SUMOylation. We now demonstrate that RSUME interacts with the GR and increases its SUMOylation. RSUME regulates GR transcriptional activity and the expression of its endogenous targets genes FKBP51and S100P. RSUME uncovers a positive role for the third SUMOylation site, K721, on GR-mediated transcription demonstrating that GR SUMOylation acts positively in the presence of a SUMOylation enhancer. Both mutation of K721 and siRNA-mediated RSUME knock-down diminish GRIP1 co-activator activity. RSUME, whose expression is induced under stress conditions, is a key factor in heat shock-induced GR SUMOylation. These results show that inhibitory and stimulatory SUMO-sites are present in the GR and at higher SUMOylation levels the stimulatory one becomes dominant.
  Molecular and cellular biology 03/2013; · 6.06 Impact Factor
• Article: Homer1 mediates acute stress-induced cognitive deficits in the dorsal hippocampus.

  Klaus V Wagner, Jakob Hartmann, Katharina Mangold, Xiao-Dong Wang, Christiana Labermaier, Claudia Liebl, Miriam Wolf, Nils C Gassen, Florian Holsboer, Theo Rein, Marianne B Müller, Mathias V Schmidt
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  ABSTRACT: In recent years, the glutamatergic system has been implicated in the development and treatment of psychiatric disorders. Glutamate signaling is processed by different receptors, including metabotropic glutamate receptors (mGluRs), which in turn interact with the scaffolding protein Homer1 to modulate downstream Ca signaling. Stress is a major risk factor for the incidence of psychiatric diseases, yet acute stress episodes may have diverging effects on individuals. Cognitive impairments have often been shown to occur after episodes of stress, however the specific role of mGluR5/Homer1 signaling in the interaction of stress and cognition has not yet been elucidated. In this study we show that a single episode of social defeat stress is sufficient to specifically induce cognitive impairments in mice 8 h after the stressor without affecting the animals' locomotion or anxiety levels. We also demonstrate that Homer1b/c levels as well as mGluR5/Homer1b/c interactions in the dorsal hippocampus are reduced up to 8 h after stress. Blockade of mGluR5 during the occurrence of social stress was able to rescue the cognitive impairments. In addition, a specific overexpression of Homer1b/c in the dorsal hippocampus also reversed the behavioral phenotype, indicating that both mGluR5 and Homer1b/c play a crucial role in the mediation of the stress effects. In summary, we could demonstrate that stress induces a cognitive deficit that is likely mediated by mGluR5/Homer1 signaling in the hippocampus. These findings help to reveal the underlying effects of cognitive impairments in patients suffering from stress-related psychiatric disorders.
  Journal of Neuroscience 02/2013; 33(9):3857-64. · 7.11 Impact Factor
• Article: Genetic variation in FKBP5 associated with the extent of stress hormone dysregulation in major depression.

  A Menke, T Klengel, J Rubel, T Brückl, H Pfister, S Lucae, M Uhr, F Holsboer, E B Binder
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  ABSTRACT: The FK506 binding protein 51 or FKBP5 has been implicated in the regulation of glucocorticoid receptor (GR) sensitivity, and genetic variants in this gene have been associated with mood and anxiety disorders. GR resistance and associated stress hormone dysregulation are among the most robust biological findings in major depression, the extent of which may be moderated by FKBP5 polymorphisms. FKBP5 mRNA expression in peripheral blood cells (baseline and following in vivo GR stimulation with 1.5 mg dexamethasone p.o.) was analyzed together with plasma cortisol, ACTH, dexamethasone levels and the FKBP5 polymorphism rs1360780 in 68 depressed patients and 87 healthy controls. We observed a significant (P = 0.02) interaction between disease status and FKBP5 risk allele carrier status (minor allele T) on GR-stimulated FKBP5 mRNA expression. Patients carrying the risk T allele, but not the CC genotype, showed a reduced induction of FKBP5 mRNA. This FKBP5 polymorphism by disease status interaction was paralleled by the extent of plasma cortisol and ACTH suppression following dexamethasone administration, with a reduced suppression only observed in depressed patients carrying the T allele. Only depressed patients carrying the FKBP5 rs1360780 risk allele showed significant GR resistance compared with healthy controls, as measured by dexamethasone-induced FKBP5 mRNA induction in peripheral blood cells and suppression of plasma cortisol and ACTH concentrations. This finding suggests that endocrine alterations in depressed patients are determined by genetic variants and may allow identification of specific subgroups.
  Genes Brain and Behavior 02/2013; · 3.48 Impact Factor
• Article: B-Raf and CRHR1 Internalization Mediate Biphasic ERK1/2 Activation by CRH in Hippocampal HT22 Cells.

  Juan J Bonfiglio, Carolina Inda, Sergio Senin, Giuseppina Maccarrone, Damián Refojo, Damiana Giacomini, Christoph W Turck, Florian Holsboer, Eduardo Arzt, Susana Silberstein
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  ABSTRACT: CRH is a key regulator of neuroendocrine, autonomic, and behavioral response to stress. CRH-stimulated CRH receptor 1 (CRHR1) activates ERK1/2 depending on intracellular context. In a previous work, we demonstrated that CRH activates ERK1/2 in limbic areas of the mouse brain (hippocampus and basolateral amygdala). ERK1/2 is an essential mediator of hippocampal physiological processes including emotional behavior, synaptic plasticity, learning, and memory. To elucidate the molecular mechanisms by which CRH activates ERK1/2 in hippocampal neurons, we used the mouse hippocampal cell line HT22. We document for the first time that ERK1/2 activation in response to CRH is biphasic, involving a first cAMP- and B-Raf-dependent early phase and a second phase that critically depends on CRHR1 internalization and β-arrestin2. By means of mass-spectrometry-based screening, we identified B-Raf-associated proteins that coimmunoprecipitate with endogenous B-Raf after CRHR1 activation. Using molecular and pharmacological tools, the functional impact of selected B-Raf partners in CRH-dependent ERK1/2 activation was dissected. These results indicate that 14-3-3 proteins, protein kinase A, and Rap1, are essential for early CRH-induced ERK1/2 activation, whereas dynamin and vimentin are required for the CRHR1 internalization-dependent phase. Both phases of ERK1/2 activation depend on calcium influx and are affected by calcium/calmodulin-dependent protein kinase II inactivation. Thus, this report describes the dynamics and biphasic nature of ERK1/2 activation downstream neuronal CRHR1 and identifies several new critical components of the CRHR1 signaling machinery that selectively controls the early and late phases of ERK1/2 activation, thus providing new potential therapeutic targets for stress-related disorders.
  Molecular Endocrinology 01/2013; · 4.54 Impact Factor
• Article: Mirtazapine Provokes Periodic Leg Movements during Sleep in Young Healthy Men.

  Stephany Fulda, Stefan Kloiber, Tatjana Dose, Susanne Lucae, Florian Holsboer, Ludwig Schaaf, Johannes Hennings
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  ABSTRACT: Recent evidence suggests that certain antidepressants are associated with an increase of periodic leg movements (PLMS) that may disturb sleep. So far, this has been shown in patients clinically treated for depression and in cross-sectional studies for various substances, but not mirtazapine. It is unclear whether antidepressants induce the new onset of PLMS or only increase preexisting PLMS, and whether this is a general property of the antidepressant or only seen in depressed patients. We report here the effect of mirtazapine on PLMS in young healthy men. Open-labeled clinical trial (NCT00878540) including a 3-week preparatory phase with standardized food, physical activity, and sleep-wake behavior, and a 10-day experimental inpatient phase with an adaptation day, 2 baseline days, and 7 days with mirtazapine. Research institute. Twelve healthy young (20-25 years) men. Seven days of nightly intake (22:00) of 30 mg mirtazapine. Sleep was recorded on 2 drug-free baseline nights, the first 2 drug nights, and the last 2 drug nights. Eight of the 12 subjects showed increased PLMS after the first dose of mirtazapine. Frequency of PLMS was highest on the first drug night and attenuated over the course of the next 6 days. Three subjects reported transient restless legs symptoms. Mirtazapine provoked PLMS in 67% of young healthy males. The effect was most pronounced in the first days. The possible role of serotonergic, noradrenergic and histaminergic mechanisms in mirtazapine-induced PLMS is discussed. CITATION: Fulda S; Kloiber S; Dose T; Lucae S. Mirtazapine provokes periodic leg movements during sleep in young healthy men. SLEEP 2013;36(5):661-669.
  Sleep 01/2013; 36(5):661-9. · 5.05 Impact Factor
• Article: In Silico Structural and Functional Characterization of the RSUME Splice Variants.

  Juan Gerez, Mariana Fuertes, Lucas Tedesco, Susana Silberstein, Gustavo Sevlever, Marcelo Paez-Pereda, Florian Holsboer, Adrián G Turjanski, Eduardo Arzt
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  ABSTRACT: RSUME (RWD-containing SUMO Enhancer) is a small protein that increases SUMO conjugation to proteins. To date, four splice variants that codify three RSUME isoforms have been described, which differ in their C-terminal end. Comparing the structure of the RSUME isoforms we found that, in addition to the previously described RWD domain in the N-terminal, all these RSUME variants also contain an intermediate domain. Only the longest RSUME isoform presents a C-terminal domain that is absent in the others. Given these differences, we used the shortest and longest RSUME variants for comparative studies. We found that the C-terminal domain is dispensable for the SUMO-conjugation enhancer properties of RSUME. We also demonstrate that these two RSUME variants are equally induced by hypoxia. The NF-κB signaling pathway is inhibited and the HIF-1 pathway is increased more efficiently by the longest RSUME, by means of a greater physical interaction of RSUME267 with the target proteins. In addition, the mRNA and protein levels of these isoforms differ in human glioma samples; while the shortest RSUME isoform is expressed in all the tumors analyzed, the longest variant is expressed in most but not all of them. The results presented here show a degree of redundancy of the RSUME variants on the SUMO pathway. However, the increased inhibition conferred by RSUME267 over the NF-κB signaling pathway, the increased activation over the HIF-1 pathway and the different expression of the RSUME isoforms suggest specific roles for each RSUME isoform which may be relevant in certain types of brain tumors that express RSUME, like human pituitary adenomas and gliomas.
  PLoS ONE 01/2013; 8(2):e57795. · 4.09 Impact Factor
• Article: Identification of a role for the ventral hippocampus in neuropeptide s-elicited anxiolysis.

  Julien Dine, Irina A Ionescu, Jens Stepan, Yi-Chun Yen, Florian Holsboer, Rainer Landgraf, Matthias Eder, Ulrike Schmidt
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  ABSTRACT: Neuropeptide S (NPS) increasingly emerges as a potential novel treatment option for anxiety diseases like panic and posttraumatic stress disorder. However, the neural underpinnings of its anxiolytic action are still not clearly understood. Recently, we reported that neurons of the ventral hippocampus (VH) take up intranasally administered fluorophore-conjugated NPS and, moreover, that application of NPS to mouse brain slices affects neurotransmission and plasticity at hippocampal CA3-CA1 synapses. Although these previous findings define the VH as a novel NPS target structure, they leave open whether this brain region is directly involved in NPS-mediated anxiolysis and how NPS impacts on neuronal activity propagation in the VH. Here, we fill this knowledge gap by demonstrating, first, that microinjections of NPS into the ventral CA1 region are sufficient to reduce anxiety-like behavior of C57BL/6N mice and, second, that NPS, via the NPS receptor, rapidly weakens evoked neuronal activity flow from the dentate gyrus to area CA1 in vitro. Additionally, we show that intranasally applied NPS alters neurotransmission and plasticity at CA3-CA1 synapses in the same way as NPS administered to hippocampal slices. Thus, our study provides, for the first time, strong experimental evidence for a direct involvement of the VH in NPS-induced anxiolysis and furthermore presents a novel mechanism of NPS action.
  PLoS ONE 01/2013; 8(3):e60219. · 4.09 Impact Factor
• Article: Resting state functional MRI connectivity predicts hypothalamus-pituitary-axis status in healthy males.

  Sara A Kiem, Kátia C Andrade, Victor I Spoormaker, Florian Holsboer, Michael Czisch, Philipp G Sämann
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  ABSTRACT: Homeostasis of the human stress response system is critically maintained by a hierarchical system of neural and endocrine elements for which intact negative feedback is important to prevent maladaptation towards stress. Such feedback is efficiently probed by the established combined dexamethasone-suppression/corticotropin-releasing hormone stimulation (dex/CRH) test. Here we investigate which suprahypothalamic networks might modulate the response assessed by this neuroendocrine test. Combined resting state fMRI (rs-fMRI)/EEG was acquired in 20 healthy male volunteers along with dex/CRH profiles obtained on a different day outside the scanner. Seed-based network analysis and inter-seed cross correlation analysis for selected atlas-based limbic, paralimbic and medial prefrontal cortex seeds were correlated with stimulated cortisol and adrenocorticotropin hormone (ACTH) concentrations. Lower connectivity between a left hippocampus-based network and the right hippocampus significantly predicted stimulated cortisol concentration (R(2)=0.70, corrected p(cluster)=0.001). Six further significantly negative correlations were detected mainly in the left anterior cingulate cortex (ACC) and the medial prefrontal cortex (mPFC). The strongest positive correlation with stimulated hormone concentration was detected for the left subcallosal ACC (ACTH, R(2)=0.57, corrected p(cluster)=0.009). Inter-seed connectivity mainly pointed to hippocampal/amygdala interactions as correlates of the dex/CRH response. In conclusion, resting state functional connectivity patterns of limbic, particularly hippocampal, as well as cingulate and medial prefrontal areas can explain some of the variance of the dex/CRH test in healthy subjects. Functional connectivity analysis can be considered useful to study supra-hypothalamic control systems of the HPA axis.
  Psychoneuroendocrinology 12/2012; · 5.81 Impact Factor
• Source

  Available from: Chris G Parsons

  Article: Lipid raft integrity affects GABAA receptor, but not NMDA receptor modulation by psychopharmacological compounds.

  Caroline Nothdurfter, Sascha Tanasic, Barbara Di Benedetto, Manfred Uhr, Eva-Maria Wagner, Kate E Gilling, Chris G Parsons, Theo Rein, Florian Holsboer, Rainer Rupprecht, Gerhard Rammes
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  ABSTRACT: Lipid rafts have been shown to play an important role for G-protein mediated signal transduction and the function of ligand-gated ion channels including their modulation by psychopharmacological compounds. In this study, we investigated the functional significance of the membrane distribution of NMDA and GABAA receptor subunits in relation to the accumulation of the tricyclic antidepressant desipramine (DMI) and the benzodiazepine diazepam (Diaz). In the presence of Triton X-100, which allowed proper separation of the lipid raft marker proteins caveolin-1 and flotillin-1 from the transferrin receptor, all receptor subunits were shifted to the non-raft fractions. In contrast, under detergent-free conditions, NMDA and GABAA receptor subunits were detected both in raft and non-raft fractions. Diaz was enriched in non-raft fractions without Triton X-100 in contrast to DMI, which preferentially accumulated in lipid rafts. Impairment of lipid raft integrity by methyl-β-cyclodextrine (MβCD)-induced cholesterol depletion did not change the inhibitory effect of DMI at the NMDA receptor, whereas it enhanced the potentiating effect of Diaz at the GABAA receptor at non-saturating concentrations of GABA. These results support the hypothesis that the interaction of benzodiazepines with the GABAA receptor likely occurs outside of lipid rafts while the antidepressant DMI acts on ionotropic receptors both within and outside these membrane microdomains.
  The International Journal of Neuropsychopharmacology 12/2012; · 4.58 Impact Factor
• Source

  Available from: Charles B Nemeroff

  Article: Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions.

  Torsten Klengel, Divya Mehta, Christoph Anacker, Monika Rex-Haffner, Jens C Pruessner, Carmine M Pariante, Thaddeus W W Pace, Kristina B Mercer, Helen S Mayberg, Bekh Bradley, Charles B Nemeroff, Florian Holsboer, Christine M Heim, Kerry J Ressler, Theo Rein, Elisabeth B Binder
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  ABSTRACT: Although the fact that genetic predisposition and environmental exposures interact to shape development and function of the human brain and, ultimately, the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not yet been elucidated. We found that a functional polymorphism altering chromatin interaction between the transcription start site and long-range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increased the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements of FKBP5. This demethylation was linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global effect on the function of immune cells and brain areas associated with stress regulation. This identification of molecular mechanisms of genotype-directed long-term environmental reactivity will be useful for designing more effective treatment strategies for stress-related disorders.
  Nature Neuroscience 12/2012; · 15.53 Impact Factor
• Article: Proteomic and metabolomic profiling reveals time-dependent changes in hippocampal metabolism upon paroxetine treatment and biomarker candidates.

  Christian Webhofer, Philipp Gormanns, Stefan Reckow, Maria Lebar, Giuseppina Maccarrone, Tonia Ludwig, Benno Pütz, John M Asara, Florian Holsboer, Inge Sillaber, Walter Zieglgänsberger, Christoph W Turck
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  ABSTRACT: Most of the commonly used antidepressants block monoamine reuptake transporters to enhance serotonergic or noradrenergic neurotransmission. Effects besides or downstream of monoamine reuptake inhibition are poorly understood and yet presumably important for the drugs' mode of action. In the present study we aimed at identifying hippocampal cellular pathway alterations in DBA/2 mice using paroxetine as a representative Selective Serotonin Reuptake Inhibitor (SSRI). Furthermore we identified biomarker candidates for the assessment of antidepressant treatment effects in plasma. Hippocampal protein levels were compared between chronic paroxetine- and vehicle-treated animals using in vivo(15)N metabolic labeling combined with mass spectrometry. We also studied the time course of metabolite level changes in hippocampus and plasma using a targeted polar metabolomics profiling platform. In silico pathway analyses revealed profound alterations related to hippocampal energy metabolism. Glycolytic metabolite levels acutely increased while Krebs cycle metabolite levels decreased upon chronic treatment. Changes in energy metabolism were influenced by altered glycogen metabolism rather than by altered glycolytic or Krebs cycle enzyme levels. Increased energy levels were reflected by an increased ATP/ADP ratio and by increased ratios of high-to-low energy purines and pyrimidines. In the course of our analyses we also identified myo-inositol as a biomarker candidate for the assessment of antidepressant treatment effects in the periphery. This study defines the cellular response to paroxetine treatment at the proteome and metabolome levels in the hippocampus of DBA/2 mice and suggests novel SSRI modes of action that warrant consideration in antidepressant development efforts.
  Journal of psychiatric research 11/2012; · 3.72 Impact Factor
• Article: The Seven Pillars of Molecular Pharmacology: GPCR Research Honored with Nobel Prize for Chemistry.

  Felix Hausch, Florian Holsboer
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  ABSTRACT: G protein-coupled receptors with seven transmembrane helices are the most important drug targets in medicine. Their molecular and structural characterization has now been honored with the Nobel Prize for Chemistry to Robert J. Lefkowitz and Brian K. Kobilka.
  Angewandte Chemie International Edition 11/2012; · 13.45 Impact Factor
• Article: The endocrine stress response is linked to one specific locus on chromosome 3 in a mouse model based on extremes in trait anxiety.

  Mariya Gonik, Elisabeth Frank, Melanie S Keßler, Darina Czamara, Mirjam Bunck, Yi-Chun Yen, Benno Pütz, Florian Holsboer, Thomas Bettecken, Rainer Landgraf, Bertram Müller-Myhsok, Chadi Touma, Ludwig Czibere
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  ABSTRACT: BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis is essential to control physiological stress responses in mammals. Its dysfunction is related to several mental disorders, including anxiety and depression. The aim of this study was to identify genetic loci underlying the endocrine regulation of the HPA axis. METHOD: High (HAB) and low (LAB) anxiety-related behaviour mice were established by selective inbreeding of outbred CD-1 mice to model extremes in trait anxiety. Additionally, HAB vs. LAB mice exhibit comorbid characteristics including a differential corticosterone response upon stress exposure. We crossbred HAB and LAB lines to create F1 and F2 offspring. To identify the contribution of the endocrine phenotypes to the total phenotypic variance, we examined multiple behavioural paradigms together with corticosterone secretion-based phenotypes in F2 mice by principal component analysis. Further, to pinpoint the genomic loci of the quantitative trait of the HPA axis stress response, we conducted genome-wide multipoint oligogenic linkage analyses based on Bayesian Markov chain Monte Carlo approach as well as parametric linkage in three-generation pedigrees, followed by a two-dimensional scan for epistasis and association analysis in freely segregating F2 mice using 267 single-nucleotide polymorphisms (SNPs), which were identified to consistently differ between HAB and LAB mice as genetic markers. RESULTS: HPA axis reactivity measurements and behavioural phenotypes were represented by independent principal components and demonstrated no correlation. Based on this finding, we identified one single quantitative trait locus (QTL) on chromosome 3 showing a very strong evidence for linkage (2ln (L-score) > 10, LOD > 23) and significant association (lowest Bonferroni adjusted p < 10-28) to the neuroendocrine stress response. The location of the linkage peak was estimated at 42.3 cM (95% confidence interval: 41.3 - 43.3 cM) and was shown to be in epistasis (p-adjusted < 0.004) with the locus at 35.3 cM on the same chromosome. The QTL harbours genes involved in steroid synthesis and cardiovascular effects. CONCLUSION: The very prominent effect on stress-induced corticosterone secretion of the genomic locus on chromosome 3 and its involvement in epistasis highlights the critical role of this specific locus in the regulation of the HPA axis.
  BMC Genomics 10/2012; 13(1):579. · 4.07 Impact Factor
• Article: Structural biology: Snapshot of an activated peptide receptor.

  Felix Hausch, Florian Holsboer
  Nature 10/2012; 490(7421):492-3. · 36.28 Impact Factor
• Article: Resistance to antidepressant treatment is associated with polymorphisms in the leptin gene, decreased leptin mRNA expression, and decreased leptin serum levels.

  Stefan Kloiber, Stephan Ripke, Martin A Kohli, Simone Reppermund, Daria Salyakina, Rudolf Uher, Peter McGuffin, Roy H Perlis, Steven P Hamilton, Benno Pütz, [......], Thomas Bettecken, Marcus Ising, Manfred Uhr, Tatjana Dose, Paul G Unschuld, Josef Zihl, Elisabeth Binder, Bertram Müller-Myhsok, Florian Holsboer, Susanne Lucae
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  ABSTRACT: Leptin, a peptide hormone from adipose tissue and key player in weight regulation, has been suggested to be involved in sleep and cognition and to exert antidepressant-like effects, presumably via its action on the HPA-axis and hippocampal function. This led us to investigate whether genetic variants in the leptin gene, the level of leptin mRNA-expression and leptin serum concentrations are associated with response to antidepressant treatment. Our sample consisted of inpatients from the Munich Antidepressant Response Signature (MARS) project with weekly Hamilton Depression ratings, divided into two subsamples. In the exploratory sample (n=251) 17 single nucleotide polymorphisms (SNPs) covering the leptin gene region were genotyped. We found significant associations of several SNPs with impaired antidepressant treatment outcome and impaired cognitive performance after correction for multiple testing. The SNP (rs10487506) showing the highest association with treatment response (p=3.9×10(-5)) was analyzed in the replication sample (n=358) and the association could be verified (p=0.021) with response to tricyclic antidepressants. In an additional meta-analysis combining results from the MARS study with data from the Genome-based Therapeutic Drugs for Depression (GENDEP) and the Sequenced Treatment Alternatives to Relieve Depression (STAR(⁎)D) studies, nominal associations of several polymorphisms in the upstream vicinity of rs10487506 with treatment outcome were detected (p=0.001). In addition, we determined leptin mRNA expression in lymphocytes and leptin serum levels in subsamples of the MARS study. Unfavorable treatment outcome was accompanied with decreased leptin mRNA and leptin serum levels. Our results suggest an involvement of leptin in antidepressant action and cognitive function in depression with genetic polymorphisms in the leptin gene, decreased leptin gene expression and leptin deficiency in serum being risk factors for resistance to antidepressant therapy in depressed patients.
  European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 09/2012; · 3.68 Impact Factor
• Article: Antidepressants inhibit DNA methyltransferase 1 through reducing G9a levels.

  Nicole Zimmermann, Jürgen Zschocke, Tatjana Perisic, Shuang Yu, Florian Holsboer, Theo Rein
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  ABSTRACT: The discovery of epigenetic processes as possible pivotal regulatory mechanisms in psychiatric diseases raised the question of how psychoactive drugs may impact the epigenetic machinery. In the present study we set out to explore the specificity and the mode of action of the reported inhibitory effect of the TCA (tricyclic antidepressant) amitriptyline on DNMT (DNA methyltransferase) activity in primary astrocytes from the rat cortex. We found that the impact on DNMT was shared by another TCA, imipramine, and by paroxetine, but not by venlafaxine or the mood stabilizers carbamazepine and valproic acid. DNMT activity in subventricular neural stem cells was refractory to the action of ADs (antidepressants). Among the established DNMTs, ADs primarily targeted DNMT1. The reduction of enzymatic DNMT1 activity was neither due to reduced DNMT1 expression nor due to direct drug interference. We tested putative DNMT1-inhibitory mechanisms and discovered that a known stimulator of DNMT1, the histone methyltransferase G9a, exhibited decreased protein levels and interactions with DNMT1 upon AD exposure. Adding recombinant G9a completely reversed the AD repressive effect on DNMT1 function. In conclusion, the present study presents a model where distinct ADs affect DNMT1 activity via G9a with important repercussions for possible novel treatment regimes.
  Biochemical Journal 08/2012; 448(1):93-102. · 4.90 Impact Factor
• Article: Differences in FKBP51 Regulation Following Chronic Social Defeat Stress Correlate with Individual Stress Sensitivity: Influence of Paroxetine Treatment.

  Klaus V Wagner, Daria Marinescu, Jakob Hartmann, Xiao-Dong Wang, Christiana Labermaier, Sebastian H Scharf, Claudia Liebl, Manfred Uhr, Florian Holsboer, Marianne B Müller, Mathias V Schmidt
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  ABSTRACT: Various clinical studies have identified FK506-binding protein 51 (FKBP51) as a target gene involved in the development of psychiatric disorders such as depression. Furthermore, FKBP51 has been shown to affect glucocorticoid receptor signaling by sensitivity modulation and it is implicated in stress reactivity as well as in molecular mechanisms of stress vulnerability and resilience. We investigated the physiological, behavioral, and neuroendocrine parameters in an established chronic stress model both directly after stress and after a recovery period of 3 weeks and also studied the efficacy of paroxetine in this model. We then examined FKBP51 mRNA levels in the dorsal and ventral part of the hippocampus and correlated the expression to behavioral and endocrine parameters. We show robust chronic stress effects in physiological, behavioral, and neuroendocrine parameters, which were only slightly affected by paroxetine treatment. On the contrary, paroxetine led to a disruption of the neuroendocrine system. FKBP51 expression was significantly increased directly after the stress period and correlated with behavioral and neuroendocrine parameters. Taken together, we were able to further elucidate the role of FKBP51 in the mechanisms of stress resilience and vulnerability, especially with respect to behavioral and neuroendocrine parameters. These findings strongly support the concept of FKBP51 as a marker for glucocorticoid receptor sensitivity and its involvement in the development of psychiatric disorders.Neuropsychopharmacology advance online publication, 8 August 2012; doi:10.1038/npp.2012.150.
  Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2012; · 6.99 Impact Factor
• Source

  Available from: Xiao-Dong Wang

  Article: Early-life stress-induced anxiety-related behavior in adult mice partially requires forebrain corticotropin-releasing hormone receptor 1.

  Xiao-Dong Wang, Christiana Labermaier, Florian Holsboer, Wolfgang Wurst, Jan M Deussing, Marianne B Müller, Mathias V Schmidt
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  ABSTRACT: Early-life stress may lead to persistent changes in central corticotropin-releasing hormone (CRH) and the CRH receptor 1 (CRHR1) system that modulates anxiety-related behavior. However, it remains unknown whether CRH-CRHR1 signaling is involved in early-life stress-induced anxiety-related behavior in adult animals. In the present study, we used conditional forebrain CRHR1 knockout (CRHR1-CKO) mice and examined the potential role of forebrain CRHR1 in the anxiogenic effects of early-life stress. As adults, wild-type mice that received unstable maternal care during the first postnatal week showed reduced body weight gain and increased anxiety levels in the open field test, which were prevented in stressed CRHR1-CKO mice. In the light-dark box test, control CRHR1-CKO mice were less anxious, but early-life stress increased anxiety levels in both wild-type and CRHR1-CKO mice. In the elevated plus maze test, early-life stress had only subtle effects on anxiety-related behavior. Moreover, early-life stress did not alter the basal home cage activity and gene expression levels of key hypothalamic-pituitary-adrenal axis regulators in adult wild-type and CRHR1-CKO mice, but enhanced neuroendocrine reactivity to acute immobilization stress in CRHR1-CKO mice. Our findings highlight the importance of forebrain CRHR1 in modulating some of the anxiogenic effects of early-life stress, and suggest that other neural circuits are also involved in the programming effects of early-life stress on anxiety-related behavior.
  European Journal of Neuroscience 06/2012; 36(3):2360-7. · 3.63 Impact Factor
• Article: Corticotropin-releasing hormone regulates common target genes with divergent functions in corticotrope and neuronal cells.

  Cornelia Graf, Claudia Kuehne, Markus Panhuysen, Benno Puetz, Peter Weber, Florian Holsboer, Wolfgang Wurst, Jan M Deussing
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  ABSTRACT: As a key regulator of the neuroendocrine stress axis and as a neuromodulator in the brain, the neuropeptide corticotropin-releasing hormone (CRH) plays an important role in various diseases of the central nervous system. Its cognate receptor CRH receptor type 1 (CRHR1) is a potential novel target for the therapeutic intervention in major depressive disorder. Therefore, a more precise understanding of involved intracellular signaling mechanisms is essential. The objective of this project was to identify specific target genes of CRHR1-mediated signaling pathways in the corticotrope cell line AtT-20 and in the neuronal cell line HN9 using microarray technology and qRT-PCR, respectively. In addition, we assessed the capacity of validated target genes to directly impact on CRHR1-dependent signaling using reporter assays. Thereby, we identified a set of CRHR1 downstream targets with diverging and cell type-specific roles which strengthen the role of CRH and CRHR1 as dynamic modulators of a variety of signal transduction mechanisms and cellular processes.
  Molecular and Cellular Endocrinology 05/2012; 362(1-2):29-38. · 4.19 Impact Factor