Christoph W Turck

Max Planck Institute of Psychiatry, München, Bavaria, Germany

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Publications (265)1529.45 Total impact

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    ABSTRACT: Despite intense research efforts the molecular mechanisms affecting stress-vulnerable brain regions in posttraumatic stress disorder (PTSD) remain elusive. In the current study we have applied global transcriptomic profiling to a PTSD mouse model induced by foot shock fear conditioning. We compared the transcriptomes of prelimbic cortex, anterior cingulate cortex (ACC), basolateral amygdala, central nucleus of amygdala, nucleus accumbens (NAc) and CA1 of the dorsal hippocampus between shocked and non-shocked (control) mice, with and without fluoxetine treatment by RNA sequencing. Differentially expressed (DE) genes were identified and clustered for in silico pathway analysis. Findings in relevant brain regions were further validated with immunohistochemistry. DE genes belonging to 11 clusters were identified including increased inflammatory response in ACC in shocked mice. In line with this finding, we noted higher microglial activation in ACC of shocked mice. Chronic fluoxetine treatment initiated in the aftermath of the trauma prevented inflammatory gene expression alterations in ACC and ameliorated PTSD-like symptoms, implying an important role of the immune response in PTSD pathobiology. Our results provide novel insights into molecular mechanisms affected in PTSD and suggest therapeutic applications with anti-inflammatory agents.
    No preview · Article · Feb 2016
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    ABSTRACT: Current treatment strategies for anxiety disorders are predominantly symptom-based. However, a third of anxiety patients remain unresponsive to anxiolytics highlighting the need for more effective, mechanism-based therapeutic approaches. We have previously compared high vs. low anxiety mice and identified changes in mitochondrial pathways, including oxidative phosphorylation and oxidative stress. In this work, we show that selective pharmacological targeting of these mitochondrial pathways exerts anxiolytic effects in vivo. We treated high anxiety-related behavior (HAB) mice with MitoQ, an antioxidant that selectively targets mitochondria. MitoQ administration resulted in decreased anxiety-related behavior in HAB mice. This anxiolytic effect was specific for high anxiety as MitoQ treatment did not affect the anxiety phenotype of C57BL/6N and DBA/2J mouse strains. We furthermore investigated the molecular underpinnings of the MitoQ-driven anxiolytic effect and found that MitoQ treatment alters the brain metabolome and that the response to MitoQ treatment is characterized by distinct molecular signatures. These results indicate that a mechanism-driven approach based on selective mitochondrial targeting has the potential to attenuate the high anxiety phenotype in vivo, thus paving the way for translational implementation as long-term MitoQ administration is well-tolerated with no side-effects in mice and humans.Neuropsychopharmacology accepted article preview online, 16 November 2015. doi:10.1038/npp.2015.341.
    No preview · Article · Nov 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
  • M Filiou · P Wood · L Teplytska · D Otte · A Zimmer · C Turck

    No preview · Article · Sep 2015 · Pharmacopsychiatry

  • No preview · Article · Sep 2015 · Pharmacopsychiatry

  • No preview · Article · Sep 2015 · Pharmacopsychiatry
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    Christoph W. Turck · Michaela D. Filiou

    Preview · Article · May 2015
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    ABSTRACT: As a multifactorial disease, the underlying causes of schizophrenia require analysis by multiplex methods such as proteomics to allow identification of whole protein networks. Previous post-mortem proteomic studies on brain tissues from schizophrenia patients have demonstrated changes in activation of glycolytic and energy metabolism pathways. However, it is not known whether these changes occur in neurons or in glial cells. To address this question, we treated neuronal, astrocyte and oligodendrocyte cell lines with the NMDA receptor antagonist MK-801 and measured the levels of six glycolytic enzymes by Western blot analysis. MK-801 acts on the glutamatergic system and has been proposed as a pharmacological means of modeling schizophrenia. Treatment with MK-801 resulted in significant changes in the levels of glycolytic enzymes in all cell types. Most of the differences were found in oligodendrocytes, which had altered levels of hexokinase 1 (HK1), enolase 2 (ENO2), phosphoglycerate kinase (PGK) and phosphoglycerate mutase 1 (PGAM1) after acute MK-801 treatment (8 hours), and HK1, ENO2, PGK and triosphosphate isomerase (TPI) following long term treatment (72 hours). Addition of the antipsychotic clozapine to the cultures resulted in counter-regulatory effects to the MK-801 treatment by normalizing the levels of ENO2 and PGK in both the acute and long term cultures. In astrocytes, MK-801 affected only aldolase C (ALDOC) under both acute conditions and HK1 and ALDOC following long term treatment, and TPI was the only enzyme affected under long term conditions in the neuronal cells. In conclusion, MK-801 affects glycolysis in oligodendrocytes to a larger extent than neuronal cells and this may be modulated by antipsychotic treatment. Although cell culture studies do not necessarily reflect the in vivo pathophysiology and drug effects within the brain, these results suggest that neurons, astrocytes and oligodendrocytes are affected differently in schizophrenia.
    Full-text · Article · May 2015 · Frontiers in Cellular Neuroscience
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    Full-text · Article · Apr 2015
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    ABSTRACT: Collapsin response mediator protein-2 (CRMP2) is a central nervous system protein involved in neuronal development, axonal and neuronal growth, cell migration, and protein trafficking. Recent studies have linked perturbations in CRMP2 function to neurodegenerative disorders such as Alzheimer's disease, neuropathic pain and Batten disease, and to psychiatric disorders such as schizophrenia. Like most proteins, CRMP2 functions though interactions with a molecular network of proteins and other molecules. Here, we have attempted to identify additional proteins of the CRMP2 interactome to provide further leads about its roles in neurological functions. We used a combined co-immunoprecipitation and shotgun proteomic approach in order to identify CRMP2 protein partners. We identified 78 CRMP2 protein partners not previously reported in public protein interaction databases. These were involved in 7 biological processes, which included cell signaling, growth, metabolism, trafficking and immune function, according to Gene Ontology classifications. Furthermore, 32 different molecular functions were found to be associated with these proteins, such as RNA binding, ribosomal functions, transporter activity, receptor activity, serine/threonine phosphatase activity, cell adhesion, cytoskeletal protein binding and catalytic activity. In silico pathway interactome construction revealed a highly connected network with the most overrepresented functions corresponding to semaphorin interactions, along with axon guidance and WNT5A-signalling. Taken together, these findings suggest that the CRMP2 pathway is critical for regulating neuronal and synaptic architecture. Further studies along these lines might uncover novel biomarkers and drug targets for use in drug discovery. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Apr 2015 · PROTEOMICS - CLINICAL APPLICATIONS
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    ABSTRACT: The second Think-Tank, sponsored by the Collegium Internationale Neuropsychopharmacologium (CINP), debated the status and prospects of biological markers for psychiatric disorders, focusing on schizophrenia and major depressive disorder. Discussions covered markers defining and predicting specific disorders or domains of dysfunction, as well as predicting and monitoring medication efficacy. Deliberations included clinically useful and viable biomarkers, why suitable markers are not available and the need for tightly-controlled sample collection. Different types of biomarker, appropriate sensitivity, specificity and broad-based exploitability were discussed. Whilst a number of candidates are in discovery phase, all require replication in larger, real-life cohorts. Clinical cost effectiveness also needs to be established. Since a single measure is unlikely to suffice, multi-modal strategies look more promising, although they bring greater technical and implementation complexities. Identifying reproducible, robust biomarkers will probably require pre-competitive consortia to provide the resources needed to identify, validate and develop the relevant clinical tests. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    Preview · Article · Apr 2015 · The International Journal of Neuropsychopharmacology
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    ABSTRACT: Psychotropic medications target glycogen synthase kinase 3β (GSK3β), but the functional integration with other factors relevant for drug efficacy is poorly understood. We discovered that the suggested psychiatric risk factor FK506 binding protein 51 (FKBP51) increases phosphorylation of GSK3β at serine 9 (pGSK3β(S9)). FKBP51 associates with GSK3β mainly through its FK1 domain; furthermore, it also changes GSK3β's heterocomplex assembly by associating with the phosphatase PP2A and the kinase cyclin-dependent kinase 5. FKBP51 acts through GSK3β on the downstream targets Tau, β-catenin and T-cell factor/lymphoid enhancing factor (TCF/LEF). Lithium and the antidepressant (AD) paroxetine (PAR) functionally synergize with FKBP51, as revealed by reporter gene and protein association analyses. Deletion of FKBP51 blunted the PAR- or lithium-induced increase in pGSK3β(S9) in cells and mice and attenuated the behavioral effects of lithium treatment. Clinical improvement in depressive patients was predicted by baseline GSK3β pathway activity and by pGSK3β(S9) reactivity to ex vivo treatment of peripheral blood mononuclear lymphocytes with lithium or PAR. In sum, FKBP51-directed GSK3β activity contributes to the action of psychotropic medications. Components of the FKBP51-GSK3β pathway may be useful as biomarkers predicting AD response and as targets for the development of novel ADs.Molecular Psychiatry advance online publication, 7 April 2015; doi:10.1038/mp.2015.38.
    Full-text · Article · Apr 2015 · Molecular Psychiatry
  • F. Iris · M. Filiou · C. W. Turck

    No preview · Article · Mar 2015 · European Psychiatry
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    ABSTRACT: Neddylation is a ubiquitylation-like pathway that controls cell cycle and proliferation by covalently conjugating Nedd8 to specific targets. However, its role in neurons, nonreplicating postmitotic cells, remains unexplored. Here we report that Nedd8 conjugation increased during postnatal brain development and is active in mature synapses, where many proteins are neddylated. We show that neddylation controls spine development during neuronal maturation and spine stability in mature neurons. We found that neddylated PSD-95 was present in spines and that neddylation on Lys202 of PSD-95 is required for the proactive role of the scaffolding protein in spine maturation and synaptic transmission. Finally, we developed Nae1(CamKIIα-CreERT2) mice, in which neddylation is conditionally ablated in adult excitatory forebrain neurons. These mice showed synaptic loss, impaired neurotransmission and severe cognitive deficits. In summary, our results establish neddylation as an active post-translational modification in the synapse regulating the maturation, stability and function of dendritic spines.
    Full-text · Article · Jan 2015 · Nature Neuroscience
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    ABSTRACT: Stress-induced psychiatric disorders, such as depression, have recently been linked to changes in glutamate transmission in the central nervous system. Glutamate signaling is mediated by a range of receptors, including metabotropic glutamate receptors (mGluRs). In particular, mGluR subtype 5 (mGluR5) is highly implicated in stress-induced psychopathology. The major scaffold protein Homer1 critically interacts with mGluR5 and has also been linked to several psychopathologies. Yet, the specific role of Homer1 in this context remains poorly understood. We used chronic social defeat stress as an established animal model of depression and investigated changes in transcription of Homer1a and Homer1b/c isoforms and functional coupling of Homer1 to mGluR5. Next, we investigated the consequences of Homer1 deletion, overexpression of Homer1a and chronic administration of the mGluR5 inverse agonist CTEP on the effects of chronic stress. In mice exposed to chronic stress, Homer1b/c, but not Homer1a, mRNA was upregulated, and accordingly, Homer1/mGluR5 coupling was disrupted. We found a marked hyperactivity behavior as well as a dysregulated hypothalamic-pituitary-adrenal axis activity in chronically stressed Homer1 KO mice. Chronic administration of the selective and orally bioavailable mGluR5 inverse agonist, CTEP, was able to recover behavioral alterations induced by chronic stress, while overexpression of Homer1a in the hippocampus led to an increased vulnerability to chronic stress, reflected in an increased physiological response to stress as well as enhanced depression-like behavior. Overall, our results implicate the glutamatergic system in the emergence of stress-induced psychiatric disorders, and support the Homer1/mGluR5 complex as a target for the development of novel antidepressant agents.Neuropsychopharmacology accepted article preview online, 20 November 2014. doi:10.1038/npp.2014.308.
    Full-text · Article · Nov 2014 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    ABSTRACT: Clozapine displays stronger systemic metabolic side effects than haloperidol and it has been hypothesized that therapeutic antipsychotic and adverse metabolic effects of these drugs are related. Considering that cerebral disconnectivity through oligodendrocyte dysfunction has been implicated in schizophrenia, it is important to determine the effect of these drugs on oligodendrocyte energy metabolism and myelin lipid production. Effects of clozapine and haloperidol on glucose and myelin lipid metabolism were evaluated and compared in cultured OLN-93 oligodendrocytes. First, glycolytic activity was assessed by measurement of extra- and intracellular glucose and lactate levels. Next, the expression of glucose (GLUT) and monocarboxylate (MCT) transporters was determined after 6 and 24 h. And finally mitochondrial respiration, acetyl-CoA carboxylase, free fatty acids, and expression of the myelin lipid galactocerebroside were analyzed. Both drugs altered oligodendrocyte glucose metabolism, but in opposite directions. Clozapine improved the glucose uptake, production and release of lactate, without altering GLUT and MCT. In contrast, haloperidol led to higher extracellular levels of glucose and lower levels of lactate, suggesting reduced glycolysis. Antipsychotics did not alter significantly the number of functionally intact mitochondria, but clozapine enhanced the efficacy of oxidative phosphorylation and expression of galactocerebroside. Our findings support the superior impact of clozapine on white matter integrity in schizophrenia as previously observed, suggesting that this drug improves the energy supply and myelin lipid synthesis in oligodendrocytes. Characterizing the underlying signal transduction pathways may pave the way for novel oligodendrocyte-directed schizophrenia therapies.
    Full-text · Article · Nov 2014 · Frontiers in Cellular Neuroscience
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    ABSTRACT: Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has fast-acting antidepressant activities and is used for major depressive disorder (MDD) patients who show treatment resistance towards drugs of the selective serotonin reuptake inhibitor (SSRI) type. In order to better understand Ketamine's mode of action, a prerequisite for improved drug development efforts, a detailed understanding of the molecular events elicited by the drug is mandatory. In the present study we have carried out a time-dependent hippocampal metabolite profiling analysis of mice treated with Ketamine. After a single injection of Ketamine, our metabolomics data indicate time-dependent metabolite level alterations starting already after 2 h reflecting the fast antidepressant effect of the drug. In silico pathway analyses revealed that several hippocampal pathways including glycolysis/gluconeogenesis, pentose phosphate pathway and citrate cycle are affected, apparent by changes not only in metabolite levels but also connected metabolite level ratios. The results show that a single injection of Ketamine has an impact on the major energy metabolism pathways. Furthermore, seven of the identified metabolites qualify as biomarkers for the Ketamine drug response.
    Full-text · Article · Nov 2014 · Translational Psychiatry
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    Y He · C E Hogrefe · D Grapov · M Palazoglu · O Fiehn · C W Turck · M S Golub
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    ABSTRACT: Fluoxetine is the only psychopharmacological agent approved for depression by the US Food and Drug Administration for children and is commonly used therapeutically in a variety of neurodevelopmental disorders. Therapeutic response shows high individual variability, and severe side effects have been observed. In the current study we set out to identify biomarkers of response to fluoxetine as well as biomarkers that correlate with impulsivity, a measure of reward delay behavior and potential side effect of the drug, in juvenile male rhesus monkeys. The study group was also genotyped for polymorphisms of monoamine oxidase A (MAOA), a gene that has been associated with psychiatric disorders. We used peripheral metabolite profiling of blood and cerebrospinal fluid (CSF) from animals treated daily with fluoxetine or vehicle for one year. Fluoxetine response metabolite profiles and metabolite/reward delay behavior associations were evaluated using multivariate analysis. Our analyses identified a set of plasma and CSF metabolites that distinguish fluoxetine- from vehicle-treated animals and metabolites that correlate with impulsivity. Some metabolites displayed an interaction between fluoxetine and MAOA genotype. The identified metabolite biomarkers belong to pathways that have important functions in central nervous system physiology. Biomarkers of response to fluoxetine in the normally functioning brain of juvenile nonhuman primates may aid in finding predictors of response to treatment in young psychiatric populations and in progress toward the realization of a precision medicine approach in the area of neurodevelopmental disorders.
    Full-text · Article · Nov 2014 · Translational Psychiatry
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    ABSTRACT: Although antidepressants have been used in the treatment of affective disorders for over 50 years, the precise mechanism of their action remains unknown. Treatment regimens are based by and large on empirical parameters and characterized by a trial and error scheme. A better understanding of the mechanisms involved in antidepressant drug response is of fundamental importance for the development of new compounds that have a higher success rate and specificity. In order to elucidate the molecular pathways involved in the action of antidepressants, we wish to identify brain areas, cell types and organelles that are targeted by antidepressant treatment in mice. Multi-isotope imaging mass spectrometry allows a quantitative approach to this analysis, enabling us to delineate antidepressant effect on protein synthesis in the brain at single cell and organelle resolution. In these experiments, we obtained a global analysis of protein turnover in the hippocampus dentate gyrus and in the Cornu Ammonis regions, together with a subcellular analysis in the granular cells and others. Copyright © 2014 John Wiley & Sons, Ltd.
    No preview · Article · Nov 2014 · Surface and Interface Analysis
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    ABSTRACT: No comprehensive metabolic profile of trait anxiety is to date available. To identify metabolic biosignatures for different anxiety states, we compared mice selectively inbred for ∼40 generations for high (HAB), normal (NAB) or low (LAB) anxiety-related behavior. Using a mass spectrometry-based targeted metabolomics approach, we quantified the levels of 257 unique metabolites in the cingulate cortex and plasma of HAB, NAB and LAB mice. We then pinpointed affected molecular systems in anxiety-related behavior by an in silico pathway and network prediction analysis followed by validation of in silico predicted alterations with molecular assays. We found distinct metabolic profiles for different trait anxiety states and detected metabolites with altered levels both in cingulate cortex and plasma. Metabolomics data revealed common candidate biomarkers in cingulate cortex and plasma for anxiety traits and in silico pathway analysis implicated amino acid metabolism, pyruvate metabolism, oxidative stress and apoptosis in the regulation of anxiety-related behavior. We report characteristic biosignatures for trait anxiety states and provide a network map of pathways involved in anxiety-related behavior. Pharmacological targeting of these pathways will enable a mechanism-based approach for identifying novel therapeutic targets for anxiety disorders.
    No preview · Article · Nov 2014 · Journal of Psychiatric Research

  • No preview · Article · Oct 2014 · Biological psychiatry

Publication Stats

14k Citations
1,529.45 Total Impact Points


  • 2003-2015
    • Max Planck Institute of Psychiatry
      München, Bavaria, Germany
  • 2012
    • Ludwig-Maximilians-University of Munich
      • Graduate School of Systemic Neurosciences
      München, Bavaria, Germany
  • 2011
    • Vanderbilt University
      • Mass Spectrometry Research Center
      Нашвилл, Michigan, United States
  • 2009
    • University of Campinas
      • Departamento de Bioquímica
      Conceição de Campinas, São Paulo, Brazil
  • 2006
    • Agilent Technologies
      Santa Clara, California, United States
  • 1987-2004
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States
    • Stanford University
      • Department of Medicine
      Palo Alto, California, United States
  • 1987-2003
    • University of California, San Francisco
      • • Department of Medicine
      • • Division of Hospital Medicine
      • • Cardiovascular Research Institute
      • • Department of Psychiatry
      San Francisco, California, United States
  • 1999
    • The Scripps Research Institute
      La Jolla, California, United States
  • 1995-1996
    • Cardiovascular Research Foundation
      New York, New York, United States