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      TS-EUROTRAIN: A European-Wide Investigation and Training Network on the Etiology and Pathophysiology of Gilles de la Tourette Syndrome

      brief-report
      1 , 2 , 3 , 4 , 2 , 5 , 6 , 7 , 5 , 8 , 9 , 10 , 11 , 8 , 12 , 13 , 7 , 14 , 15 , 16 , 9 , 17 , 16 , 18 , 15 , 17 , 14 , 19 , 20 , 2 , 21 , 9 , 1 , 2 , 22 , 23 , 3 , 2 , 6 , 10 , 11 , 8 , 4 , 3 , 1 , 2 , 24 , 25 , 26 , 27 , 12 , 8 , 10 , 11 , 28 , 1 , 7 , 5
      Frontiers in Neuroscience
      Frontiers Media S.A.
      Initial Training Network, Gilles de la Tourette Syndrome, tourette disorder, etiology, genetics, neuroimaging, animal models

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          Abstract

          Gilles de la Tourette Syndrome (GTS) is characterized by the presence of multiple motor and phonic tics with a fluctuating course of intensity, frequency, and severity. Up to 90% of patients with GTS present with comorbid conditions, most commonly attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD), thus providing an excellent model for the exploration of shared etiology across disorders. TS-EUROTRAIN (FP7-PEOPLE-2012-ITN, Grant Agr.No. 316978) is a Marie Curie Initial Training Network ( http://ts-eurotrain.eu) that aims to elucidate the complex etiology of the onset and clinical course of GTS, investigate the neurobiological underpinnings of GTS and related disorders, translate research findings into clinical applications, and establish a pan-European infrastructure for the study of GTS. This includes the challenges of (i) assembling a large genetic database for the evaluation of the genetic architecture with high statistical power; (ii) exploring the role of gene-environment interactions including the effects of epigenetic phenomena; (iii) employing endophenotype-based approaches to understand the shared etiology between GTS, OCD, and ADHD; (iv) establishing a developmental animal model for GTS; (v) gaining new insights into the neurobiological mechanisms of GTS via cross-sectional and longitudinal neuroimaging studies; and (vi) partaking in outreach activities including the dissemination of scientific knowledge about GTS to the public. Fifteen partners from academia and industry and 12 PhD candidates pursue the project. Here, we aim to share the design of an interdisciplinary project, showcasing the potential of large-scale collaborative efforts in the field of GTS. Our ultimate aims are to elucidate the complex etiology and neurobiological underpinnings of GTS, translate research findings into clinical applications, and establish Pan-European infrastructure for the study of GTS and associated disorders.

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          Most cited references17

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          Genome-wide association study of obsessive-compulsive disorder

          Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10(-6) and P=3.44 × 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 × 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P<0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.
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            L-DOPA-induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin- and glutamic acid decarboxylase mRNA.

            Rats sustaining unilateral near-complete 6-hydroxydopamine lesions of the mesostriatal dopamine pathway received daily injections of 3, 4 dihydroxyphenyl-l-alanine (L-DOPA, 8 mg/kg plus 15 mg/kg benserazide) for 3 weeks. During this period, about 50% of the rats gradually developed abnormal involuntary movements, lasting for 2-3 h following each L-DOPA dose. Rats were killed 3 days after the last L-DOPA injection, and sections through the striatum were processed for in situ hybridization histochemistry. Within the L-DOPA-treated group, levels of preproenkephalin (PPE) mRNA, glutamic acid decarboxylase (GAD67) mRNA, and prodynorphin (PDyn) mRNA in the dopamine-denervated caudate-putamen, as well as GAD67 mRNA expression in the globus pallidus ipsilateral to the 6-hydroxydopamine (6-OHDA) lesion, were higher in dyskinetic than non-dyskinetic animals, and positively correlated with the rats' dyskinesia scores. By contrast, striatal preprotachykinin mRNA expression and D2 receptor-radioligand binding were not significantly associated with dyskinesia. Among all these markers, PDyn mRNA levels showed the most pronounced treatment-dependence (three times higher in the L-DOPA-treated group than in saline-injected lesion-only controls), and the strongest correlation with the rats' dyskinesia scores (r2 = 0.82). However, a multiple regression equation including the three factors, GAD67 mRNA levels in the GP, GAD67 mRNA in the lateral CPu, and striatal PDyn mRNA, gave a better fit for dyskinesia scores than PDyn mRNA alone (r2 = 0.92). The results show that L-DOPA-induced dyskinesia is associated with overexpression of PDyn and GAD67 mRNA in the striatal projection neurons, and GAD67 mRNA levels in the globus pallidus. Due to its treatment-dependent expression, and strong correlation with the associated dyskinetic symptoms, striatal PDyn mRNA, in particular, may play a role in the mechanisms of behavioural sensitization brought about by the drug.
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              The functional anatomy of Gilles de la Tourette syndrome.

              Gilles de la Tourette syndrome (GTS) holds a prime position as a disorder transgressing the brittle boundaries of neurology and psychiatry with an entangling web of motor and behavioral problems. With tics as the disorder's hallmark and myriads of related signs such as echo-, pali- and coprophenomena, paralleled by a broad neuropsychiatric spectrum of comorbidities encompassing attention deficit hyperactivity disorder, obsessive-compulsive disorder and self-injurious behavior and depression, GTS pathophysiology remains enigmatic. In this review, in the light of GTS phenomenology, we will focus on current theories of tic-emergence related to aberrant activity in the basal ganglia and abnormal basal ganglia-cortex interplay through cortico-striato-thalamocortical loops from an anatomical, neurophysiological and functional-neuroimaging perspective. We will attempt a holistic view to the countless major and minor drawbacks of the GTS brain and comment on future directions of neuroscientific research to elucidate this common and complex neuropsychiatric syndrome, which merits scientific understanding and social acceptance. Copyright © 2012 Elsevier Ltd. All rights reserved.
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                Journal
                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                1662-4548
                1662-453X
                23 August 2016
                2016
                : 10
                : 384
                Affiliations
                [1] 1Department of Psychiatry, University of Groningen, University Medical Center Groningen Groningen, Netherlands
                [2] 2Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center Nijmegen, Netherlands
                [3] 3Clinic of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School Hannover, Germany
                [4] 4Max Planck Institute for Human Cognitive and Brain Sciences Leipzig, Germany
                [5] 5Department of Molecular Biology and Genetics, Democritus University of Thrace Alexandropoulos, Greece
                [6] 6Boehringer Ingelheim Pharma GmbH & Co. KG, CNS Research Biberach an der Riss, Germany
                [7] 7Department of Child and Adolescent Psychiatry, University of Ulm Ulm, Germany
                [8] 8Department of Clinical Genetics, Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital Rigshospitalet, Denmark
                [9] 9Department of Clinical and health Psychology, Utrecht University Utrecht, Netherlands
                [10] 10Department of Psychiatry, VU University Medical Center Amsterdam, Netherlands
                [11] 11Department of Anatomy and Neurosciences, VU University Medical Center Amsterdam, Netherlands
                [12] 12deCODE Genetics/Amgen Reykjavik, Iceland
                [13] 13Faculty of Medicine, University of Iceland Reykjavik, Iceland
                [14] 14Institute for Anatomy and Cell Biology, Ulm University Ulm, Germany
                [15] 15Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University Budapest, Hungary
                [16] 16Research Centre for Natural Sciences, Institute of Enzymology, Hungarian Academy of Sciences Budapest, Hungary
                [17] 17Department of Biological Psychology, VU University Amsterdam, Netherlands
                [18] 18Université d'Angers, BNMI (Institut national de la santé et de la recherche médicale 1083 / Centre National de la Recherche Scientifique 6214) Angers, France
                [19] 19EMGO+ Institute for Health and Care Research, VU University Medical Centre Amsterdam, Netherlands
                [20] 20Stichting Gilles de la Tourette Rhoon, Netherlands
                [21] 21Karakter Child and Adolescent Psychiatry, University Centre Nijmegen, Netherlands
                [22] 22Rensselaer Polytechnic Institute Troy, NY, USA
                [23] 23Tourette-Gesellschaft Deutschland e.V. Hannover, Germany
                [24] 24Department of Human Genetics, Radboud University Medical Center Nijmegen, Netherlands
                [25] 25Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Netherlands
                [26] 26Department of Physics and Medical Technology, VU University Medical Center Amsterdam, Netherlands
                [27] 27Psychiatric and Neurodevelopmental Genetics Unit, Departments of Psychiatry and Neurology, Center for Human Genetic Research, Harvard Medical School, Massachusetts General Hospital Boston, MA, USA
                [28] 28Netherlands Institute for Neuroscience Amsterdam, Netherlands
                Author notes

                Edited by: Ahmet O. Caglayan, Yale University, USA

                Reviewed by: Munis Dundar, Erciyes University, Turkey; Jessica A. Church-Lang, University of Texas at Austin, USA; Asif Doja, Children's Hospital of Eastern Ontario, Canada; Eric R. Gamazon, University of Chicago, USA

                *Correspondence: Peristera Paschou ppaschou@ 123456mbg.duth.gr

                This article was submitted to Child and Adolescent Psychiatry, a section of the journal Frontiers in Neuroscience

                †These authors have contributed equally to this work.

                Article
                10.3389/fnins.2016.00384
                4994475
                27601976
                dfaf13aa-b30d-49b8-a634-ecd0cb9e4b6c
                Copyright © 2016 Forde, Kanaan, Widomska, Padmanabhuni, Nespoli, Alexander, Rodriguez Arranz, Fan, Houssari, Nawaz, Rizzo, Pagliaroli, Zilhäo, Aranyi, Barta, Boeckers, Boomsma, Buisman, Buitelaar, Cath, Dietrich, Driessen, Drineas, Dunlap, Gerasch, Glennon, Hengerer, van den Heuvel, Jespersgaard, Möller, Müller-Vahl, Openneer, Poelmans, Pouwels, Scharf, Stefansson, Tümer, Veltman, van der Werf, Hoekstra, Ludolph and Paschou.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 16 March 2016
                : 08 August 2016
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 48, Pages: 9, Words: 6525
                Funding
                Funded by: Seventh Framework Programme 10.13039/501100004963
                Award ID: 316978
                Award ID: 278948
                Award ID: 278367
                Categories
                Neuroscience
                Perspective

                Neurosciences
                initial training network,gilles de la tourette syndrome,tourette disorder,etiology,genetics,neuroimaging,animal models

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