Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment.
Identifieur interne : 000D34 ( Main/Exploration ); précédent : 000D33; suivant : 000D35Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment.
Auteurs : M M Juki [Suède] ; N. Opel [Allemagne] ; J. Ström [Suède] ; T. Carrillo-Roa [Allemagne] ; S. Miksys [Canada] ; M. Novalen [Canada] ; A. Renblom [Suède] ; S C Sim [Suède] ; E M Pe As-Lled [Espagne] ; P. Courtet [France] ; A. Llerena [Canada] ; B T Baune [Australie] ; D J De Quervain [Suisse] ; A. Papassotiropoulos [Suisse] ; R F Tyndale [Canada] ; E B Binder [Allemagne] ; U. Dannlowski [Allemagne] ; M. Ingelman-Sundberg [Suède]Source :
- Molecular psychiatry [ 1476-5578 ] ; 2017.
Descripteurs français
- KwdFr :
- Afro-Américains (génétique), Agonistes des récepteurs 5-HT1 de la sérotonine (pharmacologie), Animaux, Anxiété (génétique), Anxiété (imagerie diagnostique), Citalopram (pharmacologie), Comportement animal (), Cytochrome P-450 CYP2C19 (), Cytochrome P-450 CYP2C19 (génétique), Cytochrome P-450 CYP2C19 (métabolisme), Dépression (génétique), Dépression (traitement médicamenteux), Facteur neurotrophique dérivé du cerveau (métabolisme), Hippocampe (métabolisme), Homéostasie (génétique), Homéostasie (physiologie), Humains, Neurogenèse (génétique), Récepteur de la sérotonine de type 5-HT1A (métabolisme), Souris, Souris transgéniques, Sérotonine (métabolisme), Trouble dépressif majeur (imagerie diagnostique), Trouble dépressif majeur (métabolisme), Troubles anxieux (génétique).
- MESH :
- génétique : Afro-Américains, Anxiété, Cytochrome P-450 CYP2C19, Dépression, Homéostasie, Neurogenèse, Troubles anxieux.
- imagerie diagnostique : Anxiété, Trouble dépressif majeur.
- métabolisme : Cytochrome P-450 CYP2C19, Facteur neurotrophique dérivé du cerveau, Hippocampe, Récepteur de la sérotonine de type 5-HT1A, Sérotonine, Trouble dépressif majeur.
- pharmacologie : Agonistes des récepteurs 5-HT1 de la sérotonine, Citalopram.
- physiologie : Homéostasie.
- traitement médicamenteux : Dépression.
- Animaux, Comportement animal, Cytochrome P-450 CYP2C19, Humains, Souris, Souris transgéniques.
English descriptors
- KwdEn :
- African Americans (genetics), Animals, Anxiety (diagnostic imaging), Anxiety (genetics), Anxiety Disorders (genetics), Behavior, Animal (drug effects), Brain-Derived Neurotrophic Factor (metabolism), Citalopram (pharmacology), Cytochrome P-450 CYP2C19 (drug effects), Cytochrome P-450 CYP2C19 (genetics), Cytochrome P-450 CYP2C19 (metabolism), Depression (drug therapy), Depression (genetics), Depressive Disorder, Major (diagnostic imaging), Depressive Disorder, Major (metabolism), Hippocampus (metabolism), Homeostasis (genetics), Homeostasis (physiology), Humans, Mice, Mice, Transgenic, Neurogenesis (genetics), Receptor, Serotonin, 5-HT1A (metabolism), Serotonin (metabolism), Serotonin 5-HT1 Receptor Agonists (pharmacology).
- MESH :
- chemical , drug effects : Cytochrome P-450 CYP2C19.
- chemical , genetics : Cytochrome P-450 CYP2C19.
- chemical , metabolism : Brain-Derived Neurotrophic Factor, Cytochrome P-450 CYP2C19, Receptor, Serotonin, 5-HT1A, Serotonin.
- diagnostic imaging : Anxiety, Depressive Disorder, Major.
- drug effects : Behavior, Animal.
- drug therapy : Depression.
- genetics : African Americans, Anxiety, Anxiety Disorders, Depression, Homeostasis, Neurogenesis.
- metabolism : Depressive Disorder, Major, Hippocampus.
- chemical , pharmacology : Citalopram, Serotonin 5-HT1 Receptor Agonists.
- physiology : Homeostasis.
- Animals, Humans, Mice, Mice, Transgenic.
Abstract
The polymorphic CYP2C19 enzyme metabolizes psychoactive compounds and is expressed in the adult liver and fetal brain. Previously, we demonstrated that the absence of CYP2C19 is associated with lower levels of depressive symptoms in 1472 Swedes. Conversely, transgenic mice carrying the human CYP2C19 gene (2C19TG) have shown an anxious phenotype and decrease in hippocampal volume and adult neurogenesis. The aims of this study were to: (1) examine whether the 2C19TG findings could be translated to humans, (2) evaluate the usefulness of the 2C19TG strain as a tool for preclinical screening of new antidepressants and (3) provide an insight into the molecular underpinnings of the 2C19TG phenotype. In humans, we found that the absence of CYP2C19 was associated with a bilateral hippocampal volume increase in two independent healthy cohorts (N=386 and 1032) and a lower prevalence of major depressive disorder and depression severity in African-Americans (N=3848). Moreover, genetically determined high CYP2C19 enzymatic capacity was associated with higher suicidality in depressed suicide attempters (N=209). 2C19TG mice showed high stress sensitivity, impaired hippocampal Bdnf homeostasis in stress, and more despair-like behavior in the forced swim test (FST). After the treatment with citalopram and 5-HT1A receptor agonist 8OH-DPAT, the reduction in immobility time in the FST was more pronounced in 2C19TG mice compared with WTs. Conversely, in the 2C19TG hippocampus, metabolic turnover of serotonin was reduced, whereas ERK1/2 and GSK3β phosphorylation was increased. Altogether, this study indicates that elevated CYP2C19 expression is associated with depressive symptoms, reduced hippocampal volume and impairment of hippocampal serotonin and BDNF homeostasis.
DOI: 10.1038/mp.2016.204
PubMed: 27895323
Affiliations:
- Allemagne, Australie, Canada, Espagne, France, Suisse, Suède
- Bavière, District de Haute-Bavière, District de Münster, Languedoc-Roussillon, Occitanie (région administrative), Rhénanie-du-Nord-Westphalie, Svealand
- Montpellier, Munich, Münster, Stockholm
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Le document en format XML
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Opel</name><affiliation wicri:level="3"><nlm:affiliation>Department of Psychiatry, University of Münster, Münster, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Psychiatry, University of Münster, Münster</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Münster</region><settlement type="city">Münster</settlement></placeName></affiliation></author><author><name sortKey="Strom, J" sort="Strom, J" uniqKey="Strom J" first="J" last="Ström">J. Ström</name><affiliation wicri:level="3"><nlm:affiliation>Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Carrillo Roa, T" sort="Carrillo Roa, T" uniqKey="Carrillo Roa T" first="T" last="Carrillo-Roa">T. Carrillo-Roa</name><affiliation wicri:level="3"><nlm:affiliation>Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Miksys, S" sort="Miksys, S" uniqKey="Miksys S" first="S" last="Miksys">S. 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Novalen</name><affiliation wicri:level="1"><nlm:affiliation>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON</wicri:regionArea><wicri:noRegion>ON</wicri:noRegion></affiliation></author><author><name sortKey="Renblom, A" sort="Renblom, A" uniqKey="Renblom A" first="A" last="Renblom">A. Renblom</name><affiliation wicri:level="3"><nlm:affiliation>Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Sim, S C" sort="Sim, S C" uniqKey="Sim S" first="S C" last="Sim">S C Sim</name><affiliation wicri:level="3"><nlm:affiliation>Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Pe As Lled, E M" sort="Pe As Lled, E M" uniqKey="Pe As Lled E" first="E M" last="Pe As-Lled">E M Pe As-Lled</name><affiliation wicri:level="1"><nlm:affiliation>CICAB Clinical Research Center, Extremadura University Hospital and Medical School, Badajoz, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>CICAB Clinical Research Center, Extremadura University Hospital and Medical School, Badajoz</wicri:regionArea><wicri:noRegion>Badajoz</wicri:noRegion></affiliation></author><author><name sortKey="Courtet, P" sort="Courtet, P" uniqKey="Courtet P" first="P" last="Courtet">P. Courtet</name><affiliation wicri:level="3"><nlm:affiliation>CHU Montpellier, Hôpital Lapeyronie, Psychiatric Emergency and Post-Acute Care Department, Pole Urgence, Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>CHU Montpellier, Hôpital Lapeyronie, Psychiatric Emergency and Post-Acute Care Department, Pole Urgence, Montpellier</wicri:regionArea><placeName><region type="region">Occitanie (région administrative)</region><region type="old region">Languedoc-Roussillon</region><settlement type="city">Montpellier</settlement></placeName></affiliation></author><author><name sortKey="Llerena, A" sort="Llerena, A" uniqKey="Llerena A" first="A" last="Llerena">A. Llerena</name><affiliation wicri:level="1"><nlm:affiliation>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON</wicri:regionArea><wicri:noRegion>ON</wicri:noRegion></affiliation></author><author><name sortKey="Baune, B T" sort="Baune, B T" uniqKey="Baune B" first="B T" last="Baune">B T Baune</name><affiliation wicri:level="1"><nlm:affiliation>Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA</wicri:regionArea><wicri:noRegion>SA</wicri:noRegion></affiliation></author><author><name sortKey="De Quervain, D J" sort="De Quervain, D J" uniqKey="De Quervain D" first="D J" last="De Quervain">D J De Quervain</name><affiliation wicri:level="1"><nlm:affiliation>Transfaculty Research Platform, Department of Psychology, University Psychiatric Clinics, University of Basel, Basel, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Transfaculty Research Platform, Department of Psychology, University Psychiatric Clinics, University of Basel, Basel</wicri:regionArea><wicri:noRegion>Basel</wicri:noRegion></affiliation></author><author><name sortKey="Papassotiropoulos, A" sort="Papassotiropoulos, A" uniqKey="Papassotiropoulos A" first="A" last="Papassotiropoulos">A. Papassotiropoulos</name><affiliation wicri:level="1"><nlm:affiliation>Transfaculty Research Platform, Department of Psychology, University Psychiatric Clinics, University of Basel, Basel, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Transfaculty Research Platform, Department of Psychology, University Psychiatric Clinics, University of Basel, Basel</wicri:regionArea><wicri:noRegion>Basel</wicri:noRegion></affiliation></author><author><name sortKey="Tyndale, R F" sort="Tyndale, R F" uniqKey="Tyndale R" first="R F" last="Tyndale">R F Tyndale</name><affiliation wicri:level="1"><nlm:affiliation>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON</wicri:regionArea><wicri:noRegion>ON</wicri:noRegion></affiliation></author><author><name sortKey="Binder, E B" sort="Binder, E B" uniqKey="Binder E" first="E B" last="Binder">E B Binder</name><affiliation wicri:level="3"><nlm:affiliation>Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Dannlowski, U" sort="Dannlowski, U" uniqKey="Dannlowski U" first="U" last="Dannlowski">U. Dannlowski</name><affiliation wicri:level="3"><nlm:affiliation>Department of Psychiatry, University of Münster, Münster, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Psychiatry, University of Münster, Münster</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Münster</region><settlement type="city">Münster</settlement></placeName></affiliation></author><author><name sortKey="Ingelman Sundberg, M" sort="Ingelman Sundberg, M" uniqKey="Ingelman Sundberg M" first="M" last="Ingelman-Sundberg">M. Ingelman-Sundberg</name><affiliation wicri:level="3"><nlm:affiliation>Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2017">2017</date><idno type="RBID">pubmed:27895323</idno><idno type="pmid">27895323</idno><idno type="doi">10.1038/mp.2016.204</idno><idno type="wicri:Area/PubMed/Corpus">000852</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000852</idno><idno type="wicri:Area/PubMed/Curation">000849</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000849</idno><idno type="wicri:Area/PubMed/Checkpoint">000849</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000849</idno><idno type="wicri:Area/Ncbi/Merge">003F41</idno><idno type="wicri:Area/Ncbi/Curation">003F41</idno><idno type="wicri:Area/Ncbi/Checkpoint">003F41</idno><idno type="wicri:Area/Main/Merge">000D29</idno><idno type="wicri:Area/Main/Curation">000D34</idno><idno type="wicri:Area/Main/Exploration">000D34</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment.</title><author><name sortKey="Juki, M M" sort="Juki, M M" uniqKey="Juki M" first="M M" last="Juki">M M Juki</name><affiliation wicri:level="3"><nlm:affiliation>Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Opel, N" sort="Opel, N" uniqKey="Opel N" first="N" last="Opel">N. Opel</name><affiliation wicri:level="3"><nlm:affiliation>Department of Psychiatry, University of Münster, Münster, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Psychiatry, University of Münster, Münster</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Münster</region><settlement type="city">Münster</settlement></placeName></affiliation></author><author><name sortKey="Strom, J" sort="Strom, J" uniqKey="Strom J" first="J" last="Ström">J. Ström</name><affiliation wicri:level="3"><nlm:affiliation>Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Carrillo Roa, T" sort="Carrillo Roa, T" uniqKey="Carrillo Roa T" first="T" last="Carrillo-Roa">T. Carrillo-Roa</name><affiliation wicri:level="3"><nlm:affiliation>Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Miksys, S" sort="Miksys, S" uniqKey="Miksys S" first="S" last="Miksys">S. Miksys</name><affiliation wicri:level="1"><nlm:affiliation>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON</wicri:regionArea><wicri:noRegion>ON</wicri:noRegion></affiliation></author><author><name sortKey="Novalen, M" sort="Novalen, M" uniqKey="Novalen M" first="M" last="Novalen">M. Novalen</name><affiliation wicri:level="1"><nlm:affiliation>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON</wicri:regionArea><wicri:noRegion>ON</wicri:noRegion></affiliation></author><author><name sortKey="Renblom, A" sort="Renblom, A" uniqKey="Renblom A" first="A" last="Renblom">A. Renblom</name><affiliation wicri:level="3"><nlm:affiliation>Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Sim, S C" sort="Sim, S C" uniqKey="Sim S" first="S C" last="Sim">S C Sim</name><affiliation wicri:level="3"><nlm:affiliation>Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Pe As Lled, E M" sort="Pe As Lled, E M" uniqKey="Pe As Lled E" first="E M" last="Pe As-Lled">E M Pe As-Lled</name><affiliation wicri:level="1"><nlm:affiliation>CICAB Clinical Research Center, Extremadura University Hospital and Medical School, Badajoz, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>CICAB Clinical Research Center, Extremadura University Hospital and Medical School, Badajoz</wicri:regionArea><wicri:noRegion>Badajoz</wicri:noRegion></affiliation></author><author><name sortKey="Courtet, P" sort="Courtet, P" uniqKey="Courtet P" first="P" last="Courtet">P. Courtet</name><affiliation wicri:level="3"><nlm:affiliation>CHU Montpellier, Hôpital Lapeyronie, Psychiatric Emergency and Post-Acute Care Department, Pole Urgence, Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>CHU Montpellier, Hôpital Lapeyronie, Psychiatric Emergency and Post-Acute Care Department, Pole Urgence, Montpellier</wicri:regionArea><placeName><region type="region">Occitanie (région administrative)</region><region type="old region">Languedoc-Roussillon</region><settlement type="city">Montpellier</settlement></placeName></affiliation></author><author><name sortKey="Llerena, A" sort="Llerena, A" uniqKey="Llerena A" first="A" last="Llerena">A. Llerena</name><affiliation wicri:level="1"><nlm:affiliation>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON</wicri:regionArea><wicri:noRegion>ON</wicri:noRegion></affiliation></author><author><name sortKey="Baune, B T" sort="Baune, B T" uniqKey="Baune B" first="B T" last="Baune">B T Baune</name><affiliation wicri:level="1"><nlm:affiliation>Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA</wicri:regionArea><wicri:noRegion>SA</wicri:noRegion></affiliation></author><author><name sortKey="De Quervain, D J" sort="De Quervain, D J" uniqKey="De Quervain D" first="D J" last="De Quervain">D J De Quervain</name><affiliation wicri:level="1"><nlm:affiliation>Transfaculty Research Platform, Department of Psychology, University Psychiatric Clinics, University of Basel, Basel, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Transfaculty Research Platform, Department of Psychology, University Psychiatric Clinics, University of Basel, Basel</wicri:regionArea><wicri:noRegion>Basel</wicri:noRegion></affiliation></author><author><name sortKey="Papassotiropoulos, A" sort="Papassotiropoulos, A" uniqKey="Papassotiropoulos A" first="A" last="Papassotiropoulos">A. Papassotiropoulos</name><affiliation wicri:level="1"><nlm:affiliation>Transfaculty Research Platform, Department of Psychology, University Psychiatric Clinics, University of Basel, Basel, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Transfaculty Research Platform, Department of Psychology, University Psychiatric Clinics, University of Basel, Basel</wicri:regionArea><wicri:noRegion>Basel</wicri:noRegion></affiliation></author><author><name sortKey="Tyndale, R F" sort="Tyndale, R F" uniqKey="Tyndale R" first="R F" last="Tyndale">R F Tyndale</name><affiliation wicri:level="1"><nlm:affiliation>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON</wicri:regionArea><wicri:noRegion>ON</wicri:noRegion></affiliation></author><author><name sortKey="Binder, E B" sort="Binder, E B" uniqKey="Binder E" first="E B" last="Binder">E B Binder</name><affiliation wicri:level="3"><nlm:affiliation>Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Dannlowski, U" sort="Dannlowski, U" uniqKey="Dannlowski U" first="U" last="Dannlowski">U. Dannlowski</name><affiliation wicri:level="3"><nlm:affiliation>Department of Psychiatry, University of Münster, Münster, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Psychiatry, University of Münster, Münster</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Münster</region><settlement type="city">Münster</settlement></placeName></affiliation></author><author><name sortKey="Ingelman Sundberg, M" sort="Ingelman Sundberg, M" uniqKey="Ingelman Sundberg M" first="M" last="Ingelman-Sundberg">M. Ingelman-Sundberg</name><affiliation wicri:level="3"><nlm:affiliation>Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author></analytic><series><title level="j">Molecular psychiatry</title><idno type="eISSN">1476-5578</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>African Americans (genetics)</term><term>Animals</term><term>Anxiety (diagnostic imaging)</term><term>Anxiety (genetics)</term><term>Anxiety Disorders (genetics)</term><term>Behavior, Animal (drug effects)</term><term>Brain-Derived Neurotrophic Factor (metabolism)</term><term>Citalopram (pharmacology)</term><term>Cytochrome P-450 CYP2C19 (drug effects)</term><term>Cytochrome P-450 CYP2C19 (genetics)</term><term>Cytochrome P-450 CYP2C19 (metabolism)</term><term>Depression (drug therapy)</term><term>Depression (genetics)</term><term>Depressive Disorder, Major (diagnostic imaging)</term><term>Depressive Disorder, Major (metabolism)</term><term>Hippocampus (metabolism)</term><term>Homeostasis (genetics)</term><term>Homeostasis (physiology)</term><term>Humans</term><term>Mice</term><term>Mice, Transgenic</term><term>Neurogenesis (genetics)</term><term>Receptor, Serotonin, 5-HT1A (metabolism)</term><term>Serotonin (metabolism)</term><term>Serotonin 5-HT1 Receptor Agonists (pharmacology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Afro-Américains (génétique)</term><term>Agonistes des récepteurs 5-HT1 de la sérotonine (pharmacologie)</term><term>Animaux</term><term>Anxiété (génétique)</term><term>Anxiété (imagerie diagnostique)</term><term>Citalopram (pharmacologie)</term><term>Comportement animal ()</term><term>Cytochrome P-450 CYP2C19 ()</term><term>Cytochrome P-450 CYP2C19 (génétique)</term><term>Cytochrome P-450 CYP2C19 (métabolisme)</term><term>Dépression (génétique)</term><term>Dépression (traitement médicamenteux)</term><term>Facteur neurotrophique dérivé du cerveau (métabolisme)</term><term>Hippocampe (métabolisme)</term><term>Homéostasie (génétique)</term><term>Homéostasie (physiologie)</term><term>Humains</term><term>Neurogenèse (génétique)</term><term>Récepteur de la sérotonine de type 5-HT1A (métabolisme)</term><term>Souris</term><term>Souris transgéniques</term><term>Sérotonine (métabolisme)</term><term>Trouble dépressif majeur (imagerie diagnostique)</term><term>Trouble dépressif majeur (métabolisme)</term><term>Troubles anxieux (génétique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="drug effects" xml:lang="en"><term>Cytochrome P-450 CYP2C19</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Cytochrome P-450 CYP2C19</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Brain-Derived Neurotrophic Factor</term><term>Cytochrome P-450 CYP2C19</term><term>Receptor, Serotonin, 5-HT1A</term><term>Serotonin</term></keywords><keywords scheme="MESH" qualifier="diagnostic imaging" xml:lang="en"><term>Anxiety</term><term>Depressive Disorder, Major</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Behavior, Animal</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Depression</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>African Americans</term><term>Anxiety</term><term>Anxiety Disorders</term><term>Depression</term><term>Homeostasis</term><term>Neurogenesis</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Afro-Américains</term><term>Anxiété</term><term>Cytochrome P-450 CYP2C19</term><term>Dépression</term><term>Homéostasie</term><term>Neurogenèse</term><term>Troubles anxieux</term></keywords><keywords scheme="MESH" qualifier="imagerie diagnostique" xml:lang="fr"><term>Anxiété</term><term>Trouble dépressif majeur</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Depressive Disorder, Major</term><term>Hippocampus</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Cytochrome P-450 CYP2C19</term><term>Facteur neurotrophique dérivé du cerveau</term><term>Hippocampe</term><term>Récepteur de la sérotonine de type 5-HT1A</term><term>Sérotonine</term><term>Trouble dépressif majeur</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Agonistes des récepteurs 5-HT1 de la sérotonine</term><term>Citalopram</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Citalopram</term><term>Serotonin 5-HT1 Receptor Agonists</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Homéostasie</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Homeostasis</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Dépression</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Humans</term><term>Mice</term><term>Mice, Transgenic</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Comportement animal</term><term>Cytochrome P-450 CYP2C19</term><term>Humains</term><term>Souris</term><term>Souris transgéniques</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The polymorphic CYP2C19 enzyme metabolizes psychoactive compounds and is expressed in the adult liver and fetal brain. Previously, we demonstrated that the absence of CYP2C19 is associated with lower levels of depressive symptoms in 1472 Swedes. Conversely, transgenic mice carrying the human CYP2C19 gene (2C19TG) have shown an anxious phenotype and decrease in hippocampal volume and adult neurogenesis. The aims of this study were to: (1) examine whether the 2C19TG findings could be translated to humans, (2) evaluate the usefulness of the 2C19TG strain as a tool for preclinical screening of new antidepressants and (3) provide an insight into the molecular underpinnings of the 2C19TG phenotype. In humans, we found that the absence of CYP2C19 was associated with a bilateral hippocampal volume increase in two independent healthy cohorts (N=386 and 1032) and a lower prevalence of major depressive disorder and depression severity in African-Americans (N=3848). Moreover, genetically determined high CYP2C19 enzymatic capacity was associated with higher suicidality in depressed suicide attempters (N=209). 2C19TG mice showed high stress sensitivity, impaired hippocampal Bdnf homeostasis in stress, and more despair-like behavior in the forced swim test (FST). After the treatment with citalopram and 5-HT1A receptor agonist 8OH-DPAT, the reduction in immobility time in the FST was more pronounced in 2C19TG mice compared with WTs. Conversely, in the 2C19TG hippocampus, metabolic turnover of serotonin was reduced, whereas ERK1/2 and GSK3β phosphorylation was increased. Altogether, this study indicates that elevated CYP2C19 expression is associated with depressive symptoms, reduced hippocampal volume and impairment of hippocampal serotonin and BDNF homeostasis.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Australie</li><li>Canada</li><li>Espagne</li><li>France</li><li>Suisse</li><li>Suède</li></country><region><li>Bavière</li><li>District de Haute-Bavière</li><li>District de Münster</li><li>Languedoc-Roussillon</li><li>Occitanie (région administrative)</li><li>Rhénanie-du-Nord-Westphalie</li><li>Svealand</li></region><settlement><li>Montpellier</li><li>Munich</li><li>Münster</li><li>Stockholm</li></settlement></list><tree><country name="Suède"><region name="Svealand"><name sortKey="Juki, M M" sort="Juki, M M" uniqKey="Juki M" first="M M" last="Juki">M M Juki</name></region><name sortKey="Ingelman Sundberg, M" sort="Ingelman Sundberg, M" uniqKey="Ingelman Sundberg M" first="M" last="Ingelman-Sundberg">M. Ingelman-Sundberg</name><name sortKey="Renblom, A" sort="Renblom, A" uniqKey="Renblom A" first="A" last="Renblom">A. Renblom</name><name sortKey="Sim, S C" sort="Sim, S C" uniqKey="Sim S" first="S C" last="Sim">S C Sim</name><name sortKey="Strom, J" sort="Strom, J" uniqKey="Strom J" first="J" last="Ström">J. Ström</name></country><country name="Allemagne"><region name="Rhénanie-du-Nord-Westphalie"><name sortKey="Opel, N" sort="Opel, N" uniqKey="Opel N" first="N" last="Opel">N. Opel</name></region><name sortKey="Binder, E B" sort="Binder, E B" uniqKey="Binder E" first="E B" last="Binder">E B Binder</name><name sortKey="Carrillo Roa, T" sort="Carrillo Roa, T" uniqKey="Carrillo Roa T" first="T" last="Carrillo-Roa">T. Carrillo-Roa</name><name sortKey="Dannlowski, U" sort="Dannlowski, U" uniqKey="Dannlowski U" first="U" last="Dannlowski">U. Dannlowski</name></country><country name="Canada"><noRegion><name sortKey="Miksys, S" sort="Miksys, S" uniqKey="Miksys S" first="S" last="Miksys">S. Miksys</name></noRegion><name sortKey="Llerena, A" sort="Llerena, A" uniqKey="Llerena A" first="A" last="Llerena">A. Llerena</name><name sortKey="Novalen, M" sort="Novalen, M" uniqKey="Novalen M" first="M" last="Novalen">M. Novalen</name><name sortKey="Tyndale, R F" sort="Tyndale, R F" uniqKey="Tyndale R" first="R F" last="Tyndale">R F Tyndale</name></country><country name="Espagne"><noRegion><name sortKey="Pe As Lled, E M" sort="Pe As Lled, E M" uniqKey="Pe As Lled E" first="E M" last="Pe As-Lled">E M Pe As-Lled</name></noRegion></country><country name="France"><region name="Occitanie (région administrative)"><name sortKey="Courtet, P" sort="Courtet, P" uniqKey="Courtet P" first="P" last="Courtet">P. Courtet</name></region></country><country name="Australie"><noRegion><name sortKey="Baune, B T" sort="Baune, B T" uniqKey="Baune B" first="B T" last="Baune">B T Baune</name></noRegion></country><country name="Suisse"><noRegion><name sortKey="De Quervain, D J" sort="De Quervain, D J" uniqKey="De Quervain D" first="D J" last="De Quervain">D J De Quervain</name></noRegion><name sortKey="Papassotiropoulos, A" sort="Papassotiropoulos, A" uniqKey="Papassotiropoulos A" first="A" last="Papassotiropoulos">A. Papassotiropoulos</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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