المؤلفون: Patricia Bermudez-Martin, Jérôme A. J. Becker, Nicolas Caramello, Sebastian P. Fernandez, Renan Costa-Campos, Juliette Canaguier, Susana Barbosa, Laura Martinez-Gili, Antonis Myridakis, Marc-Emmanuel Dumas, Aurélia Bruneau, Claire Cherbuy, Philippe Langella, Jacques Callebert, Jean-Marie Launay, Joëlle Chabry, Jacques Barik, Julie Le Merrer, Nicolas Glaichenhaus, Laetitia Davidovic

المصدر: Microbiome, Vol 9, Iss 1, Pp 1-23 (2021)

مصطلحات موضوعية: Microbiota, Autism, Behavior, Reward system, Metabolite, p-Cresol, Microbial ecology, QR100-130

الوصف: Abstract Background Autism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice. Results Mice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol excretion, compared to mice transplanted with the microbiota of control mice. In addition, we identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability, and fecal p-Cresol levels when transplanted to p-Cresol-treated mice. Conclusions The microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition. Our study paves the way for therapeutic interventions targeting the microbiota and p-Cresol production to treat patients with ASD. Video abstract

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2049-2618Test

الوصول الحر: https://doaj.org/article/528d90be0f624b76bc049fae162ed6dcTest

المؤلفون: Antoine Leboucher, Didier F. Pisani, Laura Martinez-Gili, Julien Chilloux, Patricia Bermudez-Martin, Anke Van Dijck, Tariq Ganief, Boris Macek, Jérôme A.J. Becker, Julie Le Merrer, R. Frank Kooy, Ez-Zoubir Amri, Edouard W. Khandjian, Marc-Emmanuel Dumas, Laetitia Davidovic

المصدر: Molecular Metabolism, Vol 21, Iss , Pp 22-35 (2019)

مصطلحات موضوعية: Internal medicine, RC31-1245

الوصف: Objectives: The Fragile X Mental Retardation Protein (FMRP) is a widely expressed RNA-binding protein involved in translation regulation. Since the absence of FMRP leads to Fragile X Syndrome (FXS) and autism, FMRP has been extensively studied in brain. The functions of FMRP in peripheral organs and on metabolic homeostasis remain elusive; therefore, we sought to investigate the systemic consequences of its absence. Methods: Using metabolomics, in vivo metabolic phenotyping of the Fmr1-KO FXS mouse model and in vitro approaches, we show that the absence of FMRP induced a metabolic shift towards enhanced glucose tolerance and insulin sensitivity, reduced adiposity, and increased β-adrenergic-driven lipolysis and lipid utilization. Results: Combining proteomics and cellular assays, we highlight that FMRP loss increased hepatic protein synthesis and impacted pathways notably linked to lipid metabolism. Mapping metabolomic and proteomic phenotypes onto a signaling and metabolic network, we predicted that the coordinated metabolic response to FMRP loss was mediated by dysregulation in the abundances of specific hepatic proteins. We experimentally validated these predictions, demonstrating that the translational regulator FMRP associates with a subset of mRNAs involved in lipid metabolism. Finally, we highlight that FXS patients mirror metabolic variations observed in Fmr1-KO mice with reduced circulating glucose and insulin and increased free fatty acids. Conclusions: Loss of FMRP results in a widespread coordinated systemic response that notably involves upregulation of protein translation in the liver, increased utilization of lipids, and significant changes in metabolic homeostasis. Our study unravels metabolic phenotypes in FXS and further supports the importance of translational regulation in the homeostatic control of systemic metabolism. Keywords: Fragile X mental retardation protein, RNA-binding protein, Translation, Metabolism, Glucose, Lipids

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2212877818311591Test; https://doaj.org/toc/2212-8778Test

الوصول الحر: https://doaj.org/article/bf35ddf6316a40d5be9efe3bf42b1cc8Test

المؤلفون: Thibaut Laboute, Jorge Gandía, Lucie P Pellissier, Yannick Corde, Florian Rebeillard, Maria Gallo, Christophe Gauthier, Audrey Léauté, Jorge Diaz, Anne Poupon, Brigitte L Kieffer, Julie Le Merrer, Jérôme AJ Becker

المصدر: eLife, Vol 9 (2020)

مصطلحات موضوعية: in vitro pharmacology, BRET experiments, beta-arrestin, GPCR oligomerisation, knockout animals, in vivo pharmacology, Medicine, Science, Biology (General), QH301-705.5

الوصف: GPR88 is an orphan G protein-coupled receptor (GPCR) considered as a promising therapeutic target for neuropsychiatric disorders; its pharmacology, however, remains scarcely understood. Based on our previous report of increased delta opioid receptor activity in Gpr88 null mice, we investigated the impact of GPR88 co-expression on the signaling of opioid receptors in vitro and revealed that GPR88 inhibits the activation of both their G protein- and β-arrestin-dependent signaling pathways. In Gpr88 knockout mice, morphine-induced locomotor sensitization, withdrawal and supra-spinal analgesia were facilitated, consistent with a tonic inhibitory action of GPR88 on µOR signaling. We then explored GPR88 interactions with more striatal versus non-neuronal GPCRs, and revealed that GPR88 can decrease the G protein-dependent signaling of most receptors in close proximity, but impedes β-arrestin recruitment by all receptors tested. Our study unravels an unsuspected buffering role of GPR88 expression on GPCR signaling, with intriguing consequences for opioid and striatal functions.

وصف الملف: electronic resource

العلاقة: https://elifesciences.org/articles/50519Test; https://doaj.org/toc/2050-084XTest

الوصول الحر: https://doaj.org/article/68fc1b1b72044d1da177f37a7c4ff79fTest

المؤلفون: Patricia Bermudez-Martin (7454168), Jérôme A. J. Becker (11101278), Nicolas Caramello (11101281), Sebastian P. Fernandez (11101284), Renan Costa-Campos (11101287), Juliette Canaguier (11101290), Susana Barbosa (340521), Laura Martinez-Gili (11101293), Antonis Myridakis (1430782), Marc-Emmanuel Dumas (40913), Aurélia Bruneau (444513), Claire Cherbuy (190609), Philippe Langella (78457), Jacques Callebert (257104), Jean-Marie Launay (161583), Joëlle Chabry (325556), Jacques Barik (11101296), Julie Le Merrer (5782949), Nicolas Glaichenhaus (239803), Laetitia Davidovic (11101299)

مصطلحات موضوعية: Microbiology, Genetics, Neuroscience, Ecology, Cancer, Science Policy, Mental Health, Chemical Sciences not elsewhere classified, Microbiota, Autism, Behavior, Reward system, Metabolite, p-Cresol, 4-Cresol

الوصف: Additional file 1: Fig. S1. p-Cresol treatment does not impact general physiological parameters, increases urinary and fecal p-Cresol excretion but not its serum levels. Fig. S2. p-Cresol treatment-induced behavioral alterations: additional parameters in the 3-chamber, dyadic social interactions and stereotypies tests and results from tests assessing locomotor activity, anxiety or cognition (relative to Fig. 1). Fig. S3. Autistic-like behaviors persist after discontinuation of p-Cresol for 4 weeks. Fig. S4. Additional behavioral parameters for the 3-chamber, dyadic social interactions, motor stereotypies tests and anxiety in FMTControl and FMTp-Cresol mice (relative to Fig. 4). Fig. S5. p-Cresol microbial biosynthetic pathways (relative to Fig. 5). Fig. S6. FMT experiments from control donors (FMTControl) to Control or p-Cresol-treated recipient mice: additional behavioral parameters in the 3-chamber, dyadic social interactions and stereotypies tests (relative to Fig. 6). Tab. S5: Recapitulation of the behavioral tests performed in the course of the study.

العلاقة: https://figshare.com/articles/journal_contribution/Additional_file_2_of_The_microbial_metabolite_p-Cresol_induces_autistic-like_behaviors_in_mice_by_remodeling_the_gut_microbiota/14936553Test

الإتاحة: https://doi.org/10.6084/m9.figshare.14936553.v1Test

المؤلفون: Julie Le Merrer, Bérangère Detraux, Jorge Gandía, De Groote, Mathieu Aurélie, Fonteneau, Alban de Kerchove d’Exaerde, Jérôme A.J. Becker

المصدر: Biological Psychiatry.

مصطلحات موضوعية: Biological Psychiatry

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::63065a65ba85e02f9b84c7d8829637d5Test
https://doi.org/10.1016/j.biopsych.2023.05.008Test

المؤلفون: Jiyong Meng, Chanjuan Xu, Pierre-André Lafon, Salomé Roux, Michaël Mathieu, Rui Zhou, Pauline Scholler, Emilie Blanc, Jérôme A. J. Becker, Julie Le Merrer, Javier González-Maeso, Patrick Chames, Jianfeng Liu, Jean-Philippe Pin, Philippe Rondard

المساهمون: Huazhong University of Science and Technology [Wuhan] (HUST), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virginia Commonwealth University (VCU), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Guerineau, Nathalie C., ANR-20-CE18-0011,Nano4Schizo,Les nanobodies des récepteurs mGlu comme agents pharmacologiques innovants pour le traitement des symptômes de la schizophrénie(2020), ANR-20-CE44-0006,SchizoGlu,Signalisation du Récepteur mGlu2 dans le Cerveau: Altérations dans les modèles précliniques de Schizophrénie et Interférences entre Antipsychotiques(2020)

المصدر: Nature Chemical Biology
Nature Chemical Biology, 2022, 18, pp.894-903. ⟨10.1038/s41589-022-01050-2⟩

مصطلحات موضوعية: [SDV.BIO]Life Sciences [q-bio]/Biotechnology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Fluorescence Resonance Energy Transfer, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Brain, Glutamic Acid, Cell Biology, Receptors, Metabotropic Glutamate, Molecular Biology, [SDV.BIO] Life Sciences [q-bio]/Biotechnology

الوصف: International audience; Membrane proteins, including ion channels, receptors and transporters, are often composed of multiple subunits and can form large complexes. Their specific composition in native tissues is difficult to determine and remains largely unknown. In this study, we developed a method for determining the subunit composition of endogenous cell surface protein complexes from isolated native tissues. Our method relies on nanobody-based sensors, which enable proximity detection between subunits in time-resolved Förster resonance energy transfer (FRET) measurements. Additionally, given conformation-specific nanobodies, the activation of these complexes can be recorded in native brain tissue. Applied to the metabotropic glutamate receptors in different brain regions, this approach revealed the clear existence of functional metabotropic glutamate (mGlu)2-mGlu4 heterodimers in addition to mGlu2 and mGlu4 homodimers. Strikingly, the mGlu4 subunits appear to be mainly heterodimers in the brain. Overall, these versatile biosensors can determine the presence and activity of endogenous membrane proteins in native tissues with high fidelity and convenience.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::047b294d11390a4ebb7d45c816ec59d6Test
https://hal.science/hal-03699580/documentTest

المؤلفون: Cécile Derieux, Audrey Léauté, Agathe Brugoux, Déborah Jaccaz, Claire Terrier, Jean-Philippe Pin, Julie Kniazeff, Julie Le Merrer, Jerome A. J. Becker

المساهمون: Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Unité Expérimentale de Physiologie Animale de l‘Orfrasiére (UE PAO), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Guerineau, Nathalie C.

المصدر: Neuropsychopharmacology
Neuropsychopharmacology, 2022, 47 (9), pp.1680-1692. ⟨10.1038/s41386-022-01317-1⟩

مصطلحات موضوعية: Pharmacology, Bromides, Mice, Knockout, Behavior, Animal, Autism Spectrum Disorder, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Microfilament Proteins, Nerve Tissue Proteins, Receptors, GABA-A, Sodium Compounds, Psychiatry and Mental health, Disease Models, Animal, Fragile X Mental Retardation Protein, Mice, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Animals, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Autistic Disorder, Social Behavior

الوصف: International audience; Autism Spectrum Disorders (ASD) are neurodevelopmental disorders whose diagnosis relies on deficient social interaction and communication together with repetitive behavior. To date, no pharmacological treatment has been approved that ameliorates social behavior in patients with ASD. Based on the excitation/inhibition imbalance theory of autism, we hypothesized that bromide ions, long used as an antiepileptic medication, could relieve core symptoms of ASD. We evaluated the effects of chronic sodium bromide (NaBr) administration on autistic-like symptoms in three genetic mouse models of autism: Oprm1-/-, Fmr1-/- and Shank3Δex13-16-/- mice. We showed that chronic NaBr treatment relieved autistic-like behaviors in these three models. In Oprm1-/- mice, these beneficial effects were superior to those of chronic bumetanide administration. At transcriptional level, chronic NaBr in Oprm1 null mice was associated with increased expression of genes coding for chloride ions transporters, GABAA receptor subunits, oxytocin and mGlu4 receptor. Lastly, we uncovered synergistic alleviating effects of chronic NaBr and a positive allosteric modulator (PAM) of mGlu4 receptor on autistic-like behavior in Oprm1-/- mice. We evidenced in heterologous cells that bromide ions behave as PAMs of mGlu4, providing a molecular mechanism for such synergy. Our data reveal the therapeutic potential of bromide ions, alone or in combination with a PAM of mGlu4 receptor, for the treatment of ASDs.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::db63ac6b6c4703b5b52f506775b612b5Test
https://pubmed.ncbi.nlm.nih.gov/35418620Test

المؤلفون: Joëlle Chabry, R. Costa-Campos, Jean-Marie Launay, Philippe Langella, Laura Martinez-Gili, Nicolas Caramello, Claire Cherbuy, Antonis Myridakis, Jacques Barik, Laetitia Davidovic, Aurélia Bruneau, Julie Le Merrer, Sebastian P. Fernandez, Jacques Callebert, Susana Barbosa, Marc-Emmanuel Dumas, Nicolas Glaichenhaus, Juliette Canaguier, Patricia Bermudez-Martin, Jérôme A.J. Becker

المساهمون: Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imperial College London, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), McGill University and Genome Quebec Innovation Centre, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Université Sorbonne Paris Nord, Fondation FondaMental [Créteil], Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Parasitology [São Paulo] (IBS), Institute of Biomedical Sciences (ICB/USP), Universidade de São Paulo (USP)-Universidade de São Paulo (USP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), CHU Lille, McGill University = Université McGill [Montréal, Canada], Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours, Department of Metabolism, Digestion and Reproduction, National Heart and Lung Institute [London] (NHLI), Royal Brompton and Harefield NHS Foundation Trust-Imperial College London, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, UK Research & Innovation (UKRI) Medical Research Council UK (MRC)MR/M501797/1, Region the Centre-Val de Loire (ARD2020 Biomedicaments GPCRAb), ANR-19-CE14-0024,MICROBIAUTISM,L'axe microbiome-intestin-cerveau dans les troubles du spectre de l'autisme(2019), European Project: 291840,EC:FP7:HEALTH,FP7-ERANET-2011-RTD,ERA-NET NEURON II(2012), Institute of Environmental Assessment and Water Research (IDAEA), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Laboratoire d'Énergétique Moléculaire et Macroscopique, Combustion (EM2C), CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université Paris Saclay (COmUE), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Emerging Methods Section, Environment and Climate Change Canada, FERNANDEZ, SEBASTIAN PABLO, L'axe microbiome-intestin-cerveau dans les troubles du spectre de l'autisme - - MICROBIAUTISM2019 - ANR-19-CE14-0024 - AAPG2019 - VALID, Network of European funding for Neuroscience research - ERA-NET NEURON II - - EC:FP7:HEALTH2012-01-01 - 2015-12-31 - 291840 - VALID, Université Côte d'Azur (UCA), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours (UT), Commission of the European Communities, Medical Research Council (MRC)

المصدر: Microbiome
Microbiome, BioMed Central, 2021, 9 (1), pp.1-23. ⟨10.1186/s40168-021-01103-z⟩
Microbiome, BioMed Central, 2021, 9 (1), pp.157. ⟨10.1186/s40168-021-01103-z⟩
Microbiome, BioMed Central, 2021, 9 (1), pp.1-23. ⟨10.1101/2020.05.18.101147⟩
Microbiome, BioMed Central, 2021, 9 (1), ⟨10.1186/s40168-021-01103-z⟩
Microbiome, 2021, 9 (1), pp.1-23. ⟨10.1186/s40168-021-01103-z⟩
Microbiome, Vol 9, Iss 1, Pp 1-23 (2021)

مصطلحات موضوعية: 0301 basic medicine, SYMPTOMS, Autism Spectrum Disorder, Metabolite, Autism, [SDV]Life Sciences [q-bio], CHILDREN, Gut flora, Microbial ecology, DOPAMINE, Cresols, Mice, chemistry.chemical_compound, 0302 clinical medicine, fluids and secretions, 1108 Medical Microbiology, MESH: Fecal Microbiota Transplantation, ANXIETY, p-Cresol, MESH: Animals, SEQUENCE ALIGNMENT, MESH: Autism Spectrum Disorder, 0303 health sciences, SOCIAL REWARD, Microbiota, QR100-130, Cognition, MOUSE MODEL, Fecal Microbiota Transplantation, GASTROINTESTINAL DYSFUNCTION, [SDV] Life Sciences [q-bio], MESH: Cresols, Reward system, Anxiety, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Life Sciences & Biomedicine, Neurotypical, 0605 Microbiology, medicine.drug, Microbiology (medical), medicine.medical_specialty, MESH: Autistic Disorder, MU-OPIOID RECEPTOR, Biology, Microbiology, MESH: Gastrointestinal Microbiome, Excretion, 03 medical and health sciences, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Dopamine, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], parasitic diseases, medicine, Animals, Humans, [CHIM]Chemical Sciences, Autistic Disorder, MESH: Mice, Feces, SPECTRUM DISORDER, 030304 developmental biology, Behavior, Science & Technology, MESH: Humans, 0602 Ecology, Mechanism (biology), Research, medicine.disease, biology.organism_classification, 4-Cresol, Gastrointestinal Microbiome, Transplantation, 030104 developmental biology, Endocrinology, chemistry, Immunology, 030217 neurology & neurosurgery

الوصف: Background Autism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice. Results Mice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol excretion, compared to mice transplanted with the microbiota of control mice. In addition, we identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability, and fecal p-Cresol levels when transplanted to p-Cresol-treated mice. Conclusions The microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition. Our study paves the way for therapeutic interventions targeting the microbiota and p-Cresol production to treat patients with ASD.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6dae1f3fb97915219b8e415a42fc0d81Test
https://hal.archives-ouvertes.fr/hal-03434993/documentTest

المؤلفون: Claire Marsol, Christel Valencia, Thierry Durroux, Marcel Hibert, Dominique Bonnet, Julie Le Merrer, Pascal Villa, Marie-Céline Frantz, Jérôme A.J. Becker, Stéphanie Loison, Elsa Pflimlin, Bernard Mouillac, Lucie P. Pellissier, Jorge Gandía

المساهمون: Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), Laboratoire d'Innovation Thérapeutique (LIT), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Bonnet, Dominique, International Mobility Programme to Strengthen Skills and Excellence in Research for Agriculture - AGREENSKILLS - - EC:FP7:PEOPLE2012-09-01 - 2017-02-28 - 267196 - VALID, Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de recherche du médicament Medalis - Drug Discovery Center [LabEx], Université de Strasbourg (UNISTRA), Plate-forme de chimie biologique intégrative de Strasbourg (PCBiS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS-Mission Interdisciplinaire, programme ITMM), Universite de Strasbourg, LabEx Medalis (Programme Investissement d'Avenir) [ANR-10-LABX-0034], French government [ANR-14-CE16-0005-01], Region Centre (ARD2020 Biomedicament-GPCRAb), LabEx MabImprove (Tours-Montpellier), Marie-Curie/AgreenSkills Program, European Project: 267196,EC:FP7:PEOPLE,FP7-PEOPLE-2010-COFUND,AGREENSKILLS(2012), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)

المصدر: Journal of Medicinal Chemistry
Journal of Medicinal Chemistry, American Chemical Society, 2018, 61 (19), pp.8670-8692. ⟨10.1021/ACS.JMEDCHEM.8B00697⟩
Journal of Medicinal Chemistry, 2018, 61 (19), pp.8670-8692. ⟨10.1021/acs.jmedchem.8b00697⟩
Journal of Medicinal Chemistry, American Chemical Society, 2018, 61 (19), pp.8670-8692. ⟨10.1021/acs.jmedchem.8b00697⟩

مصطلحات موضوعية: Male, 0301 basic medicine, Vasopressin, Pyrrolidines, Receptors, Opioid, mu, mu-opioid-receptor, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Pharmacology, Ligands, in-vivo, Mice, 0302 clinical medicine, [CHIM] Chemical Sciences, Drug Discovery, human vasopressin, Receptor, ComputingMilieux_MISCELLANEOUS, Vasopressin receptor, Mice, Knockout, Chemistry, 3. Good health, Blood-Brain Barrier, Receptors, Oxytocin, randomized controlled-trial, Molecular Medicine, Female, μ-opioid receptor, hormones, hormone substitutes, and hormone antagonists, medicine.drug, Agonist, medicine.drug_class, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, united-states, Structure-Activity Relationship, 03 medical and health sciences, mice lacking, medicine, Animals, Humans, [CHIM]Chemical Sciences, Interpersonal Relations, Autistic Disorder, Psychotropic Drugs, behavior, antagonist, medicine.disease, spectrum disorder, Oxytocin receptor, Disease Models, Animal, HEK293 Cells, 030104 developmental biology, Oxytocin, intranasal oxytocin, Pyrazoles, Autism, 030217 neurology & neurosurgery

الوصف: International audience; Oxytocin (OT) and its receptor (OT-R) are implicated in the etiology of autism spectrum disorders (ASD), and OT-R is a potential target for therapeutic intervention. Very few nonpeptide oxytocin agonists have currently been reported. Their molecular and in vivo pharmacology remain to be clarified, and none of them has been shown to be efficient in improving social interaction in animal models relevant to ASD. In an attempt to rationalize the design of centrally active nonpeptide full agonists, we studied in a systematic way the structural determinants of the affinity and efficacy of representative ligands of the V-1a and V-2 vasopressin receptor subtypes (V-1a-R and V-2-R) and of the oxytocin receptor. Our results confirm the subtlety of the structure affinity and structure efficacy relationships around vasopressin/oxytocin receptor ligands and lead however to the first nonpeptide OT receptor agonist active in a mouse model of ASD after peripheral ip administration.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::726f80c9ac13303b955bab138bf1919cTest
https://doi.org/10.1021/acs.jmedchem.8b00697Test

المؤلفون: Julie Le Merrer, Jérôme A.J. Becker, Camille N. Pujol, Lucie P. Pellissier, Céline Clément

المساهمون: Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), Laboratoire Interuniversitaire en Sciences de l’Education et de la Communication, Médecine Translationelle et Neurogénétique, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), European Project: 267196,EC:FP7:PEOPLE,FP7-PEOPLE-2010-COFUND,AGREENSKILLS(2012), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Interuniversitaire des Sciences de l'Education et de la Communication (LISEC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université de Lorraine (UL), Le Merrer, Julie, Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)

المصدر: Translational Psychiatry, Vol 8, Iss 1, Pp 1-15 (2018)
Translational Psychiatry
Translational Psychiatry, Nature Pub. Group, 2018, 8 (1), pp.1-15. ⟨10.1038/s41398-018-0247-y⟩
Translational Psychiatry, 2018, 8 (1), pp.1-15. ⟨10.1038/s41398-018-0247-y⟩
Translational Psychiatry 1 (8), 1-15. (2018)

مصطلحات موضوعية: Male, 0301 basic medicine, Autism Spectrum Disorder, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Receptors, Opioid, mu, mu-opioid-receptor, Mice, 0302 clinical medicine, pivotal response treatment, Behavior Therapy, circuitry, Reinforcement, Applied behavior analysis, Mice, Knockout, Neuronal Plasticity, Behavior, Animal, nucleus-accumbens shell, Psychiatry and Mental health, Autism spectrum disorder, Schizophrenia, young-children, Female, Psychology, medicine.drug, Mice, 129 Strain, lcsh:RC321-571, Applied Behavior Analysis, 03 medical and health sciences, Cellular and Molecular Neuroscience, Reward, Intervention (counseling), mental disorders, medicine, Animals, mouse models, Social Behavior, gene, differential reinforcement, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, intranasal oxytocin, schizophrenia, medicine.disease, Social relation, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Opioid, Autism, Neuroscience, 030217 neurology & neurosurgery

الوصف: The mu opioid receptor (MOR) plays a critical role in modulating social behavior in humans and animals. Accordingly, MOR null mice display severe alterations in their social repertoire as well as multiple other behavioral deficits, recapitulating core and secondary symptoms of autism spectrum disorder (ASD). Such behavioral profile suggests that MOR dysfunction, and beyond this, altered reward processes may contribute to ASD etiopathology. Interestingly, the only treatments that proved efficacy in relieving core symptoms of ASD, early behavioral intervention programs, rely principally on positive reinforcement to ameliorate behavior. The neurobiological underpinnings of their beneficial effects, however, remain poorly understood. Here we back-translated applied behavior analysis (ABA)-based behavioral interventions to mice lacking the MOR (Oprm1−/−), as a model of autism with blunted reward processing. By associating a positive reinforcement, palatable food reward, to daily encounter with a wild-type congener, we were able to rescue durably social interaction and preference in Oprm1−/− mice. Along with behavioral improvements, the expression of marker genes of neuronal activity and plasticity as well as genes of the oxytocin/vasopressin system were remarkably normalized in the reward/social circuitry. Our study provides further evidence for a critical involvement of reward processes in driving social behavior and opens new perspectives regarding therapeutic intervention in ASD.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::eb54bdaa21dd88de1a2d6b5bcc0648f8Test
http://link.springer.com/article/10.1038/s41398-018-0247-yTest