1. A multiscale analysis in CD38 −/− mice unveils major prefrontal cortex dysfunctions
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José-Manuel Cancela, Oscar Bauer, Jean-Marc Edeline, Gabriel Benet, Antoine De Zelicourt, Catherine Sebrié, Cyrille Vaillend, Muriel Amar, Sabine De La Porte, Antony Galione, Philippe Fossier, Lora L Martucci, Anne Nosjean, Jacques Callebert, Rémi Chaussenot, Sylvie Granon, Jean-Marie Launay, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unite de recherche en résonance magnétique médicale (U2R2M), Université Paris-Sud - Paris 11 (UP11)-Hôpital Bicêtre-Centre National de la Recherche Scientifique (CNRS), Department of Pharmacology, University of Oxford, Edeline, Jean-Marc, University of Oxford [Oxford], Laboratoire de neurobiologie cellulaire et moléculaire (NBCM), Centre National de la Recherche Scientifique (CNRS), Hôpital Lariboisière, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Canalopathies épithéliales: la mucoviscidose et autres maladies, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Substances Naturelles (ICSN), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)
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0301 basic medicine ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,[SDV]Life Sciences [q-bio] ,autism ,Biology ,Biochemistry ,03 medical and health sciences ,monoamines ,0302 clinical medicine ,Cortex (anatomy) ,oxytocin ,Genetics ,medicine ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Prefrontal cortex ,Molecular Biology ,behavior ,excitation ,Cognition ,medicine.disease ,3. Good health ,[SDV] Life Sciences [q-bio] ,030104 developmental biology ,Monoamine neurotransmitter ,medicine.anatomical_structure ,Oxytocin ,Autism spectrum disorder ,Synaptic plasticity ,Autism ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Neuroscience ,030217 neurology & neurosurgery ,Biotechnology ,medicine.drug - Abstract
International audience; Autism spectrum disorder (ASD) is characterized by early onset of behavioral and cognitive alterations. Low plasma levels of oxytocin (OT) have also been found in ASD patients; recently, a critical role for the enzyme CD38 in the regulation of OT release was demonstrated. CD38 is important in regulating several Ca 2+-dependent pathways, but beyond its role in regulating OT secretion, it is not known whether a deficit in CD38 expression leads to functional modifications of the prefrontal cortex (PFC), a structure involved in social behavior. Here, we report that CD38 2/2 male mice show an abnormal cortex development, an excitation-inhibition balance shifted toward a higher excitation, and impaired synaptic plasticity in the PFC such as those observed in various mouse models of ASD. We also show that a lack of CD38 alters social behavior and emotional responses. Finally, examining neu-romodulators known to control behavioral flexibility, we found elevated monoamine levels in the PFC of CD38 2/2 adult mice. Overall, our study unveiled major changes in PFC physiologic mechanisms and provides new evidence that the CD38 2/2 mouse could be a relevant model to study pathophysiological brain mechanisms of mental disorders such as ASD.-Martucci, L. A multiscale analysis in CD38-/-mice unveils major prefrontal cortex dysfunctions. FASEB J. 33, 000-000 (2019). www.fasebj.org KEY WORDS: behavior • oxytocin • autism • monoamines • excitation Autism spectrum disorder (ASD) covers a group of neu-rodevelopmental disorders characterized by behavior-al and cognitive disturbances with early-onset deficits in language acquisition and social interaction. ASD is highly inherited but the genetic determinants are poorly understood. The genetic basis of ASD has been associated with copy-number variations or single-nucleotide poly-morphism (SNP) in genes involved in brain development, synapse formation, or cell signaling (1). ASD is frequently associated with excessive cortical growth (2), and a current hypothesis is that the behavioral defects observed in ASD are due to impairments in synaptic functioning and plasticity (1, 3-5). For example, some mutations affect gluta-matergic synaptic transmission such as for the SH3 and multiple ankyrin repeat domain (SHANK) proteins (4-6) or the neuroligins (3, 7). One important consequence of these mutations is that the mechanisms of synaptic plasticity are altered and affect ionotropic NMDA receptors or metabotropic glutamate receptors regulating learning processes and cognitive functions (8, 9). Recently, the hypothesis of an increase in the excitation-inhibition (E-I) ratio in neuronal circuits emerged as a common patho-physiological principle that could explain the genesis of cognitive and social behavior deficits in ASD (10).
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- 2019
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