1. Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2
- Author
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Juergen Bockmann, Thomas Bourgeron, A. Vanessa Stempel, Ehab Shiban, Michael R. Kreutz, Dirk Montag, Karl-Heinz Smalla, Roberto Toro, Tobias M. Boeckers, Andreas M. Grabrucker, Elodie Ey, Angelika Kuebler, Nicolas Torquet, Christina Spilker, Claire S. Leblond, Anne-Marie Le Sourd, Philippe Faure, Boris V. Skryabin, Detlef Balschun, Dietmar Schmitz, Anna-Lena Janssen, Susanne tom Dieck, Stephanie Wegener, Patrick T Udvardi, Sarah A. Shoichet, Eckart D. Gundelfinger, Michael J. Schmeisser, Institut for Anatomy and Cell Biology, Universität Ulm - Ulm University [Ulm, Allemagne], Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Leibniz Institute for Neurobiology, research institution for learning and memory, Laboratory of Biological Psychology, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of Münster, Max Planck Institute for Brain Research, Max-Planck-Gesellschaft, Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), M.J.S. is further supported by Baustein 3.2 (L.SBN.0081), E.E. by the Fondation de France and the Agence Nationale de la Recherche (ANR) FLEXNEURIM (ANR09BLAN034003), S.W. and A.V.S. by the Deutsche Forschungsgemeinschaft (DFG) (GRK 1123), A.M.G. by Baustein 3.2 (L.SBN.0083), S.A.S by the DFG (EXC 257), D.S. by the DFG (SFB 618, SFB 665, EXC 257), theBundesministerium für Bildung und Forschung (BMBF) (BCCN, BFNL) and the Einstein Foundation, M.R.K.by the DFG(SFB779),C.S.L.,R.T.,N.T., A.LS. and T.B.by the ANR (ANR-08-MNPS-037-01 - SynGen), Neuron-ERANET (EUHF-AUTISM), Fondation Orange and the Fondation FondaMentale, P.F.by the Bettencourt-Schueller Fondation, R.T.,T.B.,P.F.by the CNRS Neuroinformatic, E.D.G. by the DFG(SFB779) and the BMBF (EraNET Neuron), and T.M.B. by the DFG (Bo 1718/3-1 and 1718/4-1, SFB 497/B8)., ANR-09-BLAN-0340,FLEXNEURIM,Neurobiologie intégrative des comportements flexibles dans des modèles animaux par imagerie computationnelle : application en conditions normales et pathologiques(2009), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Westfälische Wilhelms-Universität Münster = University of Münster (WWU)
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Male ,Dendritic spine ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,MESH: Synapses ,Synapse ,Mice ,0302 clinical medicine ,MESH: Behavior, Animal ,MESH: Up-Regulation ,MESH: Animals ,MESH: Nerve Tissue Proteins ,Psychomotor Agitation ,0303 health sciences ,Multidisciplinary ,MESH: Receptors, Ionotropic Glutamate ,Behavior, Animal ,Glutamate receptor ,MESH: Psychomotor Agitation ,SHANK2 ,Up-Regulation ,Excitatory postsynaptic potential ,Female ,Dendritic Spines ,MESH: Vocalization, Animal ,MESH: Autistic Disorder ,Nerve Tissue Proteins ,Neurotransmission ,Biology ,Receptors, Ionotropic Glutamate ,MESH: Dendritic Spines ,03 medical and health sciences ,MESH: Mice, Inbred C57BL ,medicine ,Animals ,Autistic Disorder ,MESH: Mice ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,MESH: Adaptor Proteins, Signal Transducing ,medicine.disease ,MESH: Male ,Mice, Inbred C57BL ,Immunology ,Synapses ,Autism ,Vocalization, Animal ,Postsynaptic density ,Neuroscience ,MESH: Female ,030217 neurology & neurosurgery - Abstract
International audience; Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour. Mutations in synaptic proteins such as neuroligins, neurexins, GKAPs/SAPAPs and ProSAPs/Shanks were identified in patients with autism spectrum disorder, but the causative mechanisms remain largely unknown. ProSAPs/Shanks build large homo- and heteromeric protein complexes at excitatory synapses and organize the complex protein machinery of the postsynaptic density in a laminar fashion. Here we demonstrate that genetic deletion of ProSAP1/Shank2 results in an early, brain-region-specific upregulation of ionotropic glutamate receptors at the synapse and increased levels of ProSAP2/Shank3. Moreover, ProSAP1/Shank2(-/-) mutants exhibit fewer dendritic spines and show reduced basal synaptic transmission, a reduced frequency of miniature excitatory postsynaptic currents and enhanced N-methyl-d-aspartate receptor-mediated excitatory currents at the physiological level. Mutants are extremely hyperactive and display profound autistic-like behavioural alterations including repetitive grooming as well as abnormalities in vocal and social behaviours. By comparing the data on ProSAP1/Shank2(-/-) mutants with ProSAP2/Shank3αβ(-/-) mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype.
- Published
- 2012
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