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Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2

Item Type:Article
Title:Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2
Creators Name:Schmeisser, M.J. and Ey, E. and Wegener, S. and Bockmann, J. and Stempel, A.V. and Kuebler, A. and Janssen, A.L. and Udvardi, P.T. and Shiban, E. and Spilker, C. and Balschun, D. and Skryabin, B.V. and Dieck, S.t. and Smalla, K.H. and Montag, D. and Leblond, C.S. and Faure, P. and Torquet, N. and Le Sourd, A.M. and Toro, R. and Grabrucker, A.M. and Shoichet, S.A. and Schmitz, D. and Kreutz, M.R. and Bourgeron, T. and Gundelfinger, E.D. and Boeckers, T.M.
Abstract: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/Shank3{alpha}{beta}(-/-) 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.
Keywords:Animal Behavior, Animal Vocalization, Autistic Disorder, Dendritic Spines, Ionotropic Glutamate Receptors, Nerve Tissue Proteins, Psychomotor Agitation, Signal Transducing Adaptor Proteins, Synapses, Up-Regulation, Animals, Mice
Source:Nature
ISSN:0028-0836
Publisher:Nature Publishing Group (U.K.)
Volume:486
Number:7402
Page Range:256-260
Date:29 April 2012
Official Publication:https://doi.org/10.1038/nature11015
PubMed:View item in PubMed

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