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Title: Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2
Authors: Schmeisser, Michael J. ×
Ey, Elodie
Bockmann, Juergen
Stempel, A.Vanessa
Kuebler, Angelika
Janssen, Anna-Lena
Udvardi, Patrick T.
Shiban, Ehab
Spilker, Christina
Balschun, Detlef
Skryabin, BOris V.
Dieck, Susanne tom
Smalla, Karl-Heinz
Leblond, Claire S.
Faure, Philippe
Torquet, Nicolas
Le Sourd, Anne-Marie
Toro, Roberto
Grabrucker, AndreasM.
Shoichet, Sarah A.
Schmitz, Dietmar
Kreutz, Michael R.
Bourgeron, Thomas
Gundelfinger, Eckart D.
Boeckers, Tobias M. #
Issue Date: Jun-2012
Publisher: Nature Publishing Group
Series Title: Nature vol:486 pages:256-260
Article number: 10.1038/nature11015
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/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.
URI: 
ISSN: 0028-0836
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Biological Psychology
× corresponding author
# (joint) last author

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