Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour1. Mutations in synaptic proteins such as neuroligins2,3, neurexins4, GKAPs/SAPAPs5 and ProSAPs/Shanks6,7,8,9,10 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 fashion11,12. 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.
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We thank M. Manz, R. Zienecker, S. Gerlach-Arbeiter, N. Damm, H. Riederer, C. Jean, S. Rieckmann, S. Hochmuth and K. Sowa for technical assistance. M.J.S., A.-L.J. and P.T.U. are members of the International Graduate School in Molecular Medicine at Ulm University. 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), the Bundesministerium für Bildung und Forschung (BMBF) (BCCN, BFNL) and the Einstein Foundation, M.R.K. by the DFG (SFB 779), 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 (SFB 779) and the BMBF (EraNET Neuron), and T.M.B. by the DFG (Bo 1718/3-1 and 1718/4-1; SFB 497/B8).
This file contains Supplementary Figures 1-15, Supplementary Methods, Supplementary References and Supplementary Tables.
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Journal of Cellular Biochemistry (2019)