Autism spectrum disorder (ASD) is a group of conditions characterized by impaired social interaction and communication, and restricted and repetitive behaviours. ASD is a highly heritable disorder involving various genetic determinants1. Shank2 (also known as ProSAP1) is a multi-domain scaffolding protein and signalling adaptor enriched at excitatory neuronal synapses2,3,4, and mutations in the human SHANK2 gene have recently been associated with ASD and intellectual disablility5. Although ASD-associated genes are being increasingly identified and studied using various approaches, including mouse genetics6,7,8,9,10,11,12,13,14,15,16, further efforts are required to delineate important causal mechanisms with the potential for therapeutic application. Here we show that Shank2-mutant (Shank2−/−) mice carrying a mutation identical to the ASD-associated microdeletion in the human SHANK2 gene exhibit ASD-like behaviours including reduced social interaction, reduced social communication by ultrasonic vocalizations, and repetitive jumping. These mice show a marked decrease in NMDA (N-methyl-d-aspartate) glutamate receptor (NMDAR) function. Direct stimulation of NMDARs with d-cycloserine, a partial agonist of NMDARs, normalizes NMDAR function and improves social interaction in Shank2−/− mice. Furthermore, treatment of Shank2−/− mice with a positive allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), which enhances NMDAR function via mGluR5 activation17, also normalizes NMDAR function and markedly enhances social interaction. These results suggest that reduced NMDAR function may contribute to the development of ASD-like phenotypes in Shank2−/− mice, and mGluR modulation of NMDARs offers a potential strategy to treat ASD.
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We would like to thank Macrogen for assistance in the production of mice. This work was supported by the National Creative Research Initiative Program, WCU program (R31-2008-000-10071-0), and Institute for Basic Science (to E.K.), the National Research Foundation of Korea (to M.G.L.; grant 2012-0000812), the National Creative Research Initiative Program & WCU program (to B.-K.K.; 2007-0054846), the Basic Science Research Program through the National Research Foundation of Korea (to K.L. and Y.C.B.; 2011-0028240), and the National Leading Research Laboratory Program (to D.K.; 2011-0028772). H.-R.L. and J.-I.K. are supported by the BK21 fellowship, and H.W. is supported by the TJ Park Doctoral Fellowship and National Junior Research Fellowship.
This movie shows a pup retrieval assay with a wild-type mouse.
This movie shows a pup retrieval assay with a Shank2−/− mouse.
This movie shows an example of repetitive jumping mixed with upright scrabbling in a Shank2−/− mouse.
This movie shows an example of repetitive grooming in a Shank2−/− mouse.
This movie shows an example of repetitive digging in a Shank2−/− mouse.