Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function

Hyejung Won, Hye Ryeon Lee, Heon Yung Gee, Won Mah, Jae Ick Kim, Jiseok Lee, Seungmin Ha, Changuk Chung, Eun Suk Jung, Yi Sul Cho, Sae Geun Park, Jung Soo Lee, Kyungmin Lee, Daesoo Kim, Yong Chul Bae, Bong Kiun Kaang, Min Goo Lee, Eunjoon Kim

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Abstract

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 determinants. Shank2 (also known as ProSAP1) is a multi-domain scaffolding protein and signalling adaptor enriched at excitatory neuronal synapses, and mutations in the human SHANK2 gene have recently been associated with ASD and intellectual disablility. Although ASD-associated genes are being increasingly identified and studied using various approaches, including mouse genetics, 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 activation, 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.

Original languageEnglish
Pages (from-to)261-265
Number of pages5
JournalNature
Volume486
Issue number7402
DOIs
Publication statusPublished - 2012 Jun 14

All Science Journal Classification (ASJC) codes

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    Won, H., Lee, H. R., Gee, H. Y., Mah, W., Kim, J. I., Lee, J., Ha, S., Chung, C., Jung, E. S., Cho, Y. S., Park, S. G., Lee, J. S., Lee, K., Kim, D., Bae, Y. C., Kaang, B. K., Lee, M. G., & Kim, E. (2012). Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature, 486(7402), 261-265. https://doi.org/10.1038/nature11208