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

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Title: Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function.
Authors: Won, Hyejung, Lee, Hye-Ryeon, Gee, Heon Yung, Mah, Won, Kim, Jae-Ick, Lee, Jiseok, Ha, Seungmin, Chung, Changuk, Jung, Eun Suk, Cho, Yi Sul, Park, Sae-Geun, Lee, Jung-Soo, Lee, Kyungmin, Kim, Daesoo, Bae, Yong Chul, Kaang, Bong-Kiun, Lee, Min Goo, Kim, Eunjoon
Source: Nature. 6/14/2012, Vol. 486 Issue 7402, p261-265. 5p. 4 Graphs.
Subjects: Autism -- Social aspects, Interpersonal relations, Methyl aspartate receptors, Autism spectrum disorders, Social interaction, Glutamate receptors, Mice as carriers of disease
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. [ABSTRACT FROM AUTHOR]
Copyright of Nature is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function.
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  Data: <searchLink fieldCode="AR" term="%22Won%2C+Hyejung%22">Won, Hyejung</searchLink><br /><searchLink fieldCode="AR" term="%22Lee%2C+Hye-Ryeon%22">Lee, Hye-Ryeon</searchLink><br /><searchLink fieldCode="AR" term="%22Gee%2C+Heon+Yung%22">Gee, Heon Yung</searchLink><br /><searchLink fieldCode="AR" term="%22Mah%2C+Won%22">Mah, Won</searchLink><br /><searchLink fieldCode="AR" term="%22Kim%2C+Jae-Ick%22">Kim, Jae-Ick</searchLink><br /><searchLink fieldCode="AR" term="%22Lee%2C+Jiseok%22">Lee, Jiseok</searchLink><br /><searchLink fieldCode="AR" term="%22Ha%2C+Seungmin%22">Ha, Seungmin</searchLink><br /><searchLink fieldCode="AR" term="%22Chung%2C+Changuk%22">Chung, Changuk</searchLink><br /><searchLink fieldCode="AR" term="%22Jung%2C+Eun+Suk%22">Jung, Eun Suk</searchLink><br /><searchLink fieldCode="AR" term="%22Cho%2C+Yi+Sul%22">Cho, Yi Sul</searchLink><br /><searchLink fieldCode="AR" term="%22Park%2C+Sae-Geun%22">Park, Sae-Geun</searchLink><br /><searchLink fieldCode="AR" term="%22Lee%2C+Jung-Soo%22">Lee, Jung-Soo</searchLink><br /><searchLink fieldCode="AR" term="%22Lee%2C+Kyungmin%22">Lee, Kyungmin</searchLink><br /><searchLink fieldCode="AR" term="%22Kim%2C+Daesoo%22">Kim, Daesoo</searchLink><br /><searchLink fieldCode="AR" term="%22Bae%2C+Yong+Chul%22">Bae, Yong Chul</searchLink><br /><searchLink fieldCode="AR" term="%22Kaang%2C+Bong-Kiun%22">Kaang, Bong-Kiun</searchLink><br /><searchLink fieldCode="AR" term="%22Lee%2C+Min+Goo%22">Lee, Min Goo</searchLink><br /><searchLink fieldCode="AR" term="%22Kim%2C+Eunjoon%22">Kim, Eunjoon</searchLink>
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  Data: <searchLink fieldCode="JN" term="%22Nature%22">Nature</searchLink>. 6/14/2012, Vol. 486 Issue 7402, p261-265. 5p. 4 Graphs.
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  Data: <searchLink fieldCode="DE" term="%22Autism+--+Social+aspects%22">Autism -- Social aspects</searchLink><br /><searchLink fieldCode="DE" term="%22Interpersonal+relations%22">Interpersonal relations</searchLink><br /><searchLink fieldCode="DE" term="%22Methyl+aspartate+receptors%22">Methyl aspartate receptors</searchLink><br /><searchLink fieldCode="DE" term="%22Autism+spectrum+disorders%22">Autism spectrum disorders</searchLink><br /><searchLink fieldCode="DE" term="%22Social+interaction%22">Social interaction</searchLink><br /><searchLink fieldCode="DE" term="%22Glutamate+receptors%22">Glutamate receptors</searchLink><br /><searchLink fieldCode="DE" term="%22Mice+as+carriers+of+disease%22">Mice as carriers of disease</searchLink>
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  Data: 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. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Nature is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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