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

作者：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

来源：Nature, 2012, 486(7402): 261-265.

DOI：10.1038/nature11208

• METABOTROPIC GLUTAMATE RECEPTORS
• POSITIVE ALLOSTERIC MODULATOR
• POSTSYNAPTIC DENSITY
• SYNAPTIC PLASTICITY
• SPECTRUM DISORDER
• SHANK3
• PROTEINS
• COMMUNICATION
• TRAFFICKING
• DYSFUNCTION

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(1). Shank2 (also known as ProSAP1) is a multi-domain scaffolding protein and signalling adaptor enriched at excitatory neuronal synapses(2-4), and mutations in the human SHANK2 gene have recently been associated with ASD and intellectual disability(5). Although ASD-associated genes are being increasingly identified and studied using various approaches, including mouse genetics(6-16), 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 activation(17), 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.

• 出版日期2012-6-14