Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function.
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 disability. 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.
Department of Biological Sciences, KAIST, Daejeon 305-701, Korea.
Hyejung
H
Won
Hye-Ryeon
HR
Lee
Heon Yung
HY
Gee
Won
W
Mah
Jae-Ick
JI
Kim
Jiseok
J
Lee
Seungmin
S
Ha
Changuk
C
Chung
Eun Suk
ES
Jung
Yi Sul
YS
Cho
Sae-Geun
SG
Park
Jung-Soo
JS
Lee
Kyungmin
K
Lee
Daesoo
D
Kim
Yong Chul
YC
Bae
Bong-Kiun
BK
Kaang
Min Goo
MG
Lee
Eunjoon
E
Kim
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001549:Benzamides / Q000494:pharmacology*; D003523:Cycloserine / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011720:Pyrazoles / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000378:metabolism*
C494553:3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide; D048868:Adaptor Proteins, Signal Transducing; D000963:Antimetabolites; D001549:Benzamides; D009419:Nerve Tissue Proteins; D011720:Pyrazoles; D016194:Receptors, N-Methyl-D-Aspartate; C488222:Shank2 protein, mouse; D003523:Cycloserine