SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties
- Authors
- Han K.; Holder Jr J.L.; Schaaf C.P.; Lu H.; Chen H.; Kang H.; Tang J.; Wu Z.; Hao S.; Cheung S.W.; Yu P.; Sun H.; Breman A.M.; Patel A.; Lu H.-C.; Zoghbi H.Y.
- Issue Date
- Nov-2013
- Citation
- Nature, v.503, no.7474, pp 72 - 77
- Pages
- 6
- Indexed
- SCI
SCIE
SCOPUS
- Journal Title
- Nature
- Volume
- 503
- Number
- 7474
- Start Page
- 72
- End Page
- 77
- URI
- https://scholarworks.korea.ac.kr/kumedicine/handle/2020.sw.kumedicine/11395
- DOI
- 10.1038/nature12630
- ISSN
- 0028-0836
1476-4687
- Abstract
- Mutations in SHANK3 and large duplications of the region spanning SHANK3 both cause a spectrum of neuropsychiatric disorders, indicating that proper SHANK3 dosage is critical for normal brain function. However, SHANK3 overexpression per se has not been established as a cause of human disorders because 22q13 duplications involve several genes. Here we report that Shank3 transgenic mice modelling a human SHANK3 duplication exhibit manic-like behaviour and seizures consistent with synaptic excitatory/inhibitory imbalance. We also identified two patients with hyperkinetic disorders carrying the smallest SHANK3-spanning duplications reported so far. These findings indicate that SHANK3 overexpression causes a hyperkinetic neuropsychiatric disorder. To probe the mechanism underlying the phenotype, we generated a Shank3 in vivo interactome and found that Shank3 directly interacts with the Arp2/3 complex to increase F-actin levels in Shank3 transgenic mice. The mood-stabilizing drug valproate, but not lithium, rescues the manic-like behaviour of Shank3 transgenic mice raising the possibility that this hyperkinetic disorder has a unique pharmacogenetic profile. © 2013 Macmillan Publishers Limited.
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- Appears in
Collections - 1. Basic Science > Department of Neuroscience > 1. Journal Articles
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