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- Title
SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties.
- Authors
Han, Kihoon; Holder, J Lloyd, Jr; Schaaf, Christian P; Lu, Hui; Chen, Hongmei; Kang, Hyojin; Tang, Jianrong; Wu, Zhenyu; Hao, Shuang; Cheung, Sau Wai; Yu, Peng; Sun, Hao; Breman, Amy M; Patel, Ankita; Lu, Hui-Chen; Zoghbi, Huda Y
- 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.
- Publication
Nature, 2013, Vol 503, Issue 7474, p72
- ISSN
1476-4687
- Publication type
Journal Article
- DOI
10.1038/nature12630