SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties

Kihoon Han, J. Lloyd Holder, Christian P. Schaaf, Hui Lu, Hongmei Chen, Hyojin Kang, Jianrong Tang, Zhenyu Wu, Shuang Hao, Sau Wai Cheung, Peng Yu, Hao Sun, Amy M. Breman, Ankita Patel, Hui Chen Lu, Huda Y. Zoghbi

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281 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)72-77
Number of pages6
Issue number7474
Publication statusPublished - 2013
Externally publishedYes

Bibliographical note

Funding Information:
Acknowledgements We are indebted to the patients and families who participated in this study; to J. W. Belmont and N. Miller for contributing patients to this study; G. Feng for sharing Shank3B mice; G. Schuster for injection of Shank3 BAC; and C. Spencer for behavioural assays training. This project was supported by The Howard Hughes Medical Institute (H.Y.Z.), National Institutes of Health (NIH) ARRA grant (1R01NS070302) (H.Y.Z.), the Baylor Intellectual and Developmental Disabilities Research Center (P30HD024064) confocal, electrophysiology and mouse neurobehavioral cores, and the Cancer Prevention and Research Institute of Texas (CPRIT) RP110784. J.L.H. was supported by an Early Career Award from the Thrasher Research Fund, NIH 2T32NS043124 and the Ting Tsung and Wei Fong Chao Foundation; C.P.S. was supported by the Joan and Stanford Alexander family, the Ting Tsung and Wei Fong Chao Foundation and the Doris Duke Clinical Scientist Development Award.

ASJC Scopus subject areas

  • General


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