Details

Autor(en) / Beteiligte

• Han, Kihoon
• Holder Jr, J. Lloyd
• 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.

Titel

SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties

Ist Teil von

• Nature (London), 2013-11, Vol.503 (7474), p.72-77

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2013

Quelle

EBSCO Psychology and Behavioral Sciences Collection

Beschreibungen/Notizen

• 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. Mouse and human studies reveal that incorrect gene dosage of SHANK3 (a gene linked to some human neuropsychiatric disorders, including autism spectrum disorder) is associated with behavioural abnormalities including mania, possibly because of actin regulation problems in excitatory/inhibitory synapses. SHANK3 crucial for mental health Mutations in SHANK3 , the gene encoding the SHANK3 synaptic scaffolding protein, are associated with autism, intellectual disability and schizophrenia, but the effect of SHANK3 overexpression is much less clear. Huda Zoghbi and colleagues now show that mice overexpressing Shank3 exhibit mania-like behaviour, seizures and alterations in excitatory/inhibitory balance of neuronal activity. Consistent with the findings in mouse, they identify two patients with hyperkinetic disorders carrying a genetic duplication of the SHANK3 -containing region on chromosome 22. These findings support the hypothesis that incorrect gene dosage in either direction (both over- and under-expression) may be detrimental. The authors suggest that the mice used in this work provide a model for the pharmacogenetic underpinnings of some forms of bipolar disorder.