SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties

摘要

发生的突变与自闭症、智残和精神分裂症有关，但过度表达的效应却不大清楚。 现在，Huda Zoghbi及同事发现，过度表达 Stenk3的小鼠会表现出类似狂躁的行为以及癫痫发作和神经活动的激发/抑制平衡发生改变等。与在小鼠身上的这些发现相一致的是，他们识别出了在22号染色体上携带含SHAHK3区域的一个基因复本的两个多动症患者。这些发现支持以下假设：任何一个方向上（过度表 达和表达不足）的不正确基因剂量都可能是有害的。作者提出，这项研究中所用的小鼠为了解某些形式的躁郁症的药物遗传机理提供了一 个模型。%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.