SHANK3 overexpression causes manic-like behavior with unique pharmacogenetic properties

Mutations in SHANK3 and large duplications of the region spanning SHANK3 both cause a spectrum of neuropsychiatric disorders, suggesting that proper SHANK3 dosage is critical for normal brain function. SHANK3 overexpression per se has not been established as a cause of human disorders, however, because 22q13 duplications involve several genes. Here we report that Shank3 transgenic mice modeling a human SHANK3 duplication exhibit manic-like behavior 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 suggest 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 behavior of Shank3 transgenic mice raising the possibility that this hyperkinetic disorder has a unique pharmacogenetic profile.