SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties.
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.
Pubmed ID: 24153177 RIS Download
Actin-Related Protein 2-3 Complex | Actins | Adult | Animals | Behavior, Animal | Bipolar Disorder | Chromosomes, Human, Pair 22 | Disease Models, Animal | Excitatory Postsynaptic Potentials | Female | Gene Dosage | Gene Expression | Genes, Duplicate | Humans | Hyperkinesis | Inhibitory Postsynaptic Potentials | Lithium | Male | Mice | Mice, Transgenic | Nerve Tissue Proteins | Seizures | Valproic Acid