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SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties.

Nature | Nov 7, 2013

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

Mesh terms: 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

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Associated grants

  • Agency: NINDS NIH HHS, Id: 1R01NS070302
  • Agency: NINDS NIH HHS, Id: 2T32NS043124
  • Agency: NINDS NIH HHS, Id: R01 NS048884
  • Agency: NICHD NIH HHS, Id: P30 HD024064
  • Agency: Howard Hughes Medical Institute, Id: T32 NS043124
  • Agency: NINDS NIH HHS, Id: P30HD024064
  • Agency: NICHD NIH HHS, Id: R01 NS070302
  • Agency: NINDS NIH HHS, Id:

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