SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties

Nature. 2013 Nov 7;503(7474):72-7. doi: 10.1038/nature12630. Epub 2013 Oct 23.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin-Related Protein 2-3 Complex / metabolism
  • Actins / metabolism
  • Adult
  • Animals
  • Behavior, Animal
  • Bipolar Disorder / drug therapy*
  • Bipolar Disorder / genetics
  • Bipolar Disorder / physiopathology*
  • Chromosomes, Human, Pair 22 / genetics
  • Disease Models, Animal
  • Excitatory Postsynaptic Potentials
  • Female
  • Gene Dosage / genetics
  • Gene Expression / genetics
  • Genes, Duplicate / genetics
  • Humans
  • Hyperkinesis / genetics
  • Hyperkinesis / physiopathology
  • Inhibitory Postsynaptic Potentials
  • Lithium / pharmacology
  • Male
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • Seizures / genetics
  • Valproic Acid / pharmacology
  • Valproic Acid / therapeutic use

Substances

  • Actin-Related Protein 2-3 Complex
  • Actins
  • Nerve Tissue Proteins
  • Shank3 protein, mouse
  • Valproic Acid
  • Lithium