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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

Authors

  • Han K
  • Holder JL
  • Schaaf CP
  • Lu H
  • Chen H
  • Kang H
  • Tang J
  • Wu Z
  • Hao S
  • Cheung SW
  • Yu P
  • Sun H
  • Breman AM
  • Patel A
  • Lu HC
  • Zoghbi HY

Journal

Nature

Publication Data

November 7, 2013

Associated Grants

  • Agency: NINDS NIH HHS, Id: 1R01NS070302
  • Agency: NINDS NIH HHS, Id: 2T32NS043124
  • Agency: NICHD NIH HHS, Id: P30HD024064
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

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