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SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties.
- Source :
-
Nature . 11/7/2013, Vol. 503 Issue 7474, p72-77. 6p. 3 Diagrams, 13 Graphs. - Publication Year :
- 2013
-
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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00280836
- Volume :
- 503
- Issue :
- 7474
- Database :
- Academic Search Index
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 91860663
- Full Text :
- https://doi.org/10.1038/nature12630