Nature (London), 2013-11, Vol.503 (7474), p.72-77
2013
Details
- Autor(en) / Beteiligte
- Titel
- SHANK3 overexpression causes manic―like behaviour with unique pharmacogenetic properties
- Ist Teil von
- Nature (London), 2013-11, Vol.503 (7474), p.72-77
- Ort / Verlag
- London: Nature Publishing Group
- Erscheinungsjahr
- 2013
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0028-0836eISSN: 1476-4687DOI: 10.1038/nature12630Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3923348
- Format
- –
- Schlagworte
- Actin-Related Protein 2-3 Complex - metabolism, Actins - metabolism, Adult, Animals, Attention-deficit hyperactivity disorder, Autism, Behavior, Animal, Biological and medical sciences, Bipolar disorder, Bipolar Disorder - drug therapy, Bipolar Disorder - genetics, Bipolar Disorder - physiopathology, Chromosomes, Human, Pair 22 - genetics, Disease Models, Animal, Excitatory Postsynaptic Potentials, Female, Fundamental and applied biological sciences. Psychology, Gene Dosage - genetics, Gene expression, Gene Expression - genetics, Gene mutations, Genes, Genes, Duplicate - genetics, Genetic aspects, Health aspects, Humans, Hyperactivity, Hyperkinesis - genetics, Hyperkinesis - physiopathology, Inhibitory Postsynaptic Potentials, Lithium - pharmacology, Male, Medical sciences, Mice, Mice, Transgenic, Microfilament Proteins, Nerve Tissue Proteins - genetics, Nerve Tissue Proteins - metabolism, Neuropharmacology, Neuropsychiatry, Pharmacogenetics, Pharmacology. Drug treatments, Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer, Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease), Psychological aspects, Psychology. Psychoanalysis. Psychiatry, Psychopharmacology, Rodents, Seizures - genetics, Transgenic animals, Valproic Acid - pharmacology, Valproic Acid - therapeutic use, Vertebrates: nervous system and sense organs