December 2013

Many neuropsychiatric disorders such as autism spectrum disorder, intellectual disability, schizophrenia, obsessive compulsive disorder and bipolar disorder are being classified as synaptopathies. The SHANK gene family (SHANK1, SHANK2 and SHANK3), which encode for core scaffolding proteins organizing macromolecular complexes at the postsynaptic density, have been linked to human synaptopathies. In this study, Shank3 transgenic mice modeling a human SHANK3 duplication on chromosome 22q13 exhibit manic-like behavior and seizures consistent with synaptic dysfunction related to excitatory/inhibitory imbalance. The investigators also found morphological and functional changes in excitatory/inhibitory synapses of transgenic neurons favoring excitation, which might account for both the seizures and hyperkinetic behavior. The investigators also identified patients with duplications in SHANK3 who manifested a phenotypically similar hyperkinetic movement disorder. The remarkable similarity of the neurobehavioral phenotypes between the mouse model and these patients supports the notion that SHANK3 overexpression causes a hyperkinetic neuropsychiatric disorder that approximates mania. When the investigators interrogated a Shank3 in vivo interactome, they 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, rescued the manic-like behavior of Shank3 transgenic mice raising the possibility that this hyperkinetic disorder has a unique pharmacogenetic profile. Indeed, patients with the rapid-cycling form of bipolar disorder are highly resistant to lithium. GSK3 is considered the major target for lithium’s efficacy in the treatment of bipolar disorder, the lithium-resistance of Shank3 transgenic mice and their normal GSK-3b activity are congruent with a mechanism independent of GSK-3 and possibly more dependent upon synaptic alterations, including the excitatory/inhibitory imbalance described here. Synaptic excitatory/inhibitory imbalance is likely to underlie the hyperkinetic phenotype with unique responsiveness to valproate (Nature 2013, 503:72-77).