SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties

Abstract

Mutations in SHANK3 and large duplications of the region spanning SHANK3 both cause a spectrum of neuropsychiatric disorders, suggesting that proper SHANK3 dosage is critical for normal brain function. SHANK3 overexpression per se has not been established as a cause of human disorders, however, because 22q13 duplications involve several genes. Here we report that Shank3 transgenic mice modeling a human SHANK3 duplication exhibit manic-like behavior 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 suggest 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 behavior of Shank3 transgenic mice raising the possibility that this hyperkinetic disorder has a unique pharmacogenetic profile.

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…spanning duplications reported so far 179 . SHANK3 was found to directly interact with Arp2/3 and to increase F-actin levels in the Shank3 transgenic mice, and treating the mice with the moodstabilizing drug valproate, but not lithium, ameliorated the manic-like behavior 179 .…”

“…SHANK3 was found to directly interact with Arp2/3 and to increase F-actin levels in the Shank3 transgenic mice, and treating the mice with the moodstabilizing drug valproate, but not lithium, ameliorated the manic-like behavior 179 . Consistent with previous results showing that NMDA receptor membrane delivery and stability depend on the integrity of actin cytoskeleton 331 , these findings further highlight that the dysregulation of synaptic actin filaments and the loss of synaptic NMDA receptors contribute to the manifestation of autism-like phenotypes, and thus provide strategies for the treatment of autism 178 .…”

“…Shank3 knockout mice suffer from a loss of cortical actin filaments, in association with reduced Rac1/p21-activated kinase (PAK) activity together with increased activity of cofilin 178 . Overexpression of Shank3 has been found to enhance actin polymerization 168 and increase F-actin levels 179 . The SHANK proteins can regulate Rac1 activity through RhoGEF beta-PIX 163 and RhoGAP RICH2 180 .…”

Actinin-4 Governs Dendritic Spine Dynamics and Promotes Their Remodeling by Metabotropic Glutamate Receptors

“…Therefore, in mature spines, actinins are positioned to participate in the group 1 mGluR-dependent modification of the actin cytoskeleton that may underlie spine shrinkage accompanying long-term depression. Recently, actinins have been identified as nodal points in the protein interactome of autism genes (77), including Shank (78,79), and Actn4 mRNA has been found to be a target for regulation by fragile X mental retardation protein (FMRP) (80), encoded by the Fmr1 gene, which is silenced in fragile X syndrome. Whether abnormalities in actinin expression and/or function(s) are involved in spine dysmorphogenesis, which accompanies these pathological conditions, remains to be established.…”

Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review

“…After demonstrating that SHANK3, a postsynaptic density protein that interacts with NMDA receptors, duplication mice display manic-like behaviors [Han et al 2013], we investigated peripheral SHANK3 levels as a potential biomarker of ketamine's antidepressant efficacy in treatment-resistant BDep. Greater baseline SHANK3 levels predicted ketamine's increased antidepressant efficacy at day 1 and day 3 post infusion [Ortiz et al 2014].…”