![]() There was no significant change in levels of other synaptic proteins in the hippocampus and striatum of TG mice ( Extended Data Fig. 1e, f), which parallels expression in human SHANK3 duplication patients. Compared to wild-type (WT) mice, TG mice expressed 1.2 to 2-fold higher levels of each of the three major Shank3 isoforms (α, β and γ), with ~50% more total Shank3 protein ( Fig. EGFP-Shank3 was targeted to the dendritic spines and co-localized with excitatory postsynaptic marker PSD-95, but not with inhibitory postsynaptic marker Gephyrin ( Fig. The regional and developmental expression of EGFP-Shank3 recapitulated those of endogenous Shank3 ( Extended Data Fig. Similar to endogenous Shank3 16, EGFP-Shank3 transcript was detected in cortex, hippocampus and striatum ( Fig. We introduced an N-terminal EGFP-tag into mouse Shank3 to generate EGFP-Shank3 transgenic (TG) mice ( Fig. We identify a mechanism that contributes to the neuronal phenotype and report pharmacological therapies that might benefit individuals with SHANK3 overexpression. Here, we describe the generation and characterization of Shank3-overexpressing mice and on the role of SHANK3 duplication in hyperkinetic neuropsychiatric disorders in humans. Because duplication cases involve large genomic regions (>0.8 Mb) with more than 20 genes, however, it is unclear if it is SHANK3 overexpression that causes a neurological phenotype. ![]() Interestingly, a few 22q13 duplications spanning SHANK3 have been reported in patients diagnosed with Asperger syndrome, attention deficit-hyperactivity disorder (ADHD) or schizophrenia 9, 10, 18, suggesting that increased expression of SHANK3 could be also deleterious. Furthermore, mice modeling SHANK3 deletion mirror the human behavioral phenotypes and display synaptic abnormalities 15– 17. Point mutations in SHANK3 (also called ProSAP2) are seen in non-syndromic autism, ID and schizophrenia 8– 12, and deletions of the region containing SHANK3 cause Phelan-McDermid syndrome (22q13 deletion syndrome) 13, 14. For example, all members of the SHANK gene family ( SHANK1, 2 and 3), which encode for core scaffolding proteins organizing macromolecular complexes at the postsynaptic density (PSD) 5, have been linked to human synaptopathies 6– 8. 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.Īn increasing number of neuropsychiatric disorders such as autism spectrum disorder (ASD), intellectual disability (ID), schizophrenia, obsessive-compulsive disorder and bipolar disorder are being classified as "synaptopathies" 1– 4, because the genes mutated in these disorders lead to abnormal synaptic development or function. 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. These findings suggest SHANK3 overexpression causes a hyperkinetic neuropsychiatric disorder. We also identified two patients with hyperkinetic disorders carrying the smallest SHANK3-spanning duplications reported so far. ![]() Here we report that Shank3 transgenic mice modeling a human SHANK3 duplication exhibit manic-like behavior and seizures consistent with synaptic excitatory/inhibitory imbalance. ![]() SHANK3 overexpression per se has not been established as a cause of human disorders, however, because 22q13 duplications involve several genes. 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.
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