2015
DOI: 10.1016/j.celrep.2015.04.064
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Autism-like Deficits in Shank3-Deficient Mice Are Rescued by Targeting Actin Regulators

Abstract: Haploinsufficiency of the Shank3 gene, which encodes a scaffolding protein at glutamatergic synapses, is a highly prevalent and penetrant risk factor for autism. Using combined behavioral, electrophysiological, biochemical, imaging and molecular approaches, we find that Shank3-deficient mice exhibit autism-like social deficits and repetitive behaviors, as well as the significantly diminished NMDAR synaptic function and synaptic distribution in prefrontal cortex. Concomitantly, Shank3-deficient mice have a mark… Show more

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Cited by 248 publications
(343 citation statements)
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References 58 publications
(99 reference statements)
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“…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 .…”
Section: Accepted Manuscriptsupporting
confidence: 90%
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“…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 .…”
Section: Accepted Manuscriptsupporting
confidence: 90%
“…In support of this, deficiency or autism-related mutations of Shank3, the most prevalent of the three, result in altered cortactin, Abp1, cofilin and Rac1 expression or activity, increased integrin activation and a reduction in dendritic spines and synaptic dystrophy 168,170,178,188 . Furthermore, rare de novo CNVs, deletions and duplications in genes encoding SHANK interacting proteins such as Disk large-associated protein 2 (DLGAP2) have been associated with ASD 64,[189][190][191][192] .…”
Section: Accepted Manuscriptmentioning
confidence: 92%
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“…The cytoplasmic FMRP-interacting protein (CYFIP) directly links Rac1 and FMRP to modulate cytoskeleton remodeling (45); Tsc1 functionally regulates Rac1 activity (46,60); Ube3a promotes Rho-GEF Pbl degradation via ubiquitination to affect Rac1 activation (47); and upon synaptic activation Rho-GEF Kal-7 disassembles from the Nrx-1/Nlg4/DISC1 complex to modulate the Rac1 pathway (48). Several other autism-risk genes, such as Nlg1, Nrx-4, P-Rex1, and Shank-3, have also been reported to participate in the Rac1-signaling pathway (61)(62)(63)(64). In addition, when the gene-environment interactions of 122 genes and 191 factors in the autistic context were analyzed by systems biology, Rac1 was predicted to be a converging node that genetically links to the neurobiology of autism (27,65)…”
Section: Discussionmentioning
confidence: 99%
“…In addition, functional alterations of the mPFC have been observed in mouse models of ASDs that show impaired social interactions. For instance, reduced inhibitory synaptic transmission and decreased NMDA receptor function have been demonstrated in the mPFC of neuroligin-2-and Shank3-deficient mice, respectively (Duffney et al, 2015;Liang et al, 2015). Moreover, an NMDA receptor antagonist has been shown to normalize suppressed mPFC neural activity in mice lacking the excitatory postsynaptic adapter protein IRSp53 and rescue their associated social deficits (Chung et al, 2015).…”
Section: Introductionmentioning
confidence: 99%