SHANK3 Mutations Research Articles

A 29 Mainland Chinese cohort of patients with Phelan\u2013McDermid syndrome: genotype\u2013phenotype correlations and the role of SHANK3 haploinsufficiency in the important phenotypes

BackgroundPhelan–McDermid syndrome (PMS) or 22q13 deletion syndrome is a rare developmental disorder characterized by hypotonia, developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD) and dysmorphic features. Most cases are caused by 22q13 deletions encompassing many genes including SHANK3. Phenotype comparisons between patients with SHANK3 mutations (or deletions only disrupt SHANK3) and 22q13 deletions encompassing more than SHANK3 gene are lacking.MethodsA total of 29 Mainland China patients were clinically and genetically evaluated. Data were obtained from medical record review and a standardized medical history questionnaire, and dysmorphology evaluation was conducted via photographic evaluation. We analyzed 22q13 deletions and SHANK3 small mutations and performed genotype–phenotype analysis to determine whether neurological features and other important clinical features are responsible for haploinsufficiency of SHANK3.ResultsNineteen patients with 22q13.3 deletions ranging in size from 34 kb to 8.7 Mb, one patient with terminal deletions and duplications, and nine patients with SHANK3 mutations were included. All mutations would cause loss-of function effect and six novel heterozygous variants, c.3838_3839insGG, c.3088delC, c.3526G > T, c.3372dupC, c.3120delC and c.3942delC, were firstly reported. Besides, we demonstrated speech delay (100%), DD/ID (88%), ASD (80%), hypotonia (83%) and hyperactivity (83%) were prominent clinical features. Finally, 100% of cases with monogenic SHANK3 deletion had hypotonia and there was no significant difference between loss of SHANK3 alone and deletions encompassing more than SHANK3 gene in the prevalence of hypotonia, DD/ID, ASD, increased pain tolerance, gait abnormalities, impulsiveness, repetitive behaviors, regression and nonstop crying which were high in loss of SHANK3 alone group.ConclusionsThis is the first work describing a cohort of Mainland China patients broaden the clinical and molecular spectrum of PMS. Our findings support the effect of 22q13 deletions and SHANK3 point mutations on language impairment and several clinical manifestations, such as DD/ID. We also demonstrated SHANK3 haploinsufficiency was a major contributor to the neurological phenotypes of PMS and also responsible for other important phenotypes such as hypotonia, increased pain tolerance, impulsiveness, repetitive behaviors, regression and nonstop crying.

Altered synaptic ultrastructure in the prefrontal cortex of Shank3-deficient rats

BackgroundDeletion or mutations of SHANK3 lead to Phelan–McDermid syndrome and monogenic forms of autism spectrum disorder (ASD). SHANK3 encodes its eponymous scaffolding protein at excitatory glutamatergic synapses. Altered morphology of dendrites and spines in the hippocampus, cerebellum, and striatum have been associated with behavioral impairments in Shank3-deficient animal models. Given the attentional deficit in these animals, our study explored whether deficiency of Shank3 in a rat model alters neuron morphology and synaptic ultrastructure in the medial prefrontal cortex (mPFC).MethodsWe assessed dendrite and spine morphology and spine density in mPFC layer III neurons in Shank3-homozygous knockout (Shank3-KO), heterozygous (Shank3-Het), and wild-type (WT) rats. We used electron microscopy to determine the density of asymmetric synapses in mPFC layer III excitatory neurons in these rats. We measured postsynaptic density (PSD) length, PSD area, and head diameter (HD) of spines at these synapses.ResultsBasal dendritic morphology was similar among the three genotypes. Spine density and morphology were comparable, but more thin and mushroom spines had larger head volumes in Shank3-Het compared to WT and Shank3-KO. All three groups had comparable synapse density and PSD length. Spine HD of total and non-perforated synapses in Shank3-Het rats, but not Shank3-KO rats, was significantly larger than in WT rats. The total and non-perforated PSD area was significantly larger in Shank3-Het rats compared to Shank3-KO rats. These findings represent preliminary evidence for synaptic ultrastructural alterations in the mPFC of rats that lack one copy of Shank3 and mimic the heterozygous loss of SHANK3 in Phelan–McDermid syndrome.LimitationsThe Shank3 deletion in the rat model we used does not affect all isoforms of the protein and would only model the effect of mutations resulting in loss of the N-terminus of the protein. Given the higher prevalence of ASD in males, the ultrastructural study focused only on synaptic structure in male Shank3-deficient rats.ConclusionsWe observed increased HD and PSD area in Shank3-Het rats. These observations suggest the occurrence of altered synaptic ultrastructure in this animal model, further pointing to a key role of defective expression of the Shank3 protein in ASD and Phelan–McDermid syndrome.

Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mouse model of autism Shank3B

BackgroundPartial or an entire deletion of SHANK3 are considered as major drivers in the Phelan–McDermid syndrome, in which 75% of patients are diagnosed with autism spectrum disorder (ASD). During the recent years, there was an increasing interest in stem cell therapy in ASD, and specifically, mesenchymal stem cells (MSC). Moreover, it has been suggested that the therapeutic effect of the MSC is mediated mainly via the secretion of small extracellular vesicle that contains important molecular information of the cell and are used for cell-to-cell communication. Within the fraction of the extracellular vesicles, exosomes were highlighted as the most effective ones to convey the therapeutic effect.MethodsExosomes derived from MSC (MSC-exo) were purified, characterized, and given via intranasal administration to Shank3B KO mice (in the concentration of 107 particles/ml). Three weeks post treatment, the mice were tested for behavioral scoring, and their results were compared with saline-treated control and their wild-type littermates.ResultsIntranasal treatment with MSC-exo improves the social behavior deficit in multiple paradigms, increases vocalization, and reduces repetitive behaviors. We also observed an increase of GABARB1 in the prefrontal cortex.ConclusionsHerein, we hypothesized that MSC-exo would have a direct beneficial effect on the behavioral autistic-like phenotype of the genetically modified Shank3B KO mouse model of autism. Taken together, our data indicate that intranasal treatment with MSC-exo improves the core ASD-like deficits of this mouse model of autism and therefore has the potential to treat ASD patients carrying the Shank3 mutation.

A chimeric mouse model to study human iPSC-derived neurons: the case of a truncating SHANK3 mutation

Using human induced pluripotent stem cells (iPSC), recent studies have shown that the events underlying autism spectrum disorders (ASD) can occur during neonatal development. We previously analyzed the iPSC-derived pyramidal cortical neurons of a subset of patients with ASD carrying de novo heterozygous mutations in postsynaptic SHANK3 protein, in culture. We reported altered spinogenesis of those neurons. The transplantation of human iPSC-derived neuronal precursors into mouse brain represents a novel option for in vivo analysis of mutations affecting the human brain. In this study, we transplanted the neuronal precursor cells (NPC) into the cortex of newborn mice to analyze their integration and maturation at early stages of development and studied axonal projections of transplanted human neurons into adult mouse brain. We then co-transplanted NPC from a control individual and from a patient carrying a de novo heterozygous SHANK3 mutation. We observed a reduction in cell soma size of selective neuronal categories and in axonal projections at 30 days post-transplantation. In contrast to previous in vitro studies, we did not observe any alteration in spinogenesis at this early age. The humanized chimeric mouse models offer the means to analyze ASD-associated mutations further and provide the opportunity to visualize phenotypes in vivo.

In Silico Elucidation of Deleterious Non-synonymous SNPs in SHANK3, the Autism Spectrum Disorder Gene.

SHANK3, a member of SH3 and multiple ankyrin repeat domains (SHANK) proteins, plays a crucial role in synaptic development and functions. Mutations in SHANK3 have been linked to a number of neuropsychiatric and neurodevelopmental disorders, including autism spectrum disorder. In this study, the functional and structural impacts of non-synonymous single-nucleotide polymorphisms (SNPs) on SHANK3 were predicted. Various databases were used to extract 16,894 non-redundant SNPs, out of which 1179 were annotated as missense variants. Missense variants were categorized as deleterious or non-deleterious. Twenty-nine missense variants were unanimously recognized as deleterious and subjected to structural and stability analyses. Mutations, including L47P, G54W, G172D, G250C/D, and G627E, which posed drastic effects on the secondary structure of SHANK3, were modeled. Stability analyses introduced L47P, G54W, and G250D as the most destabilizing mutations, thus they were subjected to molecular dynamics simulation. Simulation revealed significant changes in intramolecular interactions and high fluctuations in residues of 1-350 that significantly affect the ANK functional domain. G250C/D and G635R consensus deleterious mutations were found in the first and second binding domains of SHANK3, and none were found in the post-translational modification sites. This study suggests L47P, G54W, and G250C/D deleterious mutations as priorities for future studies on SHANK3.

Autism-associated SHANK3 mutations impair maturation of neuromuscular junctions and striated muscles

Autism-associated SHANK3 mutations impair maturation of neuromuscular junctions and striated muscles

Autism-associated SHANK3 mutations impair maturation of neuromuscular junctions and striated muscles.

Heterozygous mutations of the gene encoding the postsynaptic protein SHANK3 are associated with syndromic forms of autism spectrum disorders (ASDs). One of the earliest clinical symptoms in SHANK3-associated ASD is neonatal skeletal muscle hypotonia. This symptom can be critical for the early diagnosis of affected children; however, the mechanism mediating hypotonia in ASD is not completely understood. Here, we used a combination of patient-derived human induced pluripotent stem cells (hiPSCs), Shank3Δ11(-/-) mice, and Phelan-McDermid syndrome (PMDS) muscle biopsies from patients of different ages to analyze the role of SHANK3 on motor unit development. Our results suggest that the hypotonia in SHANK3 deficiency might be caused by dysfunctions in all elements of the voluntary motor system: motoneurons, neuromuscular junctions (NMJs), and striated muscles. We found that SHANK3 localizes in Z-discs in the skeletal muscle sarcomere and co-immunoprecipitates with α-ACTININ. SHANK3 deficiency lead to shortened Z-discs and severe impairment of acetylcholine receptor clustering in hiPSC-derived myotubes and in muscle from Shank3Δ11(-/-) mice and patients with PMDS, indicating a crucial role for SHANK3 in the maturation of NMJs and striated muscle. Functional motor defects in Shank3Δ11(-/-) mice could be rescued with the troponin activator Tirasemtiv that sensitizes muscle fibers to calcium. Our observations give insight into the function of SHANK3 besides the central nervous system and imply potential treatment strategies for SHANK3-associated ASD.

Truncating mutations in SHANK3 associated with global developmental delay interfere with nuclear β-catenin signaling.

Mutations in SHANK3, coding for a large scaffold protein of excitatory synapses in the CNS, are associated with neurodevelopmental disorders including autism spectrum disorders and intellectual disability (ID). Several cases have been identified in which the mutation leads to truncation of the protein, eliminating C-terminal sequences required for post-synaptic targeting of the protein. We identify here a patient with a truncating mutation in SHANK3, affected by severe global developmental delay and intellectual disability. By analyzing the subcellular distribution of this truncated form of Shank3, we identified a nuclear localization signal (NLS) in the N-terminal part of the protein which is responsible for targeting Shank3 fragments to the nucleus. To determine the relevance of Shank3 for nuclear signaling, we analyze how it affects signaling by β-catenin, a component of the Wnt pathway. We show that full length as well as truncated variants of Shank3 interact with β-catenin via the PDZ domain of Shank3, and the armadillo repeats of β-catenin. As a result of this interaction, truncated forms of Shank3 and β-catenin strictly co-localize in small intra-nuclear bodies both in 293T cells and in rat hippocampal neurons. On a functional level, the sequestration of both proteins in these nuclear bodies is associated with a strongly repressed transcriptional activation by β-catenin owing to interaction with the truncated Shank3 fragment found in patients. Our data suggest that truncating mutations in SHANK3 may not only lead to a reduction in Shank3 protein available at postsynaptic sites but also negatively affect the Wnt signaling pathway.

Autism-Associated Shank3 Is Essential for Homeostatic Compensation in Rodent V1

Mutations in Shank3 are strongly associated with autism spectrum disorders and neural circuit changes in several brain areas, but the cellular mechanisms that underlie these defects are not understood. Homeostatic forms of plasticity allow central circuits to maintain stable function during experience-dependent development, leading us to ask whether loss of Shank3 might impair homeostatic plasticity and circuit-level compensation to perturbations. We found that Shank3 loss invitro abolished synaptic scaling and intrinsic homeostatic plasticity, deficits that could be rescued by treatment with lithium. Further, Shank3 knockout severely compromised the invivo ability of visual cortical circuits to recover from perturbations to sensory drive. Finally, lithium treatment ameliorated a repetitive self-grooming phenotype in Shank3 knockout mice. These findings demonstrate that Shank3 loss severely impairs the ability of central circuits to harness homeostatic mechanisms to compensate for perturbations in drive, which, in turn, may render them more vulnerable to such perturbations.

Inhibitory regulation of calcium transients in prefrontal dendritic spines is compromised by a nonsense Shank3 mutation

The SHANK3 gene encodes a postsynaptic scaffold protein in excitatory synapses, and its disruption is implicated in neurodevelopmental disorders such as Phelan-McDermid syndrome, autism spectrum disorder, and schizophrenia. Most studies of SHANK3 in the neocortex and hippocampus have focused on disturbances in pyramidal neurons. However, GABAergic interneurons likewise receive excitatory inputs and presumably would also be a target of constitutive SHANK3 perturbations. In this study, we characterize the prefrontal cortical microcircuit in awake mice using subcellular-resolution two-photon microscopy. We focused on a nonsense R1117X mutation, which leads to truncated SHANK3 and has been linked previously to cortical dysfunction. We find that R1117X mutants have abnormally elevated calcium transients in apical dendritic spines. The synaptic calcium dysregulation is due to a loss of dendritic inhibition via decreased NMDAR currents and reduced firing of dendrite-targeting somatostatin-expressing (SST) GABAergic interneurons. Notably, upregulation of the NMDAR subunit GluN2B in SST interneurons corrects the excessive synaptic calcium signals and ameliorates learning deficits in R1117X mutants. These findings reveal dendrite-targeting interneurons, and more broadly the inhibitory control of dendritic spines, as a key microcircuit mechanism compromised by the SHANK3 dysfunction.

Deficiency of SHANK3 isoforms impairs thermal hyperalgesia and dysregulates the expression of postsynaptic proteins in the spinal cord

SHANK3 is one of the scaffolding proteins in the postsynaptic density (PSD). Pain perception and underlying mechanisms were investigated in Shank3 exon 21 deficient (Shank3△C) mice. Sixty-six mice were attributed according to their genotype to three groups: (1) wild-type (WT), (2) heterozygous Shank3△C/+, and (3) homozygous Shank3△C/△C. Complete Freund’s adjuvant (CFA) was used to induce inflammatory pain, and thermal hyperalgesia was determined. CFA treatment reduced the thermal threshold in the WT group; groups expressing mutations of Shank3 (△C/+ and △C/△C) had higher thresholds after CFA administration compared to the WT group. Mice with Shank3 mutations (△C/+ or △C/△C) had a lower expression of GluN2A and IP3R proteins and a higher expression of mGluR5 protein in the PSD compared to WT mice without changes in GluN1, GluN2B, and Homer expression. The crosslinking of Homer-IP3R, but not Homer-mGluR5, was decreased in the total lysate. Deficit of Shank3 exon 21 may lead to impaired perception of thermal pain in mice under inflammatory conditions. This impairment may result from protein dysregulation in the PSD like downregulation of the GluN2A subunit, which may reduce NMDAR-mediated currents, and/or decreased crosslinking between Homer and IP3R, which may reduce the release of Ca2+ from intracellular stores.

Severe white matter damage in SHANK3 deficiency: a human and translational study

ObjectiveHeterozygous SHANK3 mutations or partial deletions of the long arm of chromosome 22, also known as Phelan–McDermid syndrome, result in a syndromic form of the autism spectrum as well as in global developmental delay, intellectual disability, and several neuropsychiatric comorbidities. The exact pathophysiological mechanisms underlying the disease are still far from being deciphered but studies of SHANK3 models have contributed to the understanding of how the loss of the synaptic protein SHANK3 affects neuronal function.Methods and resultsDiffusion tensor imaging‐based and automatic volumetric brain mapping were performed in 12 SHANK3‐deficient participants (mean age 19 ± 15 years) versus 14 age‐ and gender‐matched controls (mean age 29 ± 5 years). Using whole brain–based spatial statistics, we observed a highly significant pattern of white matter alterations in participants with SHANK3 mutations with focus on the long association fiber tracts, particularly the uncinate tract and the inferior fronto‐occipital fasciculus. In contrast, only subtle gray matter volumetric abnormalities were detectable. In a back‐translational approach, we observed similar white matter alterations in heterozygous isoform–specific Shank3 knockout (KO) mice. Here, in the baseline data sets, the comparison of Shank3 heterozygous KO vs wildtype showed significant fractional anisotropy reduction of the long fiber tract systems in the KO model. The multiparametric Magnetic Resonance Imaging (MRI) analysis by DTI and volumetry demonstrated a pathology pattern with severe white matter alterations and only subtle gray matter changes in the animal model.InterpretationIn summary, these translational data provide strong evidence that the SHANK3‐deficiency–associated pathomechanism presents predominantly with a white matter disease. Further studies should concentrate on the role of SHANK3 during early axonal pathfinding/wiring and in myelin formation.

Abnormal Striatal Development Underlies the Early Onset of Behavioral Deficits in Shank3B−/− Mice

SUMMARYThe neural substrates and pathophysiological mechanisms underlying the onset of cognitive and motor deficits in autism spectrum disorders (ASDs) remain unclear. Mutations in ASD-associated SHANK3 in mice (Shank3B−/−) result in the accelerated maturation of corticostriatal circuits during the second and third postnatal weeks. Here, we show that during this period, there is extensive remodeling of the striatal synaptic proteome and a developmental switch in glutamatergic synaptic plasticity induced by cortical hyperactivity in striatal spiny projection neurons (SPNs). Behavioral abnormalities in Shank3B−/− mice emerge during this stage and are ameliorated by normalizing excitatory synapse connectivity in medial striatal regions by the downregulation of PKA activity. These results suggest that the abnormal postnatal development of striatal circuits is implicated in the onset of behavioral deficits in Shank3B−/− mice and that modulation of postsynaptic PKA activity can be used to regulate corticostriatal drive in developing SPNs of mouse models of ASDs and other neurodevelopmental disorders.

Shank3 Exons 14-16 Deletion in Glutamatergic Neurons Leads to Social and Repetitive Behavioral Deficits Associated With Increased Cortical Layer 2/3 Neuronal Excitability.

Shank3, an abundant excitatory postsynaptic scaffolding protein, has been associated with multiple brain disorders, including autism spectrum disorders (ASD) and Phelan-McDermid syndrome (PMS). However, how cell type-specific Shank3 deletion affects disease-related neuronal and brain functions remains largely unclear. Here, we investigated the impacts of Shank3 deletion in glutamatergic neurons on synaptic and behavioral phenotypes in mice and compared results with those previously obtained from mice with global Shank3 mutation and GABAergic neuron-specific Shank3 mutation. Neuronal excitability was abnormally increased in layer 2/3 pyramidal neurons in the medial prefrontal cortex (mPFC) in mice with a glutamatergic Shank3 deletion, similar to results obtained in mice with a global Shank3 deletion. In addition, excitatory synaptic transmission was abnormally increased in layer 2/3 neurons in mice with a global, but not a glutamatergic, Shank3 deletion, suggesting that Shank3 in glutamatergic neurons are important for the increased neuronal excitability, but not for the increased excitatory synaptic transmission. Neither excitatory nor inhibitory synaptic transmission was altered in the dorsal striatum of Shank3-deficient glutamatergic neurons, a finding that contrasts with the decreased excitatory synaptic transmission in global and Shank3-deficient GABAergic neurons. Behaviorally, glutamatergic Shank3-deficient mice displayed abnormally increased direct social interaction and repetitive self-grooming, similar to global and GABAergic Shank3-deficient mice. These results suggest that glutamatergic and GABAergic Shank3 deletions lead to distinct synaptic and neuronal changes in cortical layer 2/3 and dorsal striatal neurons, but cause similar social and repetitive behavioral abnormalities likely through distinct mechanisms.

Unexpected Compensatory Increase in Shank3 Transcripts in Shank3 Knock-Out Mice Having Partial Deletions of Exons.

Genetic variants of the SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene, which encodes excitatory postsynaptic core scaffolds cause numerous brain disorders. Several lines of Shank3 knock-out (KO) mice with deletions of different Shank3 exons have previously been generated and characterized. The different Shank3 KO mouse lines have both common and line-specific phenotypes. Shank3 isoform diversity is considered a mechanism underlying phenotypic heterogeneity, and compensatory changes through regulation of Shank3 expression may contribute to this heterogeneity. However, whether such compensatory changes occur in Shank3 KO mouse lines has not been investigated in detail. Using previously reported RNA-sequencing analyses, we identified an unexpected increase in Shank3 transcripts in two different Shank3 mutant mouse lines (Shank3B and Shank3ΔC) having partial deletions of Shank3 exons. We validated an increase in Shank3 transcripts in the hippocampus, cortex, and striatum, but not in the cerebellum, of Shank3B heterozygous (HET) and KO mice, using qRT-PCR analyses. In particular, expression of the N-terminal exons 1–12, but not the more C-terminal exons 19–22, was observed to increase in Shank3B mice with deletion of exons 13–16. This suggests a selective compensatory activation of upstream Shank3 promoters. Furthermore, using domain-specific Shank3 antibodies, we confirmed that the increased Shank3 transcripts in Shank3B KO mice produced a small Shank3 isoform that was not detected in wild-type mice. Taken together, our results illustrate another layer of complexity in the regulation of Shank3 expression in the brain, which may also contribute to the phenotypic heterogeneity of different Shank3 KO mouse lines.

Spatial memory deficits caused by reduced inhibitory synaptic function in Shank2 mutant mice

Spatial memory deficits caused by reduced inhibitory synaptic function in Shank2 mutant mice

Characterization of synaptic and behavioral phenotypes in mice carrying a de novo Shank3 mutation Q321R

Characterization of synaptic and behavioral phenotypes in mice carrying a de novo Shank3 mutation Q321R

Apparent Genetic Rescue of Adult Shank3 Exon 21 Insertion Mutation Mice Tempered by Appropriate Control Experiments.

SHANK3 (ProSAP2) is among the most common genes mutated in autism spectrum disorders (ASD) and is the causative gene in Phelan–McDermid syndrome (PMS). We performed genetic rescue of Shank3 mutant phenotypes in adult mice expressing a Shank3 exon 21 insertion mutation (Shank3G). We used a tamoxifen-inducible Cre/loxP system (CreTam) to revert Shank3G to wild-type (WT) Shank3+/+. We found that tamoxifen treatment in adult Shank3GCreTam+ mice resulted in complete rescue of SHANK3 protein expression in the brain and appeared to rescue synaptic transmission and some behavioral differences compared to Shank3+/+CreTam+ controls. However, follow-up comparisons between vehicle-treated, WT Cre-negative mice (Shank3+/+CreTam− and Shank3+/+CreTam+) demonstrated clear effects of CreTam on baseline synaptic transmission and some behaviors, making apparently positive genetic reversal effects difficult to interpret. Thus, while the CreTam tamoxifen-inducible system is a powerful tool that successfully rescues Shank3 expression in our Shank3G/G reversible mutants, one must exercise caution and use appropriate control comparisons to ensure sound interpretation.

Targeting Peripheral Somatosensory Neurons to Improve Tactile-Related Phenotypes in ASD Models.

Somatosensory over-reactivity is common among patients with autism spectrum disorders (ASDs) and is hypothesized to contribute to core ASD behaviors. However, effective treatments for sensory over-reactivityand ASDs are lacking. We found distinct somatosensoryneuron pathophysiological mechanisms underlie tactile abnormalities in different ASD mouse models and contribute to some ASD-related behaviors. Developmental loss of ASD-associated genes Shank3 or Mecp2 in peripheral mechanosensory neurons leads to region-specific brain abnormalities, revealing links between developmental somatosensory over-reactivity and the genesis of aberrant behaviors. Moreover, acute treatment with a peripherally restricted GABAA receptor agonist that acts directly on mechanosensory neurons reduced tactile over-reactivity in six distinct ASD models. Chronic treatment of Mecp2 and Shank3 mutant mice improved body condition, some brain abnormalities, anxiety-like behaviors, and some social impairments but not memory impairments, motor deficits, or overgrooming. Our findings reveal a potential therapeutic strategy targeting peripheral mechanosensory neurons to treat tactile over-reactivity and select ASD-related behaviors.

Anterior cingulate cortex dysfunction underlies social deficits in Shank3 mutant mice

Social deficit is a core clinical feature of autism spectrum disorder (ASD) but the underlying neural mechanisms remain largely unclear. We demonstrate that structural and functional impairments occur in glutamatergic synapses in the pyramidal neurons of the anterior cingulate cortex (ACC) in mice with a mutation in Shank3, a high-confidence candidate ASD gene. Conditional knockout of Shank3 in the ACC was sufficient to generate excitatory synaptic dysfunction and social interaction deficits, whereas selective enhancement of ACC activity, restoration of SHANK3 expression in the ACC, or systemic administration of an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-positive modulator improved social behavior in Shank3 mutant mice. Our findings provide direct evidence for the notion that the ACC has a role in the regulation of social behavior in mice and indicate that ACC dysfunction may be involved in social impairments in ASD.