Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition

Qin, Luye; Ma, Kaijie; Wang, Zijun; Hu, Zihua; Matas, Emmanuel; Wei, Jing; Yan, Zhen

doi:10.1038/s41593-018-0110-8

Cited by 187 publications

(228 citation statements)

References 46 publications

(77 reference statements)

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“…For example, Duffney et al, (2015) recently demonstrated that reduced social preference in Shank3 +/ΔC mice is associated with diminished NMDA receptor function and distribution in prefrontal regions. In the same mouse model, social deficits were ameliorated by treatment with a histone deacetylase (HDAC) inhibitor, highlighting a contribution of epigenetic mechanisms to the expression of social deficits in Shank3-deficiency (Qin et al, 2018). Our results are in keeping with these observations, and suggest that the prefrontal dysfunction that characterizes SHANK3-deficient mice affects complex socio-communicative behavior via a large-scale involvement of distributed fronto-striatal and fronto-cortical substrates.…”

Section: Discussionsupporting

confidence: 82%

Deletion of autism risk gene Shank3 disrupts prefrontal connectivity

Pagani

Bertero

Liska

et al. 2018

Preprint

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Mutations in the synaptic scaffolding protein Shank3 are a major cause of autism, and are associated with prominent intellectual and language deficits. However, the neural mechanisms whereby SHANK3 deficiency affects higher order socio-communicative functions remain unclear. Using highresolution functional and structural MRI in mice, here we show that loss of Shank3 (Shank3B −/− ) results in disrupted local and long-range prefrontal functional connectivity, as well as fronto-striatal decoupling. We document that prefrontal hypo-connectivity is associated with reduced short-range cortical projections density, and reduced gray matter volume. Finally, we show that prefrontal disconnectivity is predictive of social communication deficits, as assessed with ultrasound vocalization recordings. Collectively, our results reveal a critical role of SHANK3 in the development of prefrontal anatomy and function, and suggest that SHANK3 deficiency may predispose to intellectual disability and socio-communicative impairments via dysregulation of higher-order cortical connectivity.

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Section: Discussionsupporting

confidence: 82%

Deletion of autism risk gene Shank3 disrupts prefrontal connectivity

Pagani

Bertero

Liska

et al. 2018

Preprint

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“…Histone deacetylase activity, GPCR signaling, proteasome function, MYC targets, and cell cycle processes are representative examples. Some of the enumerated biological functions have previously been related to both ASD and cancer(59–64). These abnormalities could help explain putative inverse comorbid associations between ASD and cancer.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic metaanalyses of autistic brains reveals shared gene expression and biological pathway abnormalities with cancer

Martos

Catalá-López

Valle

et al. 2018

Preprint

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Epidemiological and clinical evidence points to cancer as a comorbidity in people with autism spectrum disorders (ASD). A significant overlap of genes and biological processes between both diseases has also been reported. Here, for the first time, we compared the gene expression profiles of ASD frontal cortex tissues and 22 cancer types obtained by differential expression meta-analysis. Four cancer types (brain, thyroid, kidney, and pancreatic cancers) presented a significant overlap in gene expression deregulations in the same direction as ASD whereas two cancer types (lung and prostate cancers) showed differential expression profiles significantly deregulated in the opposite direction from ASD. Functional enrichment and LINCS L1000 based drug set enrichment analyses revealed the implication of several biological processes and pathways that were affected jointly in both diseases, including impairments of the immune system, and impairments in oxidative phosphorylation and ATP synthesis among others. Our data also suggest that brain and kidney cancer have patterns of transcriptomic dysregulation in the PI3K/AKT/MTOR axis that are similar to those found in ASD. These shared transcriptomic alterations could help explain epidemiological observations suggesting direct and inverse comorbid associations between ASD and particular cancer types.

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“…Effect on the morphology of dendritic spine and synaptic transmission Expression of SHANK3 was strongly regulated by methylated CpG island. [195,196] Histone modification…”

Section: Shank3mentioning

confidence: 99%

Genetic and Epigenetic Etiology Underlying Autism Spectrum Disorder

Yoon

Choi

Lee

et al. 2020

JCM

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Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder characterized by difficulties in social interaction, language development delays, repeated body movements, and markedly deteriorated activities and interests. Environmental factors, such as viral infection, parental age, and zinc deficiency, can be plausible contributors to ASD susceptibility. As ASD is highly heritable, genetic risk factors involved in neurodevelopment, neural communication, and social interaction provide important clues in explaining the etiology of ASD. Accumulated evidence also shows an important role of epigenetic factors, such as DNA methylation, histone modification, and noncoding RNA, in ASD etiology. In this review, we compiled the research published to date and described the genetic and epigenetic epidemiology together with environmental risk factors underlying the etiology of the different phenotypes of ASD.

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Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition

Cited by 187 publications

References 46 publications

Deletion of autism risk gene Shank3 disrupts prefrontal connectivity

Deletion of autism risk gene Shank3 disrupts prefrontal connectivity

Transcriptomic metaanalyses of autistic brains reveals shared gene expression and biological pathway abnormalities with cancer

Genetic and Epigenetic Etiology Underlying Autism Spectrum Disorder

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