Shank3 -deficient rats exhibit degraded cortical responses to sound

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Abstract

Individuals with SHANK3 mutations have severely impaired receptive and expressive language abilities. While brain responses are known to be abnormal in these individuals, the auditory cortex response to sound has remained largely understudied. In this study, we document the auditory cortex response to speech and non-speech sounds in the novel Shank3-deficient rat model. We predicted that the auditory cortex response to sounds would be impaired in Shank3-deficient rats. We found that auditory cortex responses were weaker in Shank3 heterozygous rats compared to wild-type rats. Additionally, Shank3 heterozygous responses had less spontaneous auditory cortex firing and were unable to respond well to rapid trains of noise bursts. The rat model of the auditory impairments in SHANK3 mutation could be used to test potential rehabilitation or drug therapies to improve the communication impairments observed in individuals with Phelan-McDermid syndrome. <div class="section"> <a class="named-anchor" id="S1">  </a> <h5 class="section-title" id="d933232e264">Lay Summary</h5> Individuals with SHANK3 mutations have severely impaired language abilities, yet the auditory cortex response to sound has remained largely understudied. In this study, we found that auditory cortex responses were weaker and were unable to respond well to rapid sounds in Shank3-deficient rats compared to control rats. The rat model of the auditory impairments in SHANK3 mutation could be used to test potential rehabilitation or drug therapies to improve the communication impairments observed in individuals with Phelan-McDermid syndrome. </div>

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Modeling autism by SHANK gene mutations in mice.

Yong-Hui Jiang, Michael Ehlers (2013)

Shank family proteins (Shank1, Shank2, and Shank3) are synaptic scaffolding proteins that organize an extensive protein complex at the postsynaptic density (PSD) of excitatory glutamatergic synapses. Recent human genetic studies indicate that SHANK family genes (SHANK1, SHANK2, and SHANK3) are causative genes for idiopathic autism spectrum disorders (ASD). Neurobiological studies of Shank mutations in mice support a general hypothesis of synaptic dysfunction in the pathophysiology of ASD. However, the molecular diversity of SHANK family gene products, as well as the heterogeneity in human and mouse phenotypes, pose challenges to modeling human SHANK mutations. Here, we review the molecular genetics of SHANK mutations in human ASD and discuss recent findings where such mutations have been modeled in mice. Conserved features of synaptic dysfunction and corresponding behaviors in Shank mouse mutants may help dissect the pathophysiology of ASD, but also highlight divergent phenotypes that arise from different mutations in the same gene. Copyright © 2013 Elsevier Inc. All rights reserved.

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Early behavioral intervention is associated with normalized brain activity in young children with autism.

Geraldine Dawson, Emily Jones, Kristen Merkle … (2012)

A previously published randomized clinical trial indicated that a developmental behavioral intervention, the Early Start Denver Model (ESDM), resulted in gains in IQ, language, and adaptive behavior of children with autism spectrum disorder. This report describes a secondary outcome measurement from this trial, EEG activity. Forty-eight 18- to 30-month-old children with autism spectrum disorder were randomized to receive the ESDM or referral to community intervention for 2 years. After the intervention (age 48 to 77 months), EEG activity (event-related potentials and spectral power) was measured during the presentation of faces versus objects. Age-matched typical children were also assessed. The ESDM group exhibited greater improvements in autism symptoms, IQ, language, and adaptive and social behaviors than the community intervention group. The ESDM group and typical children showed a shorter Nc latency and increased cortical activation (decreased α power and increased θ power) when viewing faces, whereas the community intervention group showed the opposite pattern (shorter latency event-related potential [ERP] and greater cortical activation when viewing objects). Greater cortical activation while viewing faces was associated with improved social behavior. This was the first trial to demonstrate that early behavioral intervention is associated with normalized patterns of brain activity, which is associated with improvements in social behavior, in young children with autism spectrum disorder. Copyright © 2012 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

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Adult Restoration of Shank3 Expression Rescues Selective Autistic-Like Phenotypes

Yuan Mei-Rong, Patricia Monteiro, Yang Zhou … (2016)

Because ASD is a neurodevelopmental disorder and patients typically display symptoms before the age of three 1 , one of the key questions in autism research is whether the pathology is reversible in adults. Here we investigated the developmental requirement of Shank3, one of the most prominent monogenic ASD genes that is estimated to contribute to ~1% of all ASD cases 2–6 . SHANK3 is a postsynaptic scaffold protein that regulates synaptic development, function and plasticity by orchestrating the assembly of postsynaptic density (PSD) macromolecular signaling complex 7–9 . Disruptions of the Shank3 gene in mouse models have resulted in synaptic defects and autistic-like behaviors including anxiety, social interaction deficits, and repetitive behavior 10–13 . We generated a novel Shank3 conditional knock-in mouse model and used it to demonstrate that re-expression of the Shank3 gene in adult led to improvements in synaptic protein composition, spine density and neural function in the striatum. We also provided behavioral evidence that certain behavioral abnormalities including social interaction deficit and repetitive grooming behavior could be rescued, while anxiety and motor coordination deficit could not be recovered in adulthood. Together, these results elucidate the profound impact of post-developmental activation of Shank3 expression on neural function and demonstrate certain degree of continued plasticity in the adult diseased brain.

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Author and article information

Journal

Title: Autism Research

Abbreviated Title: Autism Research

Publisher: Wiley

ISSN: 19393792

Publication date Created: January 2018

Publication date (Print): January 2018

Publication date (Electronic): October 20 2017

Volume: 11

Issue: 1

Pages: 59-68

Affiliations

[1 ]School of Behavioral and Brain Sciences; The University of Texas at Dallas, 800 West Campbell Road BSB11; Richardson TX 75080

[2 ]Texas Biomedical Device Center; The University of Texas at Dallas, 800 West Campbell Road BSB11; Richardson TX 75080

[3 ]Seaver Autism Center for Research and Treatment; Icahn School of Medicine at Mount Sinai; New York NY

[4 ]Department of Psychiatry; Icahn School of Medicine at Mount Sinai; New York NY

[5 ]Friedman Brain Institute, Icahn School of Medicine at Mount Sinai; New York NY

[6 ]Fishberg Department of Neuroscience; Icahn School of Medicine at Mount Sinai; New York NY

[7 ]Department of Genetics and Genomic Sciences; Icahn School of Medicine at Mount Sinai; New York NY. The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai; New York NY