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      Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism


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          Human neuroimaging studies suggest that aberrant neural connectivity underlies behavioural deficits in autism spectrum disorders (ASDs), but the molecular and neural circuit mechanisms underlying ASDs remain elusive. Here, we describe a complete knockout mouse model of the autism-associated Shank3 gene, with a deletion of exons 4–22 (Δe4–22). Both mGluR5-Homer scaffolds and mGluR5-mediated signalling are selectively altered in striatal neurons. These changes are associated with perturbed function at striatal synapses, abnormal brain morphology, aberrant structural connectivity and ASD-like behaviour. In vivo recording reveals that the cortico-striatal-thalamic circuit is tonically hyperactive in mutants, but becomes hypoactive during social behaviour. Manipulation of mGluR5 activity attenuates excessive grooming and instrumental learning differentially, and rescues impaired striatal synaptic plasticity in Δe4–22 −/− mice. These findings show that deficiency of Shank3 can impair mGluR5-Homer scaffolding, resulting in cortico-striatal circuit abnormalities that underlie deficits in learning and ASD-like behaviours. These data suggest causal links between genetic, molecular, and circuit mechanisms underlying the pathophysiology of ASDs.


          SHANK3 mutations have been linked to autism spectrum disorders, although the underlying mechanisms remain unclear. Here, the authors generate a complete knockout Shank3 mouse model, identifying ASD-like behaviours associated with impaired mGluR5-Homer scaffolding and abnormal brain connectivity.

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          Most cited references55

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          Shank3 mutant mice display autistic-like behaviours and striatal dysfunction

          Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. Shank3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for development of 22q13 deletion syndrome (Phelan-McDermid Syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for Shank3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic like-behaviours in mice.
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            Autism spectrum disorders: developmental disconnection syndromes.

            Autism is a common and heterogeneous childhood neurodevelopmental disorder. Analogous to broad syndromes such as mental retardation, autism has many etiologies and should be considered not as a single disorder but, rather, as 'the autisms'. However, recent genetic findings, coupled with emerging anatomical and functional imaging studies, suggest a potential unifying model in which higher-order association areas of the brain that normally connect to the frontal lobe are partially disconnected during development. This concept of developmental disconnection can accommodate the specific neurobehavioral features that are observed in autism, their emergence during development, and the heterogeneity of autism etiology, behaviors and cognition.
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              Cortical activation and synchronization during sentence comprehension in high-functioning autism: evidence of underconnectivity.

              The brain activation of a group of high-functioning autistic participants was measured using functional MRI during sentence comprehension and the results compared with those of a Verbal IQ-matched control group. The groups differed in the distribution of activation in two of the key language areas. The autism group produced reliably more activation than the control group in Wernicke's (left laterosuperior temporal) area and reliably less activation than the control group in Broca's (left inferior frontal gyrus) area. Furthermore, the functional connectivity, i.e. the degree of synchronization or correlation of the time series of the activation, between the various participating cortical areas was consistently lower for the autistic than the control participants. These findings suggest that the neural basis of disordered language in autism entails a lower degree of information integration and synchronization across the large-scale cortical network for language processing. The article presents a theoretical account of the findings, related to neurobiological foundations of underconnectivity in autism.

                Author and article information

                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group
                10 May 2016
                : 7
                : 11459
                [1 ]Department of Pediatrics, Duke University , Durham, North Carolina 27710, USA
                [2 ]Department of Neurobiology, Duke University , Durham, North Carolina 27710, USA
                [3 ]Department of Psychiatry and Behavioral Sciences, Duke University , Durham, North Carolina 27710, USA
                [4 ]Department of Radiology, Duke University , Durham, North Carolina 27710, USA
                [5 ]Department of Psychology and Neuroscience, Duke University , Durham, North Carolina 27710, USA
                [6 ]Department of Cell Biology, Duke University , Durham, North Carolina 27710, USA
                [7 ]Department of Ophthalmology, Duke University , Durham, North Carolina 27710, USA
                [8 ]Department of Child Health Care, The Children's Hospital of Fudan University , 399 Wanyuan Road, Shanghai 201102, China
                [9 ]Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill , North Carolina 27599, USA
                [10 ]Duke Institute for Brain Sciences, Duke University , Durham, North Carolina 27710, USA
                [11 ]University Program in Genetics and Genomics, Duke University , Durham, North Carolina 27710, USA
                Author notes

                These authors contributed equally to this work

                Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                : 15 October 2015
                : 29 March 2016



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