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      Shank3 mutant mice display autistic-like behaviours and striatal dysfunction

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          Abstract

          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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          Most cited references 47

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          Advances in autism genetics: on the threshold of a new neurobiology.

          Autism is a heterogeneous syndrome defined by impairments in three core domains: social interaction, language and range of interests. Recent work has led to the identification of several autism susceptibility genes and an increased appreciation of the contribution of de novo and inherited copy number variation. Promising strategies are also being applied to identify common genetic risk variants. Systems biology approaches, including array-based expression profiling, are poised to provide additional insights into this group of disorders, in which heterogeneity, both genetic and phenotypic, is emerging as a dominant theme.
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            Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism.

            Many studies have supported a genetic etiology for autism. Here we report mutations in two X-linked genes encoding neuroligins NLGN3 and NLGN4 in siblings with autism-spectrum disorders. These mutations affect cell-adhesion molecules localized at the synapse and suggest that a defect of synaptogenesis may predispose to autism.
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              Pten regulates neuronal arborization and social interaction in mice.

              CNS deletion of Pten in the mouse has revealed its roles in controlling cell size and number, thus providing compelling etiology for macrocephaly and Lhermitte-Duclos disease. PTEN mutations in individuals with autism spectrum disorders (ASD) have also been reported, although a causal link between PTEN and ASD remains unclear. In the present study, we deleted Pten in limited differentiated neuronal populations in the cerebral cortex and hippocampus of mice. Resulting mutant mice showed abnormal social interaction and exaggerated responses to sensory stimuli. We observed macrocephaly and neuronal hypertrophy, including hypertrophic and ectopic dendrites and axonal tracts with increased synapses. This abnormal morphology was associated with activation of the Akt/mTor/S6k pathway and inactivation of Gsk3beta. Thus, our data suggest that abnormal activation of the PI3K/AKT pathway in specific neuronal populations can underlie macrocephaly and behavioral abnormalities reminiscent of certain features of human ASD.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                3 March 2011
                20 March 2011
                28 April 2011
                28 October 2011
                : 472
                : 7344
                : 437-442
                Affiliations
                [1 ] Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA
                [2 ] PhD Programme in Biomedicine and Experimental Biology (BEB), Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
                [3 ] Gulbenkian PhD Programme in Biomedicine, Gulbenkian Science Institute, 2781-901 Oeiras, Portugal
                [4 ] Department of Radiology, and Brain Imaging and Analysis Center, Duke University Medical Center, Durham, NC 27710, USA
                [5 ] Department of Psychiatry and Behavioral Science, Duke University Medical Center, Durham, NC 27710, USA
                [6 ] Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02142, USA
                [7 ] McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
                Author notes
                []Corresponding author: Guoping Feng ( fengg@ 123456mit.edu )
                [*]

                These authors contributed equally to this work

                Article
                nihpa275551
                10.1038/nature09965
                3090611
                21423165

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                Funding
                Funded by: National Institute of Mental Health : NIMH
                Award ID: R01 MH081201-05 ||MH
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