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      Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication.

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          Abstract

          SHANK3 is a protein in the core of the postsynaptic density (PSD) and has a critical role in recruiting many key functional elements to the PSD and to the synapse, including components of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA), metabotropic glutamate (mGlu) and N-methyl-D-aspartic acid (NMDA) glutamate receptors, as well as cytoskeletal elements. Loss of a functional copy of the SHANK3 gene leads to the neurobehavioral manifestations of 22q13 deletion syndrome and/or to autism spectrum disorders. The goal of this study was to examine the effects of haploinsufficiency of full-length Shank3 in mice, focusing on synaptic development, transmission and plasticity, as well as on social behaviors, as a model for understanding SHANK3 haploinsufficiency in humans.

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          Conserved Role of Intragenic DNA Methylation in Regulating Alternative Promoters

          Alika Maunakea, Raman P. Nagarajan, Mikhail Bilenky … (2010)
          While the methylation of DNA in 5′ promoters suppresses gene expression, the role of DNA methylation in gene bodies is unclear 1–5 . In mammals, tissue- and cell type-specific methylation is present in a small percentage of 5′ CpG island (CGI) promoters, while a far greater proportion occurs across gene bodies, coinciding with highly conserved sequences 5–10 . Tissue-specific intragenic methylation might reduce, 3 or, paradoxically, enhance transcription elongation efficiency 1,2,4,5 . Capped analysis of gene expression (CAGE) experiments also indicate that transcription commonly initiates within and between genes 11–15 . To investigate the role of intragenic methylation, we generated a map of DNA methylation from human brain encompassing 24.7 million of the 28 million CpG sites. From the dense, high-resolution coverage of CpG islands, the majority of methylated CpG islands were revealed to be in intragenic and intergenic regions, while less than 3% of CpG islands in 5′ promoters were methylated. The CpG islands in all three locations overlapped with RNA markers of transcription initiation, and unmethylated CpG islands also overlapped significantly with trimethylation of H3K4, a histone modification enriched at promoters 16 . The general and CpG-island-specific patterns of methylation are conserved in mouse tissues. An in-depth investigation of the human SHANK3 locus 17,18 and its mouse homologue demonstrated that this tissue-specific DNA methylation regulates intragenic promoter activity in vitro and in vivo. These methylation-regulated, alternative transcripts are expressed in a tissue and cell type-specific manner, and are expressed differentially within a single cell type from distinct brain regions. These results support a major role for intragenic methylation in regulating cell context-specific alternative promoters in gene bodies.
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            Behavioural phenotyping assays for mouse models of autism.

            Jill L. Silverman, Mu Yang, Catherine Lord … (2010)
            Autism is a heterogeneous neurodevelopmental disorder of unknown aetiology that affects 1 in 100-150 individuals. Diagnosis is based on three categories of behavioural criteria: abnormal social interactions, communication deficits and repetitive behaviours. Strong evidence for a genetic basis has prompted the development of mouse models with targeted mutations in candidate genes for autism. As the diagnostic criteria for autism are behavioural, phenotyping these mouse models requires behavioural assays with high relevance to each category of the diagnostic symptoms. Behavioural neuroscientists are generating a comprehensive set of assays for social interaction, communication and repetitive behaviours to test hypotheses about the causes of autism. Robust phenotypes in mouse models hold great promise as translational tools for discovering effective treatments for components of autism spectrum disorders.
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              AMPA receptor trafficking and synaptic plasticity.

              Roberto Malinow, Robert Malenka (2002)
              Activity-dependent changes in synaptic function are believed to underlie the formation of memories. Two prominent examples are long-term potentiation (LTP) and long-term depression (LTD), whose mechanisms have been the subject of considerable scrutiny over the past few decades. Here we review the growing literature that supports a critical role for AMPA receptor trafficking in LTP and LTD, focusing on the roles proposed for specific AMPA receptor subunits and their interacting proteins. While much work remains to understand the molecular basis for synaptic plasticity, recent results on AMPA receptor trafficking provide a clear conceptual framework for future studies.
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Mol Autism
                Title: Molecular autism
                Publisher: Springer Science and Business Media LLC
                ISSN (Electronic): 2040-2392
                Publication date (Electronic): Dec 17 2010
                Volume: 1
                Issue: 1
                Affiliations
                [1 ] Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine, New York, NY 10029, USA.
                [2 ] Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.
                [3 ] Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA.
                [4 ] Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
                [5 ] Laboratory of Behavioral Neuroscience, National Institute of Mental Health, Bethesda, MD 20892-3730, USA.
                [6 ] Istituto Superiore di Sanità, Rome, Italy.
                [7 ] Genentech, South San Francisco, CA 94080, USA.
                [8 ] Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
                Article
                Publisher Item ID: 2040-2392-1-15
                DOI: 10.1186/2040-2392-1-15
                PMC ID: 3019144
                PubMed ID: 21167025
                SO-VID: 8dd28974-004c-4a0f-923d-00db55abd739
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