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Papers of the Week

  • 1) J Neurosci. 2014 Mar 26;34(13):4558-66. doi: 10.1523/JNEUROSCI.1846-13.2014.

    Changes in mGlu5 Receptor-Dependent Synaptic Plasticity and Coupling to Homer Proteins in the Hippocampus of Ube3A Hemizygous Mice Modeling Angelman Syndrome.

    Pignatelli M(1), Piccinin S, Molinaro G, Di Menna L, Riozzi B, Cannella M,
    Motolese M, Vetere G, Catania MV, Battaglia G, Nicoletti F, Nisticò R, Bruno V.
    
    Author information: 
    (1)Department of Physiology and Pharmacology, Sapienza University of Rome, 00185
    Rome, Italy, Pharmacology of Synaptic Plasticity Unit, European Brain Research
    Institute, 00143 Rome, Italy, Istituto di Ricovero e Cura a Carattere Scientifico
    (IRCCS) Neuromed, 86077 Pozzilli, Italy, IRCCS Fondazione Santa Lucia, 00143
    Rome, Italy, Institute of Cell Biology and Neurobiology, National Research
    Council, 00143 Rome, Italy, Institute of Neurological Sciences, National Research
    Council, 95126 Catania, Italy, and IRCCS Oasi Maria SS, 94018 Troina, Italy.
    
    Angelman syndrome (AS) is caused by the loss of Ube3A, an ubiquitin ligase that
    commits specific proteins to proteasomal degradation. How this defect causes
    autism and other pathological phenotypes associated with AS is unknown. Long-term
    depression (LTD) of excitatory synaptic transmission mediated by type 5
    metabotropic glutamate (mGlu5) receptors was enhanced in hippocampal slices of
    Ube3A(m-/p+) mice, which model AS. No changes were found in NMDA-dependent LTD
    induced by low-frequency stimulation. mGlu5 receptor-dependent LTD in AS mice was
    sensitive to the protein synthesis inhibitor anisomycin, and relied on the same
    signaling pathways as in wild-type mice, e.g., the mitogen-activated protein
    kinase (MAPK) pathway, the phosphatidylinositol-3-kinase (PI3K)/mammalian target 
    of rapamycine pathway, and protein tyrosine phosphatase. Neither the stimulation 
    of MAPK and PI3K nor the increase in Arc (activity-regulated
    cytoskeleton-associated protein) levels in response to mGlu5 receptor activation 
    were abnormal in hippocampal slices from AS mice compared with wild-type mice.
    mGlu5 receptor expression and mGlu1/5 receptor-mediated polyphosphoinositide
    hydrolysis were also unchanged in the hippocampus of AS mice. In contrast, AS
    mice showed a reduced expression of the short Homer protein isoform Homer 1a, and
    an increased coupling of mGlu5 receptors to Homer 1b/c proteins in the
    hippocampus. These findings support the link between Homer proteins and monogenic
    autism, and lay the groundwork for the use of mGlu5 receptor antagonists in AS.
    
    PMID: 24672001  [PubMed - in process]
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  • 2) MMWR Surveill Summ. 2014 Mar 28;63 Suppl 2:1-21.

    Prevalence of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2010.

    Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal
    Investigators.
    
    Problem/Condition: Autism spectrum disorder (ASD). Period Covered: 2010.
    Description of System: The Autism and Developmental Disabilities Monitoring
    (ADDM) Network is an active surveillance system in the United States that
    provides estimates of the prevalence of ASD and other characteristics among
    children aged 8 years whose parents or guardians live in 11 ADDM sites in the
    United States. ADDM surveillance is conducted in two phases. The first phase
    consists of screening and abstracting comprehensive evaluations performed by
    professional providers in the community. Multiple data sources for these
    evaluations include general pediatric health clinics and specialized programs for
    children with developmental disabilities. In addition, most ADDM Network sites
    also review and abstract records of children receiving special education services
    in public schools. The second phase involves review of all abstracted evaluations
    by trained clinicians to determine ASD surveillance case status. A child meets
    the surveillance case definition for ASD if a comprehensive evaluation of that
    child completed by a qualified professional describes behaviors consistent with
    the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text
    Revision (DSM-IV-TR) diagnostic criteria for any of the following conditions:
    autistic disorder, pervasive developmental disorder-not otherwise specified
    (including atypical autism), or Asperger disorder. This report provides updated
    prevalence estimates for ASD from the 2010 surveillance year. In addition to
    prevalence estimates, characteristics of the population of children with ASD are 
    described. Results: For 2010, the overall prevalence of ASD among the ADDM sites 
    was 14.7 per 1,000 (one in 68) children aged 8 years. Overall ASD prevalence
    estimates varied among sites from 5.7 to 21.9 per 1,000 children aged 8 years.
    ASD prevalence estimates also varied by sex and racial/ethnic group.
    Approximately one in 42 boys and one in 189 girls living in the ADDM Network
    communities were identified as having ASD. Non-Hispanic white children were
    approximately 30% more likely to be identified with ASD than non-Hispanic black
    children and were almost 50% more likely to be identified with ASD than Hispanic 
    children. Among the seven sites with sufficient data on intellectual ability, 31%
    of children with ASD were classified as having IQ scores in the range of
    intellectual disability (IQ ≤70), 23% in the borderline range (IQ = 71-85), and
    46% in the average or above average range of intellectual ability (IQ >85). The
    proportion of children classified in the range of intellectual disability
    differed by race/ethnicity. Approximately 48% of non-Hispanic black children with
    ASD were classified in the range of intellectual disability compared with 38% of 
    Hispanic children and 25% of non-Hispanic white children. The median age of
    earliest known ASD diagnosis was 53 months and did not differ significantly by
    sex or race/ethnicity. Interpretation: These findings from CDC's ADDM Network,
    which are based on 2010 data reported from 11 sites, provide updated
    population-based estimates of the prevalence of ASD in multiple communities in
    the United States. Because the ADDM Network sites do not provide a representative
    sample of the entire United States, the combined prevalence estimates presented
    in this report cannot be generalized to all children aged 8 years in the United
    States population. Consistent with previous reports from the ADDM Network,
    findings from the 2010 surveillance year were marked by significant variations in
    ASD prevalence by geographic area, sex, race/ethnicity, and level of intellectual
    ability. The extent to which this variation might be attributable to diagnostic
    practices, underrecognition of ASD symptoms in some racial/ethnic groups,
    socioeconomic disparities in access to services, and regional differences in
    clinical or school-based practices that might influence the findings in this
    report is unclear. Public Health Action: ADDM Network investigators will continue
    to monitor the prevalence of ASD in select communities, with a focus on exploring
    changes within these communities that might affect both the observed prevalence
    of ASD and population-based characteristics of children identified with ASD.
    Although ASD is sometimes diagnosed by 2 years of age, the median age of the
    first ASD diagnosis remains older than age 4 years in the ADDM Network
    communities. Recommendations from the ADDM Network include enhancing strategies
    to address the need for 1) standardized, widely adopted measures to document ASD 
    severity and functional limitations associated with ASD diagnosis; 2) improved
    recognition and documentation of symptoms of ASD, particularly among both boys
    and girls, children without intellectual disability, and children in all
    racial/ethnic groups; and 3) decreasing the age when children receive their first
    evaluation for and a diagnosis of ASD and are enrolled in community-based support
    systems.
    
    PMID: 24670961  [PubMed - in process]
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  • 3) N Engl J Med. 2014 Mar 27;370(13):1209-19. doi: 10.1056/NEJMoa1307491.

    Patches of disorganization in the neocortex of children with autism.

    Stoner R(1), Chow ML, Boyle MP, Sunkin SM, Mouton PR, Roy S, Wynshaw-Boris A,
    Colamarino SA, Lein ES, Courchesne E.
    
    Author information: 
    (1)From the University of California, San Diego, Autism Center of Excellence (R.S., 
    M.L.C., M.P.B., E.C.), and the Departments of Neuroscience (R.S., M.L.C., M.P.B.,
    S.R., E.C.) and Pathology (S.R.), University of California, San Diego, School of 
    Medicine, La Jolla; Allen Institute for Brain Science, Seattle (M.P.B., S.M.S.,
    E.S.L.); the Department of Pathology and Cell Biology, University of South
    Florida School of Medicine and Alzheimer's Institute and Research Center, Tampa
    (P.R.M.); the Department of Genetics and Genome Sciences, Case Western Reserve
    University School of Medicine, Cleveland (A.W.-B.); and the Department of
    Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo 
    Alto, CA (S.A.C.).
    
    BACKGROUND: Autism involves early brain overgrowth and dysfunction, which is most
    strongly evident in the prefrontal cortex. As assessed on pathological analysis, 
    an excess of neurons in the prefrontal cortex among children with autism signals 
    a disturbance in prenatal development and may be concomitant with abnormal cell
    type and laminar development.
    METHODS: To systematically examine neocortical architecture during the early
    years after the onset of autism, we used RNA in situ hybridization with a panel
    of layer- and cell-type-specific molecular markers to phenotype cortical
    microstructure. We assayed markers for neurons and glia, along with genes that
    have been implicated in the risk of autism, in prefrontal, temporal, and
    occipital neocortical tissue from postmortem samples obtained from children with 
    autism and unaffected children between the ages of 2 and 15 years.
    RESULTS: We observed focal patches of abnormal laminar cytoarchitecture and
    cortical disorganization of neurons, but not glia, in prefrontal and temporal
    cortical tissue from 10 of 11 children with autism and from 1 of 11 unaffected
    children. We observed heterogeneity between cases with respect to cell types that
    were most abnormal in the patches and the layers that were most affected by the
    pathological features. No cortical layer was uniformly spared, with the clearest 
    signs of abnormal expression in layers 4 and 5. Three-dimensional reconstruction 
    of layer markers confirmed the focal geometry and size of patches.
    CONCLUSIONS: In this small, explorative study, we found focal disruption of
    cortical laminar architecture in the cortexes of a majority of young children
    with autism. Our data support a probable dysregulation of layer formation and
    layer-specific neuronal differentiation at prenatal developmental stages. (Funded
    by the Simons Foundation and others.).
    
    PMID: 24670167  [PubMed - in process]
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  • 4) J Autism Dev Disord. 2014 Mar 26. [Epub ahead of print]

    Downregulation of GABAA Receptor Protein Subunits α6, β2, δ, ε, γ2, θ, and ρ2 in Superior Frontal Cortex of Subjects with Autism.

    Fatemi SH(1), Reutiman TJ, Folsom TD, Rustan OG, Rooney RJ, Thuras PD.
    
    Author information: 
    (1)Division of Neuroscience Research, Department of Psychiatry, University of
    Minnesota Medical School, 420 Delaware St SE, MMC 392, Minneapolis, MN, 55455,
    USA, fatem002@umn.edu.
    
    We measured protein and mRNA levels for nine gamma-aminobutyric acid A (GABAA)
    receptor subunits in three brain regions (cerebellum, superior frontal cortex,
    and parietal cortex) in subjects with autism versus matched controls. We observed
    changes in mRNA for a number of GABAA and GABAB subunits and overall reduced
    protein expression for GABAA receptor alpha 6 (GABRα6), GABAA receptor beta 2
    (GABRβ2), GABAA receptor delta (GABRδ), GABAA receptor epsilon (GABRε), GABAA
    receptor gamma 2 (GABRγ2), GABAA receptor theta (GABRθ), and GABAA receptor rho 2
    (GABRρ2) in superior frontal cortex from subjects with autism. Our data
    demonstrate systematic changes in GABAA&B subunit expression in brains of
    subjects with autism, which may help explain the presence of cognitive
    abnormalities in subjects with autism.
    
    PMID: 24668190  [PubMed - as supplied by publisher]
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  • 5) Transl Psychiatry. 2014 Mar 25;4:e374. doi: 10.1038/tp.2014.16.

    The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines.

    Pathania M, Davenport EC, Muir J, Sheehan DF, López-Doménech G, Kittler JT.
    
    Author information: 
    Department of Neuroscience, Physiology and Pharmacology, University College
    London, London, UK.
    
    Copy number variation (CNV) at the 15q11.2 region has been identified as a
    significant risk locus for neurological and neuropsychiatric conditions such as
    schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the individual
    roles for genes at this locus in nervous system development, function and
    connectivity remain poorly understood. Haploinsufficiency of one gene in this
    region, Cyfip1, may provide a model for 15q11.2 CNV-associated neuropsychiatric
    phenotypes. Here we show that altering CYFIP1 expression levels in neurons both
    in vitro and in vivo influences dendritic complexity, spine morphology, spine
    actin dynamics and synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid 
    (AMPA) receptor lateral diffusion. CYFIP1 is highly enriched at synapses and its 
    overexpression in vitro leads to increased dendritic complexity. Neurons derived 
    from Cyfip1 heterozygous animals on the other hand, possess reduced dendritic
    complexity, increased mobile F-actin and enhanced GluA2-containing AMPA receptor 
    mobility at synapses. Interestingly, Cyfip1 overexpression or haploinsufficiency 
    increased immature spine number, whereas activity-dependent changes in spine
    volume were occluded in Cyfip1 haploinsufficient neurons. In vivo, Cyfip1
    heterozygous animals exhibited deficits in dendritic complexity as well as an
    altered ratio of immature-to-mature spines in hippocampal CA1 neurons. In
    summary, we provide evidence that dysregulation of CYFIP1 expression levels leads
    to pathological changes in CNS maturation and neuronal connectivity, both of
    which may contribute to the development of the neurological symptoms seen in ASD 
    and SCZ.
    
    PMID: 24667445  [PubMed - in process]
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  • 6) PLoS One. 2014 Mar 25;9(3):e90947. doi: 10.1371/journal.pone.0090947. eCollection 2014.

    Assessing the Impact of Copy Number Variants on miRNA Genes in Autism by Monte Carlo Simulation.

    Marrale M(1), Albanese NN(1), Calì F(2), Romano V(3).
    
    Author information: 
    (1)Dipartimento di Fisica e Chimica, Università di Palermo, Palermo, Italy.
    (2)U.O.C. di Genetica Medica Laboratorio di Genetica Molecolare, Associazione Oasi
    Maria SS. (I.R.C.C.S.), Troina, Italy.
    (3)Dipartimento di Fisica e Chimica, Università di Palermo, Palermo, Italy; U.O.C.
    di Genetica Medica Laboratorio di Genetica Molecolare, Associazione Oasi Maria
    SS. (I.R.C.C.S.), Troina, Italy.
    
    Autism Spectrum Disorders (ASDs) are childhood neurodevelopmental disorders with 
    complex genetic origins. Previous studies have investigated the role of de novo
    Copy Number Variants (CNVs) and microRNAs as important but distinct etiological
    factors in ASD. We developed a novel computational procedure to assess the
    potential pathogenic role of microRNA genes overlapping de novo CNVs in ASD
    patients. Here we show that for chromosomes # 1, 2 and 22 the actual number of
    miRNA loci affected by de novo CNVs in patients was found significantly higher
    than that estimated by Monte Carlo simulation of random CNV events. Out of 24
    miRNA genes over-represented in CNVs from these three chromosomes only
    hsa-mir-4436b-1 and hsa-mir-4436b-2 have not been detected in CNVs from
    non-autistic subjects as reported in the Database of Genomic Variants. Altogether
    the results reported in this study represent a first step towards a full
    understanding of how a dysregulated expression of the 24 miRNAs genes affect
    neurodevelopment in autism. We also propose that the procedure used in this study
    can be effectively applied to CNVs/miRNA genes association data in other genomic 
    disorders beyond autism.
    
    PMID: 24667286  [PubMed - in process]
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  • 7) J Autism Dev Disord. 2014 Mar 30. [Epub ahead of print]

    Brief Report: Can Metrics of Reporting Bias Enhance Early Autism Screening Measures?

    Taylor CM(1), Vehorn A, Noble H, Weitlauf AS, Warren ZE.
    
    Author information: 
    (1)Vanderbilt Kennedy Center, Treatment and Research in Autism Spectrum Disorders,
    Vanderbilt University, Nashville, TN, USA, cmtaylor1@geisinger.edu.
    
    The goal of the current study was to develop and pilot the utility of two simple 
    internal response bias metrics, over-reporting and under-reporting, in terms of
    additive clinical value within common screening practices for early detection of 
    autism spectrum disorder risk. Participants were caregivers and children under
    36 months of age (n = 145) participating in first-time diagnostic appointments
    across our clinical research center due to developmental concerns. Caregivers
    were asked to complete the Modified Checklist for Autism in Toddlers (MCHAT) as
    well as a questionnaire embedding six response bias indicator questions. These
    questions were items that in previous clinical studies had been endorsed by an
    overwhelming majority of parents within clinically identified populations.
    Results indicated that removal of self-reports indicative of potential response
    bias dramatically reduced both false positives and false negatives on the MCHAT
    within this sample. This suggests that future work developing internal metrics of
    response bias may be promising in addressing limits of current screening measures
    and practices.
    
    PMID: 24682706  [PubMed - as supplied by publisher]
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  • 8) Am J Hum Genet. 2014 Mar 26. pii: S0002-9297(14)00108-6. doi: 10.1016/j.ajhg.2014.03.006. [Epub ahead of print]

    De Novo Loss-of-Function Mutations in SETD5, Encoding a Methyltransferase in a 3p25 Microdeletion Syndrome Critical Region, Cause Intellectual Disability.

    Grozeva D(1), Carss K(2), Spasic-Boskovic O(1), Parker MJ(3), Archer H(4), Firth 
    HV(5), Park SM(5), Canham N(6), Holder SE(6), Wilson M(7), Hackett A(8), Field
    M(9), Floyd JA(10); UK10K Consortium, Hurles M(2), Raymond FL(11).
    
    Author information: 
    (1)Department of Medical Genetics, Cambridge Institute for Medical Research,
    University of Cambridge, Cambridge CB2 0XY, UK.
    (2)The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton,
    Cambridge CB10 1SA, UK.
    (3)Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Western Bank,
    Sheffield S10 2TH, UK.
    (4)Institute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff 
    CF14 4XW, UK.
    (5)Clinical Genetics, Addenbrooke's Treatment Centre, Cambridge University Hospitals
    NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.
    (6)North West Thames Regional Genetics Service (Kennedy Galton Centre), North West
    London Hospitals NHS Trust, Harrow, Middlesex HA1 3UJ, UK.
    (7)Department of Clinical Genetics, Children's Hospital at Westmead, Westmead, NSW
    2145, Australia.
    (8)Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298,
    Australia.
    (9)Department of Medical Genetics, Royal North Shore Hospital, St. Leonards, NSW
    2298, Australia.
    (10)The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton,
    Cambridge CB10 1SA, UK; The Genome Centre, John Vane Science Centre, Queen Mary
    University of London, Charterhouse Square, London EC1M 6BQ, UK.
    (11)Department of Medical Genetics, Cambridge Institute for Medical Research,
    University of Cambridge, Cambridge CB2 0XY, UK. Electronic address:
    flr24@cam.ac.uk.
    
    To identify further Mendelian causes of intellectual disability (ID), we screened
    a cohort of 996 individuals with ID for variants in 565 known or candidate genes 
    by using a targeted next-generation sequencing approach. Seven loss-of-function
    (LoF) mutations-four nonsense (c.1195A>T [p.Lys399(∗)], c.1333C>T [p.Arg445(∗)], 
    c.1866C>G [p.Tyr622(∗)], and c.3001C>T [p.Arg1001(∗)]) and three frameshift
    (c.2177_2178del [p.Thr726Asnfs(∗)39], c.3771dup [p.Ser1258Glufs(∗)65], and
    c.3856del [p.Ser1286Leufs(∗)84])-were identified in SETD5, a gene predicted to
    encode a methyltransferase. All mutations were compatible with de novo dominant
    inheritance. The affected individuals had moderate to severe ID with additional
    variable features of brachycephaly; a prominent high forehead with synophrys or
    striking full and broad eyebrows; a long, thin, and tubular nose; long, narrow
    upslanting palpebral fissures; and large, fleshy low-set ears. Skeletal
    anomalies, including significant leg-length discrepancy, were a frequent finding 
    in two individuals. Congenital heart defects, inguinal hernia, or hypospadias
    were also reported. Behavioral problems, including obsessive-compulsive disorder,
    hand flapping with ritualized behavior, and autism, were prominent features.
    SETD5 lies within the critical interval for 3p25 microdeletion syndrome. The
    individuals with SETD5 mutations showed phenotypic similarity to those previously
    reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to
    account for many of the clinical features observed in this condition. Our
    findings add to the growing evidence that mutations in genes encoding
    methyltransferases regulating histone modification are important causes of ID.
    This analysis provides sufficient evidence that rare de novo LoF mutations in
    SETD5 are a relatively frequent (0.7%) cause of ID.
    
    Copyright © 2014 The American Society of Human Genetics. Published by Elsevier
    Inc. All rights reserved.
    
    PMID: 24680889  [PubMed - as supplied by publisher]
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  • 9) Mol Autism. 2014 Mar 31;5(1):25. [Epub ahead of print]

    Single nucleotide polymorphism rs6716901 in SLC25A12 gene is associated with Asperger syndrome.

    Durdiaková J, Warrier V, Baron-Cohen S, Chakrabarti B.
    
    BACKGROUND: Autism Spectrum Conditions (ASC) are a group of developmental
    conditions which affect communication, social interactions and behaviour.
    Mitochondrial oxidative dysfunction has been suggested as a mechanism of autism
    based on the results of multiple genetic association and expression studies.
    SLC25A12 is a gene encoding a calcium-binding carrier protein that localizes to
    the mitochondria and is involved in the exchange of aspartate for glutamate in
    the inner membrane of the mitochondria regulating the cytosolic redox state.
    rs2056202 SNP in this gene has previously been associated with ASC. SNPs
    rs6716901 and rs3765166 analysed in this study have not been previously explored 
    in association with AS.
    METHODS: We genotyped three SNPs (rs2056202, rs3765166, and rs6716901) in
    SLC25A12 in n = 117 individuals with Asperger syndrome (AS) and n = 426 controls,
    all of Caucasian ancestry.
    RESULTS: rs6716901 showed significant association with AS (P = 0.008) after
    correcting for multiple testing. We did not replicate the previously identified
    association between rs2056202 and AS in our sample. Similarly, rs3765166 (P =
    0.11) showed no significant association with AS.
    CONCLUSION: The present study, in combination with previous studies, provides
    evidence for SLC25A12 as involved in the etiology of AS. Further cellular and
    molecular studies are required to elucidate the role of this gene in ASC.
    
    PMID: 24679184  [PubMed - as supplied by publisher]
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  • 10) J Neurochem. 2014 Mar 28. doi: 10.1111/jnc.12726. [Epub ahead of print]

    Reversal of reduced parvalbumin neurons in hippocampus and amygdala of Angelman syndrome model mice by chronic treatment of fluoxetine.

    Godavarthi SK(1), Sharma A, Jana NR.
    
    Author information: 
    (1)Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre,
    122 050, Manesar, Gurgaon, India.
    
    Angelman syndrome (AS) is a neuropsychiatric disorder characterised by autism,
    intellectual disability and motor disturbances. The disease is primarily caused
    by the loss of function of maternally inherited UBE3A. Ube3a-maternal deficient
    mice recapitulates many essential feature of AS. These AS mice have been shown to
    be under chronic stress and exhibits anxiety-like behaviour due to defective
    glucocorticoid receptor signalling. Here we demonstrate that chronic stress in
    these mice could lead to down-regulation of parvalbumin-positive interneurons in 
    the hippocampus and basolateral amygdala from early postnatal days.
    Down-regulation of parvalbumin-positive interneurons number could be because of
    decrease in the expression of parvalbumin in these neurons. We also find that
    treatment with fluoxetine, a selective serotonin reuptake inhibitor, results in
    restoration of impaired glucocorticoid signalling, elevated serum corticosterone 
    level, parvalbumin-positive interneurons and anxiety-like behaviours. Our
    findings suggest that impaired glucocorticod signalling in hippocampus and
    amygdala of AS mice is critical for the decrease in parvalbumin interneurons
    number, emergence of anxiety and other behavioural deficits and highlights the
    importance of fluoxetine in the recovery of these abnormalities. This article is 
    protected by copyright. All rights reserved.
    
    This article is protected by copyright. All rights reserved.
    
    PMID: 24678582  [PubMed - as supplied by publisher]
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  • 11) PLoS One. 2014 Mar 25;9(3):e92169. doi: 10.1371/journal.pone.0092169. eCollection 2014.

    GABA and Glutamate Pathways Are Spatially and Developmentally Affected in the Brain of Mecp2-Deficient Mice.

    El-Khoury R(1), Panayotis N(2), Matagne V(1), Ghata A(1), Villard L(1), Roux
    JC(1).
    
    Author information: 
    (1)Aix Marseille Université, GMGF, Marseille, France; Inserm, UMR_S 910, Marseille, 
    France.
    (2)Aix Marseille Université, GMGF, Marseille, France; Inserm, UMR_S 910, Marseille, 
    France; Department of Biological Chemistry, Weizmann Institute of Science,
    Rehovot, Israel.
    
    Proper brain functioning requires a fine-tuning between excitatory and inhibitory
    neurotransmission, a balance maintained through the regulation and release of
    glutamate and GABA. Rett syndrome (RTT) is a rare genetic disorder caused by
    mutations in the methyl-CpG binding protein 2 (MECP2) gene affecting the
    postnatal brain development. Dysfunctions in the GABAergic and glutamatergic
    systems have been implicated in the neuropathology of RTT and a disruption of the
    balance between excitation and inhibition, together with a perturbation of the
    electrophysiological properties of GABA and glutamate neurons, were reported in
    the brain of the Mecp2-deficient mouse. However, to date, the extent and the
    nature of the GABA/glutamate deficit affecting the Mecp2-deficient mouse brain
    are unclear. In order to better characterize these deficits, we simultaneously
    analyzed the GABA and glutamate levels in Mecp2-deficient mice at 2 different
    ages (P35 and P55) and in several brain areas. We used a multilevel approach
    including the quantification of GABA and glutamate levels, as well as the
    quantification of the mRNA and protein expression levels of key genes involved in
    the GABAergic and glutamatergic pathways. Our results show that Mecp2-deficient
    mice displayed regional- and age-dependent variations in the GABA pathway and, to
    a lesser extent, in the glutamate pathway. The implication of the GABA pathway in
    the RTT neuropathology was further confirmed using an in vivo treatment with a
    GABA reuptake inhibitor that significantly improved the lifespan of
    Mecp2-deficient mice. Our results confirm that RTT mouse present a deficit in the
    GABAergic pathway and suggest that GABAergic modulators could be interesting
    therapeutic agents for this severe neurological disorder.
    
    PMID: 24667344  [PubMed - in process]
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  • 12) J Speech Lang Hear Res. 2014 Mar 1. doi: 10.1044/2014_JSLHR-L-13-0064. [Epub ahead of print]

    A Comparison of Pragmatic Language in Boys with Autism and Fragile X Syndrome.

    Klusek J, Martin GE, Losh M.
    
    PURPOSE Impaired pragmatic language (i.e., language use for social interaction)
    is a hallmark feature of both autism spectrum disorder (ASD) and fragile X
    syndrome (FXS), the most common known monogenic disorder associated with ASD.
    However, few cross-population comparisons of ASD and FXS have been conducted, and
    it is unclear whether pragmatic language profiles in these conditions overlap.
    METHOD This study used semi-naturalistic and standardized assessment methods to
    characterize pragmatic language abilities of 29 school-aged boys with idiopathic 
    ASD, 38 with FXS and comorbid ASD, 16 with FXS without ASD, 20 with Down syndrome
    and 20 with typical development. RESULTS Similar severity of pragmatic language
    deficits was observed in both of the groups with ASD (idiopathic and fragile
    X-associated). ASD comorbidity had a detrimental effect on the pragmatic language
    skills of boys with FXS. Some different patterns emerged across the two pragmatic
    assessment tools, with more robust group differences observed in pragmatics
    assessed in a semi-naturalistic conversational context. CONCLUSIONS These
    findings have implications for pragmatic language assessment and intervention, as
    well as for understanding the potential role of the fragile X gene, Fragile X
    Mental Retardation-1, in the pragmatic language phenotype of ASD.
    
    PMID: 24686468  [PubMed - as supplied by publisher]
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  • 13) Exp Neurol. 2014 Mar 28. pii: S0014-4886(14)00091-0. doi: 10.1016/j.expneurol.2014.03.014. [Epub ahead of print]

    Early-life seizures result in deficits in social behavior and learning.

    Lugo JN(1), Swann JW(2), Anderson AE(3).
    
    Author information: 
    (1)Department of Psychology and Neuroscience, Baylor University; Waco, TX 76798;
    Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute 
    at Texas Children's Hospital; Department of Pediatrics, Baylor College of
    Medicine; Houston, TX 77030. Electronic address: joaquin_lugo@baylor.edu.
    (2)Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute 
    at Texas Children's Hospital; Department of Pediatrics, Baylor College of
    Medicine; Houston, TX 77030; Department of Neurology, Baylor College of Medicine;
    Houston, TX 77030.
    (3)Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute 
    at Texas Children's Hospital; Department of Pediatrics, Baylor College of
    Medicine; Houston, TX 77030; Department of Neurology, Baylor College of Medicine;
    Houston, TX 77030; Department of Neuroscience, Baylor College of Medicine;
    Houston, TX 77030.
    
    Children with epilepsy show a high co-morbidity with psychiatric disorders and
    autism. One of the critical determinants of a child's behavioral outcome with
    autism and cognitive dysfunction is the age of onset of seizures. In order to
    examine whether seizures during postnatal days 7-11 result in learning and memory
    deficits and behavioral features of autism we administered the inhalant flurothyl
    to induce seizures in C57BL/6 mice. Mice received three seizures per day for five
    days starting on postnatal day 7. Parallel control groups consisted of similarly 
    handled animals that were not exposed to flurothyl and naïve mice. Subjects were 
    then processed through a battery of behavioral tests in adulthood: elevated-plus 
    maze, nose-poke assay, marble burying, social partition, social chamber, fear
    conditioning, and Morris water maze. Mice with early-life seizures had learning
    and memory deficits in the training portion of the Morris water maze (p<0.05) and
    probe trial (p<0.01). Mice with seizures showed no differences in marble burying,
    the nose-poke assay, or elevated plus-maze testing compared to controls. However,
    they showed a significant difference in the social chamber and social partition
    tests. Mice with seizures during postnatal days 7-11 showed a significant
    decrease in social interaction in the social chamber test and had a significant
    impairment in social behavior in the social partition test. Together, these
    results indicate that early life seizures result in deficits in
    hippocampal-dependent memory tasks and produce long-term disruptions in social
    behavior.
    
    Copyright © 2014. Published by Elsevier Inc.
    
    PMID: 24685665  [PubMed - as supplied by publisher]
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  • 14) J Autism Dev Disord. 2014 Apr 3. [Epub ahead of print]

    Binding of Multiple Features in Memory by High-Functioning Adults with Autism Spectrum Disorder.

    Bowler DM(1), Gaigg SB, Gardiner JM.
    
    Author information: 
    (1)Autism Research Group, Department of Psychology, City University London,
    Northampton Square, London, EC1V 0HB, UK, d.m.bowler@city.ac.uk.
    
    Diminished episodic memory and diminished use of semantic information to aid
    recall by individuals with autism spectrum disorder (ASD) are both thought to
    result from diminished relational binding of elements of complex stimuli. To test
    this hypothesis, we asked high-functioning adults with ASD and typical comparison
    participants to study grids in which some cells contained drawings of objects in 
    non-canonical colours. Participants were told at study which features (colour,
    item, location) would be tested in a later memory test. In a second experiment,
    participants studied similar grids and were told that they would be tested on
    object-location or object-colour combinations. Recognition of combinations was
    significantly diminished in ASD, which survived covarying performance on the
    Color Trails Test (D'Elia et al. Color trails test. Professional manual.
    Psychological Assessment Resources, Lutz, 1996), a test of executive
    difficulties. The findings raise the possibility that medial temporal as well as 
    frontal lobe processes are dysfunctional in ASD.
    
    PMID: 24696375  [PubMed - as supplied by publisher]
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  • 15) Neurosci Biobehav Rev. 2014 Mar 30. pii: S0149-7634(14)00068-2. doi: 10.1016/j.neubiorev.2014.03.013. [Epub ahead of print]

    Visual social attention in Autism Spectrum Disorder: insights from eye tracking studies.

    Guillon Q(1), Hadjikhani N(2), Baduel S(3), Rogé B(4).
    
    Author information: 
    (1)URI Octogone-CERPP, University of Toulouse, 5 allée Antonio Machado, 31058
    Toulouse Cedex9, France. Electronic address: quentin.guillon@univ-tlse2.fr.
    (2)Harvard Medical School/MGH/MIT, Martinos Center for Biomedical Imaging, Building 
    75, 3rd Avenue, Charlestown, MA 02129, USA; Gillberg Neuropsychiatry Center,
    Gothenburg University, Sweden. Electronic address: nouchine@nmr.mgh.harvard.edu.
    (3)URI Octogone-CERPP, University of Toulouse, 5 allée Antonio Machado, 31058
    Toulouse Cedex9, France. Electronic address: baduel@univ-tlse2.fr.
    (4)URI Octogone-CERPP, University of Toulouse, 5 allée Antonio Machado, 31058
    Toulouse Cedex9, France. Electronic address: roge@univ-tlse2.fr.
    
    We review different aspects of visual social attention in autism spectrum
    disorders (ASD) from infancy to adulthood in light of the eye-tracking
    literature. We first assess the assumption that individuals with ASD demonstrate 
    a deficit in social orienting together with decreased attention to socially
    relevant stimuli such as faces compared to TD individuals. Results show that
    social orienting is actually not qualitatively impaired and that decreased
    attention to faces does not generalized across contexts. We also assess the
    assumption that individuals with ASD demonstrate excess mouth and diminished eye 
    gaze compared to TD individuals. We find that this assumption receives little
    support across ages and discuss some factors that might have initially lead to
    this conjecture. We report that the assessment of the ability to follow the
    direction of another person's gaze needs to be further examined and that
    eye-tracking studies add to the evidence that individuals with ASD demonstrate
    difficulties in interpreting gaze cues. Finally, we highlight innovative data
    acquisition and analyses that are increasingly shedding light on the more subtle 
    nature of the profound social difficulties experienced by individuals with ASD.
    
    Copyright © 2014. Published by Elsevier Ltd.
    
    PMID: 24694721  [PubMed - as supplied by publisher]
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  • 16) Mol Autism. 2014 Apr 3;5(1):26. [Epub ahead of print]

    First evidence of sensory atypicality in mothers of children with Autism Spectrum Disorder (ASD).

    Uljarevi M, Prior MR, Leekam SR.
    
    BACKGROUND: Atypical reactions to sensory stimuli show heritability in the
    general population and are a known risk factor for affective disorders. As
    sensory problems are highly prevalent in individuals with ASD and their siblings,
    and the occurrence of affective disorders is elevated in parents of children with
    ASD, investigating sensory symptoms in parents is important both from clinical
    and theoretical standpoints.Fifty mothers of children and adolescents with ASD
    completed the Adolescent and Adult Sensory Profile (AASP). The AASP is a
    norm-referenced questionnaire that provides scores for four types of responses to
    sensory stimuli (sensory quadrants): hypo-sensitivity, hyper-sensitivity,
    sensation seeking, and sensory avoiding.
    FINDINGS: Mothers' scores were compared with AASP norms. Ninety eight percent of 
    mothers had sensory scores at least one standard deviation (SD) above the
    normative mean and 44% were two or more SDs above the mean for at least one
    sensory quadrant.
    CONCLUSIONS: This study provides the first evidence for sensory atypicality in
    parents of children with ASD. Further research is needed to elucidate the
    contribution of genetic and environmental influences on the expression of sensory
    problems in ASD.
    
    PMID: 24694290  [PubMed - as supplied by publisher]
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  • 17) PLoS One. 2014 Apr 1;9(4):e93409. doi: 10.1371/journal.pone.0093409. eCollection 2014.

    Massively Parallel Sequencing of Patients with Intellectual Disability, Congenital Anomalies and/or Autism Spectrum Disorders with a Targeted Gene Panel.

    Brett M(1), McPherson J(2), Zang ZJ(3), Lai A(4), Tan ES(4), Ng I(4), Ong LC(5), 
    Cham B(4), Tan P(6), Rozen S(2), Tan EC(1).
    
    Author information: 
    (1)KK Research Centre, KK Women's & Children's Hospital, Singapore, Singapore.
    (2)Duke-NUS Graduate Medical School, Singapore, Singapore.
    (3)National Cancer Centre, Singapore, Singapore.
    (4)Genetic Services, KK Women's & Children's Hospital, Singapore, Singapore.
    (5)Universiti Malaya Medical Centre, Petaling Jaya, Malaysia.
    (6)Duke-NUS Graduate Medical School, Singapore, Singapore; National Cancer Centre,
    Singapore, Singapore.
    
    Developmental delay and/or intellectual disability (DD/ID) affects 1-3% of all
    children. At least half of these are thought to have a genetic etiology. Recent
    studies have shown that massively parallel sequencing (MPS) using a targeted gene
    panel is particularly suited for diagnostic testing for genetically heterogeneous
    conditions. We report on our experiences with using massively parallel sequencing
    of a targeted gene panel of 355 genes for investigating the genetic etiology of
    eight patients with a wide range of phenotypes including DD/ID, congenital
    anomalies and/or autism spectrum disorder. Targeted sequence enrichment was
    performed using the Agilent SureSelect Target Enrichment Kit and sequenced on the
    Illumina HiSeq2000 using paired-end reads. For all eight patients, 81-84% of the 
    targeted regions achieved read depths of at least 20×, with average read depths
    overlapping targets ranging from 322× to 798×. Causative variants were
    successfully identified in two of the eight patients: a nonsense mutation in the 
    ATRX gene and a canonical splice site mutation in the L1CAM gene. In a third
    patient, a canonical splice site variant in the USP9X gene could likely explain
    all or some of her clinical phenotypes. These results confirm the value of
    targeted MPS for investigating DD/ID in children for diagnostic purposes.
    However, targeted gene MPS was less likely to provide a genetic diagnosis for
    children whose phenotype includes autism.
    
    PMID: 24690944  [PubMed - in process]
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