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Papers of the Week

  • 1) Mol Psychiatry. 2014 Nov 11. doi: 10.1038/mp.2014.141. [Epub ahead of print]

    Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons.

    Griesi-Oliveira K(1), Acab A(2), Gupta AR(3), Sunaga DY(4), Chailangkarn T(2),
    Nicol X(5), Nunez Y(2), Walker MF(6), Murdoch JD(6), Sanders SJ(6), Fernandez
    TV(6), Ji W(7), Lifton RP(7), Vadasz E(8), Dietrich A(9), Pradhan D(10), Song
    H(10), Ming GL(10), Gu X(11), Haddad G(11), Marchetto MC(12), Spitzer N(5),
    Passos-Bueno MR(4), State MW(6), Muotri AR(2).
    Author information: 
    (1)1] Department of Pediatrics/Rady Children's Hospital San Diego, Department of
    Cellular and Molecular Medicine, Stem Cell Program, University of California San 
    Diego, School of Medicine, La Jolla, CA, USA [2] Departamento de Genética e
    Biologia Evolutiva, Centro de Estudos do Genoma Humano, Instituto de Biociências,
    Universidade de São Paulo, São Paulo, SP, Brasil.
    (2)Department of Pediatrics/Rady Children's Hospital San Diego, Department of
    Cellular and Molecular Medicine, Stem Cell Program, University of California San 
    Diego, School of Medicine, La Jolla, CA, USA.
    (3)Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.
    (4)Departamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma
    Humano, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP,
    (5)Division of Biological Sciences, Kavli Institute for Brain and Mind, University
    of California San Diego, La Jolla, CA, USA.
    (6)Program on Neurogenetics, Child Study Center, Departments of Genetics and
    Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
    (7)Departments of Genetics and Internal Medicine, Howard Hughes Medical Institute,
    Yale University School of Medicine, New Haven, CT, USA.
    (8)Instituto de Psiquiatria do Hospital das Clínicas, Faculdade de Medicina,
    Universidade de São Paulo, São Paulo, Brasil.
    (9)Walther-Straub-Institute for Pharmacology and Toxicology,
    Ludwig-Maximilians-Universität München, Munich, Germany.
    (10)Institute for Cell Engineering, The Solomon H Snyder Department of
    Neuroscience/Neurology, Johns Hopkins University School of Medicine, Baltimore,
    MD, USA.
    (11)Department of Pediatrics/Rady Children's Hospital San Diego, Department of
    Neurosciences, University of California San Diego, School of Medicine, La Jolla, 
    CA, USA.
    (12)Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, 
    An increasing number of genetic variants have been implicated in autism spectrum 
    disorders (ASDs), and the functional study of such variants will be critical for 
    the elucidation of autism pathophysiology. Here, we report a de novo balanced
    translocation disruption of TRPC6, a cation channel, in a non-syndromic autistic 
    individual. Using multiple models, such as dental pulp cells, induced pluripotent
    stem cell (iPSC)-derived neuronal cells and mouse models, we demonstrate that
    TRPC6 reduction or haploinsufficiency leads to altered neuronal development,
    morphology and function. The observed neuronal phenotypes could then be rescued
    by TRPC6 complementation and by treatment with insulin-like growth factor-1 or
    hyperforin, a TRPC6-specific agonist, suggesting that ASD individuals with
    alterations in this pathway may benefit from these drugs. We also demonstrate
    that methyl CpG binding protein-2 (MeCP2) levels affect TRPC6 expression.
    Mutations in MeCP2 cause Rett syndrome, revealing common pathways among ASDs.
    Genetic sequencing of TRPC6 in 1041 ASD individuals and 2872 controls revealed
    significantly more nonsynonymous mutations in the ASD population, and identified 
    loss-of-function mutations with incomplete penetrance in two patients. Taken
    together, these findings suggest that TRPC6 is a novel predisposing gene for ASD 
    that may act in a multiple-hit model. This is the first study to use iPSC-derived
    human neurons to model non-syndromic ASD and illustrate the potential of modeling
    genetically complex sporadic diseases using such cells.Molecular Psychiatry
    advance online publication, 11 November 2014; doi:10.1038/mp.2014.141.
    PMID: 25385366  [PubMed - as supplied by publisher]
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  • 2) J Autism Dev Disord. 2014 Nov 11. [Epub ahead of print]

    Comparing Diagnostic Outcomes of Autism Spectrum Disorder Using DSM-IV-TR and DSM-5 Criteria.

    Harstad EB(1), Fogler J, Sideridis G, Weas S, Mauras C, Barbaresi WJ.
    Author information: 
    (1)Division of Developmental Medicine, Boston Children's Hospital, Boston, MA, USA, 
    Controversy exists regarding the DSM-5 criteria for ASD. This study tested the
    psychometric properties of the DSM-5 model and determined how well it performed
    across different gender, IQ, and DSM-IV-TR sub-type, using clinically collected
    data on 227 subjects (median age = 3.95 years, majority had IQ > 70). DSM-5 was
    psychometrically superior to the DSM-IV-TR model (Comparative Fit Index of 0.970 
    vs 0.879, respectively). Measurement invariance revealed good model fit across
    gender and IQ. Younger children tended to meet fewer diagnostic criteria. Those
    with autistic disorder were more likely to meet social communication and
    repetitive behaviors criteria (p < .001) than those with PDD-NOS. DSM-5 is a
    robust model but will identify a different, albeit overlapping population of
    individuals compared to DSM-IV-TR.
    PMID: 25384720  [PubMed - as supplied by publisher]
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  • 3) Nat Neurosci. 2014 Nov 10. doi: 10.1038/nn.3864. [Epub ahead of print]

    Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1(-/y) mice.

    Zhang Y(1), Bonnan A(1), Bony G(1), Ferezou I(2), Pietropaolo S(3), Ginger M(1), 
    Sans N(1), Rossier J(2), Oostra B(4), LeMasson G(1), Frick A(1).
    Author information: 
    (1)1] INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale,
    U862, Bordeaux, France. [2] University of Bordeaux, Neurocentre Magendie,
    Physiopathologie de la plasticité neuronale, U862, Bordeaux, France.
    (2)Laboratoire de Neurobiologie, ESPCI ParisTech CNRS UMR 7637, Paris, France.
    (3)1] University of Bordeaux, INCIA, Talence, France. [2] CNRS, INCIA, UMR 5287,
    Talence, France.
    (4)Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
    Hypersensitivity in response to sensory stimuli and neocortical hyperexcitability
    are prominent features of Fragile X Syndrome (FXS) and autism spectrum disorders,
    but little is known about the dendritic mechanisms underlying these phenomena. We
    found that the primary somatosensory neocortex (S1) was hyperexcited in response 
    to tactile sensory stimulation in Fmr1(-/y) mice. This correlated with neuronal
    and dendritic hyperexcitability of S1 pyramidal neurons, which affect all major
    aspects of neuronal computation, from the integration of synaptic input to the
    generation of action potential output. Using dendritic electrophysiological
    recordings, calcium imaging, pharmacology, biochemistry and a computer model, we 
    found that this defect was, at least in part, attributable to the reduction and
    dysfunction of dendritic h- and BKCa channels. We pharmacologically rescued
    several core hyperexcitability phenomena by targeting BKCa channels. Our results 
    provide strong evidence pointing to the utility of BKCa channel openers for the
    treatment of the sensory hypersensitivity aspects of FXS.
    PMID: 25383903  [PubMed - as supplied by publisher]
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  • 4) Mol Autism. 2014 Sep 1;5:45. doi: 10.1186/2040-2392-5-45. eCollection 2014.

    Ubiquitin-proteasome dependent degradation of GABAAα1 in autism spectrum disorder.

    Crider A(1), Pandya CD(1), Peter D(1), Ahmed AO(2), Pillai A(1).
    Author information: 
    (1)Department of Psychiatry and Health Behavior, Medical College of Georgia, Georgia
    Regents University, 997 St. Sebastian Way, Augusta, GA 30912, USA.
    (2)Department of Psychiatry, Weill Cornell Medical College, 21 Bloomingdale Rd,
    White Plains, NY 10605, USA.
    BACKGROUND: Although the neurobiological basis of autism spectrum disorder (ASD) 
    is not fully understood, recent studies have indicated the potential role of
    GABAA receptors in the pathophysiology of ASD. GABAA receptors play a crucial
    role in various neurodevelopmental processes and adult neuroplasticity. However, 
    the mechanism(s) of regulation of GABAA receptors in ASD remains poorly
    METHODS: Postmortem middle frontal gyrus tissues (13 ASD and 13 control subjects)
    were used. In vitro studies were performed in primary cortical neurons at days in
    vitro (DIV) 14. The protein levels were examined by western blotting.
    Immunofluorescence studies were employed for cellular localization. The gene
    expression was determined by RT-PCR array and qRT-PCR.
    RESULTS: A significant decrease in GABAAα1 protein, but not mRNA levels was found
    in the middle frontal gyrus of ASD subjects indicating a post-translational
    regulation of GABAA receptors in ASD. At the cellular level, treatment with
    proteasomal inhibitor, MG132, or lactacystin significantly increased GABAAα1
    protein levels and Lys48-linked polyubiquitination of GABAAα1, but reduced
    proteasome activity in mouse primary cortical neurons (DIV 14 from E16 embryos). 
    Moreover, treatment with betulinic acid, a proteasome activator significantly
    decreased GABAAα1 protein levels in cortical neurons indicating the role of
    polyubiquitination of GABAAα1 proteins with their subsequent proteasomal
    degradation in cortical neurons. Ubiquitination specific RT-PCR array followed by
    western blot analysis revealed a significant increase in SYVN1, an endoplasmic
    reticulum (ER)-associated degradation (ERAD) E3 ubiquitin ligase in the middle
    frontal gyrus of ASD subjects. In addition, the inhibition of proteasomal
    activity by MG132 increased the expression of GABAAα1 in the ER. The siRNA
    knockdown of SYVN1 significantly increased GABAAα1 protein levels in cortical
    neurons. Moreover, reduced association between SYVN1 and GABAAα1 was found in the
    middle frontal gyrus of ASD subjects.
    CONCLUSIONS: SYVN1 plays a critical role as an E3 ligase in the ubiquitin
    proteasome system (UPS)-mediated GABAAα1 degradation. Thus, inhibition of the
    ubiquitin-proteasome-mediated GABAAα1 degradation may be an important mechanism
    for preventing GABAAα1 turnover to maintain GABAAα1 levels and GABA signaling in 
    PMID: 25392730  [PubMed]
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  • 5) Mol Autism. 2014 May 20;5:34. doi: 10.1186/2040-2392-5-34. eCollection 2014.

    The Autism Simplex Collection: an international, expertly phenotyped autism sample for genetic and phenotypic analyses.

    Buxbaum JD(1), Bolshakova N(2), Brownfeld JM(1), Anney RJ(2), Bender P(3),
    Bernier R(4), Cook EH(5), Coon H(6), Cuccaro M(7), Freitag CM(8), Hallmayer J(9),
    Geschwind D(10), Klauck SM(11), Nurnberger JI(12), Oliveira G(13), Pinto D(1),
    Poustka F(8), Scherer SW(14), Shih A(15), Sutcliffe JS(16), Szatmari P(17),
    Vicente AM(18), Vieland V(19), Gallagher L(2).
    Author information: 
    (1)The Seaver Autism Center for Research and Treatment, Department of Psychiatry,
    Icahn School of Medicine at Mount Sinai, New York 10029, USA.
    (2)Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity
    College, Dublin 8, Ireland.
    (3)National Institute of Mental Health (NIMH), Bethesda, MD 20892-9663, USA.
    (4)Department of Psychiatry and Behavioral Sciences, University of Washington,
    Seattle, WA 98195, USA.
    (5)Institute for Juvenile Research, Department of Psychiatry, University of Illinois
    at Chicago, Chicago, IL 60608, USA.
    (6)Psychiatry Department, University of Utah Medical School, Salt Lake City, UT
    84108, USA.
    (7)The John P Hussman Institute for Human Genomics, University of Miami, Miami, FL
    33101, USA.
    (8)Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, 
    JW Goethe University Frankfurt, 60528 Frankfurt, Germany.
    (9)Department of Psychiatry and Behavioral Science, Child and Adolescent Psychiatry,
    Stanford School of Medicine, Stanford, CA, USA.
    (10)Department of Neurology, University of California at Los Angeles, School of
    Medicine, Los Angeles, CA 90095, USA.
    (11)German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
    (12)Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN
    46202, USA.
    (13)Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento
    da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital,
    Centro Hospitalar e Universitário de Coimbra, 3000-602 Coimbra, Portugal ;
    University Clinic of Pediatrics and Institute for Biomedical Imaging and Life
    Science, Faculty of Medicine, University of Coimbra, 3000-602 Coimbra, Portugal.
    (14)Department of Molecular Genetics, The Centre for Applied Genomics, Hospital for
    Sick Children and McLaughlin Centre and University of Toronto, Toronto, ON,
    (15)Autism Speaks, New York, NY 10016, USA.
    (16)Department of Molecular Physiology and Biophysics, Vanderbilt Kennedy Center,
    Vanderbilt University, Nashville, TN 37232, USA ; Centers for Human Genetics
    Research and Molecular Neuroscience, Vanderbilt University, Nashville, TN 37232, 
    (17)Department of Psychiatry and Behavioural Neurosciences, McMaster University,
    Hamilton, ON L8N 3Z5, Canada.
    (18)Instituto Nacional de Saúde Dr Ricardo Jorge, 1649-016 Lisbon, Portugal ;
    Instituto Gulbenkian de Ciência, P-2781-901 Oeiras, Portugal ; BioFIG-Center for 
    Biodiversity, Functional & Integrative Genomics, Campus da FCUL, C2.2.12, Campo
    Grande, 1749-016 Lisboa, Portugal.
    (19)The Research Institute at Nationwide Children's Hospital, The Ohio State
    University, Columbus, OH, USA.
    BACKGROUND: There is an urgent need for expanding and enhancing autism spectrum
    disorder (ASD) samples, in order to better understand causes of ASD.
    METHODS: In a unique public-private partnership, 13 sites with extensive
    experience in both the assessment and diagnosis of ASD embarked on an ambitious, 
    2-year program to collect samples for genetic and phenotypic research and begin
    analyses on these samples. The program was called The Autism Simplex Collection
    (TASC). TASC sample collection began in 2008 and was completed in 2010, and
    included nine sites from North America and four sites from Western Europe, as
    well as a centralized Data Coordinating Center.
    RESULTS: Over 1,700 trios are part of this collection, with DNA from transformed 
    cells now available through the National Institute of Mental Health (NIMH).
    Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation
    Schedule-Generic (ADOS-G) measures are available for all probands, as are
    standardized IQ measures, Vineland Adaptive Behavioral Scales (VABS), the Social 
    Responsiveness Scale (SRS), Peabody Picture Vocabulary Test (PPVT), and physical 
    measures (height, weight, and head circumference). At almost every site,
    additional phenotypic measures were collected, including the Broad Autism
    Phenotype Questionnaire (BAPQ) and Repetitive Behavior Scale-Revised (RBS-R), as 
    well as the non-word repetition scale, Communication Checklist (Children's or
    Adult), and Aberrant Behavior Checklist (ABC). Moreover, for nearly 1,000 trios, 
    the Autism Genome Project Consortium (AGP) has carried out Illumina 1 M SNP
    genotyping and called copy number variation (CNV) in the samples, with data being
    made available through the National Institutes of Health (NIH). Whole exome
    sequencing (WES) has been carried out in over 500 probands, together with
    ancestry matched controls, and this data is also available through the NIH.
    Additional WES is being carried out by the Autism Sequencing Consortium (ASC),
    where the focus is on sequencing complete trios. ASC sequencing for the first
    1,000 samples (all from whole-blood DNA) is complete and data will be released in
    2014. Data is being made available through NIH databases (database of Genotypes
    and Phenotypes (dbGaP) and National Database for Autism Research (NDAR)) with DNA
    released in Dist 11.0. Primary funding for the collection, genotyping, sequencing
    and distribution of TASC samples was provided by Autism Speaks and the NIH,
    including the National Institute of Mental Health (NIMH) and the National Human
    Genetics Research Institute (NHGRI).
    CONCLUSIONS: TASC represents an important sample set that leverages expert sites.
    Similar approaches, leveraging expert sites and ongoing studies, represent an
    important path towards further enhancing available ASD samples.
    PMID: 25392729  [PubMed]
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  • 6) Autism. 2014 Nov 14. pii: 1362361314554920. [Epub ahead of print]

    A comparison of WISC-IV and SB-5 intelligence scores in adolescents with autism spectrum disorder.

    Baum KT(1), Shear PK(2), Howe SR(2), Bishop SL(3).
    Author information: 
    (1)Cincinnati Children's Hospital Medical Center, USA katherine.baum@cchmc.org.
    (2)University of Cincinnati, USA.
    (3)Weill Cornell Medical College, USA.
    In autism spectrum disorders, results of cognitive testing inform clinical care, 
    theories of neurodevelopment, and research design. The Wechsler Intelligence
    Scale for Children and the Stanford-Binet are commonly used in autism spectrum
    disorder evaluations and scores from these tests have been shown to be highly
    correlated in typically developing populations. However, they have not been
    compared in individuals with autism spectrum disorder, whose core symptoms can
    make testing challenging, potentially compromising test reliability. We used a
    within-subjects research design to evaluate the convergent validity between the
    Wechsler Intelligence Scale for Children, 4th ed., and Stanford-Binet, 5th ed.,
    in 40 youth (ages 10-16 years) with autism spectrum disorder. Corresponding
    intelligence scores were highly correlated (r = 0.78 to 0.88), but full-scale
    intelligence quotient (IQ) scores (t(38) = -2.27, p = 0.03, d = -0.16) and verbal
    IQ scores (t(36) = 2.23, p = 0.03; d = 0.19) differed between the two tests. Most
    participants obtained higher full-scale IQ scores on the Stanford-Binet, 5th ed.,
    compared to Wechsler Intelligence Scale for Children, 4th ed., with 14% scoring
    more than one standard deviation higher. In contrast, verbal indices were higher 
    on the Wechsler Intelligence Scale for Children, 4th ed., Verbal-nonverbal
    discrepancy classifications were only consistent for 60% of the sample.
    Comparisons of IQ test scores in autism spectrum disorder and other special
    groups are important, as it cannot necessarily be assumed that convergent
    validity findings in typically developing children and adolescents hold true
    across all pediatric populations.
    © The Author(s) 2014.
    PMID: 25398894  [PubMed - as supplied by publisher]
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  • 7) Autism. 2014 Nov 14. pii: 1362361314555376. [Epub ahead of print]

    Interest level in 2-year-olds with autism spectrum disorder predicts rate of verbal, nonverbal, and adaptive skill acquisition.

    Klintwall L(1), Macari S(2), Eikeseth S(3), Chawarska K(2).
    Author information: 
    (1)Oslo and Akershus University College, Norway lars.klintwall@hioa.no.
    (2)Yale University School of Medicine, USA.
    (3)Oslo and Akershus University College, Norway.
    Recent studies have suggested that skill acquisition rates for children with
    autism spectrum disorders receiving early interventions can be predicted by child
    motivation. We examined whether level of interest during an Autism Diagnostic
    Observation Schedule assessment at 2 years predicts subsequent rates of verbal,
    nonverbal, and adaptive skill acquisition to the age of 3 years. A total of 70
    toddlers with autism spectrum disorder, mean age of 21.9 months, were scored
    using Interest Level Scoring for Autism, quantifying toddlers' interest in toys, 
    social routines, and activities that could serve as reinforcers in an
    intervention. Adaptive level and mental age were measured concurrently (Time 1)
    and again after a mean of 16.3 months of treatment (Time 2). Interest Level
    Scoring for Autism score, Autism Diagnostic Observation Schedule score, adaptive 
    age equivalent, verbal and nonverbal mental age, and intensity of intervention
    were entered into regression models to predict rates of skill acquisition.
    Interest level at Time 1 predicted subsequent acquisition rate of adaptive skills
    (R(2) = 0.36) and verbal mental age (R(2) = 0.30), above and beyond the effects
    of Time 1 verbal and nonverbal mental ages and Autism Diagnostic Observation
    Schedule scores. Interest level at Time 1 also contributed (R(2) = 0.30), with
    treatment intensity, to variance in development of nonverbal mental age.
    © The Author(s) 2014.
    PMID: 25398893  [PubMed - as supplied by publisher]
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  • 8) J Autism Dev Disord. 2014 Nov 15. [Epub ahead of print]

    Emergence of Autism Spectrum Disorder in Children from Simplex Families: Relations to Parental Perceptions of Etiology.

    Goin-Kochel RP(1), Mire SS, Dempsey AG.
    Author information: 
    (1)Baylor College of Medicine, Houston, TX, USA, kochel@bcm.edu.
    Current research describes a four-category scheme of Autism Spectrum Disorder
    (ASD) onset: early, regressive, plateau, delay + regression. To replicate
    prevalence of different onset types, ASD onset (per the Autism Diagnostic
    Interview-Revised) was examined in a large North American sample; for a subset,
    parents' causal beliefs were ascertained via the Revised Illness Perception
    Questionnaire to examine potential associations with ASD-onset types. Onset rates
    were similar across samples, with a slightly higher proportion of children in the
    subsample categorized with regression. Top-rated causes of ASD were genetics,
    brain structure, will of God, toxins in vaccines, and environmental pollution.
    Parents reporting regression more often believed that toxins in vaccines caused
    ASD. Influences on treatment selection and broader public-health ramifications
    are discussed.
    PMID: 25398603  [PubMed - as supplied by publisher]
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  • 9) J Autism Dev Disord. 2014 Nov 15. [Epub ahead of print]

    Increasing Adaptive Behavior Skill Deficits From Childhood to Adolescence in Autism Spectrum Disorder: Role of Executive Function.

    Pugliese CE(1), Anthony L, Strang JF, Dudley K, Wallace GL, Kenworthy L.
    Author information: 
    (1)Division of Neuropsychology, Center for Autism Spectrum Disorders, Children's
    National Health System, Rockville, MD, USA, CPuglies@childrensnational.org.
    Almost half of all children with autism spectrum disorder have average cognitive 
    abilities, yet outcome remains poor. Because outcome in HFASD is more related to 
    adaptive behavior skills than cognitive level it is important to identify
    predictors of adaptive behavior. This study examines cognitive and demographic
    factors related to adaptive behavior, with specific attention to the role of
    executive function (EF) in youth with HFASD aged 4-23. There was a negative
    relationship between age and adaptive behavior and the discrepancy between IQ and
    adaptive behavior increased with age. EF problems contributed to lower adaptive
    behavior scores across domains. As such, it is important to target adaptive
    skills, and the EF problems that may contribute to them, in youth with HFASD.
    PMID: 25398602  [PubMed - as supplied by publisher]
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  • 10) Mol Autism. 2014 Sep 16;5(1):47. doi: 10.1186/2040-2392-5-47. eCollection 2014.

    Saccadic eye movement abnormalities in autism spectrum disorder indicate dysfunctions in cerebellum and brainstem.

    Schmitt LM(1), Cook EH(2), Sweeney JA(3), Mosconi MW(4).
    Author information: 
    (1)Center for Autism and Developmental Disabilities, University of Texas
    Southwestern, 5323 Harry Hines Blvd, Dallas, TX 75390-9086 USA.
    (2)Department of Psychiatry, University of Illinois at Chicago, 1747 W. Roosevelt Rd
    (MC 747), Chicago, IL 60608 USA.
    (3)Center for Autism and Developmental Disabilities, University of Texas
    Southwestern, 5323 Harry Hines Blvd, Dallas, TX 75390-9086 USA ; Centre for
    Autism Spectrum Disorders, Bond University, Gold Coast, QLD 4229 Australia.
    (4)Center for Autism and Developmental Disabilities, University of Texas
    Southwestern, 5323 Harry Hines Blvd, Dallas, TX 75390-9086 USA ; Departments of
    Psychiatry and Pediatrics, University of Texas Southwestern Medical Center, 5323 
    Harry Hines Blvd, Dallas, TX 75390-9086 USA.
    BACKGROUND: Individuals with autism spectrum disorder (ASD) show atypical scan
    paths during social interaction and when viewing faces, and recent evidence
    suggests that they also show abnormal saccadic eye movement dynamics and accuracy
    when viewing less complex and non-social stimuli. Eye movements are a uniquely
    promising target for studies of ASD as their spatial and temporal characteristics
    can be measured precisely and the brain circuits supporting them are
    well-defined. Control of saccade metrics is supported by discrete circuits within
    the cerebellum and brainstem - two brain regions implicated in magnetic resonance
    (MR) morphometry and histopathological studies of ASD. The functional integrity
    of these distinct brain systems can be examined by evaluating different
    parameters of visually-guided saccades.
    METHODS: A total of 65 participants with ASD and 43 healthy controls, matched on 
    age (between 6 and 44-years-old), gender and nonverbal IQ made saccades to
    peripheral targets. To examine the influence of attentional processes, blocked
    gap and overlap trials were presented. We examined saccade latency, accuracy and 
    dynamics, as well as the trial-to-trial variability of participants' performance.
    RESULTS: Saccades of individuals with ASD were characterized by reduced accuracy,
    elevated variability in accuracy across trials, and reduced peak velocity and
    prolonged duration. In addition, their saccades took longer to accelerate to peak
    velocity, with no alteration in the duration of saccade deceleration. Gap/overlap
    effects on saccade latencies were similar across groups, suggesting that visual
    orienting and attention systems are relatively spared in ASD. Age-related changes
    did not differ across groups.
    CONCLUSIONS: Deficits precisely and consistently directing eye movements suggest 
    impairment in the error-reducing function of the cerebellum in ASD. Atypical
    increases in the duration of movement acceleration combined with lower peak
    saccade velocities implicate pontine nuclei, specifically suggesting reduced
    excitatory activity in burst cells that drive saccades relative to inhibitory
    activity in omnipause cells that maintain stable fixation. Thus, our findings
    suggest that both cerebellar and brainstem abnormalities contribute to altered
    sensorimotor control in ASD.
    PMID: 25400899  [PubMed]
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  • 11) J Neurodev Disord. 2014;6(1):40. doi: 10.1186/1866-1955-6-40. Epub 2014 Nov 7.

    EEG hyper-connectivity in high-risk infants is associated with later autism.

    Orekhova EV(1), Elsabbagh M(2), Jones EJ(1), Dawson G(3), Charman T(4), Johnson
    MH(1); BASIS Team.
    Author information: 
    (1)Centre for Brain and Cognitive Development, School of Psychology, Birkbeck,
    University of London, Henry Welcome Building, London, WC1E 7HX UK.
    (2)Department of Psychiatry, McGill University, Montreal, PQ H3A 1A1 Canada.
    (3)Department of Psychiatry and Behavioral Sciences, School of Medicine, Duke
    University, Durham, NC 27705 USA.
    (4)Department of Psychology, Institute of Psychiatry, Psychology & Neuroscience,
    King's College London, London, SE5 8AF UK.
    BACKGROUND: It has been previously reported that structural and functional brain 
    connectivity in individuals with autism spectrum disorders (ASD) is atypical and 
    may vary with age. However, to date, no measures of functional connectivity
    measured within the first 2 years have specifically associated with a later ASD
    METHODS: In the present study, we analyzed functional brain connectivity in
    14-month-old infants at high and low familial risk for ASD using
    electroencephalography (EEG). EEG was recorded while infants attended to videos. 
    Connectivity was assessed using debiased weighted phase lag index (dbWPLI). At
    36 months, the high-risk infants were assessed for symptoms of ASD.
    RESULTS: As a group, high-risk infants who were later diagnosed with ASD
    demonstrated elevated phase-lagged alpha-range connectivity as compared to both
    low-risk infants and high-risk infants who did not go on to ASD.
    Hyper-connectivity was most prominent over frontal and central areas. The degree 
    of hyper-connectivity at 14 months strongly correlated with the severity of
    restricted and repetitive behaviors in participants with ASD at 3 years. These
    effects were not attributable to differences in behavior during the EEG session
    or to differences in spectral power.
    CONCLUSIONS: The results suggest that early hyper-connectivity in the alpha
    frequency range is an important feature of the ASD neurophysiological phenotype.
    PMID: 25400705  [PubMed]
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  • 12) Sci Rep. 2014 Nov 17;4:7073. doi: 10.1038/srep07073.

    Shorter telomere length in peripheral blood leukocytes is associated with childhood autism.

    Li Z(1), Tang J(2), Li H(2), Chen S(1), He Y(2), Liao Y(2), Wei Z(3), Wan G(3),
    Xiang X(4), Xia K(5), Chen X(6).
    Author information: 
    (1)1] Institute of Mental Health, the Second Xiangya Hospital of Central South
    University, Changsha, Hunan, China [2] Institute of Genomic Medicine, Wenzhou
    Medical University, Wenzhou, Zhejiang, China.
    (2)Institute of Mental Health, the Second Xiangya Hospital of Central South
    University, Changsha, Hunan, China.
    (3)Department of Women's Health Care, The Affiliated Shenzhen Maternal and Child
    Health Care Hospital, Nanfang University of Medical Science, Shenzhen, Guangdong,
    (4)BGI Ark Biotechnology Co., Ltd., Shenzhen, Guangdong, China.
    (5)The State Key Laboratory of Medical Genetics, Central South University, Changsha,
    Hunan, China.
    (6)1] Institute of Mental Health, the Second Xiangya Hospital of Central South
    University, Changsha, Hunan, China [2] The State Key Laboratory of Medical
    Genetics, Central South University, Changsha, Hunan, China [3] Key Laboratory of 
    Psychiatry and Mental Health of Hunan Province, Central South University,
    Changsha, Hunan, China [4] National Technology of Institute of Psychiatry,
    Central South University, Changsha, Hunan, China.
    Telomeres are protective chromosomal structures that play a key role in
    preserving genomic stability. Epidemiologic studies have shown that the abnormal 
    telomere length in leukocytes is associated with some mental disorders and
    age-related diseases. However, the association between leukocyte telomere length 
    and autism has not been investigated. Here we investigated the possible
    association between relative telomere length (RTL) in peripheral blood leukocytes
    and childhood autism by using an established real-time polymerase chain reaction 
    method. We observed significantly shorter RTL in patients with childhood autism
    than in controls (p = 0.006). Individuals with shorter RTL had a significantly
    increased presence of childhood autism compared with those who had long RTL. In
    patients, we found that family training interventions have a significant effect
    on telomere length (P = 0.012), but no correlations between RTL and clinical
    features (paternal age, maternal age, age of onset, illness of duration, CARS
    score and ABC score) were observed in this study. These results provided the
    first evidence that shorter leukocytes telomere length is significantly
    associated with childhood autism. The molecular mechanism underlying telomere
    length may be implicated in the development of autism.
    PMID: 25399515  [PubMed - in process]
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  • 13) Nat Rev Neurol. 2014 Nov 18. doi: 10.1038/nrneurol.2014.219. [Epub ahead of print]

    Neurodevelopmental disorders: Whole-exome sequencing elucidates genetic architecture of autism spectrum disorder.

    [No authors listed]
    PMID: 25404510  [PubMed - as supplied by publisher]
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  • 14) Proc Natl Acad Sci U S A. 2014 Nov 17. pii: 201413204. [Epub ahead of print]

    Topoisomerase 1 inhibition reversibly impairs synaptic function.

    Mabb AM(1), Kullmann PH(1), Twomey MA(1), Miriyala J(1), Philpot BD(2), Zylka
    Author information: 
    (1)Department of Cell Biology and Physiology, University of North Carolina
    Neuroscience Center, Carolina Institute for Developmental Disabilities, The
    University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
    (2)Department of Cell Biology and Physiology, University of North Carolina
    Neuroscience Center, Carolina Institute for Developmental Disabilities, The
    University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
    benjamin_philpot@med.unc.edu zylka@med.unc.edu.
    Topotecan is a topoisomerase 1 (TOP1) inhibitor that is used to treat various
    forms of cancer. We recently found that topotecan reduces the expression of
    multiple long genes, including many neuronal genes linked to synapses and autism.
    However, whether topotecan alters synaptic protein levels and synapse function is
    currently unknown. Here we report that in primary cortical neurons, topotecan
    depleted synaptic proteins that are encoded by extremely long genes, including
    Neurexin-1, Neuroligin-1, Cntnap2, and GABAAβ3. Topotecan also suppressed
    spontaneous network activity without affecting resting membrane potential, action
    potential threshold, or neuron health. Topotecan strongly suppressed inhibitory
    neurotransmission via pre- and postsynaptic mechanisms and reduced excitatory
    neurotransmission. The effects on synaptic protein levels and inhibitory
    neurotransmission were fully reversible upon drug washout. Collectively, our
    findings suggest that TOP1 controls the levels of multiple synaptic proteins and 
    is required for normal excitatory and inhibitory synaptic transmission.
    PMID: 25404338  [PubMed - as supplied by publisher]
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  • 15) Mol Neurobiol. 2014 Nov 18. [Epub ahead of print]

    MeCP2 Modulates Sex Differences in the Postsynaptic Development of the Valproate Animal Model of Autism.

    Kim KC(1), Choi CS, Kim JW, Han SH, Cheong JH, Ryu JH, Shin CY.
    Author information: 
    (1)Center for Neuroscience Research, SMART Institute of Advanced Biomedical
    Sciences, Konkuk University, Seoul, South Korea.
    Males are predominantly affected by autism spectrum disorders (ASD) with a
    prevalence ratio of 5:1. However, the underlying pathological mechanisms
    governing the male preponderance of ASD remain unclear. Recent studies suggested 
    that epigenetic aberrations may cause synaptic dysfunctions, which might be
    related to the pathophysiology of ASD. In this study, we used rat offspring
    prenatally exposed to valproic acid (VPA) as an animal model of ASD. We found
    male-selective abnormalities in the kinetic profile of the excitatory
    glutamatergic synaptic protein expressions linked to N-methyl-D-aspartate
    receptor (NMDAR), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
    receptor (AMPAR) and metabotropic glutamate receptor 5 (mGluR5) pathways in the
    prefrontal cortex of the VPA-exposed offspring at postnatal weeks 1, 2, and 4.
    Furthermore, VPA exposure showed a male-specific attenuation of the
    methyl-CpG-binding protein 2 (MeCP2) expressions both in the prefrontal cortex of
    offspring and in the gender-isolated neural progenitor cells (NPCs). In the
    gender-isolated NPCs culture, higher concentration of VPA induced an increased
    glutamatergic synaptic development along with decreased MeCP2 expression in both 
    genders suggesting the role of MeCP2 in the modulation of synaptic development.
    In the small interfering RNA (siRNA) knock-down study, 50 pmol of Mecp2 siRNA
    inhibited the MeCP2 expression in male- but not in female-derived NPCs with
    concomitant induction of postsynaptic proteins such as PSD95. Taken together, we 
    suggest that the male-inclined reduction of MeCP2 expression is involved in the
    abnormal development of glutamatergic synapse and male preponderance in the VPA
    animal models of ASD.
    PMID: 25404090  [PubMed - as supplied by publisher]
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  • 16) PLoS One. 2014 Nov 19;9(11):e112399. doi: 10.1371/journal.pone.0112399. eCollection 2014.

    Protein Interaction Networks Reveal Novel Autism Risk Genes within GWAS Statistical Noise.

    Correia C(1), Oliveira G(2), Vicente AM(1).
    Author information: 
    (1)Departamento de Promoção da Saúde e Doenças não Transmissíveis, Instituto
    Nacional de Saúde Doutor Ricardo Jorge, 1649-016 Lisboa, Portugal; Center for
    Biodiversity, Functional & Integrative Genomics, Faculty of Sciences, University 
    of Lisbon, 1749-016 Lisboa, Portugal; Instituto Gulbenkian de Ciência, 2780-156
    Oeiras, Portugal.
    (2)Unidade Neurodesenvolvimento e Autismo, Centro de Desenvolvimento, Hospital
    Pediátrico (HP) do Centro Hospitalar e Universitário de Coimbra (CHUC), 3000-602 
    Coimbra, Portugal; Centro de Investigação e Formação Clinica do HP-CHUC, 3000-602
    Coimbra, Portugal; Faculdade de Medicina da Universidade de Coimbra, 3000-548
    Coimbra, Portugal.
    Genome-wide association studies (GWAS) for Autism Spectrum Disorder (ASD) thus
    far met limited success in the identification of common risk variants, consistent
    with the notion that variants with small individual effects cannot be detected
    individually in single SNP analysis. To further capture disease risk gene
    information from ASD association studies, we applied a network-based strategy to 
    the Autism Genome Project (AGP) and the Autism Genetics Resource Exchange GWAS
    datasets, combining family-based association data with Human Protein-Protein
    interaction (PPI) data. Our analysis showed that autism-associated proteins at
    higher than conventional levels of significance (P<0.1) directly interact more
    than random expectation and are involved in a limited number of interconnected
    biological processes, indicating that they are functionally related. The
    functionally coherent networks generated by this approach contain ASD-relevant
    disease biology, as demonstrated by an improved positive predictive value and
    sensitivity in retrieving known ASD candidate genes relative to the top
    associated genes from either GWAS, as well as a higher gene overlap between the
    two ASD datasets. Analysis of the intersection between the networks obtained from
    the two ASD GWAS and six unrelated disease datasets identified fourteen genes
    exclusively present in the ASD networks. These are mostly novel genes involved in
    abnormal nervous system phenotypes in animal models, and in fundamental
    biological processes previously implicated in ASD, such as axon guidance, cell
    adhesion or cytoskeleton organization. Overall, our results highlighted novel
    susceptibility genes previously hidden within GWAS statistical "noise" that
    warrant further analysis for causal variants.
    PMID: 25409314  [PubMed - as supplied by publisher]
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  • 17) J Mol Psychiatry. 2014 Jan 24;2(1):1. eCollection 2014.

    Association study in siblings and case-controls of serotonin- and oxytocin-related genes with high functioning autism.

    Nyffeler J(1), Walitza S(2), Bobrowski E(3), Gundelfinger R(1), Grünblatt E(2).
    Author information: 
    (1)University Clinics of Child and Adolescent Psychiatry (UCCAP), University of
    Zurich, Thurgauerstr. 39, CH-8050 Zurich, Switzerland.
    (2)University Clinics of Child and Adolescent Psychiatry (UCCAP), University of
    Zurich, Thurgauerstr. 39, CH-8050 Zurich, Switzerland ; Neuroscience Center
    Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.
    (3)University Clinics of Child and Adolescent Psychiatry (UCCAP), University of
    Zurich, Thurgauerstr. 39, CH-8050 Zurich, Switzerland ; Department of
    Experimental Psychology, University of Regensburg, Regensburg, Germany.
    BACKGROUND: Autism spectrum disorder (ASD) is heritable and neurodevelopmental
    with unknown causes. The serotonergic and oxytocinergic systems are of interest
    in autism for several reasons: (i) Both systems are implicated in social
    behavior, and abnormal levels of serotonin and oxytocin have been found in people
    with ASD; (ii) treatment with selective serotonin reuptake inhibitors and
    oxytocin can yield improvements; and (iii) previous association studies have
    linked the serotonin transporter (SERT; SLC6A4), serotonin receptor 2A (HTR2A),
    and oxytocin receptor (OXTR) genes with ASD. We examined their association with
    high functioning autism (HFA) including siblings and their interaction.
    METHODS: In this association study with HFA children (IQ > 80), siblings, and
    controls, participants were genotyped for four single nucleotide polymorphisms
    (SNPs) in OXTR (rs2301261, rs53576, rs2254298, rs2268494) and one in HTR2A
    (rs6311) as well as the triallelic HTTLPR (SERT polymorphism).
    RESULTS: We identified a nominal significant association with HFA for the HTTLPR 
    s allele (consisting of S and LG alleles) (p = .040; odds ratio (OR) = 1.697, 95%
    CI 1.191-2.204)). Four polymorphisms (HTTLPR, HTR2A rs6311, OXTR rs2254298 and
    rs53576) in combination conferred nominal significant risk for HFA with a genetic
    score of ≥4 (OR = 2.09, 95% CI 1.05-4.18, p = .037). The resulting area under the
    receiver operating characteristic curve was 0.595 (p = .033).
    CONCLUSIONS: Our findings, combined with those of previous reports, indicate that
    ASD, in particular HFA, is polygenetic rather than monogenetic and involves the
    serotonergic and oxytocin pathways, probably in combination with other factors.
    PMID: 25408912  [PubMed - as supplied by publisher]
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