1. Andoh M, Ikegaya Y, Koyama R. {{Autism spectrum disorders and epilepsy}}. {Nihon Yakurigaku Zasshi};2016 (Aug);148(2):121-122.
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2. Cheng C, Lau SK, Doering LC. {{Astrocyte-secreted thrombospondin-1 modulates synapse and spine defects in the fragile X mouse model}}. {Mol Brain};2016;9(1):74.
Astrocytes are key participants in various aspects of brain development and function, many of which are executed via secreted proteins. Defects in astrocyte signaling are implicated in neurodevelopmental disorders characterized by abnormal neural circuitry such as Fragile X syndrome (FXS). In animal models of FXS, the loss in expression of the Fragile X mental retardation 1 protein (FMRP) from astrocytes is associated with delayed dendrite maturation and improper synapse formation; however, the effect of astrocyte-derived factors on the development of neurons is not known. Thrombospondin-1 (TSP-1) is an important astrocyte-secreted protein that is involved in the regulation of spine development and synaptogenesis. In this study, we found that cultured astrocytes isolated from an Fmr1 knockout (Fmr1 KO) mouse model of FXS displayed a significant decrease in TSP-1 protein expression compared to the wildtype (WT) astrocytes. Correspondingly, Fmr1 KO hippocampal neurons exhibited morphological deficits in dendritic spines and alterations in excitatory synapse formation following long-term culture. All spine and synaptic abnormalities were prevented in the presence of either astrocyte-conditioned media or a feeder layer derived from FMRP-expressing astrocytes, or following the application of exogenous TSP-1. Importantly, this work demonstrates the integral role of astrocyte-secreted signals in the establishment of neuronal communication and identifies soluble TSP-1 as a potential therapeutic target for Fragile X syndrome.
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3. Chiocchetti AG, Haslinger D, Stein JL, de la Torre-Ubieta L, Cocchi E, Rothamel T, Lindlar S, Waltes R, Fulda S, Geschwind DH, Freitag CM. {{Transcriptomic signatures of neuronal differentiation and their association with risk genes for autism spectrum and related neuropsychiatric disorders}}. {Transl Psychiatry};2016;6(8):e864.
Genes for autism spectrum disorders (ASDs) are also implicated in fragile X syndrome (FXS), intellectual disabilities (ID) or schizophrenia (SCZ), and converge on neuronal function and differentiation. The SH-SY5Y neuroblastoma cell line, the most widely used system to study neurodevelopment, is currently discussed for its applicability to model cortical development. We implemented an optimal neuronal differentiation protocol of this system and evaluated neurodevelopment at the transcriptomic level using the CoNTeXT framework, a machine-learning algorithm based on human post-mortem brain data estimating developmental stage and regional identity of transcriptomic signatures. Our improved model in contrast to currently used SH-SY5Y models does capture early neurodevelopmental processes with high fidelity. We applied regression modelling, dynamic time warping analysis, parallel independent component analysis and weighted gene co-expression network analysis to identify activated gene sets and networks. Finally, we tested and compared these sets for enrichment of risk genes for neuropsychiatric disorders. We confirm a significant overlap of genes implicated in ASD with FXS, ID and SCZ. However, counterintuitive to this observation, we report that risk genes affect pathways specific for each disorder during early neurodevelopment. Genes implicated in ASD, ID, FXS and SCZ were enriched among the positive regulators, but only ID-implicated genes were also negative regulators of neuronal differentiation. ASD and ID genes were involved in dendritic branching modules, but only ASD risk genes were implicated in histone modification or axonal guidance. Only ID genes were over-represented among cell cycle modules. We conclude that the underlying signatures are disorder-specific and that the shared genetic architecture results in overlaps across disorders such as ID in ASD. Thus, adding developmental network context to genetic analyses will aid differentiating the pathophysiology of neuropsychiatric disorders.
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4. Fein D. {{Commentary on USPSTF Final Statement on Universal Screening for Autism}}. {J Dev Behav Pediatr};2016 (Aug 2)
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5. Guo YP, Commons KG. {{Serotonin neuron abnormalities in the BTBR mouse model of autism}}. {Autism Res};2016 (Aug 1)
The inbred mouse strain BTBR T+ Itpr3tf /J (BTBR) is studied as a model of idiopathic autism because they are less social and more resistant to change than other strains. Forebrain serotonin receptors and the response to serotonin drugs are altered in BTBR mice, yet it remains unknown if serotonin neurons themselves are abnormal. In this study, we found that serotonin tissue content and the density of serotonin axons is reduced in the hippocampus of BTBR mice in comparison to C57BL/6J (C57) mice. This was accompanied by possible compensatory changes in serotonin neurons that were most pronounced in regions known to provide innervation to the hippocampus: the caudal dorsal raphe (B6) and the median raphe. These changes included increased numbers of serotonin neurons and hyperactivation of Fos expression. Metrics of serotonin neurons in the rostral 2/3 of the dorsal raphe and serotonin content of the prefrontal cortex were less impacted. Thus, serotonin neurons exhibit region-dependent abnormalities in the BTBR mouse that may contribute to their altered behavioral profile. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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6. Hamada N, Ito H, Nishijo T, Iwamoto I, Morishita R, Tabata H, Momiyama T, Nagata K. {{Essential role of the nuclear isoform of RBFOX1, a candidate gene for autism spectrum disorders, in the brain development}}. {Sci Rep};2016;6:30805.
Gene abnormalities in RBFOX1, encoding an mRNA-splicing factor, have been shown to cause autism spectrum disorder and other neurodevelopmental disorders. Since pathophysiological significance of the dominant nuclear isoform in neurons, RBFOX1-isoform1 (iso1), remains to be elucidated, we performed comprehensive analyses of Rbfox1-iso1 during mouse corticogenesis. Knockdown of Rbfox1-iso1 by in utero electroporation caused abnormal neuronal positioning during corticogenesis, which was attributed to impaired migration. The defects were found to occur during radial migration and terminal translocation, perhaps due to impaired nucleokinesis. Axon extension and dendritic arborization were also suppressed in vivo in Rbfox1-iso1-deficient cortical neurons. In addition, electrophysiology experiments revealed significant defects in the membrane and synaptic properties of the deficient neurons. Aberrant morphology was further confirmed by in vitro analyses; Rbfox1-iso1-konckdown in hippocampal neurons resulted in the reduction of primary axon length, total length of dendrites, spine density and mature spine number. Taken together, this study shows that Rbfox1-iso1 plays an important role in neuronal migration and synapse network formation during corticogenesis. Defects in these critical processes may induce structural and functional defects in cortical neurons, and consequently contribute to the pathophysiology of neurodevelopmental disorders with RBFOX1 abnormalities.
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7. Jones S, Bremer E, Lloyd M. {{Autism spectrum disorder: family quality of life while waiting for intervention services}}. {Qual Life Res};2016 (Aug 2)
PURPOSE: Families of children with autism spectrum disorder (ASD) often experience high levels of stress; it is important to investigate the family quality of life (FQOL) to understand how to serve the entire family, not just the child. The purpose of this investigation was to determine: (a) how families with a child with ASD view their overall FQOL and (b) what aspects of everyday life have the greatest influence on the FQOL? METHODS: A survey designed to asses FQOL was mailed to all families (n = 454) of children with ASD (0-18 years) waiting for government-funded services. Results from 151 surveys were examined (31 % response rate). Descriptive on all variables, ordinal logistic regression, and t tests were used to analyze the data. RESULTS: The most influential factors on FQOL were whether the child with ASD had a major health concern, whether the family’s needs were met by disability-related services, and whether there were opportunities to engage in leisure and recreation activities. CONCLUSIONS: Families on waitlists experience challenges in FQOL influenced by the health of the family members; this is implicitly important for service agencies and providers. Future research should continue to explore how access to disability-related services impacts FQOL; and how these associations may be moderated by contextual factors such as socioeconomic status, health of child and family members, access and engagement in recreation, and severity of the child’s needs.
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8. Krishnan A, Zhang R, Yao V, Theesfeld CL, Wong AK, Tadych A, Volfovsky N, Packer A, Lash A, Troyanskaya OG. {{Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder}}. {Nat Neurosci};2016 (Aug 1)
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a strong genetic basis. Yet, only a small fraction of potentially causal genes-about 65 genes out of an estimated several hundred-are known with strong genetic evidence from sequencing studies. We developed a complementary machine-learning approach based on a human brain-specific gene network to present a genome-wide prediction of autism risk genes, including hundreds of candidates for which there is minimal or no prior genetic evidence. Our approach was validated in a large independent case-control sequencing study. Leveraging these genome-wide predictions and the brain-specific network, we demonstrated that the large set of ASD genes converges on a smaller number of key pathways and developmental stages of the brain. Finally, we identified likely pathogenic genes within frequent autism-associated copy-number variants and proposed genes and pathways that are likely mediators of ASD across multiple copy-number variants. All predictions and functional insights are available at http://asd.princeton.edu.
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9. Tong HJ, Lee HY, Lee YT, Low Y, Lim CR, Nair R. {{Factors influencing the inclusion of oral health education in individualized education plans of children with autism spectrum disorders in Singapore}}. {Int J Paediatr Dent};2016 (Aug 1)
BACKGROUND: Prevention of oral diseases in children with autism spectrum disorder (ASD) is possible via incorporation of oral health education (OHE) into individualized education plans. OBJECTIVES: To assess (i) whether training can improve teachers’ oral heath knowledge, (ii) whether OHE is taught to children with ASD, and (iii) factors associated with teachers’ perceived barriers to the implementation of OHE. DESIGN: Teachers working in special schools were recruited. Two pre-tested questionnaires were administered, before and after a training session. The effectiveness of the intervention was evaluated. Teachers were also surveyed on their teaching of caries prevention and perceived barriers of teaching OHE. RESULTS: There was a significant increase in knowledge scores post-intervention (P < 0.001). Teachers were more likely to incorporate OHE into their teaching if trained by dental professionals (P = 0.022) and provided teaching materials (P = 0.001). Teachers' level of baseline OHE knowledge was a predictor and significantly negatively associated with levels of perceived overall and personal barriers (both P < 0.001). CONCLUSION: OHE is included in the curriculum of the schools surveyed, but this is very limited. The training programme increased teachers' oral health knowledge competence scores. Levels of knowledge, lack of training, and teaching materials are barriers to incorporating OHE in their teaching curriculum. Lien vers le texte intégral (Open Access ou abonnement)
10. Zuckerman K, Lindly OJ, Chavez AE. {{Timeliness of Autism Spectrum Disorder Diagnosis and Use of Services Among U.S. Elementary School-Aged Children}}. {Psychiatr Serv};2016 (Aug 1):appips201500549.
OBJECTIVE: This study assessed the relationship of timeliness of autism spectrum disorder (ASD) diagnosis with current use of ASD-related services in a nationally representative sample of U.S. children. METHODS: The Centers for Disease Control’s (CDC’s) Survey of Pathways to Diagnosis and Services was used to assess experiences of 722 children ages six to 11 with ASD. Bivariate and multivariate analyses were used to explore associations between age at ASD diagnosis and delay in ASD diagnosis and use of health services. Health services included current use of behavioral intervention (BI) therapy, school-based therapy, complementary and alternative medicine (CAM), and psychotropic medications. RESULTS: Mean age at ASD diagnosis was 4.4 years, and mean diagnostic delay was 2.2 years. In adjusted analysis, older age at diagnosis (>/=4 versus <4) was associated with lower likelihood of current BI or school-based therapy use and higher likelihood of current psychotropic medication use. Analyses that treated age at diagnosis as a continuous variable found that likelihood of current psychotropic medication use increased with older age at diagnosis. A delay of two or more years between parents' first discussion of concerns with a provider and ASD diagnosis was associated with higher likelihood of current CAM use. Likelihood of current CAM use increased as delay in diagnosis became longer. CONCLUSIONS: Both older age at diagnosis and longer delay in diagnosis were associated with different health services utilization patterns among younger children with ASD. Prompt and early diagnosis may be associated with increased use of evidence-based therapies for ASD. Lien vers le texte intégral (Open Access ou abonnement)
