1. Bora E, Aydin A, Sarac T, Kadak MT, Kose S. {{Heterogeneity of subclinical autistic traits among parents of children with autism spectrum disorder: Identifying the broader autism phenotype with a data-driven method}}. {Autism Res}. 2016.
Clinical diagnosis of autism spectrum disorder (ASD) can be conceptualized as the extreme end of the distribution of subclinical autistic traits related to genetic susceptibility factors (broad autism phenotype (BAP)) in the general population. Subclinical autistic traits are significantly more common among unaffected first-degree relatives of probands with autism. However, there is a significant heterogeneity of autistic traits in family members of individuals with ASD and severity of autistic traits are not significantly different from controls in the majority of these relatives. The current study investigated the heterogeneity of autistic traits using latent class analysis (LCA) of the Autism Spectrum Quotient (AQ) ratings of 673 parents of children with ASD and 147 parents of typically developing children. Two distinct subgroups, including a « low-scoring » and a « high-scorer (BAP) » groups, were found. In comparison to control parents, a significantly larger proportion (21.1% vs. 7.5%) of parents of ASD were members of BAP group. Communication subscale made a distinctive contribution to the separation of high and low-scoring groups (d = 2.77). Further studies investigating neurobiological and genetic biomarkers and stability of these two subgroups over time are important for understanding the nature of autistic traits in the general population. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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2. English MC, Maybery MT, Visser TA. {{Threatening faces fail to guide attention for adults with autistic-like traits}}. {Autism Res}. 2016.
Individuals diagnosed with autistic spectrum conditions often show deficits in processing emotional faces relative to neurotypical peers. However, little is known about whether similar deficits exist in neurotypical individuals who show high-levels of autistic-like traits. To address this question, we compared performance on an attentional blink task in a large sample of adults who showed low- or high-levels of autistic-like traits on the Autism Spectrum Quotient. We found that threatening faces inserted as the second target in a rapid serial visual presentation were identified more accurately among individuals with low- compared to high-levels of autistic-like traits. This is the first study to show that attentional blink abnormalities seen in autism extend to the neurotypical population with autistic-like traits, adding to the growing body of research suggesting that autistic-related patterns of behaviors extend into a subset of the neurotypical population. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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3. Fairthorne JC, de Klerk NH, Leonard HM, Whitehouse AJ. {{Mothers of Children with Autism have Different Rates of Cancer According to the Presence of Intellectual Disability in Their Child}}. {J Autism Dev Disord}. 2016.
Autism spectrum disorder (ASD) and intellectual disability (ID) are neurodevelopmental disorders with strong genetic components. Increasingly, research attention has focused on whether genetic factors conveying susceptibility for these conditions, also influence the risk of other health conditions, such as cancer. We examined the occurrence of hospital admissions and treatment/services for cancer in mothers of children with ASD with or without ID compared with other mothers. After linking Western Australian administrative health databases, we used Cox regression to estimate the hazard ratios (HRs) of any hospitalisations and treatment/services for cancer in these groups of mothers. Mothers of children with ASD without ID had greater risk of admissions for cancer (HR 1.29 [95 % CI 1.1, 1.7]), and for treatment/services in particular (HR 1.41 [95 % CI 1.0, 2.0]), than mothers of children with no ASD/ID, while mothers of children with ASD with ID were no more likely to have a cancer-related hospital admission than other mothers. Mothers of children with autism without ID had increased risk of cancer, which may relate to common genetic pathways.
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4. Hartini S, Hapsara S, Herini ES, Takada S. {{Usefulness of the CBCL/6-18 to Evaluate Emotional and Behavioral Problems in Indonesian Autism Spectrum Disorder/ASD Children}}. {Pediatr Int}. 2016.
BACKGROUND: The Child Behavior Checklist (CBCL) has been widely utilized to estimate emotional and behavioral problems in children in the USA and European countries. Though the Indonesian version of the CBCL/6-18 was proven to have good validity and internal consistency in typically developing children in Indonesia, it has not been utilized for children with Autism Spectrum Disorder (ASD) in Indonesia. The purpose of this study was to investigate the usefulness of CBCL/6-18 for detecting emotional and behavioral problems in Indonesian children with ASD in Indonesia. METHODS: One hundred and eight mothers of children with ASD and Typical Development (TD) were enrolled in this study. The diagnosis of ASD in Indonesia was made by expert child neurologists based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition, Text revised. The mothers of children aged 6-18 years completed the Indonesian version of child behaviors checklist (CBCL). RESULTS: The scores of total problems, internalizing, and externalizing were significantly higher in Indonesian children with ASD in Indonesia than those with TD. Children with ASD scored significantly higher in 7 of the 8 CBCL subscales (except somatic complaints) compared with TD children. CONCLUSIONS: The CBCL/6-18 could be considered as a useful tool for detecting emotional and behavioral problems in children with ASD in Indonesia in Muslim populations. This article is protected by copyright. All rights reserved.
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5. Higashimori H, Schin CS, Chiang MS, Morel L, Shoneye TA, Nelson DL, Yang Y. {{Selective Deletion of Astroglial FMRP Dysregulates Glutamate Transporter GLT1 and Contributes to Fragile X Syndrome Phenotypes In Vivo}}. {J Neurosci}. 2016; 36(27): 7079-94.
How the loss of fragile X mental retardation protein (FMRP) in different brain cell types, especially in non-neuron glial cells, induces fragile X syndrome (FXS) phenotypes has just begun to be understood. In the current study, we generated inducible astrocyte-specific Fmr1 conditional knock-out mice (i-astro-Fmr1-cKO) and restoration mice (i-astro-Fmr1-cON) to study the in vivo modulation of FXS synaptic phenotypes by astroglial FMRP. We found that functional expression of glutamate transporter GLT1 is 40% decreased in i-astro-Fmr1-cKO somatosensory cortical astrocytes in vivo, which can be fully rescued by the selective re-expression of FMRP in astrocytes in i-astro-Fmr1-cON mice. Although the selective loss of astroglial FMRP only modestly increases spine density and length in cortical pyramidal neurons, selective re-expression of FMRP in astrocytes significantly attenuates abnormal spine morphology in these neurons of i-astro-Fmr1-cON mice. Moreover, we found that basal protein synthesis levels and immunoreactivity of phosphorylated S6 ribosomal protein (p-s6P) is significantly increased in i-astro-Fmr1-cKO mice, while the enhanced cortical protein synthesis observed in Fmr1 KO mice is mitigated in i-astro-Fmr1-cON mice. Furthermore, ceftriaxone-mediated upregulation of surface GLT1 expression restores functional glutamate uptake and attenuates enhanced neuronal excitability in Fmr1 KO mice. In particular, ceftriaxone significantly decreases the growth rate of abnormally accelerated body weight and completely corrects spine abnormality in Fmr1 KO mice. Together, these results show that the selective loss of astroglial FMRP contributes to cortical synaptic deficits in FXS, presumably through dysregulated astroglial glutamate transporter GLT1 and impaired glutamate uptake. These results suggest the involvement of astrocyte-mediated mechanisms in the pathogenesis of FXS. SIGNIFICANCE STATEMENT: Previous studies to understand how the loss of function of fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS) have largely focused on neurons; whether the selective loss of astroglial FMRP in vivo alters astrocyte functions and contributes to the pathogenesis of FXS remain essentially unknown. This has become a long-standing unanswered question in the fragile X field, which is also relevant to autism pathogenesis. Our current study generated astrocyte-specific Fmr1 conditional knock-out and restoration mice, and provided compelling evidence that the selective loss of astroglial FMRP contributes to cortical synaptic deficits in FXS, likely through the dysregulated astroglial glutamate transporter GLT1 expression and impaired glutamate uptake. These results demonstrate previously undescribed astrocyte-mediated mechanisms in the pathogenesis of FXS.
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6. Liu HH, Cline HT. {{Fragile X Mental Retardation Protein Is Required to Maintain Visual Conditioning-Induced Behavioral Plasticity by Limiting Local Protein Synthesis}}. {J Neurosci}. 2016; 36(27): 7325-39.
Fragile X mental retardation protein (FMRP) is thought to regulate neuronal plasticity by limiting dendritic protein synthesis, but direct demonstration of a requirement for FMRP control of local protein synthesis during behavioral plasticity is lacking. Here we tested whether FMRP knockdown in Xenopus optic tectum affects local protein synthesis in vivo and whether FMRP knockdown affects protein synthesis-dependent visual avoidance behavioral plasticity. We tagged newly synthesized proteins by incorporation of the noncanonical amino acid azidohomoalanine and visualized them with fluorescent noncanonical amino acid tagging (FUNCAT). Visual conditioning and FMRP knockdown produce similar increases in FUNCAT in tectal neuropil. Induction of visual conditioning-dependent behavioral plasticity occurs normally in FMRP knockdown animals, but plasticity degrades over 24 h. These results indicate that FMRP affects visual conditioning-induced local protein synthesis and is required to maintain the visual conditioning-induced behavioral plasticity. SIGNIFICANCE STATEMENT: Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. Exaggerated dendritic protein synthesis resulting from loss of fragile X mental retardation protein (FMRP) is thought to underlie cognitive deficits in FXS, but no direct evidence has demonstrated that FMRP-regulated dendritic protein synthesis affects behavioral plasticity in intact animals. Xenopus tadpoles exhibit a visual avoidance behavior that improves with visual conditioning in a protein synthesis-dependent manner. We showed that FMRP knockdown and visual conditioning dramatically increase protein synthesis in neuronal processes. Furthermore, induction of visual conditioning-dependent behavioral plasticity occurs normally after FMRP knockdown, but performance rapidly deteriorated in the absence of FMRP. These studies show that FMRP negatively regulates local protein synthesis and is required to maintain visual conditioning-induced behavioral plasticity in vivo.
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7. Martinez-Cerdeno V. {{Dendrite and spine modifications in autism and related neurodevelopmental disorders in patients and animal models}}. {Dev Neurobiol}. 2016.
Dendrites and spines are the main neuronal structures receiving input from other neurons and glial cells. Dendritic and spine number, size and morphology are some of the crucial factors determining how signals coming from individual synapses are integrated. Much remains to be understood about the characteristics of neuronal dendrites and dendritic spines in autism and related disorders. Though there have been many studies conducted using autism mouse models, few have been carried out using postmortem human tissue from patients. Available animal models of autism include those generated through genetic modifications and those non-genetic models of the disease. Here, we review how dendrite and spine morphology and number is affected in autism and related neurodevelopmental diseases, both in human, and genetic and non-genetic animal models of autism. Overall, data obtained from human and animal models point to a generalized reduction in the size and number, as well as an alteration of the morphology of dendrites; and an increase in spine densities with immature morphology, indicating a general spine immaturity state in autism. Additional human studies on dendrite and spine number and morphology in postmortem tissue are needed to understand the properties of these structures in the cerebral cortex of patients with autism. This article is protected by copyright. All rights reserved.
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8. Nakagawa Y, Chiba K. {{Involvement of neuroinflammation during brain development in social cognitive deficits in autism spectrum disorder and schizophrenia}}. {J Pharmacol Exp Ther}. 2016.
Development of social cognition, a unique and high-order function, depends on brain maturation from childhood to adulthood in humans. Autism spectrum disorder (ASD) and schizophrenia have similar social cognitive deficits while age of onset in each disorder is different. Pathogenesis of these disorders is complex and contains several features including genetic risk factors, environmental risk factors, and sites of abnormalities in the brain. Although several hypotheses have been postulated, they seem to be insufficient to explain how brain alterations associated with symptoms in these disorders develop at distinct developmental stages. Development of ASD appears to be related to cerebellar dysfunction and subsequent thalamic hyperactivation in early childhood. By contrast, schizophrenia seems to be triggered by thalamic hyperactivation in late adolescence while hippocampal aberration has been possibly initiated in childhood. One of the possible culprits is metal homeostasis disturbances that can induce dysfunction of blood-cerebrospinal fluid barrier. Thalamic hyperactivation is thought to be induced by microglia-mediated neuroinflammation and abnormalities of intracerebral environment. Consequently, it is likely that the thalamic hyperactivation triggers dysregulation of the dorsolateral prefrontal cortex for lower brain regions related to social cognition. In this review, we summarize the brain aberration in ASD and schizophrenia and provide a possible mechanism underlying social cognitive deficits in these disorders based on their distinct ages of onset.
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9. Ozsivadjian A, Hollocks MJ, Southcott J, Absoud M, Holmes E. {{Erratum to: Anxious Imagery in Children With and Without Autism Spectrum Disorder: An Investigation into Occurrence, Content, Features and Implications for Therapy}}. {J Autism Dev Disord}. 2016.
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10. Popovitchenko T, Thompson K, Viljetic B, Jiao X, Kontonyiannis DL, Kiledjian M, Hart RP, Rasin MR. {{The RNA binding protein HuR determines the differential translation of autism-associated FoxP subfamily members in the developing neocortex}}. {Sci Rep}. 2016; 6: 28998.
Forkhead-box domain (Fox) containing family members are known to play a role in neocorticogenesis and have also been associated with disorders on the autism spectrum. Here we show that a single RNA-binding protein, Hu antigen R (HuR), dictates translation specificity of bound mRNAs and is sufficient to define distinct Foxp-characterized subpopulations of neocortical projection neurons. Furthermore, distinct phosphorylation states of HuR differentially regulate translation of Foxp mRNAs in vitro. This demonstrates the importance of RNA binding proteins within the framework of the developing brain and further confirms the role of mRNA translation in autism pathogenesis.
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11. Radley KC, Dart EH, Moore JW, Battaglia AA, LaBrot ZC. {{Promoting Accurate Variability of Social Skills in Children With Autism Spectrum Disorder}}. {Behav Modif}. 2016.
Restricted and repetitive behavior is a central feature of autism spectrum disorder (ASD), with such behaviors often resulting in lack of reinforcement in social contexts. The present study investigated training multiple exemplars of target behaviors and the utilization of lag schedules of reinforcement in the context of social skills training to promote appropriate and varied social behavior in children with ASD. Five participants with ASD between the ages of 7 and 9 attended a twice-weekly social skills group for 8 weeks. A multiple probe design across skills was utilized to assess intervention effects. During baseline, participants demonstrated low levels of skill accuracy and low appropriate variability in responding. During continuous reinforcement with one trained exemplar, skill accuracy increased while appropriate variability remained low. Training of three exemplars of target skills resulted in minimal improvements in appropriate variability. Introduction of a Lag 2 schedule with three trained exemplars was generally associated with increased appropriate variability. Further appropriate variability was observed during Lag 4 with three trained exemplars. Limitations and implications are discussed.
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12. Song G, Napoli E, Wong S, Hagerman R, Liu S, Tassone F, Giulivi C. {{Altered redox mitochondrial biology in the neurodegenerative disorder fragile X-tremor/ataxia syndrome: use of antioxidants in precision medicine}}. {Mol Med}. 2016; 22.
A 55-200 expansion of the CGG nucleotide repeat in the 5′-UTR of the fragile X mental retardation 1 gene (FMR1) is the hallmark of the triplet nucleotide disease known as the « premutation » as opposed to those with >200 repeats, known as the full mutation or fragile X syndrome. Originally, premutation carriers were thought to be free of phenotypic traits; however, some are diagnosed with emotional and neurocognitive issues and, later in life, with the neurodegenerative disease fragile X-associated tremor/ataxia syndrome (FXTAS). Considering that mitochondrial dysfunction has been observed in fibroblasts and post-mortem brain samples from carriers of the premutation, we hypothesized that mitochondrial dysfunction-derived ROS may result in cumulative oxidative-nitrative damage. Fibroblasts from premutation carriers (n=31, all FXTAS-free except 8), compared to age- and sex-matched controls (n=25), showed increased mitochondrial ROS production, impaired Complex I activity, lower expression of MIA40 (rate-limiting step of the redox-regulated mitochondrial-disulfide-relay-system), increased mtDNA deletions, and increased biomarkers of lipid and protein oxidative-nitrative damage. Most of the outcomes were more pronounced in FXTAS-affected individuals. Significant recovery of mitochondrial mass and/or function was obtained with superoxide or hydroxyl radicals’ scavengers, a glutathione peroxidase analog, or by overexpressing MIA40. The effects of ethanol (a hydroxyl radical scavenger) were deleterious, while others (by N-acetyl-cysteine, quercetin and epigallocatechin-3-gallate) were outcome- and/or carrier-specifics. The use of antioxidants in the context of precision medicine is discussed with the goal of improving mitochondrial function in carriers with the potential of decreasing the morbidity and/or delaying FXTAS onset.
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13. Zheng Z, Zhu T, Qu Y, Mu D. {{Blood Glutamate Levels in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis}}. {PLoS One}. 2016; 11(7): e0158688.
OBJECTIVE: Glutamate plays an important role in brain development, neuronal migration, differentiation, survival and synaptogenesis. Recent studies have explored the relationship between blood glutamate levels and autism spectrum disorder (ASD). However, the findings are inconsistent. We undertook the first systematic review with a meta-analysis of studies examining blood glutamate levels in ASD compared with controls. METHODS: A literature search was conducted using PubMed, Embase, and the Cochrane Library for studies published before March 2016. A random-effects model was used to calculate the pooled standardized mean difference (SMD) of the outcomes. Subgroup analyses were used to explore the potential sources of heterogeneity, and the publication bias was estimated using Egger’s tests. RESULTS: Twelve studies involving 880 participants and 446 incident cases were included in this meta-analysis. The meta-analysis provided evidence for higher blood glutamate levels in ASD [SMD = 0.99, 95% confidence interval (95% CI) = 0.58-1.40; P < 0.001] with high heterogeneity (I2 = 86%, P < 0.001) across studies. The subgroup analyses revealed higher glutamate levels in ASD compared with controls in plasma [SMD = 1.04, 95% CI = 0.58-1.50; P < 0.001] but not true in serum [SMD = 0.79, 95% CI = -0.41-1.99; P = 0.20]. Studies employing high performance liquid chromatography (HPLC) or liquid chromatography-tandem mass spectrometry (LC-MS) assays also revealed higher blood glutamate levels in ASD. A sensitivity analysis found that the results were stable, and there was no evidence of publication bias. CONCLUSIONS: Blood glutamate levels might be a potential biomarker of ASD. Lien vers le texte intégral (Open Access ou abonnement)
