1. Baig DN, Yanagawa T, Tabuchi K. {{Distortion of the normal function of synaptic cell adhesion molecules by genetic variants as a risk for autism spectrum disorders}}. {Brain Res Bull};2016 (Oct 12)
Synaptic cell adhesion molecules (SCAMs) are a functional category of cell adhesion molecules that connect pre- and postsynapses by the protein-protein interaction via their extracellular cell adhesion domains. Countless numbers of common genetic variants and rare mutations in SCAMs have been identified in the patients with autism spectrum disorders (ASDs). Among these, NRXN and NLGN family proteins cooperatively function at synaptic terminals both of which genes are strongly implicated as risk genes for ASDs. Knock-in mice carrying a single rare point mutation of NLGN3 (NLGN3 R451C) discovered in the patients with ASDs display a deficit in social interaction and an enhancement of spatial learning and memory ability reminiscent of the clinical phenotype of ASDs. NLGN4 knockout (KO) and NRXN2alpha KO mice also show a deficit in sociability as well as some specific neuropsychiatric behaviors. In this review, we selected NRXNs/NLGNs, CNTNAP2/CNTNAP4, CNTN4, ITGB3, and KIRREL3 as strong ASD risk genes based on SFARI score and summarize the protein structures, functions at synapses, representative discoveries in human genetic studies, and phenotypes of the mutant model mice in light of the pathophysiology of ASDs.
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2. Constantin L. {{The Role of MicroRNAs in Cerebellar Development and Autism Spectrum Disorder During Embryogenesis}}. {Mol Neurobiol};2016 (Oct 24)
MicroRNAs (miRNAs) are a class of small non-coding RNA molecules with wide-ranging and subtle effects on protein production. Their activity during the development of the cerebellum provides a valuable exemplar of how non-coding molecules may assist the development and function of the central nervous system and drive neurodevelopmental disorders. Three distinct aspects of miRNA contribution to early cerebellar development will here be reviewed. Aspects are the establishment of the cerebellar anlage, the generation and maturation of at least two principal cell types of the developing cerebellar microcircuit, and the etiology and early progression of autism spectrum disorder. It will be argued here that the autism spectrum is an adept model to explore miRNA impact on the cognitive and affective processes that descend from the developing cerebellum.
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3. Fischer J, Smith H, Martinez-Pedraza F, Carter AS, Kanwisher N, Kaldy Z. {{Unimpaired attentional disengagement in toddlers with autism spectrum disorder}}. {Dev Sci};2016 (Nov);19(6):1095-1103.
A prominent hypothesis holds that ‘sticky’ attention early in life in children with autism spectrum disorder (ASD) limits their ability to explore and learn about the world. Under this hypothesis, the core clinical symptoms of ASD – restricted interests, repetitive behaviors and impaired social/communication abilities – could all result from impaired attentional disengagement during development. However, the existence of disengagement deficits in children with ASD is controversial, and a recent study found no deficit in 5- to 12-year-olds with ASD. Nonetheless, the possibility remains that disengagement is impaired earlier in development in children with ASD, altering their developmental trajectory even if the attentional deficit itself is remediated or compensated for by the time children with ASD reach school age. Here, we tested this possibility by characterizing attentional disengagement in a group of toddlers just diagnosed with ASD (age 21 to 37 months). We found strikingly similar performance between the ASD and age-matched typically developing (TD) toddlers, and no evidence of impaired attentional disengagement. These results show that even at a young age when the clinical symptoms of ASD are first emerging, disengagement abilities are intact. Sticky attention is not a fundamental characteristic of ASD, and probably does not play a causal role in its etiology.
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4. Fregeac J, Colleaux L, Nguyen LS. {{The emerging roles of MicroRNAs in Autism Spectrum Disorders}}. {Neurosci Biobehav Rev};2016 (Oct 25)
Autism spectrum disorders (ASD) are heritable neurodevelopmental conditions characterized by impairment in social interaction and communication and restricted, repetitive, stereotyped patterns of behavior. ASD likely involve deregulation of multiple genes related to brain function and development. MicroRNAs (miRNAs) are post-transcriptional regulators that play key roles in brain development, synapse formation and fine-tuning of genes underlying synaptic plasticity and memory formation. Here, we review recent studies providing genetic and molecular links between miRNA deregulation and ASD pathophysiology. These findings highlight the potential of miRNAs as both biomarkers and therapeutic tools in ASD.
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5. Frye RE, Rose S, Chacko J, Wynne R, Bennuri SC, Slattery JC, Tippett M, Delhey L, Melnyk S, Kahler SG, MacFabe DF. {{Modulation of mitochondrial function by the microbiome metabolite propionic acid in autism and control cell lines}}. {Transl Psychiatry};2016 (Oct 25);6(10):e927.
Propionic acid (PPA) is a ubiquitous short-chain fatty acid, which is a major fermentation product of the enteric microbiome. PPA is a normal intermediate of metabolism and is found in foods, either naturally or as a preservative. PPA and its derivatives have been implicated in both health and disease. Whereas PPA is an energy substrate and has many proposed beneficial effects, it is also associated with human disorders involving mitochondrial dysfunction, including propionic acidemia and autism spectrum disorders (ASDs). We aimed to investigate the dichotomy between the health and disease effects of PPA by measuring mitochondrial function in ASD and age- and gender-matched control lymphoblastoid cell lines (LCLs) following incubation with PPA at several concentrations and durations both with and without an in vitro increase in reactive oxygen species (ROS). Mitochondrial function was optimally increased at particular exposure durations and concentrations of PPA with ASD LCLs, demonstrating a greater enhancement. In contrast, increasing ROS negated the positive PPA effect with the ASD LCLs, showing a greater detriment. These data demonstrate that enteric microbiome metabolites such as PPA can have both beneficial and toxic effects on mitochondrial function, depending on concentration, exposure duration and microenvironment redox state with these effects amplified in LCLs derived from individuals with ASD. As PPA, as well as enteric bacteria, which produce PPA, have been implicated in a wide variety of diseases, including ASD, diabetes, obesity and inflammatory diseases, insight into this metabolic modulator from the host microbiome may have wide applications for both health and disease.
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6. Hardiman RL, Bratt A. {{Hypothalamic-pituitary-adrenal axis function in Fragile X Syndrome and its relationship to behaviour: A systematic review}}. {Physiol Behav};2016 (Oct 5);167:341-353.
Fragile X Syndrome (FXS) is characterised by features including anxiety and autistic-like behaviour, which led to early hypotheses that aberrant physiological arousal may underlie the behavioural phenotype. In line with this, several lines of evidence suggest that the hypothalamic-pituitary-adrenal (HPA) axis may be altered in the syndrome. This review collates evidence to determine the nature of HPA axis baseline activity and reactivity (as measured by glucocorticoid levels) differences in FXS, and its relationship to behaviour. Through a search of electronic databases, 15 papers were identified which provided data on humans with FXS or the FMR1 knockout mouse model. The findings across studies are mixed, though trends in the findings can be seen, including elevations in cortisol levels, particularly in males. Preliminary findings also highlight associations between cortisol levels and key behaviours associated with the syndrome, such as gaze avoidance. Areas for future research are discussed.
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7. Lane C, Milne E, Freeth M. {{Characteristics of Autism Spectrum Disorder in Sotos Syndrome}}. {J Autism Dev Disord};2016 (Oct 22)
Sotos syndrome is a congenital overgrowth disorder with an incidence of approximately 1 in 14,000. This study investigated behavioural characteristics of ASD within a large cohort of individuals with Sotos syndrome (n = 78). As measured by the Social Responsiveness Scale, second edition (SRS-2), 65 participants (83.33 %) met clinical cut-off (T-score >/=60). There was no significant gender difference in symptom severity. There was a significant effect of age, with lower scores observed in early childhood and adulthood, compared to childhood. Furthermore, individuals with Sotos syndrome appear to display a trait profile that is similar to that identified in ASD. Overall, these findings indicate that the majority of individuals with Sotos syndrome display clinically significant behavioural symptomatology associated with ASD.
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8. Martinez-Murcia FJ, Lai MC, Gorriz JM, Ramirez J, Young AM, Deoni SC, Ecker C, Lombardo MV, Baron-Cohen S, Murphy DG, Bullmore ET, Suckling J. {{On the brain structure heterogeneity of autism: Parsing out acquisition site effects with significance-weighted principal component analysis}}. {Hum Brain Mapp};2016 (Oct 24)
Neuroimaging studies have reported structural and physiological differences that could help understand the causes and development of Autism Spectrum Disorder (ASD). Many of them rely on multisite designs, with the recruitment of larger samples increasing statistical power. However, recent large-scale studies have put some findings into question, considering the results to be strongly dependent on the database used, and demonstrating the substantial heterogeneity within this clinically defined category. One major source of variance may be the acquisition of the data in multiple centres. In this work we analysed the differences found in the multisite, multi-modal neuroimaging database from the UK Medical Research Council Autism Imaging Multicentre Study (MRC AIMS) in terms of both diagnosis and acquisition sites. Since the dissimilarities between sites were higher than between diagnostic groups, we developed a technique called Significance Weighted Principal Component Analysis (SWPCA) to reduce the undesired intensity variance due to acquisition site and to increase the statistical power in detecting group differences. After eliminating site-related variance, statistically significant group differences were found, including Broca’s area and the temporo-parietal junction. However, discriminative power was not sufficient to classify diagnostic groups, yielding accuracies results close to random. Our work supports recent claims that ASD is a highly heterogeneous condition that is difficult to globally characterize by neuroimaging, and therefore different (and more homogenous) subgroups should be defined to obtain a deeper understanding of ASD. Hum Brain Mapp, 2016. (c) 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.
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9. Mesbah-Oskui L, Penna A, Orser BA, Horner RL. {{Reduced expression of alpha5GABAA receptors elicits autism-like alterations in EEG patterns and sleep-wake behavior}}. {Neurotoxicol Teratol};2016 (Oct 25)
A reduction in the activity of GABAA receptors, particularly alpha5 subunit-containing GABAA receptors (alpha5GABAARs), has been implicated in the etiology of Autism Spectrum Disorders (ASD). Genetically modified mice that lack alpha5GABAARs (Gabra5-/-) exhibit autism-like behaviors and both enhanced and impaired learning and memory, depending on the behavioral task. The aim of this study was to examine the electroencephalogram (EEG) activity and sleep-wake behaviors in Gabra5-/- mice and wild-type mice. In addition, since some individuals with ASD can exhibit elevated innate immune response, mice were treated with lipopolysaccharide (LPS; 125mg/kg intraperitoneal injection) or vehicle and EEG and sleep-wake patterns were assessed. The results showed that Gabra5-/- mice (n=3) exhibited elevated 0-2Hz EEG activity during all sleep-wake states (all p<0.04), decreased 8-12Hz EEG activity during REM sleep (p=0.04), and decreased sleep spindles under baseline conditions compared to wild-type controls (n=4) (all pLien vers le texte intégral (Open Access ou abonnement)
10. Mony TJ, Lee JW, Dreyfus C, DiCicco-Bloom E, Lee HJ. {{Valproic Acid Exposure during Early Postnatal Gliogenesis Leads to Autistic-like Behaviors in Rats}}. {Clin Psychopharmacol Neurosci};2016 (Nov 30);14(4):338-344.
Objective: We reported that postnatal exposure of rats to valproic acid (VPA) stimulated proliferation of glial precursors during cortical gliogenesis. However, there are no reports whether enhanced postnatal gliogenesis affects behaviors related to neuropsychiatric disorders. Methods: After VPA treatment during the postnatal day (PND) 2 to PND 4, four behavioral test, such as open field locomotor test, elevated plus maze test, three-chamber social interaction test, and passive avoidance test, were performed at PND 21 or 22. Results: VPA treated rats showed significant hyperactive behavior in the open field locomotor test (p<0.05). Moreover, the velocity of movement in the VPA group was increased by 69.5% (p<0.01). In the elevated plus maze test, VPA exposed rats expressed significantly lower percentage of time spent on and of entries into open arms more than the control group (p<0.05). Also, both sociability and social preference indices with strangers in the three-chamber social interaction test were significantly lower in the VPA exposed rats (p<0.05). Conclusion: Our results suggest that altered glial cell development is another locus at which pathogenetic factors can operate to contribute to the neurodevelopmental disorder. Lien vers le texte intégral (Open Access ou abonnement)
11. Pace M, Dumortier L, Favre-Juvin A, Guinot M, Bricout VA. {{Heart rate variability during sleep in children with autism spectrum disorders}}. {Physiol Behav};2016 (Sep 29);167:309-312.
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12. Pardo M, Beurel E, Jope RS. {{Cotinine administration improves impaired cognition in the mouse model of Fragile X syndrome}}. {Eur J Neurosci};2016 (Oct 24)
Cotinine is the major metabolite of nicotine and has displayed some capacity for improving cognition in mouse models following chronic administration. We tested if acute cotinine treatment is capable of improving cognition in the mouse model of Fragile X syndrome, Fmr1-/- knockout mice, and if this is related to inhibition by cotinine treatment of glycogen synthase kinase-3beta (GSK3beta), which is abnormally active in Fmr1-/- mice. Acute cotinine treatment increased the inhibitory serine-phosphorylation of GSK3beta and the activating phosphorylation of AKT, which can mediate serine-phosphorylation of GSK3beta, in both wild-type and Fmr1-/- mouse hippocampus. Acute cotinine treatment improved cognitive functions of Fmr1-/- mice in coordinate and categorical spatial processing, novel object recognition, and temporal ordering. However, cotinine failed to restore impaired cognition in GSK3beta knockin mice, in which a serine9-to-alanine9 mutation blocks the inhibitory serine phosphorylation of GSK3beta, causing GSK3beta to be hyperactive. These results indicate that acute cotinine treatment effectively repairs impairments of these four cognitive tasks in Fmr1-/- mice, and suggest that this cognition-enhancing effect of cotinine is linked to its induction of inhibitory serine-phosphorylation of GSK3. Taken together, these results show nicotinic receptor agonists can act as cognitive enhancers in a mouse model of Fragile X syndrome and highlight the potential role of inhibiting GSK3beta in mediating the effects of cotinine on memory. This article is protected by copyright. All rights reserved.
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13. Raut MS, Dubey S, Maheshwari A, Sharma M. {{Embolised ASD device in LV}}. {Indian Heart J};2016 (Sep – Oct);68(5):718-719.
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14. Schenkel LC, Schwartz C, Skinner C, Rodenhiser DI, Ainsworth PJ, Pare G, Sadikovic B. {{Clinical Validation of Fragile X Syndrome Screening by DNA Methylation Array}}. {J Mol Diagn};2016 (Nov);18(6):834-841.
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. It is most frequently caused by an abnormal expansion of the CGG trinucleotide repeat (>200 repeats) located in the promoter of the fragile X mental retardation gene (FMR1), resulting in promoter DNA hypermethylation and gene silencing. Current clinical tests for FXS are technically challenging and labor intensive, and may involve use of hazardous chemicals or radioisotopes. We clinically validated the Illumina Infinium HumanMethylation450 DNA methylation array for FXS screening. We assessed genome-wide and FMR1-specific DNA methylation in 32 males previously diagnosed with FXS, including nine with mosaicism, as well as five females with full mutation, and premutation carrier males (n = 11) and females (n = 11), who were compared to 300 normal control DNA samples. Our findings demonstrate 100% sensitivity and specificity for detection of FXS in male patients, as well as the ability to differentiate patients with mosaic methylation defects. Full mutation and premutation carrier females did not show FMR1 methylation changes. We have clinically validated this genome-wide DNA methylation assay as a cost- and labor-effective alternative for sensitive and specific screening for FXS, while ruling out the most common differential diagnoses of FXS, Prader-Willi syndrome, and Sotos syndrome in the same assay.
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15. Sharpley CF, Bitsika V, Andronicos NM, Agnew LL. {{Further evidence of HPA-axis dysregulation and its correlation with depression in Autism Spectrum Disorders: Data from girls}}. {Physiol Behav};2016 (Sep 13);167:110-117.
To further describe Hypothalamus-Pituitary-Adrenal (HPA) axis activity in children with Autism Spectrum Disorder (ASD), the Diurnal Fluctuation (DF) and Cortisol Awakening Response (CAR) were investigated in a sample of 39 high functioning girls with ASD. Although group mean data conformed to the DF and CAR models, over half of the participants showed inverse CAR and over 14% had inverted DF cortisol concentrations. Examination of three potential sets of predictor factors (physiological, ASD-related, and mood) revealed that only self-reported Major Depressive Disorder was significantly associated with CAR status, and that the girls’ concern about dying or suicide was the most powerful contributor to the variance in CAR status. These findings add to the literature regarding the HPA axis dysfunction in children with ASD.
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16. Somekh J, Peleg M, Eran A, Koren I, Feiglin A, Demishtein A, Shiloh R, Heiner M, Kong SW, Elazar Z, Kohane I. {{A model-driven methodology for exploring complex disease comorbidities applied to autism spectrum disorder and inflammatory bowel disease}}. {J Biomed Inform};2016 (Oct);63:366-378.
We propose a model-driven methodology aimed to shed light on complex disorders. Our approach enables exploring shared etiologies of comorbid diseases at the molecular pathway level. The method, Comparative Comorbidities Simulation (CCS), uses stochastic Petri net simulation for examining the phenotypic effects of perturbation of a network known to be involved in comorbidities to predict new roles for mutations in comorbid conditions. To demonstrate the utility of our novel methodology, we investigated the molecular convergence of autism spectrum disorder (ASD) and inflammatory bowel disease (IBD) on the autophagy pathway. In addition to validation by domain experts, we used formal analyses to demonstrate the model’s self-consistency. We then used CCS to compare the effects of loss of function (LoF) mutations previously implicated in either ASD or IBD on the autophagy pathway. CCS identified similar dynamic consequences of these mutations in the autophagy pathway. Our method suggests that two LoF mutations previously implicated in IBD may contribute to ASD, and one ASD-implicated LoF mutation may play a role in IBD. Future targeted genomic or functional studies could be designed to directly test these predictions.
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17. Strang JF, Meagher H, Kenworthy L, de Vries AL, Menvielle E, Leibowitz S, Janssen A, Cohen-Kettenis P, Shumer DE, Edwards-Leeper L, Pleak RR, Spack N, Karasic DH, Schreier H, Balleur A, Tishelman A, Ehrensaft D, Rodnan L, Kuschner ES, Mandel F, Caretto A, Lewis HC, Anthony LG. {{Initial Clinical Guidelines for Co-Occurring Autism Spectrum Disorder and Gender Dysphoria or Incongruence in Adolescents}}. {J Clin Child Adolesc Psychol};2016 (Oct 24):1-11.
Evidence indicates an overrepresentation of youth with co-occurring autism spectrum disorders (ASD) and gender dysphoria (GD). The clinical assessment and treatment of adolescents with this co-occurrence is often complex, related to the developmental aspects of ASD. There are no guidelines for clinical care when ASD and GD co-occur; however, there are clinicians and researchers experienced in this co-occurrence. This study develops initial clinical consensus guidelines for the assessment and care of adolescents with co-occurring ASD and GD, from the best clinical practices of current experts in the field. Expert participants were identified through a comprehensive international search process and invited to participate in a two-stage Delphi procedure to form clinical consensus statements. The Delphi Method is a well-studied research methodology for obtaining consensus among experts to define appropriate clinical care. Of 30 potential experts identified, 22 met criteria as expert in co-occurring ASD and GD youth and participated. Textual data divided into the following data nodes: guidelines for assessment; guidelines for treatment; six primary clinical/psychosocial challenges: social functioning, medical treatments and medical safety, risk of victimization/safety, school, and transition to adulthood issues (i.e., employment and romantic relationships). With a cutoff of 75% consensus for inclusion, identified experts produced a set of initial guidelines for clinical care. Primary themes include the importance of assessment for GD in ASD, and vice versa, as well as an extended diagnostic period, often with overlap/blurring of treatment and assessment.
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18. Vuong HE, Hsiao EY. {{Emerging Roles for the Gut Microbiome in Autism Spectrum Disorder}}. {Biol Psychiatry};2016 (Aug 26)
Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder that affects one in 45 children in the United States, with a similarly striking prevalence in countries around the world. However, mechanisms underlying its etiology and manifestations remain poorly understood. Although ASD is diagnosed based on the presence and severity of impaired social communication and repetitive behavior, immune dysregulation and gastrointestinal issues are common comorbidities. The microbiome is an integral part of human physiology; recent studies show that changes in the gut microbiota can modulate gastrointestinal physiology, immune function, and even behavior. Links between particular bacteria from the indigenous gut microbiota and phenotypes relevant to ASD raise the important question of whether microbial dysbiosis plays a role in the development or presentation of ASD symptoms. Here we review reports of microbial dysbiosis in ASD. We further discuss potential effects of the microbiota on ASD-associated symptoms, drawing on signaling mechanisms for reciprocal interactions among the microbiota, immunity, gut function, and behavior. In addition, we discuss recent findings supporting a role for the microbiome as an interface between environmental and genetic risk factors that are associated with ASD. These studies highlight the integration of pathways across multiple body systems that together can impact brain and behavior and suggest that changes in the microbiome may contribute to symptoms of neurodevelopmental disease.
