1. Bahey NG, Gadalla KKE, McGonigal R, Bailey MES, Edgar JM, Cobb SR. {{Reduced axonal diameter of peripheral nerve fibers in a mouse model of Rett syndrome}}. {Neuroscience};2017 (Jul 04)
Rett syndrome (RTT) is a neurological disorder characterized by motor and cognitive impairment, autonomic dysfunction and a loss of purposeful hand skills. In the majority of cases, typical RTT is caused by de novo mutations in the X-linked gene, MECP2. Alterations in the structure and function of neurons within the central nervous system of RTT patients and Mecp2-null mouse models are well established. In contrast, few studies have investigated the effects of MeCP2-deficiency on peripheral nerves. In this study, we conducted detailed morphometric as well as functional analysis of the sciatic nerves of symptomatic adult female Mecp2+/- mice. We observed a significant reduction in the mean diameter of myelinated nerve fibers in Mecp2+/- mice. In myelinated fibers, mitochondrial densities per unit area of axoplasm were significantly altered in Mecp2+/- mice. However, conduction properties of the sciatic nerve of Mecp2 knockout mice were not different from control. These subtle changes in myelinated peripheral nerve fibers in heterozygous Mecp2 knockout mice could potentially explain some RTT phenotypes.
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2. Ballouz S, Gillis J. {{Strength of functional signature correlates with effect size in autism}}. {Genome Med};2017 (Jul 07);9(1):64.
BACKGROUND: Disagreements over genetic signatures associated with disease have been particularly prominent in the field of psychiatric genetics, creating a sharp divide between disease burdens attributed to common and rare variation, with study designs independently targeting each. Meta-analysis within each of these study designs is routine, whether using raw data or summary statistics, but combining results across study designs is atypical. However, tests of functional convergence are used across all study designs, where candidate gene sets are assessed for overlaps with previously known properties. This suggests one possible avenue for combining not study data, but the functional conclusions that they reach. METHOD: In this work, we test for functional convergence in autism spectrum disorder (ASD) across different study types, and specifically whether the degree to which a gene is implicated in autism is correlated with the degree to which it drives functional convergence. Because different study designs are distinguishable by their differences in effect size, this also provides a unified means of incorporating the impact of study design into the analysis of convergence. RESULTS: We detected remarkably significant positive trends in aggregate (p < 2.2e-16) with 14 individually significant properties (false discovery rate <0.01), many in areas researchers have targeted based on different reasoning, such as the fragile X mental retardation protein (FMRP) interactor enrichment (false discovery rate 0.003). We are also able to detect novel technical effects and we see that network enrichment from protein-protein interaction data is heavily confounded with study design, arising readily in control data. CONCLUSIONS: We see a convergent functional signal for a subset of known and novel functions in ASD from all sources of genetic variation. Meta-analytic approaches explicitly accounting for different study designs can be adapted to other diseases to discover novel functional associations and increase statistical power. Lien vers le texte intégral (Open Access ou abonnement)
3. Edwards LA, Wagner JB, Tager-Flusberg H, Nelson CA. {{Differences in Neural Correlates of Speech Perception in 3 Month Olds at High and Low Risk for Autism Spectrum Disorder}}. {J Autism Dev Disord};2017 (Jul 07)
In this study, we investigated neural precursors of language acquisition as potential endophenotypes of autism spectrum disorder (ASD) in 3-month-old infants at high and low familial ASD risk. Infants were imaged using functional near-infrared spectroscopy while they listened to auditory stimuli containing syllable repetitions; their neural responses were analyzed over left and right temporal regions. While female low risk infants showed initial neural activation that decreased over exposure to repetition-based stimuli, potentially indicating a habituation response to repetition in speech, female high risk infants showed no changes in neural activity over exposure. This finding may indicate a potential neural endophenotype of language development or ASD specific to females at risk for the disorder.
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4. Hillman JL, Wentzel MC, Anderson CM. {{Grandparents’ Experience of Autism Spectrum Disorder: Identifying Primary Themes and Needs}}. {J Autism Dev Disord};2017 (Jul 07)
Limited information is available regarding the first person perspective of grandparents of children with Autism Spectrum Disorders (ASD). In the present study, 1870 grandparents of a child with ASD participated in a nationwide, online, anonymous, 30-minute survey and responded to open-ended questions including their « greatest challenges and greatest joys » as the grandparent of a child on the autism spectrum. A grounded theory approach to qualitative analysis revealed four overarching categories: a Desire for Connection, Barriers to Care, Celebration of Progress, and Personal Reactions. Despite the presence of significant challenges grandparents often experienced positivity in their role, and engaged in radical acceptance of their grandchild as well as transformative insight and advocacy. Specific recommendations are offered to help address grandparents’ needs and capitalize upon their resilience.
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5. Kloth K, Denecke J, Hempel M, Johannsen J, Strom TM, Kubisch C, Lessel D. {{First de novo ANK3 nonsense mutation in a boy with intellectual disability, speech impairment and autistic features}}. {Eur J Med Genet};2017 (Jul 04)
Ankyrin-G, encoded by ANK3, plays an important role in neurodevelopment and neuronal function. There are multiple isoforms of Ankyrin-G resulting in differential tissue expression and function. Heterozygous missense mutations in ANK3 have been associated with autism spectrum disorder. Further, in three siblings a homozygous frameshift mutation affecting only the longest isoform and a patient with a balanced translocation disrupting all isoforms were documented. The latter four patients were affected by a variable degree of intellectual disability, attention deficit hyperactivity disorder and autism. Here, we report on a boy with speech impairment, intellectual disability, autistic features, macrocephaly, macrosomia, chronic hunger and an altered sleeping pattern. By trio-whole-exome sequencing, we identified the first de novo nonsense mutation affecting all ANK3 transcripts. Thus, our data expand the phenotype of ANK3-associated diseases and suggest an isoform-based, phenotypic continuum between dominant and recessive ANK3-associated pathologies.
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6. Kuo HY, Liu FC. {{Valproic acid induces aberrant development of striatal compartments and corticostriatal pathways in a mouse model of autism spectrum disorder}}. {Faseb j};2017 (Jul 07)
The striatum comprises two neurochemical compartments: striosomes and the matrix. Striosomal and matrix compartments receive inputs from limbic-related and sensorimotor cortices, respectively. Here, we investigate the impact on the corticostriosomal pathway in the valproic acid (VPA)-induced autism spectrum disorder mouse model. VPA administration during the neurogenesis time windows of striosomes, but not the matrix, resulted in aberrant compartmentation [i.e., maternal VPA injections at embryonic day (E)12.75 decreased mu-opioid receptor-positive striosomes, but increased calbindin-positive matrix in the rostral striatum]. VPAE12.75 treatment also impaired the aggregation of cells pulse labeled with 5-bromo-2′-deoxyuridine at E12.75 into striosomal cell clusters, which suggests defective segregation of striosomal cells from matrix cells. This possibility was supported by our findings that VPAE12.75 treatment altered the expression of ephrinA5 and EphA4, two molecules that are related to compartmental segregation. In the VPAE12.75 neocortex, Foxp2-positive neurons were decreased in layer VI, but increased in layer V, which projects to the striosomal compartment. We also investigated VPA effects on the corticostriosomal pathway. VPAE12.75 treatment decreased the putative corticostriosomal synapses of striosomal neurons and induced an aberrant pattern of isolation stress-induced ultrasonic vocalizations. Of interest, risperidone treatments conjointly improved ultrasonic vocalizations and restored the striosomal compartment in VPAE12.75 pups. Collectively, dysfunctional corticostriatal pathways, particularly via the aberrant striosomal compartment, may be involved in autism spectrum disorder pathophysiology.-Kuo, H.-Y., Liu, F.-C. Valproic acid induces aberrant development of striatal compartments and corticostriatal pathways in a mouse model of autism spectrum disorder.
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7. Martinez LA, Tejada-Simon MV. {{Increased Training Intensity Induces Proper Membrane Localization of Actin Remodeling Proteins in the Hippocampus Preventing Cognitive Deficits: Implications for Fragile X Syndrome}}. {Mol Neurobiol};2017 (Jul 08)
Behavioral intervention therapy has proven beneficial in the treatment of autism and intellectual disabilities (ID), raising the possibility of certain changes in molecular mechanisms activated by these interventions that may promote learning. Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by autistic features and intellectual disability and can serve as a model to examine mechanisms that promote learning. FXS results from mutations in the fragile X mental retardation 1 gene (Fmr1) that prevents expression of the Fmr1 protein (FMRP), a messenger RNA (mRNA) translation regulator at synapses. Among many other functions, FMRP organizes a complex with the actin cytoskeleton-regulating small Rho GTPase Rac1. As in humans, Fmr1 KO mice lacking FMRP display autistic-like behaviors and deformities of actin-rich synaptic structures in addition to impaired hippocampal learning and synaptic plasticity. These features have been previously linked to proper function of actin remodeling proteins that includes Rac1. An important step in Rac1 activation and function is its translocation to the membrane, where it can influence synaptic actin cytoskeleton remodeling during hippocampus-dependent learning. Herein, we report that Fmr1 KO mouse hippocampus exhibits increased levels of membrane-bound Rac1, which may prevent proper learning-induced synaptic changes. We also determine that increasing training intensity during fear conditioning (FC) training restores contextual memory in Fmr1 KO mice and reduces membrane-bound Rac1 in Fmr1 KO hippocampus. Increased training intensity also results in normalized long-term potentiation in hippocampal slices taken from Fmr1 KO mice. These results point to interventional treatments providing new therapeutic options for FXS-related cognitive dysfunction.
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8. May CD, St George JM, Fletcher RJ, Dempsey I, Newman LK. {{Coparenting Competence in Parents of Children with ASD: A Marker of Coparenting Quality}}. {J Autism Dev Disord};2017 (Jul 07)
The coparenting relationship has been linked to parenting stress, parenting self-efficacy and many other concerns associated with the development of children with ASD. Parents of children with ASD (N = 22) were interviewed to explore three domains of their coparenting relationship; (1) adaptation to the emergence of their child’s autism, (2) parenting their child with ASD, (3) expectations for their child’s developmental outcomes. The concept of coparenting competence, developed during analysis, describes collective perceptions of parenting efficacy. Parents linked perceptions of coparenting competence to their, ability to cope with diagnosis and parenting, motivation to do what they could for their child, and hopes for their child’s development. The concept of coparenting competence could play an important role in future research and intervention.
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9. Ring M, Bowler DM, Gaigg SB. {{An Eye-Movement Study of relational Memory in Adults with Autism Spectrum Disorder}}. {J Autism Dev Disord};2017 (Jul 07)
Persons with Autism Spectrum Disorder (ASD) demonstrate good memory for single items but difficulties remembering contextual information related to these items. Recently, we found compromised explicit but intact implicit retrieval of object-location information in ASD (Ring et al. Autism Res 8(5):609-619, 2015). Eye-movement data collected from a sub-sample of the participants are the focus of the current paper. At encoding, trial-by-trial viewing durations predicted subsequent retrieval success only in typically developing (TD) participants. During retrieval, TD compared to ASD participants looked significantly longer at previously studied object-locations compared to alternative locations. These findings extend similar observations recently reported by Cooper et al. (Cognition 159:127-138, 2017a) and demonstrate that eye-movement data can shed important light on the source and nature of relational memory difficulties in ASD.
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10. Singh BD, Moore DW, Furlonger BE, Anderson A, Busacca ML, English DL. {{Teaching Reading Comprehension Skills to a Child with Autism Using Behaviour Skills Training}}. {J Autism Dev Disord};2017 (Jul 07)
A multiple probe design across skills was used to examine the effects of behaviour skills training (BST) on teaching four reading comprehension skills (predicting, questioning, clarifying, and summarizing) to a 7th grade student with autism. Following baseline, the student received 12 sessions of BST during which each skill was taught to criterion. At each session, data was also collected on the accuracy of oral responses to 10 comprehension questions. BST was associated with clear gains in the participant’s performance on each comprehension skill, along with concomitant gains in reading comprehension both on the daily probes and a standardized measure. Skills maintained at follow-up support the conclusion that BST was effective in improving the comprehension skills of a child with autism.
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11. Smith D, Ropar D, Allen HA. {{The Integration of Occlusion and Disparity Information for Judging Depth in Autism Spectrum Disorder}}. {J Autism Dev Disord};2017 (Jul 07)
In autism spectrum disorder (ASD), atypical integration of visual depth cues may be due to flattened perceptual priors or selective fusion. The current study attempts to disentangle these explanations by psychophysically assessing within-modality integration of ordinal (occlusion) and metric (disparity) depth cues while accounting for sensitivity to stereoscopic information. Participants included 22 individuals with ASD and 23 typically developing matched controls. Although adults with ASD were found to have significantly poorer stereoacuity, they were still able to automatically integrate conflicting depth cues, lending support to the idea that priors are intact in ASD. However, dissimilarities in response speed variability between the ASD and TD groups suggests that there may be differences in the perceptual decision-making aspect of the task.
