1. Bauman MD, Schumann CS. {{Advances in nonhuman primate models of autism: Integrating neuroscience and behavior}}. {Exp Neurol};2017 (Jul 31)
Given the prevalence and societal impact of autism spectrum disorders (ASD), there is an urgent need to develop innovative preventative strategies and treatments to reduce the alarming number of cases and improve core symptoms for afflicted individuals. Translational efforts between clinical and preclinical research are needed to (i) identify and evaluate putative causes of ASD, (ii) determine the underlying neurobiological mechanisms, (iii) develop and test novel therapeutic approaches and (iv) ultimately translate basic research into safe and effective clinical practices. However, modeling a uniquely human brain disorder, such as ASD, will require sophisticated animal models that capitalize on unique advantages of diverse species including drosophila, zebra fish, mice, rats, and ultimately, species more closely related to humans, such as the nonhuman primate. Here we discuss the unique contributions of the rhesus monkey (Macaca mulatta) model to ongoing efforts to understand the neurobiology of the disorder, focusing on the convergence of brain and behavior outcome measures that parallel features of human ASD.
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2. Bhattacherjee A, Mu Y, Winter MK, Knapp JR, Eggimann LS, Gunewardena SS, Kobayashi K, Kato S, Krizsan-Agbas D, Smith PG. {{Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome}}. {Proc Natl Acad Sci U S A};2017 (Jul 31)
Children with Rett syndrome show abnormal cutaneous sensitivity. The precise nature of sensory abnormalities and underlying molecular mechanisms remain largely unknown. Rats with methyl-CpG binding protein 2 (MeCP2) mutation, characteristic of Rett syndrome, show hypersensitivity to pressure and cold, but hyposensitivity to heat. They also show cutaneous hyperinnervation by nonpeptidergic sensory axons, which include subpopulations encoding noxious mechanical and cold stimuli, whereas peptidergic thermosensory innervation is reduced. MeCP2 knockdown confined to dorsal root ganglion sensory neurons replicated this phenotype in vivo, and cultured MeCP2-deficient ganglion neurons showed augmented axonogenesis. Transcriptome analysis revealed dysregulation of genes associated with cytoskeletal dynamics, particularly those controlling actin polymerization and focal-adhesion formation necessary for axon growth and mechanosensory transduction. Down-regulation of these genes by topoisomerase inhibition prevented abnormal axon sprouting. We identified eight key affected genes controlling actin signaling and adhesion formation, including members of the Arhgap, Tiam, and cadherin families. Simultaneous virally mediated knockdown of these genes in Rett rats prevented sensory hyperinnervation and reversed mechanical hypersensitivity, indicating a causal role in abnormal outgrowth and sensitivity. Thus, MeCP2 regulates ganglion neuronal genes controlling cytoskeletal dynamics, which in turn determines axon outgrowth and mechanosensory function and may contribute to altered pain sensitivity in Rett syndrome.
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3. Cameron JM, Levandovskiy V, Roberts W, Anagnostou E, Scherer S, Loh A, Schulze A. {{Variability of Creatine Metabolism Genes in Children with Autism Spectrum Disorder}}. {Int J Mol Sci};2017 (Jul 31);18(8)
Creatine deficiency syndrome (CDS) comprises three separate enzyme deficiencies with overlapping clinical presentations: arginine:glycine amidinotransferase (GATM gene, glycine amidinotransferase), guanidinoacetate methyltransferase (GAMT gene), and creatine transporter deficiency (SLC6A8 gene, solute carrier family 6 member 8). CDS presents with developmental delays/regression, intellectual disability, speech and language impairment, autistic behaviour, epileptic seizures, treatment-refractory epilepsy, and extrapyramidal movement disorders; symptoms that are also evident in children with autism. The objective of the study was to test the hypothesis that genetic variability in creatine metabolism genes is associated with autism. We sequenced GATM, GAMT and SLC6A8 genes in 166 patients with autism (coding sequence, introns and adjacent untranslated regions). A total of 29, 16 and 25 variants were identified in each gene, respectively. Four variants were novel in GATM, and 5 in SLC6A8 (not present in the 1000 Genomes, Exome Sequencing Project (ESP) or Exome Aggregation Consortium (ExAC) databases). A single variant in each gene was identified as non-synonymous, and computationally predicted to be potentially damaging. Nine variants in GATM were shown to have a lower minor allele frequency (MAF) in the autism population than in the 1000 Genomes database, specifically in the East Asian population (Fisher’s exact test). Two variants also had lower MAFs in the European population. In summary, there were no apparent associations of variants in GAMT and SLC6A8 genes with autism. The data implying there could be a lower association of some specific GATM gene variants with autism is an observation that would need to be corroborated in a larger group of autism patients, and with sub-populations of Asian ethnicities. Overall, our findings suggest that the genetic variability of creatine synthesis/transport is unlikely to play a part in the pathogenesis of autism spectrum disorder (ASD) in children.
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4. Ford TC, Nibbs R, Crewther DP. {{Glutamate/GABA+ ratio is associated with the psychosocial domain of autistic and schizotypal traits}}. {PLoS One};2017;12(7):e0181961.
BACKGROUND: The autism and schizophrenia spectra overlap to a large degree in the social and interpersonal domains. Similarly, abnormal excitatory glutamate and inhibitory gamma-aminobutyric acid (GABA) neurotransmitter concentrations have been reported for both spectra, with the interplay of these neurotransmitters important for cortical excitation to inhibition regulation. This study investigates whether these neurotransmitter abnormalities are specific to the shared symptomatology, and whether the degree of abnormality increases with increasing symptom severity. Hence, the relationship between the glutamate/GABA ratio and autism and schizophrenia spectrum traits in an unmedicated, subclinical population was investigated. METHODS: A total of 37 adults (19 female, 18 male) aged 18-38 years completed the Autism Spectrum Quotient (AQ) and Schizotypal Personality Questionnaire (SPQ), and participated in the resting state proton magnetic resonance spectroscopy study in which sequences specific for quantification of glutamate and GABA+ concentration were applied to a right and left superior temporal voxel. RESULTS: There were significant, moderate, positive relationships between right superior temporal glutamate/GABA+ ratio and AQ, SPQ and AQ+SPQ total scores (p<0.05), SPQ subscales Social Anxiety, No Close Friend, Constricted Affect, Odd Behaviour, Odd Speech, Ideas of Reference and Suspiciousness, and AQ subscales Social Skills, Communication and Attention Switching (p<0.05); increased glutamate/GABA+ coinciding with higher scores on these subscales. Only the relationships between glutamate/GABA+ ratio and Social Anxiety, Constricted Affect, Social Skills and Communication survived multiple comparison correction (p< 0.004). Left superior temporal glutamate/GABA+ ratio reduced with increasing restricted imagination (p<0.05). CONCLUSION: These findings demonstrate evidence for an association between excitatory/inhibitory neurotransmitter concentrations and symptoms that are shared between the autism and schizophrenia spectra. Lien vers le texte intégral (Open Access ou abonnement)
5. Horie M, Okamura H. {{Exploring a method for evaluation of preschool and school children with autism spectrum disorder through checking their understanding of the speaker’s emotions with the help of prosody of the voice}}. {Brain Dev};2017 (Jul 31)
PURPOSE: We attempted to evaluate the ability of 125 preschool and school children with autism spectrum disorder (ASD children) to understand the intentions of those speaking to them using prosody of the voice, by comparing it with that of 119 typically developing children (TDC) and 51 development-age-matched children with attention deficit hyperactivity disorder (ADHD children), and to explore, based on the results, a method for objective evaluation of children with ASD in the early and later periods of childhood. METHODS: Phrases routinely used by children were employed in the task administered to the children, with the prosody of the voice speaking these phrases changed to express the four emotions (acceptance, rejection, bluff and fooling). RESULTS: The percentage of children with ASD who could correctly identify the emotion of « fooling » was significantly lower than that of TDC, at each developmental age (corresponding to middle kindergarten class to sixth year of elementary school). On the other hand, in the children with ADHD, while the correct answer rate for identifying the emotion of « fooling » was significantly lower than that in the TDC and higher than that in the ASD children at development ages corresponding to the early years of elementary school, it did not differ significantly from that in the TDC and was higher than that ASD children at development ages corresponding to the later years of elementary school. CONCLUSION: These results indicate that children with ASD find it particularly difficult to understand the emotion of fooling by listening to speech with discrepancy between the meaning of the phrases and the emotion expressed by the voice, although the prosody of the voice may serve as a key to understanding the emotion of the speakers. This finding also suggests that the prosody of the voice expressing this emotion (fooling) may be used for objective evaluation of children with ASD.
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6. Kamitakahara A, Wu HH, Levitt P. {{Distinct Projection Targets Define Subpopulations of Mouse Brainstem Vagal Neurons that Express the Autism-Associated MET Receptor Tyrosine Kinase}}. {J Comp Neurol};2017 (Jul 31)
Detailed anatomical tracing and mapping of the viscerotopic organization of the vagal motor nuclei has provided insight into autonomic function in health and disease. To further define specific cellular identities, we paired information based on visceral connectivity with a cell-type specific marker of a subpopulation of neurons in the dorsal motor nucleus of the vagus (DMV) and nucleus ambiguus (nAmb) that express the autism-associated MET receptor tyrosine kinase. As gastrointestinal disturbances are common in children with autism spectrum disorder (ASD), we sought to define the relationship between MET-expressing (MET+) neurons in the DMV and nAmb, and the gastrointestinal tract. Using wholemount tissue staining and clearing, or retrograde tracing in a METEGFP transgenic mouse, we identify three novel subpopulations of EGFP+ vagal brainstem neurons: 1) EGFP+ neurons in the nAmb projecting to the esophagus or laryngeal muscles, 2) EGFP+ neurons in the medial DMV projecting to the stomach, and 3) EGFP+ neurons in the lateral DMV projecting to the cecum and/or proximal colon. Expression of the MET ligand, hepatocyte growth factor (HGF), by tissues innervated by vagal motor neurons during fetal development reveal potential sites of HGF-MET interaction. Furthermore, similar cellular expression patterns of MET in the brainstem of both the mouse and nonhuman primate suggest that MET expression at these sites is evolutionarily conserved. Together, the data suggest that MET+ neurons in the brainstem vagal motor nuclei are anatomically positioned to regulate distinct portions of the gastrointestinal tract, with implications for the pathophysiology of gastrointestinal comorbidities of ASD. This article is protected by copyright. All rights reserved.
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7. Lawson RP, Mathys C, Rees G. {{Adults with autism overestimate the volatility of the sensory environment}}. {Nat Neurosci};2017 (Jul 31)
Insistence on sameness and intolerance of change are among the diagnostic criteria for autism spectrum disorder (ASD), but little research has addressed how people with ASD represent and respond to environmental change. Here, behavioral and pupillometric measurements indicated that adults with ASD are less surprised than neurotypical adults when their expectations are violated, and decreased surprise is predictive of greater symptom severity. A hierarchical Bayesian model of learning suggested that in ASD, a tendency to overlearn about volatility in the face of environmental change drives a corresponding reduction in learning about probabilistically aberrant events, thus putatively rendering these events less surprising. Participant-specific modeled estimates of surprise about environmental conditions were linked to pupil size in the ASD group, thus suggesting heightened noradrenergic responsivity in line with compromised neural gain. This study offers insights into the behavioral, algorithmic and physiological mechanisms underlying responses to environmental volatility in ASD.
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8. Shpigler HY, Saul MC, Corona F, Block L, Cash Ahmed A, Zhao SD, Robinson GE. {{Deep evolutionary conservation of autism-related genes}}. {Proc Natl Acad Sci U S A};2017 (Jul 31)
E. O. Wilson proposed in Sociobiology that similarities between human and animal societies reflect common mechanistic and evolutionary roots. When introduced in 1975, this controversial hypothesis was beyond science’s ability to test. We used genomic analyses to determine whether superficial behavioral similarities in humans and the highly social honey bee reflect common molecular mechanisms. Here, we report that gene expression signatures for individual bees unresponsive to various salient social stimuli are significantly enriched for autism spectrum disorder-related genes. These signatures occur in the mushroom bodies, a high-level integration center of the insect brain. Furthermore, our finding of enrichment was unique to autism spectrum disorders; brain gene expression signatures from other honey bee behaviors do not show this enrichment, nor do datasets from other human behavioral and health conditions. These results demonstrate deep conservation for genes associated with a human social pathology and individual differences in insect social behavior, thus providing an example of how comparative genomics can be used to test sociobiological theory.
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9. Sturner R, Howard B, Bergmann P, Morrel T, Landa R, Walton K, Marks D. {{Accurate Autism Screening at the 18-Month Well-Child Visit Requires Different Strategies than at 24 Months}}. {J Autism Dev Disord};2017 (Jul 31)
Accuracy of autism screening using M-CHAT plus the follow-up interview (M-CHAT/F) for children screened positive at 18-months was compared to screening at 24-months. Formal ASD testing was criterion for a community sample of M-CHAT positive children (n = 98), positive predictive value (PPV) was 0.40 for the M-CHAT and 0.58 for the M-CHAT/F. MCHAT/F PPV was 0.69 among children 20+ months compared to 0.36 for <20 months. Multivariate analyses incorporating data from the Ages and Stages Questionnaire, MacArthur-Bates Communicative Development Inventory, M-CHAT and M-CHAT/F results, and M-CHAT items suggest language variables carry greatest relative importance in contributing to an age-based algorithm with potential to improve PPV for toddlers <20 months to the same level as observed in older toddlers. Lien vers le texte intégral (Open Access ou abonnement)
10. Turcios J, Cook B, Irwin J, Rispoli T, Landi N. {{A Familiarization Protocol Facilitates the Participation of Children with ASD in Electrophysiological Research}}. {J Vis Exp};2017 (Jul 31)(125)
This paper includes a detailed description of a familiarization protocol, which is used as an integral component of a larger research protocol to collect electroencephalography (EEG) data and Event-Related Potentials (ERPs). At present, the systems available for the collection of high-quality EEG/ERP data make significant demands on children with developmental disabilities, such as those with an Autism Spectrum Disorder (ASD). Children with ASD may have difficulty adapting to novel situations, tolerating uncomfortable sensory stimuli, and sitting quietly. This familiarization protocol uses Evidence-Based Practices (EBPs) to increase research participants’ knowledge and understanding of the specific activities and steps of the research protocol. The tools in this familiarization protocol are a social narrative, a visual schedule, the Premack principle, role-playing, and modeling. The goal of this familiarization protocol is to increase understanding and agency and to potentially reduce anxiety for child participants, resulting in a greater likelihood of the successful completion of the research protocol for the collection of EEG/ERP data.
