1. Bakroon A, Lakshminarayanan V. {{Visual function in autism spectrum disorders: a critical review}}. {Clin Exp Optom};2016 (May 10)
Studies have shown considerable evidence of visual dysfunction in autism spectrum disorders. Anomalies in visual information processing can have a major effect on the life quality of individuals with autism spectrum disorders. We summarise the hypotheses and theories underlying neural aetiologies and genetic factors that cause these disorders, as well as the possible influences of unusual sensory possessing on the communications and behaviour characterised by the autistics. In particular, we review the impact of these dysfunctions on visual performance.
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2. Candini M, Giuberti V, Manattini A, Grittani S, di Pellegrino G, Frassinetti F. {{Personal space regulation in childhood autism: Effects of social interaction and person’s perspective}}. {Autism Res};2016 (May 9)
Studies in children with Typical Development (TD) and with Autism Spectrum Disorder (ASD) revealed that autism affects the personal space regulation, influencing both its size (permeability) and its changes depending on social interaction (flexibility). Here, we investigate how the nature of social interaction (Cooperative vs. Uncooperative) and the person perspective influence permeability and flexibility of interpersonal distance. Moreover, we tested whether the deficit observed in ASD children, reflects the social impairment (SI) in daily interactions. The stop-distance paradigm was used to measure the preferred distance between the participant and an unfamiliar adult (first-person perspective, Experiment 1), and between two other people (third-person perspective, Experiment 2). Interpersonal distance was measured before and after the interaction with a confederate. The Wing Subgroups Questionnaire was used to evaluate SI in everyday activities, and each ASD participant was accordingly assigned either to the lower (children with low social impairment [low-SI ASD]), or to the higher SI group (children with high social impairment [high-SI ASD]). We observed larger interpersonal distance (permeability) in both ASD groups compared to TD children. Moreover, depending on the nature of social interaction, a modulation of interpersonal distance (flexibility) was observed in TD children, both from the first- and third-person perspective. Similar findings were found in low-SI but not in high-SI ASD children, in Experiment 1. Conversely, in Experiment 2, no change was observed in both ASD groups. These findings reveal that SI severity and a person’s perspective may account for the deficit observed in autism when flexibility, but not permeability, of personal space is considered. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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3. Fluegge K. {{The role of air pollution exposures in mediating nutritional biochemical profiles in autism: A reply to Jory (2015)}}. {Nutrition};2016 (Mar 6)
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4. Keil KP, Lein PJ. {{DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders?}}. {Environ Epigenet};2016 (Mar);2(1)
There is now compelling evidence that gene by environment interactions are important in the etiology of autism spectrum disorders (ASDs). However, the mechanisms by which environmental factors interact with genetic susceptibilities to confer individual risk for ASD remain a significant knowledge gap in the field. The epigenome, and in particular DNA methylation, is a critical gene expression regulatory mechanism in normal and pathogenic brain development. DNA methylation can be influenced by environmental factors such as diet, hormones, stress, drugs, or exposure to environmental chemicals, suggesting that environmental factors may contribute to adverse neurodevelopmental outcomes of relevance to ASD via effects on DNA methylation in the developing brain. In this review, we describe epidemiological and experimental evidence implicating altered DNA methylation as a potential mechanism by which environmental chemicals confer risk for ASD, using polychlorinated biphenyls (PCBs), lead, and bisphenol A (BPA) as examples. Understanding how environmental chemical exposures influence DNA methylation and how these epigenetic changes modulate the risk and/or severity of ASD will not only provide mechanistic insight regarding gene-environment interactions of relevance to ASD but may also suggest potential intervention strategies for these and potentially other neurodevelopmental disorders.
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5. Mercati O, Huguet G, Danckaert A, Andre-Leroux G, Maruani A, Bellinzoni M, Rolland T, Gouder L, Mathieu A, Buratti J, Amsellem F, Benabou M, Van-Gils J, Beggiato A, Konyukh M, Bourgeois JP, Gazzellone MJ, Yuen RK, Walker S, Delepine M, Boland A, Regnault B, Francois M, Van Den Abbeele T, Mosca-Boidron AL, Faivre L, Shimoda Y, Watanabe K, Bonneau D, Rastam M, Leboyer M, Scherer SW, Gillberg C, Delorme R, Cloez-Tayarani I, Bourgeron T. {{CNTN6 mutations are risk factors for abnormal auditory sensory perception in autism spectrum disorders}}. {Mol Psychiatry};2016 (May 10)
Contactin genes CNTN5 and CNTN6 code for neuronal cell adhesion molecules that promote neurite outgrowth in sensory-motor neuronal pathways. Mutations of CNTN5 and CNTN6 have previously been reported in individuals with autism spectrum disorders (ASDs), but very little is known on their prevalence and clinical impact. In this study, we identified CNTN5 and CNTN6 deleterious variants in individuals with ASD. Among the carriers, a girl with ASD and attention-deficit/hyperactivity disorder was carrying five copies of CNTN5. For CNTN6, both deletions (6/1534 ASD vs 1/8936 controls; P=0.00006) and private coding sequence variants (18/501 ASD vs 535/33480 controls; P=0.0005) were enriched in individuals with ASD. Among the rare CNTN6 variants, two deletions were transmitted by fathers diagnosed with ASD, one stop mutation CNTN6W923X was transmitted by a mother to her two sons with ASD and one variant CNTN6P770L was found de novo in a boy with ASD. Clinical investigations of the patients carrying CNTN5 or CNTN6 variants showed that they were hypersensitive to sounds (a condition called hyperacusis) and displayed changes in wave latency within the auditory pathway. These results reinforce the hypothesis of abnormal neuronal connectivity in the pathophysiology of ASD and shed new light on the genes that increase risk for abnormal sensory perception in ASD.Molecular Psychiatry advance online publication, 10 May 2016; doi:10.1038/mp.2016.61.
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6. Noel JP, De Niear MA, Stevenson R, Alais D, Wallace MT. {{Atypical rapid audio-visual temporal recalibration in autism spectrum disorders}}. {Autism Res};2016 (May 9)
SCIENTIFIC ABSTRACT: Changes in sensory and multisensory function are increasingly recognized as a common phenotypic characteristic of Autism Spectrum Disorders (ASD). Furthermore, much recent evidence suggests that sensory disturbances likely play an important role in contributing to social communication weaknesses-one of the core diagnostic features of ASD. An established sensory disturbance observed in ASD is reduced audiovisual temporal acuity. In the current study, we substantially extend these explorations of multisensory temporal function within the framework that an inability to rapidly recalibrate to changes in audiovisual temporal relations may play an important and under-recognized role in ASD. In the paradigm, we present ASD and typically developing (TD) children and adolescents with asynchronous audiovisual stimuli of varying levels of complexity and ask them to perform a simultaneity judgment (SJ). In the critical analysis, we test audiovisual temporal processing on trial t as a condition of trial t – 1. The results demonstrate that individuals with ASD fail to rapidly recalibrate to audiovisual asynchronies in an equivalent manner to their TD counterparts for simple and non-linguistic stimuli (i.e., flashes and beeps, hand-held tools), but exhibit comparable rapid recalibration for speech stimuli. These results are discussed in terms of prior work showing a speech-specific deficit in audiovisual temporal function in ASD, and in light of current theories of autism focusing on sensory noise and stability of perceptual representations. LAY ABSTRACT: The integration of information across the different sensory modalities constitutes a fundamental step toward building a cohesive and comprehensive perceptual representation of the world. This integration and perceptual « binding » is highly dependent on the temporal structure of the multisensory cues. In ASD, multisensory temporal acuity has been found to be impaired, most notably for the integration of audiovisual speech stimuli, a finding that is confirmed in the current study. In addition, we show a striking difference in how those with ASD recalibrate their audiovisual temporal judgments based on prior trial history relative to those who are typically-developing. Most notable is the finding that whereas recalibration for speech stimuli fails to differ between ASD and TD participants, those with ASD fail to recalibrate when making judgments concerning non-speech audiovisual stimuli. These results not only expand our understanding of multisensory temporal function in ASD, but also have important implications for models suggesting changes in predictive coding and sensory priors in autism. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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7. Nordahl CW, Mello M, Shen AM, Shen MD, Vismara LA, Li D, Harrington K, Tanase C, Goodlin-Jones B, Rogers S, Abbeduto L, Amaral DG. {{Methods for acquiring MRI data in children with autism spectrum disorder and intellectual impairment without the use of sedation}}. {J Neurodev Disord};2016;8:20.
BACKGROUND: Magnetic resonance imaging (MRI) has been widely used in studies evaluating the neuropathology of autism spectrum disorder (ASD). Studies are often limited, however, to higher functioning individuals with ASD. MRI studies of individuals with ASD and comorbid intellectual disability (ID) are lacking, due in part to the challenges of acquiring images without the use of sedation. METHODS: Utilizing principles of applied behavior analysis (ABA), we developed a protocol for acquiring structural MRI scans in school-aged children with ASD and intellectual impairment. Board certified behavior analysts worked closely with each child and their parent(s), utilizing behavior change techniques such as pairing, shaping, desensitization, and positive reinforcement, through a series of mock scanner visits to prepare the child for the MRI scan. An objective, quantitative assessment of motion artifact in T1- and diffusion-weighted scans was implemented to ensure that high-quality images were acquired. RESULTS: The sample consisted of 17 children with ASD who are participants in the UC Davis Autism Phenome Project, a longitudinal MRI study aimed at evaluating brain developmental trajectories from early to middle childhood. At the time of their initial scan (2-3.5 years), all 17 children had a diagnosis of ASD and development quotient (DQ) <70. At the time of the current scan (9-13 years), 13 participants continued to have IQs in the range of ID (mean IQ = 54.1, sd = 12.1), and four participants had IQs in the normal range (mean = 102.2, sd = 7.5). The success rate in acquiring T1-weighted images that met quality assurance for acceptable motion artifact was 100 %. The success rate for acquiring high-quality diffusion-weighted images was 94 %. CONCLUSIONS: By using principles of ABA in a research MRI setting, it is feasible to acquire high-quality images in school-aged children with ASD and intellectual impairment without the use of sedation. This is especially critical to ensure that ongoing longitudinal studies of brain development can extend from infancy and early childhood into middle childhood in children with ASD at all levels of functioning, including those with comorbid ID. Lien vers le texte intégral (Open Access ou abonnement)
8. Port RG, Edgar JC, Ku M, Bloy L, Murray R, Blaskey L, Levy SE, Roberts TP. {{Maturation of auditory neural processes in autism spectrum disorder – A longitudinal MEG study}}. {Neuroimage Clin};2016;11:566-577.
BACKGROUND: Individuals with autism spectrum disorder (ASD) show atypical brain activity, perhaps due to delayed maturation. Previous studies examining the maturation of auditory electrophysiological activity have been limited due to their use of cross-sectional designs. The present study took a first step in examining magnetoencephalography (MEG) evidence of abnormal auditory response maturation in ASD via the use of a longitudinal design. METHODS: Initially recruited for a previous study, 27 children with ASD and nine typically developing (TD) children, aged 6- to 11-years-old, were re-recruited two to five years later. At both timepoints, MEG data were obtained while participants passively listened to sinusoidal pure-tones. Bilateral primary/secondary auditory cortex time domain (100 ms evoked response latency (M100)) and spectrotemporal measures (gamma-band power and inter-trial coherence (ITC)) were examined. MEG measures were also qualitatively examined for five children who exhibited « optimal outcome », participants who were initially on spectrum, but no longer met diagnostic criteria at follow-up. RESULTS: M100 latencies were delayed in ASD versus TD at the initial exam (~ 19 ms) and at follow-up (~ 18 ms). At both exams, M100 latencies were associated with clinical ASD severity. In addition, gamma-band evoked power and ITC were reduced in ASD versus TD. M100 latency and gamma-band maturation rates did not differ between ASD and TD. Of note, the cohort of five children that demonstrated « optimal outcome » additionally exhibited M100 latency and gamma-band activity mean values in-between TD and ASD at both timepoints. Though justifying only qualitative interpretation, these « optimal outcome » related data are presented here to motivate future studies. CONCLUSIONS: Children with ASD showed perturbed auditory cortex neural activity, as evidenced by M100 latency delays as well as reduced transient gamma-band activity. Despite evidence for maturation of these responses in ASD, the neural abnormalities in ASD persisted across time. Of note, data from the five children whom demonstrated « optimal outcome » qualitatively suggest that such clinical improvements may be associated with auditory brain responses intermediate between TD and ASD. These « optimal outcome » related results are not statistically significant though, likely due to the low sample size of this cohort, and to be expected as a result of the relatively low proportion of « optimal outcome » in the ASD population. Thus, further investigations with larger cohorts are needed to determine if the above auditory response phenotypes have prognostic utility, predictive of clinical outcome.
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9. Rice CE, Zablotsky B, Avila RM, Colpe LJ, Schieve LA, Pringle B, Blumberg SJ. {{Reported Wandering Behavior among Children with Autism Spectrum Disorder and/or Intellectual Disability}}. {J Pediatr};2016 (May 2)
OBJECTIVE: To characterize wandering, or elopement, among children with autism spectrum disorder (ASD) and intellectual disability. STUDY DESIGN: Questions on wandering in the previous year were asked of parents of children with ASD with and without intellectual disability and children with intellectual disability without ASD as part of the 2011 Survey of Pathways to Diagnosis and Services. The Pathways study sample was drawn from the much larger National Survey of Children with Special Health Care Needs conducted in 2009-2010. RESULTS: For children with special healthcare needs diagnosed with either ASD, intellectual disability, or both, wandering or becoming lost during the previous year was reported for more than 1 in 4 children. Wandering was highest among children with ASD with intellectual disability (37.7%) followed by children with ASD without intellectual disability (32.7%), and then children with intellectual disability without ASD (23.7%), though the differences between these groups were not statistically significant. CONCLUSIONS: This study affirms that wandering among children with ASD, regardless of intellectual disability status, is relatively common. However, wandering or becoming lost in the past year was also reported for many children with intellectual disability, indicating the need to broaden our understanding of this safety issue to other developmental disabilities.
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10. Richards C, Moss J, Nelson L, Oliver C. {{Persistence of self-injurious behaviour in autism spectrum disorder over 3 years: a prospective cohort study of risk markers}}. {J Neurodev Disord};2016;8:21.
BACKGROUND: There are few studies documenting the persistence of self-injury in individuals with autism spectrum disorder (ASD) and consequently limited data on behavioural and demographic characteristics associated with persistence. In this longitudinal study, we investigated self-injury in a cohort of individuals with ASD over 3 years to identify behavioural and demographic characteristics associated with persistence. METHODS: Carers of 67 individuals with ASD (Median age of individuals with ASD in years = 13.5, Interquartile Range = 10.00-17.00), completed questionnaires relating to the presence and topography of self-injury at T1 and three years later at T2. Analyses were conducted to evaluate the persistence of self-injury and to evaluate the behavioural and demographic characteristics associated with persistence of self-injury. RESULTS: At T2 self-injurious behaviour had persisted in 77.8 % of individuals. Behavioural correlates of being non-verbal, having lower ability and higher levels of overactivity, impulsivity and repetitive behaviour, were associated with self-injury at both time points. Risk markers of impulsivity (p = 0.021) and deficits in social interaction (p = 0.026) at T1 were associated with the persistence of self-injury over 3 years. CONCLUSIONS: Impulsivity and deficits in social interaction are associated with persistent self-injury in ASD and thus may act as behavioural risk markers. The identification of these risk markers evidences a role for behaviour dysregulation in the development and maintenance of self-injury. The findings have clinical implications for proactive intervention; these behavioural characteristics may be utilised to identify ‘at risk’ individuals for whom self-injury is likely to be persistent and therefore those individuals for whom early intervention may be most warranted.
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11. Wang X, Bey AL, Katz BM, Badea A, Kim N, David LK, Duffney LJ, Kumar S, Mague SD, Hulbert SW, Dutta N, Hayrapetyan V, Yu C, Gaidis E, Zhao S, Ding JD, Xu Q, Chung L, Rodriguiz RM, Wang F, Weinberg RJ, Wetsel WC, Dzirasa K, Yin H, Jiang YH. {{Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism}}. {Nat Commun};2016;7:11459.
Human neuroimaging studies suggest that aberrant neural connectivity underlies behavioural deficits in autism spectrum disorders (ASDs), but the molecular and neural circuit mechanisms underlying ASDs remain elusive. Here, we describe a complete knockout mouse model of the autism-associated Shank3 gene, with a deletion of exons 4-22 (Deltae4-22). Both mGluR5-Homer scaffolds and mGluR5-mediated signalling are selectively altered in striatal neurons. These changes are associated with perturbed function at striatal synapses, abnormal brain morphology, aberrant structural connectivity and ASD-like behaviour. In vivo recording reveals that the cortico-striatal-thalamic circuit is tonically hyperactive in mutants, but becomes hypoactive during social behaviour. Manipulation of mGluR5 activity attenuates excessive grooming and instrumental learning differentially, and rescues impaired striatal synaptic plasticity in Deltae4-22(-/-) mice. These findings show that deficiency of Shank3 can impair mGluR5-Homer scaffolding, resulting in cortico-striatal circuit abnormalities that underlie deficits in learning and ASD-like behaviours. These data suggest causal links between genetic, molecular, and circuit mechanisms underlying the pathophysiology of ASDs.
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12. Wenger TL, Miller JS, DePolo LM, de Marchena AB, Clements CC, Emanuel BS, Zackai EH, McDonald-McGinn DM, Schultz RT. {{22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical screening}}. {Mol Autism};2016;7:27.
BACKGROUND: Widespread use of microarray technology has led to increasing identification of 22q11.2 duplication syndrome (22q11.2DupS), the reciprocal syndrome of the well-characterized 22q11.2 deletion syndrome (22q11.2DS). Individuals with 22q11.2DS have elevated rates of community diagnoses of autism spectrum disorder (ASD), schizophrenia, and a range of medical problems and birth defects that necessitate extensive medical screening. Case reports of 22q11.2DupS include patients with ASD, fewer medical problems, and no schizophrenia; however, no prospective cohort study has been reported. The goals of the study were to (1) characterize the neuropsychiatric functioning of a cohort of individuals with 22q11.2DupS in comparison to large samples of typically developing controls (TDCs), ASD and 22q11.2DS; (2) estimate the prevalence of ASD in 22q11.2DupS; (3) determine whether the indications that prompted the genetic testing in 22q11.2DupS differ from 22q11.2DS and (4) determine whether comprehensive medical screening should be recommended for those diagnosed with 22q11.2DupS. METHODS: Medical characterization was done by parental questionnaire and medical chart review of individuals with 22q11.2DupS (n = 37) and 22q11.2DS (n = 101). Neuropsychiatric characterization of children with 22.11.2DupS, 22q11.2DS, TDCs, and ASD was done by parent-report questionnaires; in addition, the ASD and 22q11.2DupS groups received the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. RESULTS: Individuals with 22q11.2DupS, 22q11.2DS, and ASD had significantly impaired social interaction and adaptive behavior skills compared to TDCs. Overall, 38 % of children aged 2-18 with 22q11.2DupS had community diagnoses of ASD, but fewer (14-25 %) met on the basis of best clinical judgment that included ADI-R and ADOS data. Indications for genetic testing were significantly different for 22q11.2DupS and 22q11.2DS, with the deletions more commonly tested because of birth defects or medical problems, and the duplications because of developmental delay. However, when the screening protocol for 22q11.2DS was applied to the 22q11.2DupS sample, several medical problems were identified that would pose significant risk if left undetected. CONCLUSIONS: 22q11.2DupS has a high rate of ASD at 14-25 %, among the highest of any genetic disorder. Prospective medical screening should be done for all patients with 22q11.2DupS, including those diagnosed due to developmental delays and ASD alone.
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13. Williams MR, Fricano-Kugler CJ, Getz SA, Skelton PD, Lee J, Rizzuto CP, Geller JS, Li M, Luikart BW. {{A Retroviral CRISPR-Cas9 System for Cellular Autism-Associated Phenotype Discovery in Developing Neurons}}. {Sci Rep};2016;6:25611.
Retroviruses expressing a fluorescent protein, Cas9, and a small guide RNA are used to mimic nonsense PTEN mutations from autism patients in developing mouse neurons. We compare the cellular phenotype elicited by CRISPR-Cas9 to those elicited using shRNA or Cre/Lox technologies and find that knockdown or knockout (KO) produced a corresponding moderate or severe neuronal hypertrophy in all cells. In contrast, the Cas9 approach produced missense and nonsense Pten mutations, resulting in a mix of KO-equivalent hypertrophic and wild type-like phenotypes. Importantly, despite this mixed phenotype, the neuronal hypertrophy resulting from Pten loss was evident on average in the population of manipulated cells. Having reproduced the known Pten KO phenotype using the CRISPR-Cas9 system we design viruses to target a gene that has recently been associated with autism, KATNAL2. Katnal2 deletion in the mouse results in decreased dendritic arborization of developing neurons. We conclude that retroviral implementation of the CRISPR-Cas9 system is an efficient system for cellular phenotype discovery in wild-type animals.
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14. Zainal H, Magiati I. {{A Comparison Between Caregiver-Reported Anxiety and Other Emotional and Behavioral Difficulties in Children and Adolescents with Autism Spectrum Disorders Attending Specialist or Mainstream Schools}}. {J Autism Dev Disord};2016 (May 10)
Increasing numbers of students with Autism Spectrum Disorder (ASD) are attending mainstream schools. Nonetheless, concerns about their emotional well-being and mental health in these settings have also been raised. This study sought to compare caregiver-reported anxiety and other emotional and behavioural problems in youth with ASD attending mainstream or specialist schools. Caregivers of 27 youth with ASD in mainstream schools (age 10.91 +/- 3.44 years) and 69 youth with ASD in special schools (age 10.93 +/- 2.81 years) matched for gender, age, adaptive functioning and autism symptom severity scores participated. Caregivers completed the Spence Children’s Anxiety Scale-Parent, a measure of adaptive functioning, and a checklist of other emotional and behavioral difficulties. Students with ASD attending mainstream schools experienced higher levels of social anxiety symptoms compared to their specialist school counterparts. No other statistically significant differences were found in other aspects of emotional and behavioural functioning examined, but some differences emerged in item-level analyses. Uncertainties in navigating more complex social environments and increased social relating difficulties in mainstream schools are discussed as probable environmental triggers for increased social phobia related symptomatology, although other explanations for this small effect size difference are also considered. Limitations of the present study and recommendations for future research focusing on exploring environmental socio-ecological factors influencing anxiety and mental health in young people with ASD are also discussed.
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15. Zhang JX, Zhang J, Li Y. {{Liver X receptor-beta improves autism symptoms via downregulation of beta-amyloid expression in cortical neurons}}. {Ital J Pediatr};2016;42(1):46.
BACKGROUND: We study the effect of liver X receptor beta (LXRbeta) on beta-amyloid (Abeta) peptide generation and autism behaviors by conducting an animal experiment. METHODS: In autistic mice treated with LXRbeta agonist T0901317, enzyme linked immunosorbent assay was used to measure Abeta in brain tissue homogenates. Western blot was used to detect Abeta precursors, Abeta degradation and secretase enzymes, and expression of autophagy-related proteins and Ras/Raf/Erkl/2 signaling pathway proteins in brain tissue. Changes in autism spectrum disorder syndromes of the BTBR mice were compared before and after T0901317 treatment. RESULTS: Compared with the control group, autistic mice treated with LXRbeta agonist T0901317 showed significantly lower Abeta level in brain tissue (P < 0.05), significantly higher Abeta degradation enzyme (NEP, IDE proteins) levels (all P < 0.05), significantly lower Abeta secretase enzyme BACE1 protein level (P < 0.05), and significantly lower Ras, P-C-Raf, C-Raf, P-Mekl/2, P-Erkl/2 protein levels (all P < 0.05). BTBR mice treated with T0901317 showed improvements in repetitive stereotyped behavior, inactivity, wall-facing standing time, self-combing time and center stay time, stayed longer in platform quadrant, and crossed the platform more frequently (all P < 0.05). CONCLUSIONS: LXRbeta could potentially reduce brain Abeta generation by inhibiting Abeta production and promoting Abeta degradation, thereby increasing the expression of autophagy-related proteins, reducing Ras/Raf/Erkl/2 signaling pathway proteins, and improving autism behaviors. Lien vers le texte intégral (Open Access ou abonnement)
