Pubmed du 18/04/17

mardi 18 avril 2017

1. Ahmad SF, Ansari MA, Nadeem A, Bakheet SA, Mohammad R, Attia SM. Immune Alterations in CD8+ T Cells Are Associated with Neuronal C-C and C-X-C Chemokine Receptor Regulation Through Adenosine A2A Receptor Signaling in a BTBR T+ Itpr3tf/J Autistic Mouse Model. Mol Neurobiol ;2017 (Apr 18)

Associative studies on a range of neurodevelopmental disorders have identified relationships between behavioral deficits and immune system function. The BTBR T+ Itpr3tf/J (BTBR) mouse strain displays aberrant characteristics in its social behavior and immune responses, providing a significant opportunity to examine the relationship between behavior and the immune system. This study investigated the influence of adenosine A2A receptor activity on C-C and C-X-C chemokine receptors involved in autism in the BTBR mouse model. A2A receptors have previously been targeted in clinical trials by potential therapeutics with neuroprotective, immunomodulatory, and analgesic properties. In this study, we examined the effects of A2A receptor antagonist SCH5826 (SCH) and A2A receptor agonist CGS21680 (CGS) on C-C and C-X-C chemokine receptors (CCR3, CCR4, CCR5, CCR6, CCR7, CXCR3, CXCR4, and CXCR5) on splenic CD8+ T cells in the BTBR autistic mouse model. We also assessed the C-C and C-X-C chemokine receptors mRNA levels in brain tissue. Our results showed that CCR3+, CCR4+, CCR5+, CCR6+, CCR7+, CXCR3+, CXCR4+, and CXCR5+ production in splenic CD8+ T cells decreased significantly in BTBR-CGS-treated mice in comparison with that in BTBR control and BTBR-SCH-treated mice. In addition, RT-PCR analysis revealed decreased gene expression levels for C-C and C-X-C chemokine receptors in the brain tissue of BTBR-CGS-treated mice, whereas these levels were significantly increased in BTBR control and BTBR-SCH-treated mice. Our results suggest that treating BTBR mice with CGS decreases C-C and C-X-C chemokine receptor signaling and might therefore provide a unique avenue for developing future therapies for autism and neuroimmunological disorders.

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2. Ahmadlou M, Adeli H. Complexity of Weighted Graph : A New Technique to Investigate Structural Complexity of Brain Activities with Applications to Aging and Autism. Neurosci Lett ;2017 (Apr 13)

In recent years complexity of the brain structure in healthy and disordered subjects has been studied increasingly. But to the best of the authors’ knowledge, researchers so far have investigated the structural complexity only in the context of two restricted networks known as Small-World and Scale-free networks ; whereas other aspects of the structural complexity of brain activities may be affected by aging and neurodegenerative disorders such as the Alzheimer’s disease and autism spectrum disorder. In this study, two general complexity metrics of graphs, Graph Index Complexity and Offdiagonal Complexity are proposed as general measures of complexity, not restricted to SWN only. They are adopted to measure the structural complexity of the weighted graphs instead of the common binary graphs. Fuzzy Synchronization Likelihood is applied to the EEGs and their sub-bands, as a functional connectivity metric of the brain, to construct the functional connectivity graphs. Two applications are used to evaluate the efficacy of the complexity measures : diagnosis of autism and aging, both based on EEG. It was discovered that the Graph Index Complexity of gamma band is discriminative in distinguishing autistic children from non-autistic children. Also, Offdiagonal Complexity of theta band in young subjects was observed to be significantly different than old subjects. This study shows that changes in the structure of functional connectivity of brain in disorders and different healthy states can be revealed by unrestricted metrics of graph complexity. While the applications presented in this paper are based on EEG, the approach is general and can be used with other modalities such as fMRI, MEG, etc. Further, it can be used to study every other neurological and psychiatric disorder.

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3. Brown HK, Ray JG, Wilton AS, Lunsky Y, Gomes T, Vigod SN. Association Between Serotonergic Antidepressant Use During Pregnancy and Autism Spectrum Disorder in Children. JAMA ;2017 (Apr 18) ;317(15):1544-1552.

Importance : Previous observations of a higher risk of child autism spectrum disorder with serotonergic antidepressant exposure during pregnancy may have been confounded. Objective : To evaluate the association between serotonergic antidepressant exposure during pregnancy and child autism spectrum disorder. Design, Setting, and Participants : Retrospective cohort study. Health administrative data sets were used to study children born to mothers who were receiving public prescription drug coverage during pregnancy in Ontario, Canada, from 2002-2010, reflecting 4.2% of births. Children were followed up until March 31, 2014. Exposures : Serotonergic antidepressant exposure was defined as 2 or more consecutive maternal prescriptions for a selective serotonin or serotonin-norepinephrine reuptake inhibitor between conception and delivery. Main Outcomes and Measures : Child autism spectrum disorder identified after the age of 2 years. Exposure group differences were addressed by inverse probability of treatment weighting based on derived high-dimensional propensity scores (computerized algorithm used to select a large number of potential confounders) and by comparing exposed children with unexposed siblings. Results : There were 35906 singleton births at a mean gestational age of 38.7 weeks (50.4% were male, mean maternal age was 26.7 years, and mean duration of follow-up was 4.95 years). In the 2837 pregnancies (7.9%) exposed to antidepressants, 2.0% (95% CI, 1.6%-2.6%) of children were diagnosed with autism spectrum disorder. The incidence of autism spectrum disorder was 4.51 per 1000 person-years among children exposed to antidepressants vs 2.03 per 1000 person-years among unexposed children (between-group difference, 2.48 [95% CI, 2.33-2.62] per 1000 person-years ; hazard ratio [HR], 2.16 [95% CI, 1.64-2.86] ; adjusted HR, 1.59 [95% CI, 1.17-2.17]). After inverse probability of treatment weighting based on the high-dimensional propensity score, the association was not significant (HR, 1.61 [95% CI, 0.997-2.59]). The association was also not significant when exposed children were compared with unexposed siblings (incidence of autism spectrum disorder was 3.40 per 1000 person-years vs 2.05 per 1000 person-years, respectively ; adjusted HR, 1.60 [95% CI, 0.69-3.74]). Conclusions and Relevance : In children born to mothers receiving public drug coverage in Ontario, Canada, in utero serotonergic antidepressant exposure compared with no exposure was not associated with autism spectrum disorder in the child. Although a causal relationship cannot be ruled out, the previously observed association may be explained by other factors.

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4. Georgiades S, Bishop SL, Frazier T. Editorial Perspective : Longitudinal research in autism - introducing the concept of ’chronogeneity’. J Child Psychol Psychiatry ;2017 (May) ;58(5):634-636.

Autism Spectrum Disorder (ASD or autism) is a heterogeneous neurodevelopmental disorder. We are now at a critical juncture in autism research where we have the knowledge base and expertise to begin to think about studies that view heterogeneity, not as ’statistical noise’ that can be ’accounted for’ using data-reduction techniques (such as group trajectories), but rather as ’informative variance’ that can help form a more precise and dynamic picture of autism. In this Editorial we coin a new term and introduce the concept of ’chronogeneity’ for the study of autism heterogeneity in relation to the dimension of time (chrono). Using examples of ongoing research and analytical advances we build the case for the potential utility of the concept of ’chronogeneity’ and argue that a refined approach to the longitudinal investigation of autism (and other neurodevelopmental disorders) may move us closer to more precise and adaptive models of care for the children and youth affected by these disorders.

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5. Kanat M, Spenthof I, Riedel A, van Elst LT, Heinrichs M, Domes G. Restoring effects of oxytocin on the attentional preference for faces in autism. Transl Psychiatry ;2017 (Apr 18) ;7(4):e1097.

Reduced attentional preference for faces and symptoms of social anxiety are common in autism spectrum disorders (ASDs). The neuropeptide oxytocin triggers anxiolytic functions and enhances eye gaze, facial emotion recognition and neural correlates of face processing in ASD. Here we investigated whether a single dose of oxytocin increases attention to faces in ASD. As a secondary question, we explored the influence of social anxiety on these effects. We tested for oxytocin’s effects on attention to neutral faces as compared to houses in a sample of 29 autistic individuals and 30 control participants using a dot-probe paradigm with two different presentation times (100 or 500 ms). A single dose of 24 IU oxytocin was administered in a randomized, double-blind placebo-controlled, cross-over design. Under placebo, ASD individuals paid less attention to faces presented for 500 ms than did controls. Oxytocin administration increased the allocation of attention toward faces in ASD to a level observed in controls. Secondary analyses revealed that these oxytocin effects primarily occurred in ASD individuals with high levels of social anxiety who were characterized by attentional avoidance of faces under placebo. Our results confirm a positive influence of intranasal oxytocin on social attention processes in ASD. Further, they suggest that oxytocin may in particular restore the attentional preference for facial information in ASD individuals with high social anxiety. We conclude that oxytocin’s anxiolytic properties may partially account for its positive effects on socio-cognitive functioning in ASD, such as enhanced eye gaze and facial emotion recognition.

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6. Karimi P, Kamali E, Mousavi SM, Karahmadi M. Environmental factors influencing the risk of autism. J Res Med Sci ;2017 ;22:27.

Autism is a developmental disability with age of onset in childhood (under 3 years old), which is characterized by definite impairments in social interactions, abnormalities in speech, and stereotyped pattern of behaviors. Due to the progress of autism in recent decades, a wide range of studies have been done to identify the etiological factors of autism. It has been found that genetic and environmental factors are both involved in autism pathogenesis. Hence, in this review article, a set of environmental factors involved in the occurrence of autism has been collected, and finally, some practical recommendations for reduction of the risk of this devastating disease in children are represented.

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7. King BH. Association Between Maternal Use of SSRI Medications and Autism in Their Children. JAMA ;2017 (Apr 18) ;317(15):1568-1569.

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8. Kruusvee V, Lyst MJ, Taylor C, Tarnauskaite Z, Bird AP, Cook AG. Structure of the MeCP2-TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders. Proc Natl Acad Sci U S A ;2017 (Apr 18) ;114(16):E3243-E3250.

Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the methyl-CpG-binding protein 2 (MeCP2) gene. The majority of RTT missense mutations disrupt the interaction of the MeCP2 with DNA or the nuclear receptor corepressor (NCoR)/silencing mediator of retinoic acid and thyroid receptors (SMRT) corepressor complex. Here, we show that the "NCoR/SMRT interaction domain" (NID) of MeCP2 directly contacts transducin beta-like 1 (TBL1) and TBL1 related (TBLR1), two paralogs that are core components of NCoR/SMRT. We determine the cocrystal structure of the MeCP2 NID in complex with the WD40 domain of TBLR1 and confirm by in vitro and ex vivo assays that mutation of interacting residues of TBLR1 and TBL1 disrupts binding to MeCP2. Strikingly, the four MeCP2-NID residues mutated in RTT are those residues that make the most extensive contacts with TBLR1. Moreover, missense mutations in the gene for TBLR1 that are associated with intellectual disability also prevent MeCP2 binding. Our study therefore reveals the molecular basis of an interaction that is crucial for optimal brain function.

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9. Lagercrantz H. Are extremely preterm born children with autism the victims of too much isolation in the incubator ?. Acta Paediatr ;2017 (Apr 17)

When autism was first identified by Leo Kanner in 1943, he thought it was partially due to "genuine lack of maternal warmth". This "refrigerator mother theory" has been completely discarded and there is now a consensus that there is a connection between genetic heritability and autism spectrum disorder (ASD). Although Kanner was the first to publish a work on autism, the disease had already been observed by Hans Asperger in Vienna. The history of the discovery and recognition of autism is described in the interesting book : Neurotribes by Steve Silberman (1), This article is protected by copyright. All rights reserved.

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10. Oberlander TF, Zwaigenbaum L. Disentangling Maternal Depression and Antidepressant Use During Pregnancy as Risks for Autism in Children. JAMA ;2017 (Apr 18) ;317(15):1533-1534.

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11. Parsons OE, Bayliss AP, Remington A. A few of my favorite things : circumscribed interests in autism are not accompanied by increased attentional salience on a personalized selective attention task. Mol Autism ;2017 ;8:20.

BACKGROUND : Autistic individuals commonly show circumscribed or "special" interests : areas of obsessive interest in a specific category. The present study investigated what impact these interests have on attention, an aspect of autistic cognition often reported as altered. In neurotypical individuals, interest and expertise have been shown to result in an automatic attentional priority for related items. Here, we examine whether this change in salience is also seen in autism. METHODS : Adolescents and young adults with and without autism performed a personalized selective attention task assessing the level of attentional priority afforded to images related to the participant’s specific interests. In addition, participants performed a similar task with generic images in order to isolate any effects of interest and expertise. Crucially, all autistic and non-autistic individuals recruited for this study held a strong passion or interest. As such, any differences in attention could not be solely attributed to differing prevalence of interests in the two groups. In both tasks, participants were asked to perform a central target-detection task while ignoring irrelevant distractors (related or unrelated to their interests). The level of distractor interference under various task conditions was taken as an indication of attentional priority. RESULTS : Neurotypical individuals showed the predicted attentional priority for the circumscribed interest images but not generic items, reflecting the impact of their interest and expertise. Contrary to predictions, autistic individuals did not show this priority : processing the interest-related stimuli only when task demands were low. Attention to images unrelated to circumscribed interests was equivalent in the two groups. CONCLUSIONS : These results suggest that despite autistic individuals holding an intense interest in a particular class of stimuli, there may be a reduced impact of this prior experience and expertise on attentional processing. The implications of this absence of automatic priority are discussed in terms of the behaviors associated with the condition.

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12. Sujan AC, Rickert ME, Oberg AS, Quinn PD, Hernandez-Diaz S, Almqvist C, Lichtenstein P, Larsson H, D’Onofrio BM. Associations of Maternal Antidepressant Use During the First Trimester of Pregnancy With Preterm Birth, Small for Gestational Age, Autism Spectrum Disorder, and Attention-Deficit/Hyperactivity Disorder in Offspring. JAMA ;2017 (Apr 18) ;317(15):1553-1562.

Importance : Prenatal antidepressant exposure has been associated with adverse outcomes. Previous studies, however, may not have adequately accounted for confounding. Objective : To evaluate alternative hypotheses for associations between first-trimester antidepressant exposure and birth and neurodevelopmental problems. Design, Setting, and Participants : This retrospective cohort study included Swedish offspring born between 1996 and 2012 and followed up through 2013 or censored by death or emigration. Analyses controlling for pregnancy, maternal and paternal covariates, as well as sibling comparisons, timing of exposure comparisons, and paternal comparisons, were used to examine the associations. Exposures : Maternal self-reported first-trimester antidepressant use and first-trimester antidepressant dispensations. Main Outcomes and Measures : Preterm birth (<37 gestational weeks), small for gestational age (birth weight <2 SDs below the mean for gestational age), and first inpatient or outpatient clinical diagnosis of autism spectrum disorder and attention-deficit/hyperactivity disorder in offspring. Results : Among 1580629 offspring (mean gestational age, 279 days ; 48.6% female ; 1.4% [n = 22544] with maternal first-trimester self-reported antidepressant use) born to 943776 mothers (mean age at childbirth, 30 years), 6.98% of exposed vs 4.78% of unexposed offspring were preterm, 2.54% of exposed vs 2.19% of unexposed were small for gestational age, 5.28% of exposed vs 2.14% of unexposed were diagnosed with autism spectrum disorder by age 15 years, and 12.63% of exposed vs 5.46% of unexposed were diagnosed with attention-deficit/hyperactivity disorder by age 15 years. At the population level, first-trimester exposure was associated with all outcomes compared with unexposed offspring (preterm birth odds ratio [OR], 1.47 [95% CI, 1.40-1.55] ; small for gestational age OR, 1.15 [95% CI, 1.06-1.25] ; autism spectrum disorder hazard ratio [HR], 2.02 [95% CI, 1.80-2.26] ; attention-deficit/hyperactivity disorder HR, 2.21 [95% CI, 2.04-2.39]). However, in models that compared siblings while adjusting for pregnancy, maternal, and paternal traits, first-trimester antidepressant exposure was associated with preterm birth (OR, 1.34 [95% CI, 1.18-1.52]) but not with small for gestational age (OR, 1.01 [95% CI, 0.81-1.25]), autism spectrum disorder (HR, 0.83 [95% CI, 0.62-1.13]), or attention-deficit/hyperactivity disorder (HR, 0.99 [95% CI, 0.79-1.25]). Results from analyses assessing associations with maternal dispensations before pregnancy and with paternal first-trimester dispensations were consistent with findings from the sibling comparisons. Conclusions and Relevance : Among offspring born in Sweden, after accounting for confounding factors, first-trimester exposure to antidepressants, compared with no exposure, was associated with a small increased risk of preterm birth but no increased risk of small for gestational age, autism spectrum disorder, or attention-deficit/hyperactivity disorder.

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13. Tas M, Yilmaz S, Bulut E, Polat Z, Tas A. Otoacoustic Emissions in Young Children with Autism. J Int Adv Otol ;2017 (Apr 17)

OBJECTIVE : The aim of this study is to investigate otoacoustic emissions (OAEs) in young children with autism compared with those in an age-matched control group. MATERIALS AND METHODS : Thirty-eight children with autism aged 3-6 years and 27 typically developing (normally developing) control subjects participated in this study. All the participants had normal hearing and middle-ear function. Auditory brainstem responses were used to determine the hearing status in the autism group. Transient-evoked otoacoustic emissions (TEOAEs) and distortion-product otoacoustic emissions (DPOAEs) were measured in the two groups. RESULTS : The TEOAE response level was higher in the autism group. Analysis of the DPOAE response showed that the mean emission levels at 1.5, 2 , 3, and 6 kHz and signal/noise ratios at 2, 4, 6, and 8 kHz were higher in the autism group (p<0.05). The greatest between-group differences were observed in the DPOAE signal levels at 2, 3, and 6 kHz (p=0.000). No statistically significant difference was found between the noise levels in the autism and control groups (p>0.05). CONCLUSION : The emission responses in the autism group were higher than those in the control group. The increase in DPOAEs at high frequencies may be related to the higher outer cell activation in the autism group. Further studies with larger sample sizes comprising younger children are needed to confirm the result and investigate the possible association between the increased OAEs and auditory sensitivity reported in autism.

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14. Wang W, Li C, Chen Q, van der Goes MS, Hawrot J, Yao AY, Gao X, Lu C, Zang Y, Zhang Q, Lyman K, Wang D, Guo B, Wu S, Gerfen CR, Fu Z, Feng G. Striatopallidal dysfunction underlies repetitive behavior in Shank3-deficient model of autism. J Clin Invest ;2017 (Apr 17)

The postsynaptic scaffolding protein SH3 and multiple ankyrin repeat domains 3 (SHANK3) is critical for the development and function of glutamatergic synapses. Disruption of the SHANK3-encoding gene has been strongly implicated as a monogenic cause of autism, and Shank3 mutant mice show repetitive grooming and social interaction deficits. Although basal ganglia dysfunction has been proposed to underlie repetitive behaviors, few studies have provided direct evidence to support this notion and the exact cellular mechanisms remain largely unknown. Here, we utilized the Shank3B mutant mouse model of autism to investigate how Shank3 mutation may differentially affect striatonigral (direct pathway) and striatopallidal (indirect pathway) medium spiny neurons (MSNs) and its relevance to repetitive grooming behavior in Shank3B mutant mice. We found that Shank3 deletion preferentially affects synapses onto striatopallidal MSNs. Striatopallidal MSNs showed profound defects, including alterations in synaptic transmission, synaptic plasticity, and spine density. Importantly, the repetitive grooming behavior was rescued by selectively enhancing the striatopallidal MSN activity via a Gq-coupled human M3 muscarinic receptor (hM3Dq), a type of designer receptors exclusively activated by designer drugs (DREADD). Our findings directly demonstrate the existence of distinct changes between 2 striatal pathways in a mouse model of autism and indicate that the indirect striatal pathway disruption might play a causative role in repetitive behavior of Shank3B mutant mice.

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