1. Ahmad SF, Ansari MA, Nadeem A, Bakheet SA, Almutairi MM, Attia SM. {{Adenosine A2A receptor signaling affects IL-21/IL-22 cytokines and GATA3/T-bet transcription factor expression in CD4+ T cells from a BTBR T+ Itpr3tf/J mouse model of autism}}. {J Neuroimmunol}. 2017; 311: 59-67.
Autism is a complex heterogeneous neurodevelopmental disorder; previous studies have identified altered immune responses among individuals diagnosed with autism. An imbalance in the production of pro- and anti-inflammatory cytokines and transcription factors plays a role in neurodevelopmental behavioral and autism disorders. BTBR T+ Itpr3tf/J (BTBR) mice are used as a model for autism, as they exhibit social deficits, communication deficits, and repetitive behaviors compared with C57BL/6J (B6) mice. The adenosine A2A receptor (A2AR) appears to be a potential target for the improvement of behavioral, inflammatory, immune, and neurological disorders. We investigated the effects of the A2AR antagonist SCH 5826 (SCH) and agonist CGS 21680 (CGS) on IL-21, IL-22, T-bet, T-box transcription factor (T-bet), GATA3 (GATA Binding Protein 3), and CD152 (CTLA-4) expression in BTBR mice. Our results showed that BTBR mice treated with SCH had increased CD4+IL-21+, CD4+IL-22+, CD4+GATA3+, and CD4+T-bet+ and decreased CD4+CTLA-4+ expression in spleen cells compared with BTBR control mice. Moreover, CGS efficiently decreased CD4+IL-21+, CD4+IL-22+, CD4+GATA3+, and CD4+T-bet+ and increased CD4+CTLA-4 production in spleen cells compared with SCH-treated and BTBR control mice. Additionally, SCH treatment significantly increased the mRNA and protein expression levels of IL-21, IL-22, GATA3, and T-bet in brain tissue compared with CGS-treated and BTBR control mice. The augmented levels of IL-21/IL-22 and GATA3/T-bet could be due to altered A2AR signaling. Our results indicate that A2AR agonists may represent a new class of compounds that can be developed for use in the treatment of autistic and neuroimmune dysfunctions.
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2. Altay MA, Gorker I, Aslanova R, Bozatli L, Turan N, Kaplan PB. {{Association between Beta-Sympathomimetic Tocolysis and Risk of Autistic Spectrum Disorders, Behavioural and Developmental Outcome in Toddlers}}. {Open Access Maced J Med Sci}. 2017; 5(6): 730-5.
AIM: To investigate whether maternal intravenous beta-mimetic tocolytic therapy increases the risk of autistic spectrum disorders (ASD) and poorer behavioural and developmental outcomes. METHOD: Our study is a prospective case-control study among 90 children between 1.5 and three years old. Cases (n = 46) were toddlers with betamimetic tocolytic exposure; control group toddlers (n = 44) were tocolytic untreated. Treated and untreated groups were also divided into subgroups: term and preterm delivered. The gestational age of tocolytic treatment start, the dose and duration of exposure in hours were obtained from obstetric medical records. The Brief Infant-Toddler Social and Emotional Assessment (BITSEA), the Modified Checklist for Autism in Toddlers (M-CHAT) and the Denver Developmental Screening Test (DDST) tests were applied for evaluation of social, emotional problems, autism and developmental disorders. RESULTS: Term and preterm born toddlers treated tocolytically in utero didn’t demonstrate a higher risk of autistic disorders or poorer behavioural and developmental results than controls. In the preterm group, the earliest start of tocolytic treatment was correlated with toddlers lower score of the Competencies Scale (p = 0.009) and a higher score of the Problems Scale (p = 0.048). Also, we concluded that preterm membrane rupture was associated with higher ASD risk in the untreated group (p = 0.043). CONCLUSION: Exposure to betamimetics during pregnancy was not associated with an increased risk of autism, behavioural and developmental disorders.
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3. Hahn LJ, Brady NC, McCary L, Rague L, Roberts JE. {{Early social communication in infants with fragile X syndrome and infant siblings of children with autism spectrum disorder}}. {Res Dev Disabil}. 2017; 71: 169-80.
BACKGROUND: Little research in fragile X syndrome (FXS) has prospectively examined early social communication. AIMS: To compare early social communication in infants with FXS, infant siblings of children with autism spectrum disorder (ASIBs), and typically developing (TD) infants. METHODS AND PROCEDURES: Participants were 18 infants with FXS, 21 ASIBs, and 22 TD infants between 7.5-14.5 months. Social communication was coded using the Communication Complexity Scale during the administration of Autism Observation Scale for Infants. OUTCOMES AND RESULTS: Descriptively different patterns were seen across the three groups. Overall infants with FXS had lower social communication than ASIBs or TD infants when controlling for nonverbal cognitive abilities. However, infants with FXS had similar levels of social communication as ASIBs or TD infants during peek-a-boo. No differences were observed between ASIBs and TD infants. For all infants, higher social communication was related to lower ASD risk. CONCLUSIONS AND IMPLICATIONS: Findings provide insight into the developmental course of social communication in FXS. The dynamic nature of social games may help to stimulate communication in infants with FXS. Language interventions with a strong social component may be particularly effective for promoting language development in FXS.
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4. Jhang CL, Huang TN, Hsueh YP, Liao W. {{Mice lacking cyclin-dependent kinase-like 5 manifest autistic and ADHD-like behaviors}}. {Hum Mol Genet}. 2017; 26(20): 3922-34.
Neurodevelopmental disorders frequently share common clinical features and appear high rate of comorbidity, such as those present in patients with attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). While characterizing behavioral phenotypes in the mouse model of cyclin-dependent kinase-like 5 (CDKL5) disorder, a neurodevelopmental disorder caused by mutations in the X-linked gene encoding CDKL5, we found that these mice manifested behavioral phenotypes mimicking multiple key features of ASD, such as impaired social interaction and communication, as well as increased stereotypic digging behaviors. These mice also displayed hyper-locomotion, increased aggressiveness and impulsivity, plus deficits in motor and associative learning, resembling primary symptoms of ADHD. Through brain region-specific biochemical analysis, we uncovered that loss of CDKL5 disrupts dopamine synthesis and the expression of social communication-related key genes, such as forkhead-box P2 and mu-opioid receptor, in the corticostriatal circuit. Together, our findings support that CDKL5 plays a role in the comorbid features of autism and ADHD, and mice lacking CDKL5 may serve as an animal model to study the molecular and circuit mechanisms underlying autism-ADHD comorbidity.
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5. Kaale A, Smith L, Nordahl-Hansen A, Fagerland MW, Kasari C. {{Early interaction in autism spectrum disorder: Mothers’ and children’s behaviours during joint engagement}}. {Child Care Health Dev}. 2017.
BACKGROUND: More knowledge about the interaction between young children with autism spectrum disorder and their parents is one way to improve intervention. This study aims to investigate the behaviours of mothers and children with autism spectrum disorder during joint engagement, with a focus on pacing or rate (i.e., incidences per minute) of their behaviours when being in this state. METHOD: Video recordings of 10 min of free-play between 58 children (2-4 years) diagnosed with childhood autism and their mothers were used to examine rate of mothers’ and children’s behaviours (i.e., toy introduction, toy expansion, positive affect, and language) during joint engagement, the association between rate of mothers and children’s behaviours, the relation between rate of mothers’ behaviours and time in joint engagement, and how child factors might be associated with the latter. RESULTS: Mothers(m) and children(c) showed similar rate of positive affect (Mm = 0.6/Mc = 0.5) and toy expansion (Mm = 0.7/Mc = 0.7) per minute, whereas mothers talked almost three times more than their children (Mm = 10.2/Mc = 3.8). In contrast, mothers introduced fewer toys compared to the children (Mm = 0.7/Mc = 1.2). Rate of mothers’ toy introduction, toy expansion, and positive affect was inversely related to time in joint engagement (Regression coefficient = -70.7 to -48.5, p = .006 to .024). Rates of mothers’ and children’s behaviours were associated (Spearman rank order coefficient = .53 to .29, p < .001 to .03), but neither rate of children's behaviours nor mental age was associated with the observed relation between rate of these maternal behaviours and time in joint engagement. CONCLUSION: Time in joint engagement was related to rate of mothers' behaviours and children's mental age but not to rate of children's behaviours in this study. Thus, intervention teaching parents of young children with autism strategies designed to increase time in joint engagement may be vital. The complex nature of the interaction between mother and child behaviours in promoting joint engagement warrants further elucidation. Key messages Increased understanding of parent and child behaviours during joint engagement is important for identification of targets for parent-mediated early interventions in autism spectrum disorder. Time in joint engagement was related to rate of mothers' behaviours and children's mental age but not to rate of children's behaviours in this study. Higher rate of some maternal behaviours was inversely related to time in joint engagement, but it is not clear yet if higher rate may facilitate or disrupt joint engagement. The complex nature of the interaction between mother and child behaviours in promoting joint engagement warrants further elucidation. Lien vers le texte intégral (Open Access ou abonnement)
6. Laxman DJ, Greenberg JS, DaWalt LS, Hong J, Aman MG, Mailick M. {{Medication use by adolescents and adults with fragile X syndrome}}. {J Intellect Disabil Res}. 2017.
BACKGROUND: The behavioural challenges and medical conditions associated with fragile X syndrome (FXS) can lead to increased need for medications. METHOD: This longitudinal study examined the use of prescription medications for psychotropic and non-psychotropic purposes by adolescents and adults with FXS drawn from a North American community sample (N = 105). Odds and probabilities of continuing or discontinuing medication were calculated. Predictors of medication use were calculated. RESULTS: More than two-thirds took psychotropic medication, and about one-quarter took non-psychotropic medication. Over a 3-year period, those who initially took prescription medications were considerably more likely to remain on medications than to stop. Individuals with more autism symptoms, more behavioural problems, a mental health diagnosis, and greater family income were significantly more likely to use psychotropic medication 3 years later. Individuals who had more health problems, a mental health diagnosis, and were female were more likely to use non-psychotropic medication over this time period. CONCLUSIONS: Findings highlight the elevated and ongoing use of medication by individuals with FXS. Implications for social and behavioural research on FXS are discussed.
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7. Sakano H, Zorio DAR, Wang X, Ting YS, Noble WS, MacCoss MJ, Rubel EW, Wang Y. {{Proteomic analyses of nucleus laminaris identified candidate targets of the fragile X mental retardation protein}}. {J Comp Neurol}. 2017; 525(15): 3341-59.
The avian nucleus laminaris (NL) is a brainstem nucleus necessary for binaural processing, analogous in structure and function to the mammalian medial superior olive. In chickens (Gallus gallus), NL is a well-studied model system for activity-dependent neural plasticity. Its neurons have bipolar extension of dendrites, which receive segregated inputs from two ears and display rapid and compartment-specific reorganization in response to unilateral changes in auditory input. More recently, fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates local protein translation, has been shown to be enriched in NL dendrites, suggesting its potential role in the structural dynamics of these dendrites. To explore the molecular role of FMRP in this nucleus, we performed proteomic analysis of NL, using micro laser capture and liquid chromatography tandem mass spectrometry. We identified 657 proteins, greatly represented in pathways involved in mitochondria, translation and metabolism, consistent with high levels of activity of NL neurons. Of these, 94 are potential FMRP targets, by comparative analysis with previously proposed FMRP targets in mammals. These proteins are enriched in pathways involved in cellular growth, cellular trafficking and transmembrane transport. Immunocytochemistry verified the dendritic localization of several proteins in NL. Furthermore, we confirmed the direct interaction of FMRP with one candidate, RhoC, by in vitro RNA binding assays. In summary, we provide a database of highly expressed proteins in NL and in particular a list of potential FMRP targets, with the goal of facilitating molecular characterization of FMRP signaling in future studies.
