1. Bolte S, Marschik PB, Falck-Ytter T, Charman T, Roeyers H, Elsabbagh M. {{Infants at risk for autism: a European perspective on current status, challenges and opportunities}}. {European child & adolescent psychiatry}. 2013 Jan 10.
Currently, autism cannot be reliably diagnosed before the age of 2 years, which is why longitudinal studies of high-risk populations provide the potential to generate unique knowledge about the development of autism during infancy and toddlerhood prior to symptom onset. Early autism research is an evolving field in child psychiatric science. Key objectives are fine mapping of neurodevelopmental trajectories and identifying biomarkers to improve risk assessment, diagnosis and treatment. ESSEA (Enhancing the Scientific Study of Early Autism) is a COST (European Cooperation in Science and Technology) Action striving to create a European collaboration to enhance the progress of the discovery and treatment of the earliest signs of autism, and to establish European practice guidelines on early identification and intervention by bringing together European expertise from cognitive neuroscience and clinical sciences. The objective of this article is to clarify the state of current European research on at-risk autism research, and to support the understanding of different contexts in which the research is being conducted. We present ESSEA survey data on ongoing European high-risk ASD studies, as well as perceived challenges and opportunities in this field of research. We conclude that although high-risk autism research in Europe faces several challenges, the existence of several key factors (e.g., new and/or large-scale autism grants, availability of new technologies, and involvement of experienced research groups) lead us to expect substantial scientific and clinical developments in Europe in this field during the next few years.
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2. Bringas ME, Carbajal-Flores FN, Lopez-Ramirez TA, Atzori M, Flores G. {{Rearrangement of the dendritic morphology in limbic regions and altered exploratory behavior in a rat model of Autism Spectrum Disorder}}. {Neuroscience}. 2013 Mar 24.
Valproic acid (VPA) is a blocker of histone deacetylasewidely used to treat epilepsy, bipolar disorders, and migraine; its administration during pregnancy increases the risk of autism spectrum disorder (ASD) in the child. Thus, prenatal VPA exposure has emerged as a rodent model of ASD. In the present study, we aimed to investigate the effect of prenatal administration of VPA (500 mg/kg) at E12.5 on the exploratory behavior and locomotor activity in a novel environment, as well as on neuronal morphological rearrangement in the prefrontal cortex (PFC), in the Hippocampus, in the nucleus accumbens (NAcc), and in the basolateral amygdala (BLA) at three different ages: immediately after weaning (postnatal day 21 [PD21]), pre-pubertal (PD35) and post-pubertal (PD70) ages. Hyperlocomotion was observed in a novel environment in VPA animals at PD21 and PD70. Interestingly, exploratory behavior assessed by the hole board test at PD70 showed a reduced frequency but an increase in the duration of head-dippings in VPA-animals compared to vehicle-treated animals. In addition, the latency to the first head-dip was longer in prenatal VPA-treated animals at PD70. Quantitative morphological analysis of dendritic spine density revealed a reduced number of spines at PD70 in the PFC, dorsal hippocampus and BLA, with an increase in the dendritic spine density in NAcc and ventral hippocampus, in prenatal VPA-treated rats. In addition, at PD70 increases neuronal arborization were observed in the NAcc, layer 3 of the PFC, and BLA, with retracted neuronal arborization in the ventral and dorsal hippocampus. Our results extend the list of altered behaviors (exploratory behavior) detected in this model of ASD, and indicate that the VPA behavioral phenotype is accompanied by previously undescribed morphological re-arrangement in limbic regions.
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3. Girirajan S, Johnson RL, Tassone F, Balciuniene J, Katiyar N, Fox K, Baker C, Srikanth A, Yeoh KH, Khoo SJ, Nauth TB, Hansen R, Ritchie M, Hertz-Picciotto I, Eichler EE, Pessah IN, Selleck SB. {{Global increases in both common and rare copy number load associated with autism}}. {Hum Mol Genet}. 2013 Mar 27.
Children with autism have an elevated frequency of large, rare copy number variants (CNVs). However, the global load of deletions or duplications, per se, and their size, location and relationship to clinical manifestations of autism have not been documented. We examined CNV data from 516 individuals with autism or typical development from the population-based Childhood Autism Risks from Genetics and Environment (CHARGE) study. We interrogated 120 regions flanked by segmental duplications (genomic hotspots) for events >50 kbp and the entire genomic backbone for variants >300 kbp using a custom targeted DNA microarray. This analysis was complemented by a separate study of five highly dynamic, hotspots associated with autism or developmental delay syndromes using a finely-tiled array platform (>1 kbp) in 142 children matched for gender and ethnicity. In both studies, a significant increase in the number of base pairs of duplication, but not deletion, was associated with autism. Significantly elevated levels of CNV load remained after removal of rare and likely pathogenic events. Further, the entire CNV load detected with the finely-tiled array was contributed by common variants. The impact of this variation was assessed by examining the correlation of clinical outcomes with CNV load. The level of personal and social skills, measured by Vineland Adaptive Behavior Scales, negatively correlated (Spearman’s r=-0.13, p=0.034) with the duplication CNV load for the affected children; the strongest association was found for communication (p=0.048) and socialization (p=0.022) scores. We propose that CNV load, predominantly increased genomic base pairs of duplication, predisposes to autism.
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4. Kakooza-Mwesige A, Ssebyala K, Karamagi C, Kiguli S, Smith K, Anderson MC, Croen LA, Trevathan E, Hansen R, Smith D, Grether JK. {{Adaptation of the ‘ten questions’ to screen for autism and other neuro-developmental disorders in Uganda}}. {Autism}. 2013 Mar 27.
Neurodevelopmental disorders are recognized to be relatively common in developing countries but little data exist for planning effective prevention and intervention strategies. In particular, data on autism spectrum disorders are lacking. For application in Uganda, we developed a 23-question screener (23Q) that includes the Ten Questions screener and additional questions on autism spectrum disorder behaviors. We then conducted household screening of 1169 children, 2-9 years of age, followed by clinical assessment of children who screened positive and a sample of those who screened negative to evaluate the validity of the screener. We found that 320 children (27% of the total) screened positive and 68 children received a clinical diagnosis of one or more moderate to severe neurodevelopmental disorders (autism spectrum disorder; cerebral palsy; epilepsy; cognitive, speech and language, hearing, or vision impairment), including 8 children with autism spectrum disorders. Prevalence and validity of the screener were evaluated under different statistical assumptions. Sensitivity of the 23Q ranged from 0.55 to 0.80 and prevalence for >/=1 neurodevelopmental disorders from 7.7/100 children to 12.8/100 children depending on which assumptions were used. The combination of screening positive on both autism spectrum disorders and Ten Questions items was modestly successful in identifying a subgroup of children at especially high risk of autism spectrum disorders. We recommend that autism spectrum disorders and related behavioral disorders be included in studies of neurodevelopmental disorders in low-resource settings to obtain essential data for planning local and global public health responses.
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5. Ng MC, Yang YL, Lu KT. {{Behavioral and synaptic circuit features in a zebrafish model of fragile x syndrome}}. {PLoS One}. 2013;8(3):e51456.
Fragile X syndrome (FXS) is the most frequent inherited form of human mental retardation. It is characterized by cognitive impairment and physical and behavioral problems and is caused by the silencing of fmr1 transcription and the absence of the fmr1 protein (FMRP). Recently, animal models of FXS have greatly facilitated the investigation of the molecular and cellular mechanisms of this loss-of-function disorder. The present study was aimed to further characterize the role of FMRP in behavior and synaptic function by using fmr1 knockout zebrafish. In adult zebrafish, we found that fmr1 knockout produces the anxiolytic-like responses of increased exploratory behavior in light/dark and open-field tests and avoidance learning impairment. Furthermore, electrophysiological recordings from telencephalic slice preparations of knockout fish displayed markedly reduced long-term potentiation and enhanced long-term depression compared to wild-type fish; however, basal glutamatergic transmission and presynaptic function at the lateral (Dl) and medial (Dm) division of the dorsal telencephalon synapse remained normal. Taken together, our study not only evaluates the mechanism of FRMP but also suggests that zebrafish have valuable potential as a complementary vertebrate model in studying the molecular pathogenesis of human fragile X syndrome.
