1. {{Correction: cholesterol metabolism is altered in rett syndrome: a study on plasma and primary cultured fibroblasts derived from patients}}. {PLoS One}. 2014; 9(11): e114654.
[This corrects the article DOI: 10.1371/journal.pone.0104834.].
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2. Avitzour M, Mor-Shaked H, Yanovsky-Dagan S, Aharoni S, Altarescu G, Renbaum P, Eldar-Geva T, Schonberger O, Levy-Lahad E, Epsztejn-Litman S, Eiges R. {{FMR1 epigenetic silencing commonly occurs in undifferentiated fragile x-affected embryonic stem cells}}. {Stem Cell Reports}. 2014; 3(5): 699-706.
Fragile X syndrome (FXS) is the most common heritable form of cognitive impairment. It results from epigenetic silencing of the X-linked FMR1 gene by a CGG expansion in its 5?-untranslated region. Taking advantage of a large set of FXS-affected human embryonic stem cell (HESC) lines and isogenic subclones derived from them, we show that FMR1 hypermethylation commonly occurs in the undifferentiated state (six of nine lines, ranging from 24% to 65%). In addition, we demonstrate that hypermethylation is tightly linked with FMR1 transcriptional inactivation in undifferentiated cells, coincides with loss of H3K4me2 and gain of H3K9me3, and is unrelated to CTCF binding. Taken together, these results demonstrate that FMR1 epigenetic gene silencing takes place in FXS HESCs and clearly highlights the importance of examining multiple cell lines when investigating FXS and most likely other epigenetically regulated diseases.
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3. Berry-Kravis E, Levin R, Shah H, Mathur S, Darnell JC, Ouyang B. {{Cholesterol levels in Fragile X syndrome}}. {Am J Med Genet A}. 2014.
Fragile X syndrome (FXS) is associated with intellectual disability and behavioral dysfunction, including anxiety, ADHD symptoms, and autistic features. Although individuals with FXS are largely considered healthy and lifespan is not thought to be reduced, very little is known about the long-term medical health of adults with FXS and no systematically collected information is available on standard laboratory measures from metabolic screens. During the course of follow up of a large cohort of patients with FXS we noted that many patients had low cholesterol and high density lipoprotein (HDL) values and thus initiated a systematic chart review of all cholesterol values present in charts from a clinic cohort of over 500 patients with FXS. Total cholesterol (TC), low density lipoprotein (LDL) and HDL were all significantly reduced in males from the FXS cohort relative to age-adjusted population normative data. This finding has relevance for health monitoring in individuals with FXS, for treatments with cholesterol-lowering agents that have been proposed to target the underlying CNS disorder in FXS based on work in animal models, and for potential biomarker development in FXS. (c) 2014 Wiley Periodicals, Inc.
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4. Bowers K, Lin PI, Erickson C. {{Pharmacogenomic Medicine in Autism: Challenges and Opportunities}}. {Paediatr Drugs}. 2014.
Autism spectrum disorder (ASD) affects 1 in 68 children in the US and is distinguished by core deficits in social interactions. Developing pharmacologic treatments for ASD is complicated by clinical and genetic heterogeneity. Although pharmacological treatments have not been shown to be effective in treating the core symptoms of ASD (i.e., social deficits), there is evidence that the burden of emotional and behavioral problems can be reduced with pharmacotherapy. Numerous randomized clinical trials of treatments for the core ASD deficits have been conducted; however, most have provided inconclusive results due to the substantial variation in treatment response. Variation also exists in the considerable metabolic side effects of many of the current treatments. Some of this variation may be explained by differences in the underlying genetic pathways. Exploiting the link between genetic heterogeneity and clinical variation associated with behavioral problems may provide an opportunity for targeted treatment of ASD. In this review, we summarize the recent findings from pharmacogenomics studies of ASD and suggest further how understanding how genetic liability modifies the effect of drugs may present an opportunity to address the challenges of personalized medicine in autism.
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5. Brunsdon VE, Colvert E, Ames C, Garnett T, Gillan N, Hallett V, Lietz S, Woodhouse E, Bolton P, Happe F. {{Exploring the cognitive features in children with autism spectrum disorder, their co-twins, and typically developing children within a population-based sample}}. {J Child Psychol Psychiatry}. 2014.
BACKGROUND: The behavioural symptoms of autism spectrum disorder (ASD) are thought to reflect underlying cognitive deficits/differences. The findings in the literature are somewhat mixed regarding the cognitive features of ASD. This study attempted to address this issue by investigating a range of cognitive deficits and the prevalence of multiple cognitive atypicalities in a large population-based sample comprising children with ASD, their unaffected co-twins, and typically developing comparison children. METHODS: Participants included families from the Twins Early Development Study (TEDS) where one or both children met diagnostic criteria for ASD. Overall, 181 adolescents with a diagnosis of ASD and 73 unaffected co-twins were included, plus an additional 160 comparison control participants. An extensive cognitive battery was administered to measure IQ, central coherence, executive function, and theory of mind ability. RESULTS: Differences between groups (ASD, co-twin, control) are reported on tasks assessing theory of mind, executive function, and central coherence. The ASD group performed atypically in significantly more cognitive tasks than the unaffected co-twin and control groups. Nearly a third of the ASD group presented with multiple cognitive atypicalities. CONCLUSIONS: Multiple cognitive atypicalities appear to be a characteristic, but not universal feature, of ASD. Further work is needed to investigate whether specific cognitive atypicalities, either alone or together, are related to specific behaviours characteristic of ASD.
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6. Dachtler J, Glasper J, Cohen RN, Ivorra JL, Swiffen DJ, Jackson AJ, Harte MK, Rodgers RJ, Clapcote SJ. {{Deletion of alpha-neurexin II results in autism-related behaviors in mice}}. {Transl Psychiatry}. 2014; 4: e484.
Autism is a common and frequently disabling neurodevelopmental disorder with a strong genetic basis. Human genetic studies have discovered mutations disrupting exons of the NRXN2 gene, which encodes the synaptic adhesion protein alpha-neurexin II (Nrxn2alpha), in two unrelated individuals with autism, but a causal link between NRXN2 and the disorder remains unclear. To begin to test the hypothesis that Nrxn2alpha deficiency contributes to the symptoms of autism, we employed Nrxn2alpha knockout (KO) mice that genetically model Nrxn2alpha deficiency in vivo. We report that Nrxn2alpha KO mice displayed deficits in sociability and social memory when exposed to novel conspecifics. In tests of exploratory activity, Nrxn2alpha KO mice displayed an anxiety-like phenotype in comparison with wild-type littermates, with thigmotaxis in an open field, less time spent in the open arms of an elevated plus maze, more time spent in the enclosure of an emergence test and less time spent exploring novel objects. However, Nrxn2alpha KO mice did not exhibit any obvious changes in prepulse inhibition or in passive avoidance learning. Real-time PCR analysis of the frontal cortex and hippocampus revealed significant decreases in the mRNA levels of genes encoding proteins involved in both excitatory and inhibitory transmission. Quantification of protein expression revealed that Munc18-1, encoded by Stxbp1, was significantly decreased in the hippocampus of Nrxn2alpha KO mice, which is suggestive of deficiencies in presynaptic vesicular release. Our findings demonstrate a causal role for the loss of Nrxn2alpha in the genesis of autism-related behaviors in mice.
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7. Fang WQ, Chen WW, Jiang L, Liu K, Yung WH, Fu AK, Ip NY. {{Overproduction of Upper-Layer Neurons in the Neocortex Leads to Autism-like Features in Mice}}. {Cell Rep}. 2014.
The functional integrity of the neocortex depends upon proper numbers of excitatory and inhibitory neurons; however, the consequences of dysregulated neuronal production during the development of the neocortex are unclear. As excess cortical neurons are linked to the neurodevelopmental disorder autism, we investigated whether the overproduction of neurons leads to neocortical malformation and malfunction in mice. We experimentally increased the number of pyramidal neurons in the upper neocortical layers by using the small molecule XAV939 to expand the intermediate progenitor population. The resultant overpopulation of neurons perturbs development of dendrites and spines of excitatory neurons and alters the laminar distribution of interneurons. Furthermore, these phenotypic changes are accompanied by dysregulated excitatory and inhibitory synaptic connection and balance. Importantly, these mice exhibit behavioral abnormalities resembling those of human autism. Thus, our findings collectively suggest a causal relationship between neuronal overproduction and autism-like features, providing developmental insights into the etiology of autism.
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8. Fatemi SH, Folsom TD. {{GABA receptor subunit distribution and FMRP-mGluR5 signaling abnormalities in the cerebellum of subjects with schizophrenia, mood disorders, and autism}}. {Schizophr Res}. 2014.
Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. GABAergic receptor abnormalities have been documented in several major psychiatric disorders including schizophrenia, mood disorders, and autism. Abnormal expression of mRNA and protein for multiple GABA receptors has also been observed in multiple brain regions leading to alterations in the balance between excitatory/inhibitory signaling in the brain with potential profound consequences for normal cognition and maintenance of mood and perception. Altered expression of GABAA receptor subunits has been documented in fragile X mental retardation 1 (FMR1) knockout mice, suggesting that loss of its protein product, fragile X mental retardation protein (FMRP), impacts GABAA subunit expression. Recent postmortem studies from our laboratory have shown reduced expression of FMRP in the brains of subjects with schizophrenia, bipolar disorder, major depression, and autism. FMRP acts as a translational repressor and, under normal conditions, inhibits metabotropic glutamate receptor 5 (mGluR5)-mediated signaling. In fragile X syndrome (FXS), the absence of FMRP is hypothesized to lead to unregulated mGluR5 signaling, ultimately resulting in the behavioral and intellectual impairments associated with this disorder. Our laboratory has identified changes in mGluR5 expression in autism, schizophrenia, and mood disorders. In the current review article, we discuss our postmortem data on GABA receptors, FMRP, and mGluR5 levels and compare our results with other laboratories. Finally, we discuss the interactions between these molecules and the potential for new therapeutic interventions that target these interconnected signaling systems.
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9. Fischer J, Koldewyn K, Jiang YV, Kanwisher N. {{Unimpaired Attentional Disengagement and Social Orienting in Children with Autism}}. {Clin Psychol Sci}. 2014; 2(2): 214-23.
Visual attention is often hypothesized to play a causal role in the development of autism spectrum disorder (ASD). Because attention shapes perception, learning, and social interaction, early deficits in attention could substantially impact the development of other perceptual and cognitive abilities. Here we test two key attentional phenomena thought to be disrupted in autism: attentional disengagement and social orienting. We find in a free viewing paradigm that both phenomena are present in high-functioning children with ASD (N=44; age 5-12 years) and are identical in magnitude to those in age- and IQ-matched typical children (N=40). While these attentional processes may malfunction in other circumstances, our data indicate that high-functioning children with ASD do not suffer from across-the-board disruptions of either attentional disengagement or social orienting. Combined with mounting evidence that other attentional abilities are largely intact, it seems increasingly unlikely that disruptions of core attentional abilities lie at the root of ASD.
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10. Klusek J, Roberts JE, Losh M. {{Cardiac Autonomic Regulation in Autism and Fragile X Syndrome: A Review}}. {Psychol Bull}. 2014.
Despite the significance of efforts to understand the biological basis of autism, progress in this area has been hindered, in part, by the considerable heterogeneity in the disorder. Fragile X syndrome (FXS), a monogenic condition associated with high risk for autism, may pave the way for the dissection of biological heterogeneity within idiopathic autism. This article adopts a cross-syndrome biomarker approach to evaluate potentially overlapping profiles of cardiac arousal dysregulation (and broader autonomic dysfunction) in autism and FXS. Approaches such as this, aimed at delineating shared mechanisms across genetic syndromes, hold great potential for improving diagnostic precision, promoting earlier identification, and uncovering key systems that can be targeted in pharmaceutical/behavioral interventions. Biomarker approaches may be vital to deconstructing complex psychiatric disorders and are currently promoted as such by major research initiatives such as the NIMH Research Domain Criteria (RDoC). Evidence reviewed here supports physiological dysregulation in a subset of individuals with autism, as evidenced by patterns of hyperarousal and dampened parasympathetic vagal tone that overlap with the well-documented physiological profile of FXS. Moreover, there is growing support for a link between aberrant cardiac activity and core deficits associated with autism, such as communication and social impairment. The delineation of physiological mechanisms common to autism and FXS could lend insight into relationships between genetic etiology and behavioral endstates, highlighting FMR1 as a potential candidate gene. Research gaps and potential pitfalls are discussed to inform timely, well-controlled biomarker research that will ultimately promote better diagnosis and treatment of autism and associated conditions. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
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11. Le Belle JE, Sperry J, Ngo A, Ghochani Y, Laks DR, Lopez-Aranda M, Silva AJ, Kornblum HI. {{Maternal Inflammation Contributes to Brain Overgrowth and Autism-Associated Behaviors through Altered Redox Signaling in Stem and Progenitor Cells}}. {Stem Cell Reports}. 2014; 3(5): 725-34.
A period of mild brain overgrowth with an unknown etiology has been identified as one of the most common phenotypes in autism. Here, we test the hypothesis that maternal inflammation during critical periods of embryonic development can cause brain overgrowth and autism-associated behaviors as a result of altered neural stem cell function. Pregnant mice treated with low-dose lipopolysaccharide at embryonic day 9 had offspring with brain overgrowth, with a more pronounced effect in PTEN heterozygotes. Exposure to maternal inflammation also enhanced NADPH oxidase (NOX)-PI3K pathway signaling, stimulated the hyperproliferation of neural stem and progenitor cells, increased forebrain microglia, and produced abnormal autism-associated behaviors in affected pups. Our evidence supports the idea that a prenatal neuroinflammatory dysregulation in neural stem cell redox signaling can act in concert with underlying genetic susceptibilities to affect cellular responses to environmentally altered cellular levels of reactive oxygen species.
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12. Luo S, Huang W, Xia Q, Xia Y, Du Q, Wu L, Duan R. {{Cryptic FMR1 mosaic deletion in a phenotypically normal mother of a boy with Fragile X Syndrome: case report}}. {BMC Med Genet}. 2014; 15(1): 125.
BackgroundIncreasing number of case reports of mosaic mutations and deletions have better armed clinicians and geneticists with more accurate and focused prenatal diagnoses. Since mosaicism means a significant increase of recurrence risk, detailed parental profiling is essential for risk assessments.Case presentationWe here describe a clinically unaffected mother with a son who had fragile X syndrome (FXS) caused by a large deletion that includes the entire FMR1. To assess the recurrence risk regarding her second pregnancy, a series of genetic tests were conducted to establish this mother inverted question marks status. Routine single nucleotide polymorphism (SNP) array and fluorescence in situ hybridisation (FISH) analyses detected two normal FMR1 copies in her blood. However, in-depth studies across the deleted region revealed varying proportions of mosaic deletion in her somatic tissues: lowest in the blood, moderately higher in the skin, urine sediment and menstrual discharge and highest in her eyebrow. Further FISH analysis of her skin-derived fibroblasts confirmed mosaicism of 13%.ConclusionTo our knowledge, this is the first characterized case of a female who was mosaic for an FMR1 deletion and extensive investigation of her mosaic status provided valuable information for her reproduction choices. Our case report may also alert clinicians and geneticists that a cryptic mosaicism with somatic heterogeneity should be carefully considered in families with children having clinically defined `de novo inverted question mark mutations, to avoid a second pregnancy with identical genetic abnormalities.
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13. Maillard AM, Ruef A, Pizzagalli F, Migliavacca E, Hippolyte L, Adaszewski S, Dukart J, Ferrari C, Conus P, Mannik K, Zazhytska M, Siffredi V, Maeder P, Kutalik Z, Kherif F, Hadjikhani N, Beckmann JS, Reymond A, Draganski B, Jacquemont S. {{The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity}}. {Mol Psychiatry}. 2014.
Anatomical structures and mechanisms linking genes to neuropsychiatric disorders are not deciphered. Reciprocal copy number variants at the 16p11.2 BP4-BP5 locus offer a unique opportunity to study the intermediate phenotypes in carriers at high risk for autism spectrum disorder (ASD) or schizophrenia (SZ). We investigated the variation in brain anatomy in 16p11.2 deletion and duplication carriers. Beyond gene dosage effects on global brain metrics, we show that the number of genomic copies negatively correlated to the gray matter volume and white matter tissue properties in cortico-subcortical regions implicated in reward, language and social cognition. Despite the near absence of ASD or SZ diagnoses in our 16p11.2 cohort, the pattern of brain anatomy changes in carriers spatially overlaps with the well-established structural abnormalities in ASD and SZ. Using measures of peripheral mRNA levels, we confirm our genomic copy number findings. This combined molecular, neuroimaging and clinical approach, applied to larger datasets, will help interpret the relative contributions of genes to neuropsychiatric conditions by measuring their effect on local brain anatomy.Molecular Psychiatry advance online publication, 25 November 2014; doi:10.1038/mp.2014.145.
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14. Merikangas AK, Segurado R, Heron EA, Anney RJ, Paterson AD, Cook EH, Pinto D, Scherer SW, Szatmari P, Gill M, Corvin AP, Gallagher L. {{The phenotypic manifestations of rare genic CNVs in autism spectrum disorder}}. {Mol Psychiatry}. 2014.
Significant evidence exists for the association between copy number variants (CNVs) and Autism Spectrum Disorder (ASD); however, most of this work has focused solely on the diagnosis of ASD. There is limited understanding of the impact of CNVs on the ‘sub-phenotypes’ of ASD. The objective of this paper is to evaluate associations between CNVs in differentially brain expressed (DBE) genes or genes previously implicated in ASD/intellectual disability (ASD/ID) and specific sub-phenotypes of ASD. The sample consisted of 1590 cases of European ancestry from the Autism Genome Project (AGP) with a diagnosis of an ASD and at least one rare CNV impacting any gene and a core set of phenotypic measures, including symptom severity, language impairments, seizures, gait disturbances, intelligence quotient (IQ) and adaptive function, as well as paternal and maternal age. Classification analyses using a non-parametric recursive partitioning method (random forests) were employed to define sets of phenotypic characteristics that best classify the CNV-defined groups. There was substantial variation in the classification accuracy of the two sets of genes. The best variables for classification were verbal IQ for the ASD/ID genes, paternal age at birth for the DBE genes and adaptive function for de novo CNVs. CNVs in the ASD/ID list were primarily associated with communication and language domains, whereas CNVs in DBE genes were related to broader manifestations of adaptive function. To our knowledge, this is the first study to examine the associations between sub-phenotypes and CNVs genome-wide in ASD. This work highlights the importance of examining the diverse sub-phenotypic manifestations of CNVs in ASD, including the specific features, comorbid conditions and clinical correlates of ASD that comprise underlying characteristics of the disorder.Molecular Psychiatry advance online publication, 25 November 2014; doi:10.1038/mp.2014.150.
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15. O’Roak BJ, Stessman HA, Boyle EA, Witherspoon KT, Martin B, Lee C, Vives L, Baker C, Hiatt JB, Nickerson DA, Bernier R, Shendure J, Eichler EE. {{Recurrent de novo mutations implicate novel genes underlying simplex autism risk}}. {Nat Commun}. 2014; 5: 5595.
Autism spectrum disorder (ASD) has a strong but complex genetic component. Here we report on the resequencing of 64 candidate neurodevelopmental disorder risk genes in 5,979 individuals: 3,486 probands and 2,493 unaffected siblings. We find a strong burden of de novo point mutations for these genes and specifically implicate nine genes. These include CHD2 and SYNGAP1, genes previously reported in related disorders, and novel genes TRIP12 and PAX5. We also show that mutation carriers generally have lower IQs and enrichment for seizures. These data begin to distinguish genetically distinct subtypes of autism important for aetiological classification and future therapeutics.
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16. Pandolfi V, Magyar CI, Norris M. {{Validity Study of the CBCL 6-18 for the Assessment of Emotional Problems in Youth With ASD}}. {J Ment Health Res Intellect Disabil}. 2014; 7(4): 306-22.
Youth with autism spectrum disorder (ASD) often present with emotional problems such as anxiety and depression (American Psychiatric Association, 2013). A recent study of the Child Behavior Checklist 6-18 (CBCL; Achenbach & Rescorla, 2001) indicated good sensitivity but relatively low specificity for identifying emotional problems in youth with ASD. The current study examined the extent to which variance in the CBCL’s Anxious/Depressed, Withdrawn/Depressed, Internalizing Domain, and Total Problems scales was accounted for by symptoms of emotional problems relative to ASD symptoms. Correlation and multiple regression analyses indicated that these scales measured anxiety and depression but a small statistically significant proportion of variance in Total Problems scores was also accounted for by ASD symptoms. Results contribute to the emerging evidence base for the inclusion of the CBCL in assessment protocols for assessing emotional and behavioral problems in youth with ASD.
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17. Piochon C, Kloth AD, Grasselli G, Titley HK, Nakayama H, Hashimoto K, Wan V, Simmons DH, Eissa T, Nakatani J, Cherskov A, Miyazaki T, Watanabe M, Takumi T, Kano M, Wang SS, Hansel C. {{Cerebellar plasticity and motor learning deficits in a copy-number variation mouse model of autism}}. {Nat Commun}. 2014; 5: 5586.
A common feature of autism spectrum disorder (ASD) is the impairment of motor control and learning, occurring in a majority of children with autism, consistent with perturbation in cerebellar function. Here we report alterations in motor behaviour and cerebellar synaptic plasticity in a mouse model (patDp/+) for the human 15q11-13 duplication, one of the most frequently observed genetic aberrations in autism. These mice show ASD-resembling social behaviour deficits. We find that in patDp/+ mice delay eyeblink conditioning-a form of cerebellum-dependent motor learning-is impaired, and observe deregulation of a putative cellular mechanism for motor learning, long-term depression (LTD) at parallel fibre-Purkinje cell synapses. Moreover, developmental elimination of surplus climbing fibres-a model for activity-dependent synaptic pruning-is impaired. These findings point to deficits in synaptic plasticity and pruning as potential causes for motor problems and abnormal circuit development in autism.
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18. Rieth SR, Stahmer AC, Suhrheinrich J, Schreibman L. {{Examination of the prevalence of stimulus overselectivity in children with ASD}}. {J Appl Behav Anal}. 2014.
Many individuals with autism spectrum disorders (ASD) display stimulus overselectivity, wherein a subset of relevant components in a compound stimulus controls responding, which impairs discrimination learning. The original experimental research on stimulus overselectivity in ASD was conducted several decades ago; however, interventions for children with ASD now typically include programming to target conditional discriminations in ways that might minimize the prevalence of stimulus overselectivity. The present study assessed 42 children who had been diagnosed or educationally identified with ASD using a discrimination learning assessment. Of these 42 children, 19% displayed overselective responding, which is a lower percentage than that seen in early research. Possible explanations for this decreased percentage, implications for intervention, and future directions for research are discussed.
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19. Seese RR, Wang K, Yao YQ, Lynch G, Gall CM. {{Spaced training rescues memory and ERK1/2 signaling in fragile X syndrome model mice}}. {Proc Natl Acad Sci U S A}. 2014; 111(47): 16907-12.
Recent studies have shown that short, spaced trains of afferent stimulation produce much greater long-term potentiation (LTP) than that obtained with a single, prolonged stimulation episode. The present studies demonstrate that spaced training regimens, based on these LTP timing rules, facilitate learning in wild-type (WT) mice and can offset learning and synaptic signaling impairments in the fragile X mental retardation 1 (Fmr1) knockout (KO) model of fragile X syndrome. We determined that 5 min of continuous training supports object location memory (OLM) in WT but not Fmr1 KO mice. However, the same amount of training distributed across three short trials, spaced by one hour, produced robust long-term memory in the KOs. At least three training trials were needed to realize the benefit of spacing, and intertrial intervals shorter or longer than 60 min were ineffective. Multiple short training trials also rescued novel object recognition in Fmr1 KOs. The spacing effect was surprisingly potent: just 1 min of OLM training, distributed across three trials, supported robust memory in both genotypes. Spacing also rescued training-induced activation of synaptic ERK1/2 in dorsal hippocampus of Fmr1 KO mice. These results show that a spaced training regimen designed to maximize synaptic potentiation facilitates recognition memory in WT mice and can offset synaptic signaling and memory impairments in a model of congenital intellectual disability.
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20. Shpyleva S, Ivanovsky S, de Conti A, Melnyk S, Tryndyak V, Beland FA, James SJ, Pogribny IP. {{Cerebellar Oxidative DNA Damage and Altered DNA Methylation in the BTBR T+tf/J Mouse Model of Autism and Similarities with Human Post Mortem Cerebellum}}. {PLoS One}. 2014; 9(11): e113712.
The molecular pathogenesis of autism is complex and involves numerous genomic, epigenomic, proteomic, metabolic, and physiological alterations. Elucidating and understanding the molecular processes underlying the pathogenesis of autism is critical for effective clinical management and prevention of this disorder. The goal of this study is to investigate key molecular alterations postulated to play a role in autism and their role in the pathophysiology of autism. In this study we demonstrate that DNA isolated from the cerebellum of BTBR T+tf/J mice, a relevant mouse model of autism, and from human post-mortem cerebellum of individuals with autism, are both characterized by an increased levels of 8-oxo-7-hydrodeoxyguanosine (8-oxodG), 5-methylcytosine (5mC), and 5-hydroxymethylcytosine (5hmC). The increase in 8-oxodG and 5mC content was associated with a markedly reduced expression of the 8-oxoguanine DNA-glycosylase 1 (Ogg1) and increased expression of de novo DNA methyltransferases 3a and 3b (Dnmt3a and Dnmt3b). Interestingly, a rise in the level of 5hmC occurred without changes in the expression of ten-eleven translocation expression 1 (Tet1) and Tet2 genes, but significantly correlated with the presence of 8-oxodG in DNA. This finding and similar elevation in 8-oxodG in cerebellum of individuals with autism and in the BTBR T+tf/J mouse model warrant future large-scale studies to specifically address the role of OGG1 alterations in pathogenesis of autism.
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21. Storch EA, Lewin AB, Collier AB, Arnold E, De Nadai AS, Dane BF, Nadeau JM, Mutch PJ, Murphy TK. {{A RANDOMIZED CONTROLLED TRIAL OF COGNITIVE-BEHAVIORAL THERAPY VERSUS TREATMENT AS USUAL FOR ADOLESCENTS WITH AUTISM SPECTRUM DISORDERS AND COMORBID ANXIETY}}. {Depress Anxiety}. 2014.
OBJECTIVE: Examine the efficacy of a personalized, modular cognitive-behavioral therapy (CBT) protocol among early adolescents with high-functioning autism spectrum disorders (ASDs) and co-occurring anxiety relative to treatment as usual (TAU). METHOD: Thirty-one children (11-16 years) with ASD and clinically significant anxiety were randomly assigned to receive 16 weekly CBT sessions or an equivalent duration of TAU. Participants were assessed by blinded raters at screening, posttreatment, and 1-month follow-up. RESULTS: Youth randomized to CBT demonstrated superior improvement across primary outcomes relative to those receiving TAU. Eleven of 16 adolescents randomized to CBT were treatment responders, versus 4 of 15 in the TAU condition. Gains were maintained at 1-month follow-up for CBT responders. CONCLUSIONS: These data extend findings of the promising effects of CBT in anxious youth with ASD to early adolescents.
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22. Van der Hallen R, Evers K, Brewaeys K, Van den Noortgate W, Wagemans J. {{Global Processing Takes Time: A Meta-Analysis on Local-Global Visual Processing in ASD}}. {Psychol Bull}. 2014.
What does an individual with autism spectrum disorder (ASD) perceive first: the forest or the trees? In spite of 30 years of research and influential theories like the weak central coherence (WCC) theory and the enhanced perceptual functioning (EPF) account, the interplay of local and global visual processing in ASD remains only partly understood. Research findings vary in indicating a local processing bias or a global processing deficit, and often contradict each other. We have applied a formal meta-analytic approach and combined 56 articles that tested about 1,000 ASD participants and used a wide range of stimuli and tasks to investigate local and global visual processing in ASD. Overall, results show no enhanced local visual processing nor a deficit in global visual processing. Detailed analysis reveals a difference in the temporal pattern of the local-global balance, that is, slow global processing in individuals with ASD. Whereas task-dependent interaction effects are obtained, gender, age, and IQ of either participant groups seem to have no direct influence on performance. Based on the overview of the literature, suggestions are made for future research. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
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23. Wei X, Wagner M, Christiano ER, Shattuck P, Yu JW. {{Special Education Services Received by Students with Autism Spectrum Disorders from Preschool through High School}}. {J Spec Educ}. 2014; 48(3): 167-79.
Little is known about how special education services received by students with Autism Spectrum Disorders (ASDs) differ by age, disability severity, and demographic characteristics. Using three national datasets, the Pre-Elementary Education Longitudinal Study (PEELS), the Special Education Elementary Longitudinal Study (SEELS), and the National Longitudinal Transition Study-2 (NLTS2), this study examined the age trends in special education services received by students with ASDs from preschool through high school. Elementary-school students with ASDs had higher odds of receiving adaptive physical education, specialized computer software or hardware, and special transportation, but lower odds of receiving learning strategies/study skills support than their preschool peers. Secondary-school students had lower odds of receiving speech/language or occupational therapy and of having a behavior management program, but higher odds of receiving mental health or social work services than their elementary-school peers. Both disability severity and demographic characteristics were associated with differences in special education service receipt rates.
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24. Zhang Y, Zhou B, Zhang X, Xu Q, Xu X. {{A 15q11.2 microdeletion first identified in a pair of autistic monozygotic twins with regression}}. {Psychiatr Genet}. 2014.
