1. Blanchard DC, Defensor EB, Meyza KZ, Pobbe RL, Pearson BL, Bolivar VJ, Blanchard RJ. {{BTBR T+tf/J mice: Autism-relevant behaviors and reduced fractone-associated heparan sulfate}}. {Neurosci Biobehav Rev};2011 (Jul 1)
BTBR T+tf/J (BTBR) mice have emerged as strong candidates to serve as models of a range of autism-relevant behaviors, showing deficiencies in social behaviors; reduced or unusual ultrasonic vocalizations in conspecific situations; and enhanced, repetitive self-grooming. Recent studies have described their behaviors in a seminatural visible burrow system (VBS); a Social Proximity Test in which avoidance of a conspecific is impossible; and in an object approach and investigation test evaluating attention to specific objects and potential stereotypies in the order of approaching/investigating objects. VBS results confirmed strong BTBR avoidance of conspecifics and in the Social Proximity Test, BTBR showed dramatic differences in several close-in behaviors, including specific avoidance of a nose-to-nose contact that may potentially be related to gaze-avoidance. Diazepam normalized social avoidance by BTBRs in a Three-Chamber Test, and some additional behaviors – but not nose to nose avoidance – in the Social Proximity Test. BTBR also showed higher levels of preference for particular objects, and higher levels of sequences investigating 3- or 4-objects in the same order. Heparan sulfate (HS) associated with fractal structures in the subventricular zone of the lateral ventricles was severely reduced in BTBR. HS may modulate the functions of a range of growth and guidance factors during development, and HS abnormalities are associated with relevant brain (callosal agenesis) and behavioral (reductions in sociality) changes; suggesting the value of examination of the dynamics of the HS system in the context of autism.
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2. Bolling DZ, Pitskel NB, Deen B, Crowley MJ, McPartland JC, Kaiser MD, Wyk BC, Wu J, Mayes LC, Pelphrey KA. {{Enhanced Neural Responses to Rule Violation in Children with Autism: A Comparison to Social Exclusion}}. {Dev Cogn Neurosci};2011 (Jul);1(3):280-294.
The present study aimed to explore the neural correlates of two characteristic deficits in autism spectrum disorders (ASD); social impairment and restricted, repetitive behavior patterns. To this end, we used comparable experiences of social exclusion and rule violation to probe potentially atypical neural networks in ASD. In children and adolescents with and without ASD, we used the interactive ball-toss game (Cyberball) to elicit social exclusion and a comparable game (Cybershape) to elicit a non-exclusive rule violation. Using functional magnetic resonance imaging (fMRI), we identified group differences in brain responses to social exclusion and rule violation. Though both groups reported equal distress following exclusion, the right insula and ventral anterior cingulate cortex were hypoactive during exclusion in children with ASD. In rule violation, right insula and dorsal prefrontal cortex were hyperactive in ASD. Right insula showed a dissociation in activation; it was hypoactive to social exclusion and hyperactive to rule violation in the ASD group. Further probed, different regions of right insula were modulated in each game, highlighting differences in regional specificity for which subsequent analyses revealed differences in patterns of functional connectivity. These results demonstrate neurobiological differences in processing social exclusion and rule violation in children with ASD.
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3. Carayol J, Sacco R, Tores F, Rousseau F, Lewin P, Hager J, Persico AM. {{Converging Evidence for an Association of ATP2B2 Allelic Variants with Autism in Male Subjects}}. {Biol Psychiatry};2011 (Jul 12)
BACKGROUND: Autism is a severe developmental disorder, with strong genetic underpinnings. Previous genome-wide scans unveiled a linkage region spanning 3.5 Mb, located on human chromosome 3p25. This region encompasses the ATP2B2 gene, encoding the plasma membrane calcium-transporting ATPase 2 (PMCA2), which extrudes calcium (Ca(2+)) from the cytosol into the extracellular space. Multiple lines of evidence support excessive intracellular Ca(2+) signaling in autism spectrum disorder (ASD), making ATP2B2 an attractive candidate gene. METHODS: We performed a family-based association study in an exploratory sample of 277 autism genetic resource exchange families and in a replication sample including 406 families primarily recruited in Italy. RESULTS: Several markers were significantly associated with ASD in the exploratory sample, and the same risk alleles at single nucleotide polymorphisms rs3774180, rs2278556, and rs241509 were found associated with ASD in the replication sample after correction for multiple testing. In both samples, the association was present in male subjects only. Markers associated with autism are all comprised within a single block of strong linkage disequilibrium spanning several exons, and the « risk » allele seems to follow a recessive mode of transmission. CONCLUSIONS: These results provide converging evidence for an association between ATP2B2 gene variants and autism in male subjects, spurring interest into the identification of functional variants, most likely involved in the homeostasis of Ca(2+) signaling. Additional support comes from a recent genome-wide association study by the Autism Genome Project, which highlights the same linkage disequilibrium region of the gene.
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4. Claro A, Cornish K, Gruber R. {{Association between fatigue and autistic symptoms in children with cri du chat syndrome}}. {Am J Intellect Dev Disabil};2011 (Jul);116(4):278-289.
Abstract In the current study, the authors examined whether the fatigue level of children diagnosed with cri du chat syndrome was associated with the expression of autistic symptoms. Sixty-nine children with cri du chat syndrome were compared with 47 children with moderate to severe intellectual disabilities who did not differ on intellectual severity. Participants were assessed using the Infant Sleep Questionnaire ( J. M. B. Morrell, 1999 ) for fatigue-level rating and the Childhood Autism Rating Scale ( E. Schopler, R. J. Reichler, & B. R. Renner, 1988 ) for autism-level rating. In support of the authors’ hypothesis, results indicated that children who exhibited high levels of fatigue were more likely to express high levels of autistic symptoms. Contrary to the authors’ hypothesis, children in the comparison group who exhibited high levels of fatigue conferred the greatest vulnerability to the expression of autistic symptoms.
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5. Courtemanche AB, Schroeder SR, Sheldon JB. {{Designs and analyses of psychotropic and behavioral interventions for the treatment of problem behavior among people with intellectual and developmental disabilities}}. {Am J Intellect Dev Disabil};2011 (Jul);116(4):315-328.
Abstract A combination of behavioral and medication-based interventions has been the most effective form of treatment for reducing problem behavior in individuals with intellectual and developmental disabilities. Evaluating the 2 types of interventions in combination and separately may require that researchers adapt methods traditionally used to evaluate drug interventions for individuals without disabilities. Some methodological difficulties that arise when evaluating drug treatments with this population include the withholding of treatment from control groups, identifying large homogeneous samples of participants, predicting individual clinical responsiveness, and many others. The purpose of this article is to summarize the methodological problems that arise when studying drug-behavior interactions among people with intellectual and developmental disabilities and to suggest alternative methods that may ameliorate these issues.
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6. Gallagher A, Hallahan B. {{Fragile X-associated disorders: a clinical overview}}. {J Neurol};2011 (Jul 12)
Fragile X Syndrome (FraX) is the most common inherited cause of learning disability worldwide. FraX is an X-linked neuro-developmental disorder involving an unstable trinucleotide repeat expansion of cytosine guanine guanine (CGG). Individuals with the full mutation of FraX have >200 CGG repeats with premutation carriers having 55-200 CGG repeats. A wide spectrum of physical, behavioural, cognitive, psychiatric and medical problems have been associated with both full mutation and premutation carriers of FraX. In this review, we detail the clinical profile and examine the aetiology, epidemiology, neuropathology, neuroimaging findings and possible management strategies for individuals with both the full mutation and premutation of FraX.
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7. Gillis RF, Rouleau GA. {{The ongoing dissection of the genetic architecture of Autistic Spectrum Disorder}}. {Mol Autism};2011 (Jul 8);2(1):12.
ABSTRACT: The development of robust, non-hypothesis based case/control studies has led to a large push forward towards identifying common genetic variants that contribute to complex traits. However, despite many attempts, the search for common disease-predisposing variants in childhood developmental disorders has largely failed. Recently, a role for rare causal variants and de novo mutations is emerging in the genetic architecture of some of these disorders, particularly those which incur a large degree of selection against the phenotype. Here we examine these data as well as use classic genetic epidemiological approaches to gain insights into the genetic architecture of ASD. Future studies using next generation sequencing should elucidate the precise role de novo mutations play in disorders traditionally thought to have resulted from polygenic or common disease, common variants inheritance.
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8. Guariglia SR, Jenkins EC, Jr., Chadman KK, Wen GY. {{Chlorination byproducts induce gender specific autistic-like behaviors in CD-1 mice}}. {Neurotoxicology};2011 (Jun 29)
In 2000, the Agency for Toxic Substances and Disease Registry (ATSDR) released a report concerning elevated autism prevalence and the presence water chlorination byproducts in the municipal drinking water supply in Brick Township, New Jersey. The ATSDR concluded that it was unlikely that these chemicals, specifically chloroform, bromoform (Trihalomethanes; THMs) and tetrachloroethylene (Perchloroethylene; PCE) had contributed to the prevalence of autism in this community based upon correlations between timing of exposure and/or concentration of exposure. The ATSDR conclusion may have been premature, as there is no conclusive data evidencing a correlation between a particular developmental time point that would render an individual most susceptible to toxicological insult with the development of autism. Therefore, it was our aim to determine if these chemicals could contribute to autistic like behaviors. We found that males treated with THMs and PCE have a significant reduction in the number of ultrasonic vocalizations (USVs) emitted in response to maternal separation, which are not attributed to deficits in vocal ability to or to lesser maternal care. These same males also show significantly elevated anxiety, an increase in perseverance behavior and a significant reduction in sociability. The sum of our data suggests that male, but not female mice, develop autistic like behaviors after gestational and postnatal exposure to the aforementioned chemical triad via drinking water. We believe development of such aberrant behaviors likely involves GABAergic system development.
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9. Mercier F, Cho Kwon Y, Kodama R. {{Meningeal/vascular alterations and loss of extracellular matrix in the neurogenic zone of adult BTBR T+ tf/J mice, animal model for autism}}. {Neurosci Lett};2011 (Jul 12);498(3):173-178.
Autism spectrum disorders are characterized by impaired social and communication skills and seem to result from altered neural development. We sought to determine whether the anatomy of the meninges and extracellular matrix (ECM) is altered in an animal model of autism, the BTBR T+ tf/J mouse. This mouse displays white matter tract anatomical defects and exhibits several symptoms of autism. Immunofluorescence cytochemistry for laminin, a major ECM marker, was performed on series of coronal sections of the adult BTBR T+ tf/J brain and the anatomy was analyzed in comparison to B6 wild type mice. Laminin immunoreactivity visualized meninges, blood vessels and the subventricular zone (SVZ) stem cell-associated ECM structures, which I have named fractones. All BTBR T+ tf/J mice observed showed the same forebrain defects. The lateral ventricle volume was severely reduced, the falx cerebri elongated, the arteries enlarged and the choroid plexus atrophied. Compared to B6 mice, fractone numbers in BTBR T+ tf/J mice were reduced by a factor three in the SVZ of the anterior portion of the lateral ventricle. This represents the primary neurogenic zone during adulthood. Fractones were reduced by a factor 1.5 in posterior portions of the lateral ventricle. Moreover, fractone size was reduced throughout the lateral ventricle SVZ. These results show hitherto unsuspected alterations in connective tissue/vasculature and associated ECM in the adult BTBR T+ tf/J mouse. The drastic changes of the connective tissue and ECM in the neurogenic zone of the lateral ventricle may contribute to incorrect neurogenesis during developmental and adult stages.
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10. Ross WJ. {{In Plane Sight: A Commentary on Community Inclusion for Families Affected by Autism}}. {J Dev Behav Pediatr};2011 (Jul 12)
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11. Steingass KJ, Chicoine B, McGuire D, Roizen NJ. {{Developmental Disabilities Grown Up: Down Syndrome}}. {J Dev Behav Pediatr};2011 (Jul 7)
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12. Yang WH, Jing J, Xiu LJ, Cheng MH, Wang X, Bao P, Wang QX. {{Regional cerebral blood flow in children with autism spectrum disorders: a quantitative 99mTc-ECD brain SPECT study with statistical parametric mapping evaluation}}. {Chin Med J (Engl)};2011 (May);124(9):1362-1366.
BACKGROUND: Autism spectrum disorders (ASD), which include autism, asperger syndrome (AS) and pervasive developmental disorder-not otherwise specified (PDD-NOS), are devastating neurodevelopmental disorders of childhood resulting in deficits in social interaction, repetitive patterns of behaviors, and restricted interests and activities. Single photon emission computed tomography (SPECT) is a common technique used to measure regional cerebral blood flow (rCBF). Several studies have measured rCBF in children with ASD using SPECT, however, findings are discordant. In addition, the majority of subjects used in these studies were autistic. In this study, we aimed to investigate changes in rCBF in children with ASD using SPECT. METHODS: A Technetium-99m-ethyl cysteinate dimmer ((99m)Tc-ECD) brain SPECT study was performed on an ASD group consisting of 23 children (3 girls and 20 boys; mean age (7.2 +/- 3.0) years) who were diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria and an age-matched control group with 8 children (1 girl and 7 boys, mean age (5.5 +/- 2.4) years). Image data were evaluated with Statistical Parametric Mapping, 5th version (SPM5). A Student’s t test for unpaired data was used to compare rCBF and asymmetry in the autism and corresponding control group. The covariance analysis, taking age as covariance, was performed between the ASD and control group. RESULTS: There was a significant reduction in rCBF in the bilateral frontal lobe (frontal poles, arcula frontal gyrus) and the bilateral basal ganglia in the autism group, and a reduction in the bilateral frontal, temporal, parietal, legumina nucleus and cerebellum in the AS group compared to the control. In addition, asymmetry of hemispheric hypoperfusion in the ASD group was observed. Inner-group comparison analysis revealed that rCBF decreased significantly in the bilateral frontal lobe (42.7%), basal nucleus (24.9%) and temporal lobe (22.8%) in the autism group, and in the bilateral cerebellum (22.8%), basal nucleus (19.3%) and right thalamencephalon (16.6%) in the AS group (P < 0.05). CONCLUSIONS: The decrease in rCBF in ASD is a global event, which involves the bilateral frontal, temporal, limbic system and basal ganglias. Asymmetry of hemispheric hypoperfusion was more obvious in the AS group than the autism group, which indicates a different neurobiological mechanism from that of autism.
