1. Bernier R, Golzio C, Xiong B, Stessman HA, Coe BP, Penn O, Witherspoon K, Gerdts J, Baker C, Vulto-van Silfhout AT, Schuurs-Hoeijmakers JH, Fichera M, Bosco P, Buono S, Alberti A, Failla P, Peeters H, Steyaert J, Vissers LE, Francescatto L, Mefford HC, Rosenfeld JA, Bakken T, O’Roak BJ, Pawlus M, Moon R, Shendure J, Amaral DG, Lein E, Rankin J, Romano C, de Vries BB, Katsanis N, Eichler EE. {{Disruptive CHD8 Mutations Define a Subtype of Autism Early in Development}}. {Cell}. 2014 Jul 3.
Autism spectrum disorder (ASD) is a heterogeneous disease in which efforts to define subtypes behaviorally have met with limited success. Hypothesizing that genetically based subtype identification may prove more productive, we resequenced the ASD-associated gene CHD8 in 3,730 children with developmental delay or ASD. We identified a total of 15 independent mutations; no truncating events were identified in 8,792 controls, including 2,289 unaffected siblings. In addition to a high likelihood of an ASD diagnosis among patients bearing CHD8 mutations, characteristics enriched in this group included macrocephaly, distinct faces, and gastrointestinal complaints. chd8 disruption in zebrafish recapitulates features of the human phenotype, including increased head size as a result of expansion of the forebrain/midbrain and impairment of gastrointestinal motility due to a reduction in postmitotic enteric neurons. Our findings indicate that CHD8 disruptions define a distinct ASD subtype and reveal unexpected comorbidities between brain development and enteric innervation.
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2. Hyman SE. {{How far can mice carry autism research?}}. {Cell}. 2014 Jul 3;158(1):13-4.
In the face of growing controversy about the utility of genetic mouse models of human disease, Rothwell et al. report on a shared mechanism by which two different neuroligin-3 mutations, associated with autism spectrum disorders in humans, produce an enhancement in motor learning. The open question is how much we can learn about human ills from such models.
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3. Majdalany LM, Wilder DA, Greif A, Mathisen D, Saini V. {{Comparing massed-trial instruction, distributed-trial instruction, and task interspersal to teach tacts to children with autism spectrum disorders}}. {Journal of applied behavior analysis}. 2014 Jul 3.
Although massed-trial instruction, distributed-trial instruction, and task interspersal have been shown to be effective methods of teaching skills to children with autism spectrum disorders, they have not been directly compared. In the current study, we taught 6 children to tact shapes of countries using these methods to determine which would result in the quickest acquisition. Five of the 6 participants acquired the targets in the massed-trial condition before the other 2 conditions.
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4. Ross CA. {{Problems with autism, catatonia and schizophrenia in DSM-5}}. {Schizophrenia research}. 2014 Jul 3.
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5. Rothwell PE, Fuccillo MV, Maxeiner S, Hayton SJ, Gokce O, Lim BK, Fowler SC, Malenka RC, Sudhof TC. {{Autism-associated neuroligin-3 mutations commonly impair striatal circuits to boost repetitive behaviors}}. {Cell}. 2014 Jul 3;158(1):198-212.
In humans, neuroligin-3 mutations are associated with autism, whereas in mice, the corresponding mutations produce robust synaptic and behavioral changes. However, different neuroligin-3 mutations cause largely distinct phenotypes in mice, and no causal relationship links a specific synaptic dysfunction to a behavioral change. Using rotarod motor learning as a proxy for acquired repetitive behaviors in mice, we found that different neuroligin-3 mutations uniformly enhanced formation of repetitive motor routines. Surprisingly, neuroligin-3 mutations caused this phenotype not via changes in the cerebellum or dorsal striatum but via a selective synaptic impairment in the nucleus accumbens/ventral striatum. Here, neuroligin-3 mutations increased rotarod learning by specifically impeding synaptic inhibition onto D1-dopamine receptor-expressing but not D2-dopamine receptor-expressing medium spiny neurons. Our data thus suggest that different autism-associated neuroligin-3 mutations cause a common increase in acquired repetitive behaviors by impairing a specific striatal synapse and thereby provide a plausible circuit substrate for autism pathophysiology. PAPERFLICK:
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6. Taurines R, Schwenck C, Lyttwin B, Schecklmann M, Jans T, Reefschlager L, Geissler J, Gerlach M, Romanos M. {{Oxytocin plasma concentrations in children and adolescents with autism spectrum disorder: correlation with autistic symptomatology}}. {Attention deficit and hyperactivity disorders}. 2014 Jul 3.
Findings from research in animal models and humans have shown a clear role for the neuropeptide oxytocin (OT) on complex social behaviors. This is also true in the context of autism spectrum disorder (ASD). Previous studies on peripheral OT concentrations in children and young adults have reported conflicting results with the initial studies presenting mainly decreased OT plasma levels in ASD compared to healthy controls. Our study therefore aimed to further investigate changes in peripheral OT concentrations as a potential surrogate for the effects observed in the central nervous system (CNS) in ASD. OT plasma concentrations were assessed in 19 male children and adolescents with ASD, all with an IQ > 70 (age 10.7 +/- 3.8 years), 17 healthy male children (age 13.6 +/- 2.1 years) and 19 young male patients with attention deficit hyperactivity disorder (ADHD) as a clinical control group (age 10.4 +/- 1.9 years) using a validated radioimmunoassay. Analysis of covariance revealed significant group differences in OT plasma concentrations (F(2, 48) = 9.574, p < 0.001, eta 2 = 0.285; plasma concentrations ASD 19.61 +/- 7.12 pg/ml, ADHD 8.05 +/- 5.49 pg/ml, healthy controls 14.43 +/- 9.64 pg/ml). Post hoc analyses showed significantly higher concentrations in children with ASD compared to ADHD (p < 0.001). After Bonferroni correction, there was no significant difference in ASD in comparison with healthy controls (p = 0.132). A significant strong correlation between plasma OT and autistic symptomatology, assessed by the Autism Diagnostic Observation Schedule, was observed in the ASD group (p = 0.013, r = 0.603). Patients with ADHD differed from healthy control children by significantly decreased OT concentrations (p = 0.014). No significant influences of the covariates age, IQ, medication and comorbidity could be seen. Our preliminary results point to a correlation of OT plasma concentrations with autistic symptom load in children with ASD and a modulation of the OT system also in the etiologically and phenotypically overlapping disorder ADHD. Further studies in humans and animal models are warranted to clarify the complex association of the OT system with social impairments as well as stress-related and depressive behavior and whether peripheral findings reflect primary changes of OT synthesis and/or release in relevant areas of the CNS.
