1. de Oliveira Pereira Ribeiro L, Vargas-Pinilla P, Kappel DB, Longo D, Ranzan J, Becker MM, Dos Santos Riesgo R, Schuler-Faccini L, Roman T, Schuch JB. {{Evidence for Association Between OXTR Gene and ASD Clinical Phenotypes}}. {Journal of molecular neuroscience : MN}. 2018; 65(2): 213-21.
Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder characterized by impairments in social behaviors and communication. Oxytocin and its signaling pathway are related to a range of human behaviors, from facial expression recognition to aggressive behaviors, and have been suggested as involved in the etiology of ASD. Our aim was to evaluate the influence of two polymorphisms (rs1042778, rs53576) at the oxytocin receptor gene (OXTR) on ASD diagnosis and on specific ASD-related clinical symptoms (seizures, panic, and aggressive behaviors). We also assessed if these SNPs could be related to changes in OXTR availability and functionality using a bioinformatic approach. The sample was composed by 209 probands with ASD and their biological parents. Family-based approach and logistic regression models were used to investigated the outcomes. We observed that panic and aggressive behaviors were nominally associated with presence of rs1042778 T allele (P = 0.019/Pcorr = 0.114; P = 0.046/Pcorr = 0.276 respectively). Also, in the family-based analysis, a trend towards association with ASD susceptibility was observed for rs1042778 (G allele) (P = 0.066). In a bioinformatic approach, we demonstrated that rs1042778 G allele is determinant for the binding of the transcription factor MAZ, suggesting that when the T allele is present, the absence of MAZ binding might be associated with lower transcription levels of the OXTR gene. The overall findings suggest that the OXTR gene may play a role in ASD diagnosis and some of its clinical phenotypes, supported by previous animal and clinical studies. Further investigations are necessary to replicate our findings and fully understand the effects of the oxytocin pathway on ASD.
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2. Lewis ML, Kesler M, Candy SA, Rho JM, Pittman QJ. {{Comorbid epilepsy in autism spectrum disorder: Implications of postnatal inflammation for brain excitability}}. {Epilepsia}. 2018; 59(7): 1316-26.
OBJECTIVE: In different cohorts, 5%-30% of individuals with autism spectrum disorder (ASD) also have epilepsy. The high co-occurrence of these disorders suggests that a common mechanistic link may exist. The underlying pathophysiology of this comorbidity remains unknown. To investigate the mechanism(s) involved in the pathogenesis of ASD and epilepsy, we developed and validated a novel mouse model that concurrently exhibits hallmark features of both disorders. METHODS: We utilized inbred BTBR T+ Itpr3tf/J (BTBR) mice that exhibit the core behavioral characteristics of ASD (ie, impaired sociability, altered vocalizations, and restricted interests). BTBR mice received a lipopolysaccharide (LPS) or sterile saline injection at postnatal day (P)7, P14, or P21. Cytokine expression was analyzed for interleukin (IL)-1beta, IL-10, IL-6, and tumor necrosis factor alpha in brain tissue of P7 and adult BTBR mice. Adult BTBR mice were behaviorally analyzed for seizure susceptibility, sociability, communication deficits, and motor stereotypies, and monitored using chronic video-electroencephalography (EEG). RESULTS: Adult male and female BTBR mice treated at P7-P14 with LPS were more sensitive to pentylenetetrazol-induced seizures than saline-treated controls. ASD-like behaviors and hippocampal cytokine levels were unchanged between P7 LPS-treated BTBR mice and controls. EEG recordings from the dorsal hippocampus revealed a significant increase in number and frequency of seizures over the 4-week recording period (P60-P88) in BTBR mice postnatally treated with LPS at P7. These results indicate the presence of a comorbid epileptic phenotype in BTBR mice. SIGNIFICANCE: These findings suggest that an early postnatal immune challenge can increase brain excitability in adult BTBR mice and reveal an underlying epilepsy phenotype. This novel animal model may enable the elucidation of specific molecular alterations that are associated with the concurrent presentation of ASD and epilepsy, which could facilitate the development of targeted therapies for individuals affected by this comorbidity.
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3. Ruble LA, McGrew JH, Toland M, Dalrymple N, Adams M, Snell-Rood C. {{Randomized Control Trial of COMPASS for Improving Transition Outcomes of Students with Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2018.
The postsecondary outcomes of individuals with autism spectrum disorder (ASD) are significantly worse than peers with other disabilities. One problem is the lack of empirically-supported transition planning interventions to guide services and help produce better outcomes. We applied an implementation science approach to adapt and modify an evidence-based consultation intervention originally tested with young children called the Collaborative Model for Promoting Competence and Success (COMPASS; Ruble et al., The collaborative model for promoting competence and success for students with ASD. Springer, New York, 2012a) and evaluate it for efficacy in a randomized controlled trial for transition-age youth. Results replicated findings with younger students with ASD that IEP outcomes were higher for COMPASS compared to the placebo control group (d = 2.1). Consultant fidelity was high and teacher adherence improved over time, replicating the importance of ongoing teacher coaching.
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4. Schwede M, Nagpal S, Gandal MJ, Parikshak NN, Mirnics K, Geschwind DH, Morrow EM. {{Strong correlation of downregulated genes related to synaptic transmission and mitochondria in post-mortem autism cerebral cortex}}. {J Neurodev Disord}. 2018; 10(1): 18.
BACKGROUND: Genetic studies in autism have pinpointed a heterogeneous group of loci and genes. Further, environment may be an additional factor conferring susceptibility to autism. Transcriptome studies investigate quantitative differences in gene expression between patient-derived tissues and control. These studies may pinpoint genes relevant to pathophysiology yet circumvent the need to understand genetic architecture or gene-by-environment interactions leading to disease. METHODS: We conducted alternate gene set enrichment analyses using differentially expressed genes from a previously published RNA-seq study of post-mortem autism cerebral cortex. We used three previously published microarray datasets for validation and one of the microarray datasets for additional differential expression analysis. The RNA-seq study used 26 autism and 33 control brains in differential gene expression analysis, and the largest microarray dataset contained 15 autism and 16 control post-mortem brains. RESULTS: While performing a gene set enrichment analysis of genes differentially expressed in the RNA-seq study, we discovered that genes associated with mitochondrial function were downregulated in autism cerebral cortex, as compared to control. These genes were correlated with genes related to synaptic function. We validated these findings across the multiple microarray datasets. We also did separate differential expression and gene set enrichment analyses to confirm the importance of the mitochondrial pathway among downregulated genes in post-mortem autism cerebral cortex. CONCLUSIONS: We found that genes related to mitochondrial function were differentially expressed in autism cerebral cortex and correlated with genes related to synaptic transmission. Our principal findings replicate across all datasets investigated. Further, these findings may potentially replicate in other diseases, such as in schizophrenia.
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5. Steiner AM, Gengoux GW, Smith A, Chawarska K. {{Parent-Child Interaction Synchrony for Infants At-Risk for Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2018.
This study investigated interactions between parents and 12-month-old infants at high (HR-SIBS; n = 27) and low (LR-SIBS; n = 14) familial risk for autism spectrum disorder (ASD). The contributions of parental variables, as well as child’s autism symptom severity and verbal skills, to the parent interaction style were examined. Parents of HR-SIBS exhibited a higher level of synchronous-demanding behaviors, which was associated with parental report of atypical mood in the infant, but not with autism symptom severity, verbal skills, or parental depressive symptoms. These preliminary findings suggest a need for further investigation into HR-SIBS’ emotional development and parental perception of that development, as these factors may shape parent-child interaction and influence the effectiveness of parent-assisted early intervention programs.
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6. Vogan VM, Francis KE, Morgan BR, Smith ML, Taylor MJ. {{Load matters: neural correlates of verbal working memory in children with autism spectrum disorder}}. {J Neurodev Disord}. 2018; 10(1): 19.
BACKGROUND: Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder characterised by diminished social reciprocity and communication skills and the presence of stereotyped and restricted behaviours. Executive functioning deficits, such as working memory, are associated with core ASD symptoms. Working memory allows for temporary storage and manipulation of information and relies heavily on frontal-parietal networks of the brain. There are few reports on the neural correlates of working memory in youth with ASD. The current study identified the neural systems underlying verbal working memory capacity in youth with and without ASD using functional magnetic resonance imaging (fMRI). METHODS: Fifty-seven youth, 27 with ASD and 30 sex- and age-matched typically developing (TD) controls (9-16 years), completed a one-back letter matching task (LMT) with four levels of difficulty (i.e. cognitive load) while fMRI data were recorded. Linear trend analyses were conducted to examine brain regions that were recruited as a function of increasing cognitive load. RESULTS: We found similar behavioural performance on the LMT in terms of reaction times, but in the two higher load conditions, the ASD youth had lower accuracy than the TD group. Neural patterns of activations differed significantly between TD and ASD groups. In TD youth, areas classically used for working memory, including the lateral and medial frontal, as well as superior parietal brain regions, increased in activation with increasing task difficulty, while areas related to the default mode network (DMN) showed decreasing activation (i.e., deactivation). The youth with ASD did not appear to use this opposing cognitive processing system; they showed little recruitment of frontal and parietal regions across the load but did show similar modulation of the DMN. CONCLUSIONS: In a working memory task, where the load was manipulated without changing executive demands, TD youth showed increasing recruitment with increasing load of the classic fronto-parietal brain areas and decreasing involvement in default mode regions. In contrast, although they modulated the default mode network, youth with ASD did not show the modulation of increasing brain activation with increasing load, suggesting that they may be unable to manage increasing verbal information. Impaired verbal working memory in ASD would interfere with the youths’ success academically and socially. Thus, determining the nature of atypical neural processing could help establish or monitor working memory interventions for ASD.
