1. Bambini-Junior V, Nunes GD, Schneider T, Gottfried C. {{Comment on « Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring »}}. {Science};2014 (Oct 10);346(6206):176.
Tyzio et al. (Reports, 7 February 2014, p. 675) reported that bumetanide restored the impaired oxytocin-mediated gamma-aminobutyric acid (GABA) excitatory-inhibitory shift during delivery in animal models of autism, ameliorating some autistic-like characteristics in the offspring. However, standard practices in the study of these models, such as the use of sex-dimorphic or males-only analyses and implementation of tests measuring social behavior, are lacking to definitely associate their findings to autism.
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2. Bradstreet JJ, Sych N, Antonucci N, Klunnik M, Ivankova O, Matyashchuk I, Demchuk M, Siniscalco D. {{Efficacy of fetal stem cell transplantation in autism spectrum disorders: an open-labeled pilot study}}. {Cell Transplant};2014 (Oct 9)
Autism spectrum disorders (ASDs) are heterogeneous complex neurodevelopmental pathologies defined by behavioral symptoms, but which have well characterized genetic, immunological and physiological comorbidities. Despite extensive research efforts, there are presently no agreed upon therapeutic approaches for either the core behaviors or the associated comorbidities. In particularly, the known autoimmune disorders associated with autism, are appealing targets for potential stem cell therapeutics. And of the various stem cell populations, fetal stem cells (FSCs) offer the potent immunoregulatory functions found in primordial mesenchymal stem cells, while exhibiting rapid expansion capacity and recognized plasticity. These properties enhance their potential for clinical use. Furthermore, FSCs are potent and implantable ?biopharmacies? capable of delivering trophic signals to the host which could influence brain development. This study investigated the safety and efficacy of FSC transplantations in treating children diagnosed with ASDs. Subjects were monitored at pre, and then 6 and 12 months following the transplantations which consisted of two doses of intravenously and subcutaneously administered FSCs. Autism Treatment Evaluation Checklist (ATEC) test and Aberrant Behavior Checklist (ABC) scores were performed. Laboratory examinations and clinical assessment of adverse effects were performed in order to evaluate treatment safety. No adverse events of significance were observed in ASD children treated with FSCs, including no transmitted infections or immunological complications. Statistically significant differences (p<0.05) were shown on ATEC/ABC scores for the domains of speech, sociability, sensory and overall health, as well as reductions in the total scores when compared to pre-treatment values. We recognize the use of FSCs remains controversial for the present. The results of this study, however, warrant addition investigations into the mechanisms of cell therapies for ASDs, while prompting the exploration of FSCs as ?biopharmacies? capable of manufacturing the full array of cell-signaling chemistry. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.
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3. DeRamus TP, Black BS, Pennick MR, Kana RK. {{Enhanced parietal cortex activation during location detection in children with autism}}. {J Neurodev Disord};2014;6(1):37.
BACKGROUND: Visuospatial processing has been found to be mediated primarily by two cortical routes, one of which is unique to recognizing objects (occipital-temporal, ventral or « what » pathway) and the other to detecting the location of objects in space (parietal-occipital, dorsal or « where » pathway). Considering previous findings of relative advantage in people with autism in visuospatial processing, this functional MRI study examined the connectivity in the dorsal and ventral pathways in high-functioning children with autism. METHODS: Seventeen high-functioning children and adolescents with autism spectrum disorders (ASD) and 19 age-and-IQ-matched typically developing (TD) participants took part in this study. A simple visual task involving object recognition and location detection was used. In the MRI scanner, participants were shown grey scale pictures of objects (e.g., toys, household items, etc.) and were asked to identify the objects presented or to specify the location of objects relative to a cross at the center of the screen. RESULTS: Children with ASD, relative to TD children, displayed significantly greater activation in the left inferior parietal lobule (especially the angular gyrus) while detecting the location of objects. However, there were no group differences in brain activity during object recognition. There were also differences in functional connectivity, with the ASD participants showing decreased connectivity of the inferior temporal area with parietal and occipital areas during location detection. CONCLUSIONS: The results of this study underscore previous findings of an increased reliance on visuospatial processing (increased parietal activation) for information processing in ASD individuals. In addition, such processing may be more local, focal, and detailed in ASD as evidenced from the weaker functional connectivity.
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4. Eftekhari S, Shahrokhi A, Tsintsadze V, Nardou R, Brouchoud C, Conesa M, Burnashev N, Ferrari DC, Ben-Ari Y. {{Response to Comment on « Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring »}}. {Science};2014 (Oct 10);346(6206):176.
Bambini-Junior et al. questioned whether our treatment in two rodent models of autism has a long-lasting effect into adulthood. In response, we show that bumetanide treatment around delivery attenuates autistic behavioral features in adult offspring. Therefore, the polarity of gamma-aminobutyric acid (GABA) actions during delivery exerts long-lasting priming actions after birth.
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5. Erickson CA, Ray B, Maloney B, Wink LK, Bowers K, Schaefer TL, McDougle CJ, Sokol DK, Lahiri DK. {{Impact of acamprosate on plasma amyloid-beta precursor protein in youth: A pilot analysis in fragile X syndrome-associated and idiopathic autism spectrum disorder suggests a pharmacodynamic protein marker}}. {J Psychiatr Res};2014 (Aug 19)
BACKGROUND: Understanding of the pathophysiology of autism spectrum disorder (ASD) remains limited. Brain overgrowth has been hypothesized to be associated with the development of ASD. A derivative of amyloid-beta precursor protein (APP), secreted APPalpha (sAPPalpha), has neuroproliferative effects and has been shown to be elevated in the plasma of persons with ASD compared to control subjects. Reduction in sAPPalpha holds promise as a novel molecular target of treatment in ASD. Research into the neurochemistry of ASD has repeatedly implicated excessive glutamatergic and deficient GABAergic neurotransmission in the disorder. With this in mind, acamprosate, a novel modulator of glutamate and GABA function, has been studied in ASD. No data is available on the impact of glutamate or GABA modulation on sAPPalpha function. METHODS: Plasma APP derivative levels pre- and post-treatment with acamprosate were determined in two pilot studies involving youth with idiopathic and fragile X syndrome (FXS)-associated ASD. We additionally compared baseline APP derivative levels between youth with FXS-associated or idiopathic ASD. RESULTS: Acamprosate use was associated with a significant reduction in plasma sAPP(total) and sAPPalpha levels but no change occurred in Abeta40 or Abeta42 levels in 15 youth with ASD (mean age: 11.1 years). Youth with FXS-associated ASD (n = 12) showed increased sAPPalpha processing compared to age-, gender- and IQ-match youth with idiopathic ASD (n = 11). CONCLUSIONS: Plasma APP derivative analysis holds promise as a potential biomarker for use in ASD targeted treatment. Reduction in sAPP (total) and sAPPalpha may be a novel pharmacodynamic property of acamprosate. Future study is required to address limitations of the current study to determine if baseline APP derivative analysis may predict subgroups of persons with idiopathic or FXS-associated ASD who may respond best to acamprosate or to potentially other modulators of glutamate and/or GABA neurotransmission.
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6. Foley KA, MacFabe DF, Kavaliers M, Ossenkopp KP. {{Sexually dimorphic effects of prenatal exposure to lipopolysaccharide, and prenatal and postnatal exposure to propionic acid, on acoustic startle response and prepulse inhibition in adolescent rats: Relevance to autism spectrum disorders}}. {Behav Brain Res};2014 (Oct 6)
Potential environmental risk factors for autism spectrum disorders (ASD) include viral/bacterial infection and an altered microbiome composition. The present study investigated whether administration of immune and gastrointestinal factors during gestation and early life altered startle response and prepulse inhibition in adolescent offspring using lipopolysaccharide (LPS), a bacterial mimetic, and propionic acid (PPA), a short chain fatty acid and metabolic product of antibiotic resistant enteric bacteria. Pregnant Long-Evans rats were injected once a day with PPA (500mg/kg SC) on G12-16, LPS (50mug/kg SC) on G15-16, or vehicle control on G12-16 or G15-16. Male and female offspring were injected with PPA (500mg/kg SC) or vehicle twice a day, every second day from postnatal days 10-18. Acoustic startle and prepulse inhibition were measured on postnatal days 45, 47, 49, and 51. Prenatal and postnatal treatments altered startle behavior in a sex-specific manner. Prenatal LPS treatment produced hyper-sensitivity to acoustic startle in males, but not females and did not alter prepulse inhibition. Subtle alterations in startle responses that disappeared with repeated trials occurred with prenatal PPA and postnatal PPA treatment in both male and female offspring. Prenatal PPA treatment decreased prepulse inhibition in females, but not males. Lastly, females receiving a double hit of PPA, prenatal and postnatal, showed sensitization to acoustic startle, providing evidence for the double hit hypothesis. The current study supports the hypotheses that immune activation and metabolic products of enteric bacteria may alter development and behavior in ways that resemble sensory abnormalities observed in ASD.
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7. Langley EA, Krykbaeva M, Blusztajn JK, Mellott TJ. {{High maternal choline consumption during pregnancy and nursing alleviates deficits in social interaction and improves anxiety-like behaviors in the BTBR T+Itpr3tf/J mouse model of autism}}. {Behav Brain Res};2014 (Oct 6)
Autism is a neurodevelopmental disorder with multiple genetic and environmental risk factors. Choline is a fundamental nutrient for brain development and high choline intake during prenatal and/or early postnatal periods is neuroprotective. We examined the effects of perinatal choline supplementation on social behavior, anxiety, and repetitive behaviors in the BTBR T+Itpr3tf/J (BTBR) mouse model of autism. The BTBR or the more « sociable » C57BL/6J (B6) strain females were fed a control or choline-supplemented diet from mating, throughout pregnancy and lactation. After weaning to a control diet, all offspring were evaluated at one or two ages [postnatal days 33-36 and 89-91] using open field (OF), elevated plus maze (EPM), marble burying (MB), and three-chamber social interaction tests. As expected, control-diet BTBR mice displayed higher OF locomotor activity, impaired social preference, and increased digging behavior during the MB test compared to control-diet B6 mice. Choline supplementation significantly decreased digging behavior, elevated the percentage of open arm entries and time spent in open arms in the EPM by BTBR mice, but had no effect on locomotion. Choline supplementation did not alter social interaction in B6 mice but remarkably improved impairments in social interaction in BTBR mice at both ages, indicating that the benefits of supplementation persist long after dietary choline returns to control levels. In conclusion, our results suggest that high choline intake during early development can prevent or dramatically reduce deficits in social behavior and anxiety in an autistic mouse model, revealing a novel strategy for the treatment/prevention of autism spectrum disorders.
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8. Pellicano E, Dinsmore A, Charman T. {{Views on Researcher-Community Engagement in Autism Research in the United Kingdom: A Mixed-Methods Study}}. {PLoS One};2014;9(10):e109946.
There has been a substantial increase in research activity on autism during the past decade. Research into effective ways of responding to the immediate needs of autistic people is, however, less advanced, as are efforts at translating basic science research into service provision. Involving community members in research is one potential way of reducing this gap. This study therefore investigated the views of community involvement in autism research both from the perspectives of autism researchers and of community members, including autistic adults, family members and practitioners. Results from a large-scale questionnaire study (n = 1,516) showed that researchers perceive themselves to be engaged with the autism community but that community members, most notably autistic people and their families, did not share this view. Focus groups/interviews with 72 participants further identified the potential benefits and remaining challenges to involvement in research, especially regarding the distinct perspectives of different stakeholders. Researchers were skeptical about the possibilities of dramatically increasing community engagement, while community members themselves spoke about the challenges to fully understanding and influencing the research process. We suggest that the lack of a shared approach to community engagement in UK autism research represents a key roadblock to translational endeavors.
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9. Vedora J, Grandelski K. {{A comparison of methods for teaching receptive language to toddlers with autism}}. {J Appl Behav Anal};2014 (Oct 10)
The use of a simple-conditional discrimination training procedure, in which stimuli are initially taught in isolation with no other comparison stimuli, is common in early intensive behavioral intervention programs. Researchers have suggested that this procedure may encourage the development of faulty stimulus control during training. The current study replicated previous work that compared the simple-conditional and the conditional-only methods to teach receptive labeling of pictures to young children with autism spectrum disorder. Both methods were effective, but the conditional-only method required fewer sessions to mastery.
