1. 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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2. Kidd SA, Lachiewicz A, Barbouth D, Blitz RK, Delahunty C, McBrien D, Visootsak J, Berry-Kravis E. {{Fragile X Syndrome: A Review of Associated Medical Problems}}. {Pediatrics};2014 (Oct 6)
Fragile X syndrome (FXS) is the most common known genetic cause of inherited intellectual disability and the most common known single-gene cause of autism spectrum disorder. It has been reported that a spectrum of medical problems are commonly experienced by people with FXS, such as otitis media, seizures, and gastrointestinal problems. Previous studies examining the prevalence of medical problems related to FXS have been challenging to interpret because of their marked differences in population, setting, and sampling. Through this comprehensive review, we update the literature by reviewing studies that have reported on prominent medical problems associated with FXS. We then compare prevalence results from those studies with results from a large cross-sectional database consisting of data collected by fragile X clinics that specialize in the care of children with FXS and are part of the Fragile X Clinical and Research Consortium. It is vital for pediatricians and other clinicians to be familiar with the medical problems related to FXS so that affected patients may receive proper diagnosis and treatment; improved care may lead to better quality of life for these patients and their families.
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3. 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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4. Robinson EB, Samocha KE, Kosmicki JA, McGrath L, Neale BM, Perlis RH, Daly MJ. {{Autism spectrum disorder severity reflects the average contribution of de novo and familial influences}}. {Proc Natl Acad Sci U S A};2014 (Oct 6)
Autism spectrum disorders (ASDs) are a highly heterogeneous group of conditions-phenotypically and genetically-although the link between phenotypic variation and differences in genetic architecture is unclear. This study aimed to determine whether differences in cognitive impairment and symptom severity reflect variation in the degree to which ASD cases reflect de novo or familial influences. Using data from more than 2,000 simplex cases of ASD, we examined the relationship between intelligence quotient (IQ), behavior and language assessments, and rate of de novo loss of function (LOF) mutations and family history of broadly defined psychiatric disease (depressive disorders, bipolar disorder, and schizophrenia; history of psychiatric hospitalization). Proband IQ was negatively associated with de novo LOF rate (P = 0.03) and positively associated with family history of psychiatric disease (P = 0.003). Female cases had a higher frequency of sporadic genetic events across the severity distribution (P = 0.01). High rates of LOF mutation and low frequencies of family history of psychiatric illness were seen in individuals who were unable to complete a traditional IQ test, a group with the greatest degree of language and behavioral impairment. These analyses provide strong evidence that familial risk for neuropsychiatric disease becomes more relevant to ASD etiology as cases become higher functioning. The findings of this study reinforce that there are many routes to the diagnostic category of autism and could lead to genetic studies with more specific insights into individual cases.
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5. Sinha P, Kjelgaard MM, Gandhi TK, Tsourides K, Cardinaux AL, Pantazis D, Diamond SP, Held RM. {{Autism as a disorder of prediction}}. {Proc Natl Acad Sci U S A};2014 (Oct 6)
A rich collection of empirical findings accumulated over the past three decades attests to the diversity of traits that constitute the autism phenotypes. It is unclear whether subsets of these traits share any underlying causality. This lack of a cohesive conceptualization of the disorder has complicated the search for broadly effective therapies, diagnostic markers, and neural/genetic correlates. In this paper, we describe how theoretical considerations and a review of empirical data lead to the hypothesis that some salient aspects of the autism phenotype may be manifestations of an underlying impairment in predictive abilities. With compromised prediction skills, an individual with autism inhabits a seemingly « magical » world wherein events occur unexpectedly and without cause. Immersion in such a capricious environment can prove overwhelming and compromise one’s ability to effectively interact with it. If validated, this hypothesis has the potential of providing unifying insights into multiple aspects of autism, with attendant benefits for improving diagnosis and therapy.
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6. Zwicker JD, Emery JC. {{Autism Research Funding Allocation: Can Economics Tell Us If We Have Got It Right?}}. {Autism Res};2014 (Oct 6)
There is a concern that the allocation of autism spectrum disorder (ASD) research funding may be misallocating resources, overemphasizing basic science at the expense of translational and clinical research. Anthony Bailey has proposed that an economic evaluation of autism research funding allocations could be beneficial for funding agencies by identifying under- or overfunded areas of research. In response to Bailey, we illustrate why economics cannot provide an objective, technical solution for identifying the « best » allocation of research resources. Economic evaluation has its greatest power as a late-stage research tool for interventions with identified objectives, outcomes, and data. This is not the case for evaluating whether research areas are over- or underfunded. Without an understanding of how research funding influences the likelihood and value of a discovery, or without a statement of the societal objectives for ASD research and level of risk aversion, economic analysis cannot provide a useful normative evaluation of ASD research. Autism Res 2014, : -. (c) 2014 International Society for Autism Research, Wiley Periodicals, Inc.
