1. Achuta VS, Moykkynen T, Peteri UK, Turconi G, Rivera C, Keinanen K, Castren ML. {{Functional changes of AMPA responses in human induced pluripotent stem cell-derived neural progenitors in fragile X syndrome}}. {Sci Signal}. 2018; 11(513).
Altered neuronal network formation and function involving dysregulated excitatory and inhibitory circuits are associated with fragile X syndrome (FXS). We examined functional maturation of the excitatory transmission system in FXS by investigating the response of FXS patient-derived neural progenitor cells to the glutamate analog (AMPA). Neural progenitors derived from induced pluripotent stem cell (iPSC) lines generated from boys with FXS had augmented intracellular Ca(2+) responses to AMPA and kainate that were mediated by Ca(2+)-permeable AMPA receptors (CP-AMPARs) lacking the GluA2 subunit. Together with the enhanced differentiation of glutamate-responsive cells, the proportion of CP-AMPAR and N-methyl-d-aspartate (NMDA) receptor-coexpressing cells was increased in human FXS progenitors. Differentiation of cells lacking GluA2 was also increased and paralleled the increased inward rectification in neural progenitors derived from Fmr1-knockout mice (the FXS mouse model). Human FXS progenitors had increased the expression of the precursor and mature forms of miR-181a, a microRNA that represses translation of the transcript encoding GluA2. Blocking GluA2-lacking, CP-AMPARs reduced the neurite length of human iPSC-derived control progenitors and further reduced the shortened length of neurites in human FXS progenitors, supporting the contribution of CP-AMPARs to the regulation of progenitor differentiation. Furthermore, we observed reduced expression of Gria2 (the GluA2-encoding gene) in the frontal lobe of FXS mice, consistent with functional changes of AMPARs in FXS. Increased Ca(2+) influx through CP-AMPARs may increase the vulnerability and affect the differentiation and migration of distinct cell populations, which may interfere with normal circuit formation in FXS.
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2. Friedman L, Sterling A, Barton-Hulsey A. {{Gaze avoidance and perseverative language in fragile X syndrome and autism spectrum disorder: brief report}}. {Dev Neurorehabil}. 2018: 1-4.
Gaze avoidance and perseverative language impact pragmatics in autism spectrum disorder (ASD) and fragile X syndrome (FXS). We examined these features during conversation samples in boys with ASD (n = 10) and boys with FXS and ASD (FXS+ASD; n = 10). Both groups had similar high rates of gaze avoidance and topic and conversation device perseverations, yet these features were not correlated with one another. Boys with FXS+ASD produced a higher proportion of single utterance perseverations. Results from this study highlight the need for future research to identify potential mechanisms influencing the presence of language perseverations and gaze avoidance.
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3. Guo M, Zhu J, Yang T, Lai X, Lei Y, Chen J, Li T. {{Vitamin A and vitamin D deficiencies exacerbate symptoms in children with autism spectrum disorders}}. {Nutr Neurosci}. 2018: 1-11.
OBJECTIVES: This study was designed to investigate the vitamin A (VA) and vitamin D (VD) levels in children with autism spectrum disorders (ASD) and to determine whether co-deficiency of VA and VD exacerbates clinical symptoms in autistic children. METHODS: The Autism Behavior Checklist, Childhood Autism Rating Scale (CARS), and Social Responsiveness Scale (SRS) were used to assess the symptoms of 332 children diagnosed as ASD. And the Gesell Developmental Scale (GDS) was used to evaluate neurodevelopment in children with ASD. Anthropometric measurement and questionnaire results were compared for all autistic children and 197 age- and gender-matched control children. Serum retinol levels were detected with high-performance liquid chromatography, and serum levels of 25-OH vitamin D were measured with an immunoassay method in the two groups. RESULTS: The ZHA, ZWA, and ZBMIA of the children with ASD were significantly lower than those of the control children. Furthermore, higher proportions of children with picky eating, resistance to new foods, and eating problems were observed in the ASD group when compared with the control group. Serum retinol and 25-OH vitamin D levels in autistic children were significantly lower than those in the control children. Additionally, VA and VD co-deficiency impacts more on the symptoms and development in autistic children. CONCLUSIONS: We found that children with autism have more VA and VD deficiencies than control children, and VA and VD co-deficiency may exacerbate the symptoms of children with ASD.
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4. Koberstein JN, Poplawski SG, Wimmer ME, Porcari G, Kao C, Gomes B, Risso D, Hakonarson H, Zhang NR, Schultz RT, Abel T, Peixoto L. {{Learning-dependent chromatin remodeling highlights noncoding regulatory regions linked to autism}}. {Sci Signal}. 2018; 11(513).
Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder that is associated with genetic risk factors. Most human disease-associated single-nucleotide polymorphisms (SNPs) are not located in genes but rather are in regulatory regions that control gene expression. The function of regulatory regions is determined through epigenetic mechanisms. Parallels between the cellular basis of development and the formation of long-term memory have long been recognized, particularly the role of epigenetic mechanisms in both processes. We analyzed how learning alters chromatin accessibility in the mouse hippocampus using a new high-throughput sequencing bioinformatics strategy we call DEScan (differential enrichment scan). DEScan, which enabled the analysis of data from epigenomic experiments containing multiple replicates, revealed changes in chromatin accessibility at 2365 regulatory regions-most of which were promoters. Learning-regulated promoters were active during forebrain development in mice and were enriched in epigenetic modifications indicative of bivalent promoters. These promoters were disproportionally intronic, showed a complex relationship with gene expression and alternative splicing during memory consolidation and retrieval, and were enriched in the data set relative to known ASD risk genes. Genotyping in a clinical cohort within one of these promoters (SHANK3 promoter 6) revealed that the SNP rs6010065 was associated with ASD. Our data support the idea that learning recapitulates development at the epigenetic level and demonstrate that behaviorally induced epigenetic changes in mice can highlight regulatory regions relevant to brain disorders in patients.
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5. Lei J, Sukhodolsky DG, Abdullahi SM, Braconnier ML, Ventola P. {{Brief report: Reduced anxiety following Pivotal Response Treatment in young children with Autism Spectrum Disorder}}. {Res Autism Spectr Disord}. 2017; 43-44: 1-7.
Up to 40% of children with Autism Spectrum Disorder (ASD) exhibit co-occurring anxiety symptoms. Despite recent success in mitigating anxiety symptoms in school-aged children with ASD (mean age >9 years) using adapted versions of Cognitive Behavioural Therapy, little is known about potential treatment outcomes for younger children. To address the gap in the literature, this open-label study evaluated change in anxiety following a 16-week open-label trial of Pivotal Response Treatment (PRT) in children with ASD aged 4-8 years. PRT is a behavioural treatment based on the principles of Applied Behaviour Analysis and has a primary aim of increasing social communication skills in children with ASD through natural reinforcements. To minimise conflation of anxiety and other co-occurring symptoms such as disruptive behaviour and attention-deficit hyperactivity disorder, we measured anxiety using the autism anxiety subscale of the Child and Adolescent Symptom Inventory (CASI) devised by Sukhodolsky et al. (2008). We observed significant anxiety reduction over 16-weeks of PRT. Furthermore, anxiety reduction was independent of changes in autism symptom severity. This study shows promising results for PRT as an intervention for reducing anxiety in young children with ASD.
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6. Morales DR, Slattery J, Evans S, Kurz X. {{Antidepressant use during pregnancy and risk of autism spectrum disorder and attention deficit hyperactivity disorder: systematic review of observational studies and methodological considerations}}. {BMC medicine}. 2018; 16(1): 6.
BACKGROUND: Antidepressant exposure during pregnancy has been associated with an increased risk of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) in several observational studies. We performed a systematic review of these studies to highlight the effect that important methodological limitations have on such analyses and to consider approaches to the conduct, reporting and interpretation of future studies. METHODS: A review of MEDLINE and EMBASE identified case-control, cohort and sibling studies assessing the risk of ASD and ADHD with antidepressant use during pregnancy. Approaches to confounding adjustment were described. Crude and adjusted effect estimates for comparisons between antidepressant exposure during pregnancy vs. all unexposed women were first meta-analysed using a generic inverse variance method of analysis, followed by effect estimates for alternative pre-selected comparison groups. RESULTS: A total of 15 studies measuring ASD as an outcome (involving 3,585,686 children and 40,585 cases) and seven studies measuring ADHD as an outcome (involving 2,765,723 patients and 52,313 cases) were identified. Variation in confounding adjustment existed between studies. Updated effect estimates for the association between maternal antidepressant exposure during pregnancy vs. all unexposed women remained statistically significant for ASD (adjusted random-effects risk ratio [RaRR] 1.53, 95% confidence interval [CI] 1.31-1.78). Similar significant associations were observed using pre-pregnancy maternal antidepressant exposure (RaRR 1.48, 95% CI 1.29-1.71) and paternal antidepressant exposure during pregnancy (1.29, 95% CI 1.08-1.53), but analyses restricted to using women with a history of affective disorder (1.18, 95% CI 0.91-1.52) and sibling studies (0.96, 95% CI 0.65-1.42) were not statistically significant. Corresponding associations for risk of ADHD with exposure were: RaRR 1.38, 95% CI 1.13-1.69 (during pregnancy), RaRR 1.38, 95% CI 1.14-1.69 (during pre-pregnancy), RaRR 1.71, 95% CI 1.31-2.23 (paternal exposure), RaRR 0.98, 95% CI 0.77-1.24 (women with a history of affective disorder) and RaRR 0.88, 95% CI 0.70-1.11 (sibling studies). CONCLUSIONS: Existing observational studies measuring the risk of ASD and ADHD with antidepressant exposure are heterogeneous in their design. Classical comparisons between exposed and unexposed women during pregnancy are at high risk of residual confounding. Alternative comparisons and sibling designs may aid the interpretation of causality and their utility requires further evaluation, including understanding potential limitations of undertaking meta-analyses with such data.
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7. Takata A, Miyake N, Tsurusaki Y, Fukai R, Miyatake S, Koshimizu E, Kushima I, Okada T, Morikawa M, Uno Y, Ishizuka K, Nakamura K, Tsujii M, Yoshikawa T, Toyota T, Okamoto N, Hiraki Y, Hashimoto R, Yasuda Y, Saitoh S, Ohashi K, Sakai Y, Ohga S, Hara T, Kato M, Nakamura K, Ito A, Seiwa C, Shirahata E, Osaka H, Matsumoto A, Takeshita S, Tohyama J, Saikusa T, Matsuishi T, Nakamura T, Tsuboi T, Kato T, Suzuki T, Saitsu H, Nakashima M, Mizuguchi T, Tanaka F, Mori N, Ozaki N, Matsumoto N. {{Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder}}. {Cell reports}. 2018; 22(3): 734-47.
Recent studies have established important roles of de novo mutations (DNMs) in autism spectrum disorders (ASDs). Here, we analyze DNMs in 262 ASD probands of Japanese origin and confirm the « de novo paradigm » of ASDs across ethnicities. Based on this consistency, we combine the lists of damaging DNMs in our and published ASD cohorts (total number of trios, 4,244) and perform integrative bioinformatics analyses. Besides replicating the findings of previous studies, our analyses highlight ATP-binding genes and fetal cerebellar/striatal circuits. Analysis of individual genes identified 61 genes enriched for damaging DNMs, including ten genes for which our dataset now contributes to statistical significance. Screening of compounds altering the expression of genes hit by damaging DNMs reveals a global downregulating effect of valproic acid, a known risk factor for ASDs, whereas cardiac glycosides upregulate these genes. Collectively, our integrative approach provides deeper biological and potential medical insights into ASDs.
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8. Tanaka A, Furubayashi T, Arai M, Inoue D, Kimura S, Kiriyama A, Kusamori K, Katsumi H, Yutani R, Sakane T, Yamamoto A. {{Delivery of oxytocin to the brain for the treatment of autism spectrum disorder by nasal application}}. {Molecular pharmaceutics}. 2018.
Oxytocin (OXT) is a cyclic nonapeptide, two amino acids of which are cysteine, forming an intramolecular disulfide bond. OXT is produced in the hypothalamus and is secreted into the blood stream from the posterior pituitary. As recent studies have suggested that OXT is a neurotransmitter exhibiting central effects important for social deficits, it has drawn much attention as a drug candidate for the treatment of autism. Although human-stage clinical trials of the nasal spray of OXT for the treatment of autism have already begun, few studies have examined the pharmacokinetics and brain distribution of OXT after nasal application. The aim of this study is to evaluate the disposition, nasal absorption, and therapeutic potential of OXT after nasal administration. The pharmacokinetics of OXT after intravenous bolus injection to rats followed a two-compartment model, with a rapid initial half-life of 3 min. The nasal bioavailability of OXT was approximately 2%. The brain concentration of OXT after nasal application was much higher than that after intravenous application, despite much lower concentrations in the plasma. More than 95% of OXT in the brain was directly transported from the nasal cavity. The in vivo stress-relief effect by OXT was observed only after intranasal administration. These results indicate that pharmacological active OXT was effectively delivered to the brain after intranasal administration. In conclusion, the nasal cavity is a promising route for the efficient delivery of OXT to the brain.
