1. Bahi A. {{Sustained lentiviral-mediated overexpression of microRNA124a in the dentate gyrus exacerbates anxiety- and autism-like behaviors associated with neonatal isolation in rats}}. {Behavioural brain research}. 2016 May 17.
Autism spectrum disorders (ASD) are highly disabling psychiatric disorders. Despite a strong genetic etiology, there are no efficient therapeutic interventions that target the core symptoms of ASD. Emerging evidence suggests that dysfunction of microRNA (miR) machinery may contribute to the underlying molecular mechanisms involved in ASD. Here, we report a stress model demonstrating that neonatal isolation-induced long-lasting hippocampal elevation of miR124a was associated with reduced expression of its target BDNF mRNA. In addition, we investigated the impact of lentiviral-mediated overexpression of miR124a into the dentate gyrus (DG) on social interaction, repetitive- and anxiety-like behaviors in the neonatal isolation (Iso) model of autism. Rats isolated from the dams on PND 1 to PND 11 were assessed for their social interaction, marble burying test (MBT) and repetitive self-grooming behaviors as adults following miR124a overexpression. Also, anxiety-like behavior and locomotion were evaluated in the elevated plus maze (EPM) and open-field (OF) tests. Results show that, consistent with previously published reports, Iso rats displayed decreased social interaction contacts but increased repetitive- and anxiety-like behaviors. Interestingly, across both autism- and anxiety-like behavioral assays, miR124a overexpression in the DG significantly exacerbated repetitive behaviors, social impairments and anxiety with no effect on locomotor activity. Our novel findings attribute neonatal isolation-inducible cognitive impairments to induction of miR124a and consequently suppressed BDNF mRNA, opening venues for intercepting these miR124a-mediated damages. They also highlight the importance of studying microRNAs in the context of ASD and identify miR124a as a novel potential therapeutic target for improving mood disorders.
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2. Brown HK, Cobigo V, Lunsky Y, Vigod SN. {{Maternal and offspring outcomes in women with intellectual and developmental disabilities: a population-based cohort study}}. {BJOG : an international journal of obstetrics and gynaecology}. 2016 May 24.
OBJECTIVE: To compare the risks for adverse maternal and offspring outcomes in women with and without intellectual and developmental disabilities. DESIGN: Population-based cohort study. SETTING: Ontario, Canada. POPULATION: Singleton obstetrical deliveries to 18- to 49-year-old women with and without intellectual and developmental disabilities (n = 3932 in the exposed cohort, n = 382 774 in the unexposed cohort; 2002-2011 fiscal years). METHODS: Women with intellectual and developmental disabilities were identified based on diagnoses in health administrative data or receipt of disability income support. The unexposed cohort comprised women without intellectual and developmental disabilities. Modified Poisson regression was used to compute adjusted relative risks (aRR) and 95% confidence intervals (CI) comparing the two cohorts. MAIN OUTCOME MEASURES: Primary maternal outcomes were: gestational diabetes, gestational hypertension, pre-eclampsia, eclampsia, and venous thromboembolism. Primary offspring outcomes were: preterm birth, small for gestational age, and large for gestational age. RESULTS: The exposed cohort, compared with the unexposed cohort, had increased risks for pre-eclampsia (aRR 1.47, 95% CI 1.11-1.93) and venous thromboembolism (aRR 1.60, 95% CI 1.17-2.19). Their offspring had increased risks for preterm birth (aRR 1.63, 95% CI 1.47-1.80) and small for gestational age (aRR 1.35, 95% CI 1.25-1.45). CONCLUSIONS: These findings suggest that there is a need to address modifiable risk factors for adverse outcomes among women with intellectual and developmental disabilities prior to and during pregnancy. Moreover, there is a need to enhance monitoring for maternal and offspring complications in this population. TWEETABLE ABSTRACT: Large cohort study: intellectual and developmental disabilities predispose women/babies to adverse outcomes.
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3. Chen F. {{Risperidone-Induced Acute Respiratory Distress in an Adolescent with Autism}}. {Journal of child and adolescent psychopharmacology}. 2016 May 24.
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4. Ellis SE, Panitch R, West AB, Arking DE. {{Transcriptome analysis of cortical tissue reveals shared sets of downregulated genes in autism and schizophrenia}}. {Translational psychiatry}. 2016;6:e817.
Autism (AUT), schizophrenia (SCZ) and bipolar disorder (BPD) are three highly heritable neuropsychiatric conditions. Clinical similarities and genetic overlap between the three disorders have been reported; however, the causes and the downstream effects of this overlap remain elusive. By analyzing transcriptomic RNA-sequencing data generated from post-mortem cortical brain tissues from AUT, SCZ, BPD and control subjects, we have begun to characterize the extent of gene expression overlap between these disorders. We report that the AUT and SCZ transcriptomes are significantly correlated (P<0.001), whereas the other two cross-disorder comparisons (AUT-BPD and SCZ-BPD) are not. Among AUT and SCZ, we find that the genes differentially expressed across disorders are involved in neurotransmission and synapse regulation. Despite the lack of global transcriptomic overlap across all three disorders, we highlight two genes, IQSEC3 and COPS7A, which are significantly downregulated compared with controls across all three disorders, suggesting either shared etiology or compensatory changes across these neuropsychiatric conditions. Finally, we tested for enrichment of genes differentially expressed across disorders in genetic association signals in AUT, SCZ or BPD, reporting lack of signal in any of the previously published genome-wide association study (GWAS). Together, these studies highlight the importance of examining gene expression from the primary tissue involved in neuropsychiatric conditions-the cortical brain. We identify a shared role for altered neurotransmission and synapse regulation in AUT and SCZ, in addition to two genes that may more generally contribute to neurodevelopmental and neuropsychiatric conditions. Lien vers le texte intégral (Open Access ou abonnement)
5. Hartley SL, Papp LM, Bolt D. {{Spillover of Marital Interactions and Parenting Stress in Families of Children With Autism Spectrum Disorder}}. {Journal of clinical child and adolescent psychology : the official journal for the Society of Clinical Child and Adolescent Psychology, American Psychological Association, Division 53}. 2016 May 24:1-12.
Few disorders appear to be more challenging for parents than autism spectrum disorder (ASD). Little is known about the extent to which parenting stress experienced by parents of children with ASD affects or is affected by marital quality. We examined daily spillover between level of parenting stress and marital interactions in a sample of 176 married couples (89.4% Caucasian, non-Hispanic) who have a child with ASD (5-12 years of age, 85% male) via a 14-day daily diary approach. On each day of the daily diary, parents individually reported on 8 positive and 8 negative marital interactions and their level of parenting stress. Dyadic multilevel modeling analyses using hierarchical linear modeling were conducted to examine same-day and lagged-effect associations between number of positive and negative marital interactions and level of parenting stress. Having a day with a higher number of negative marital interactions was associated with a higher level of parenting stress for both mothers and fathers of children with ASD. Having a day with fewer positive marital interactions was associated with having a more stressful parenting day for mothers of children with ASD. Same-day spillover was moderated by parent gender and the functioning of the child with ASD. Spillover flowed bidirectionally for mothers of children with ASD. Helping parents of children with ASD find ways to engage in positive marital interactions on stressful parenting days and avoid having negative affect, tension, and behaviors stemming from negative marital interactions spill into parenting experiences are important intervention targets.
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6. Jones KL, Croen LA, Yoshida CK, Heuer L, Hansen R, Zerbo O, DeLorenze GN, Kharrazi M, Yolken R, Ashwood P, Van de Water J. {{Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation}}. {Molecular psychiatry}. 2016 May 24.
Immune abnormalities have been described in some individuals with autism spectrum disorders (ASDs) as well as their family members. However, few studies have directly investigated the role of prenatal cytokine and chemokine profiles on neurodevelopmental outcomes in humans. In the current study, we characterized mid-gestational serum profiles of 22 cytokines and chemokines in mothers of children with ASD (N=415), developmental delay (DD) without ASD (N=188), and general population (GP) controls (N=428) using a bead-based multiplex technology. The ASD group was further divided into those with intellectual disabilities (developmental/cognitive and adaptive composite score<70) (ASD+ID, N=184) and those without (composite score70) (ASD-noID, N=201). Levels of cytokines and chemokines were compared between groups using multivariate logistic regression analyses, adjusting for maternal age, ethnicity, birth country and weight, as well as infant gender, birth year and birth month. Mothers of children with ASD+ID had significantly elevated mid-gestational levels of numerous cytokines and chemokines, such as granulocyte macrophage colony-stimulating factor, interferon-gamma, interleukin-1alpha (IL-1alpha) and IL-6, compared with mothers of children with either ASD-noID, those with DD, or GP controls. Conversely, mothers of children with either ASD-noID or with DD had significantly lower levels of the chemokines IL-8 and monocyte chemotactic protein-1 compared with mothers of GP controls. This observed immunologic distinction between mothers of children with ASD+ID from mothers of children with ASD-noID or DD suggests that the intellectual disability associated with ASD might be etiologically distinct from DD without ASD. These findings contribute to the ongoing efforts toward identification of early biological markers specific to subphenotypes of ASD.Molecular Psychiatry advance online publication, 24 May 2016; doi:10.1038/mp.2016.77. Lien vers le texte intégral (Open Access ou abonnement)
7. Mahmuda NA, Yokoyama S, Huang JJ, Liu L, Munesue T, Nakatani H, Hayashi K, Yagi K, Yamagishi M, Higashida H. {{A Study of Single Nucleotide Polymorphisms of the SLC19A1/RFC1 Gene in Subjects with Autism Spectrum Disorder}}. {International journal of molecular sciences}. 2016;17(5).
Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with complex genetic etiology. Recent studies have indicated that children with ASD may have altered folate or methionine metabolism, suggesting that the folate-methionine cycle may play a key role in the etiology of ASD. SLC19A1, also referred to as reduced folate carrier 1 (RFC1), is a member of the solute carrier group of transporters and is one of the key enzymes in the folate metabolism pathway. Findings from multiple genomic screens suggest the presence of an autism susceptibility locus on chromosome 21q22.3, which includes SLC19A1. Therefore, we performed a case-control study in a Japanese population. In this study, DNA samples obtained from 147 ASD patients at the Kanazawa University Hospital in Japan and 150 unrelated healthy Japanese volunteers were examined by the sequence-specific primer-polymerase chain reaction method pooled with fluorescence correlation spectroscopy. p < 0.05 was considered to represent a statistically significant outcome. Of 13 single nucleotide polymorphisms (SNPs) examined, a significant p-value was obtained for AA genotype of one SNP (rs1023159, OR = 0.39, 95% CI = 0.16-0.91, p = 0.0394; Fisher's exact test). Despite some conflicting results, our findings supported a role for the polymorphism rs1023159 of the SLC19A1 gene, alone or in combination, as a risk factor for ASD. However, the findings were not consistent after multiple testing corrections. In conclusion, although our results supported a role of the SLC19A1 gene in the etiology of ASD, it was not a significant risk factor for the ASD samples analyzed in this study. Lien vers le texte intégral (Open Access ou abonnement)
8. Oberman LM, Ifert-Miller F, Najib U, Bashir S, Heydrich JG, Picker J, Rotenberg A, Pascual-Leone A. {{Abnormal Mechanisms of Plasticity and Metaplasticity in Autism Spectrum Disorders and Fragile X Syndrome}}. {Journal of child and adolescent psychopharmacology}. 2016 May 24.
OBJECTIVES: Multiple lines of evidence from genetic linkage studies to animal models implicate aberrant cortical plasticity and metaplasticity in the pathophysiology of autism spectrum disorder (ASD) and fragile X syndrome (FXS). However, direct experimental evidence of these alterations in humans with these disorders is scarce. Transcranial magnetic stimulation (TMS) is a noninvasive tool for probing mechanisms of plasticity and metaplasticity in vivo, in humans. The aim of the current study was to examine mechanisms of plasticity and metaplasticity in humans with ASD and FXS. We employed a repetitive TMS protocol developed specifically to probe cortical plasticity, namely continuous theta burst stimulation (cTBS). METHODS: We applied a 40-second train of cTBS to primary motor cortex (M1) to healthy control participants and individuals with ASD or FXS, and we measured the cTBS-induced modulation in motor-evoked potentials (MEPs) in a contralateral intrinsic hand muscle. Each participant completed two sessions of the same protocol on two consecutive days. The degree of modulation in MEPs after cTBS on the first day was evaluated as a putative index of cortical plasticity. Examination of the changes in the effects of cTBS on the second day, as conditioned by the effects on the first day, provided an index of metaplasticity, or the propensity of a given cortical region to undergo plastic change based on its recent history. RESULTS: After a 40-second cTBS train, individuals with ASD show a significantly longer duration of suppression in MEP amplitude as compared with healthy controls, whereas individuals with FXS show a significantly shorter duration. After a second train of cTBS, 24 hours later, the ASD group was indistinguishable from the control group, and while in the FXS group MEPs were paradoxically facilitated by cTBS. CONCLUSION: These findings offer insights into the pathophysiology of ASD and FXS, specifically providing direct experimental evidence that humans with these disorders show distinct alterations in plasticity and metaplasticity, consistent with the findings in animal models. If confirmed in larger test-retest studies, repeated TMS measures of plasticity and metaplasticity may provide a valuable physiologic phenotype for ASD and FXS.
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9. Ohno K, Saito Y, Ueda R, Togawa M, Ohmae T, Matsuda Mt E, Fujiyama M, Maegaki Y. {{Effect of Serotonin 1A Agonists and Selective Serotonin Reuptake Inhibitors on Behavioral and Nighttime Respiratory Symptoms in Rett Syndrome}}. {Pediatric neurology}. 2016 Apr 1.
BACKGROUND: Rett syndrome is characterized by psychomotor regression during early childhood, autistic-like behaviors, and aberrant breathing patterns. Dysfunction of the serotonergic system has been postulated to play a role in the pathophysiology of these signs. PATIENT DESCRIPTION: We present an 11-year-old girl with Rett syndrome who exhibited marked respiratory symptoms, including frequent apneic events during sleep. She had been treated for these respiratory symptoms using noninvasive positive pressure ventilation since age six years. Treatment with serotonin 1A receptor agonist was initiated at age eight years, whereas treatment using a selective serotonin reuptake inhibitor began at age nine years. Noninvasive positive pressure ventilation therapy was effective in reducing symptoms of sleep apnea, and administration of serotonergic agents resulted in amelioration of sleep apneic events even in the absence of noninvasive positive pressure ventilation. In addition, improvements in hand stereotypy and social skills were observed after initiation of serotonin-based therapy. DISCUSSION: The respiratory difficulties our patient experienced during non-rapid eye movement (REM) sleep are characteristic of post-sigh central apnea. Exaggerated activity of expiratory neurons during such apneic events has been observed in mouse models of Rett syndrome. We suggest that prescribed serotonergic agents might serve to inhibit such activity, attenuating the imbalance between inspiratory and expiratory neurons. These agents might also be useful in the treatment of autistic-like behaviors caused by impaired serotonergic transmission in the brain.
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10. Ray B, Sokol DK, Maloney B, Lahiri DK. {{Finding novel distinctions between the sAPPalpha-mediated anabolic biochemical pathways in Autism Spectrum Disorder and Fragile X Syndrome plasma and brain tissue}}. {Scientific reports}. 2016;6:26052.
Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are developmental disorders. No validated blood-based biomarkers exist for either, which impedes bench-to-bedside approaches. Amyloid-beta (Abeta) precursor protein (APP) and metabolites are usually associated with Alzheimer’s disease (AD). APP cleavage by alpha-secretase produces potentially neurotrophic secreted APPalpha (sAPPalpha) and the P3 peptide fragment. beta-site APP cleaving enzyme (BACE1) cleavage produces secreted APPbeta (sAPPbeta) and intact Abeta. Excess Abeta is potentially neurotoxic and can lead to atrophy of brain regions such as amygdala in AD. By contrast, amygdala is enlarged in ASD but not FXS. We previously reported elevated levels of sAPPalpha in ASD and FXS vs. CONTROLS: We now report elevated plasma Abeta and total APP levels in FXS compared to both ASD and typically developing controls, and elevated levels of sAPPalpha in ASD and FXS vs. CONTROLS: By contrast, plasma and brain sAPPbeta and Abeta were lower in ASD vs. controls but elevated in FXS plasma vs. CONTROLS: We also detected age-dependent increase in an alpha-secretase in ASD brains. We report a novel mechanistic difference in APP pathways between ASD (processing) and FXS (expression) leading to distinct APP metabolite profiles in these two disorders. These novel, distinctive biochemical differences between ASD and FXS pave the way for blood-based biomarkers for ASD and FXS.