Transcriptome signatures from discordant sibling pairs reveal changes in peripheral blood immune cell composition in Autism Spectrum Disorder

Notwithstanding several research efforts in the past years, robust and replicable molecular signatures for autism spectrum disorders from peripheral blood remain elusive. The available literature on blood transcriptome in ASD suggests that through accurate experimental design it is possible to extract important information on the disease pathophysiology at the peripheral level. Here we exploit the availability of a resource for molecular biomarkers in ASD, the Italian Autism Network (ITAN) collection, for the investigation of transcriptomic signatures in ASD based on a discordant sibling pair design. Whole blood samples from 75 discordant sibling pairs selected from the ITAN network where submitted to RNASeq analysis and data analyzed by complementary approaches. Overall, differences in gene expression between affected and unaffected siblings were small. In order to assess the contribution of differences in the relative proportion of blood cells between discordant siblings, we have applied two different cell deconvolution algorithms, showing that the observed molecular signatures mainly reflect changes in peripheral blood immune cell composition, in particular NK cells. The results obtained by the cell deconvolution approach are supported by the analysis performed by WGCNA. Our report describes the largest differential gene expression profiling in peripheral blood of ASD subjects and controls conducted by RNASeq. The observed signatures are consistent with the hypothesis of immune alterations in autism and an increased risk of developing autism in subjects exposed to prenatal infections or stress. Our study also points to a potential role of NMUR1, HMGB3, and PTPRN2 in ASD

Comprehensive Analysis of the 16p11.2 Deletion and Null Cntnap2 Mouse Models of Autism Spectrum Disorder

Autism spectrum disorder comprises several neurodevelopmental conditions presenting symptoms in social communication and restricted, repetitive behaviors. A major roadblock for drug development for autism is the lack of robust behavioral signatures predictive of clinical efficacy. To address this issue, we further characterized, in a uniform and rigorous way, mouse models of autism that are of interest because of their construct validity and wide availability to the scientific community. We implemented a broad behavioral battery that included but was not restricted to core autism domains, with the goal of identifying robust, reliable phenotypes amenable for further testing. Here we describe comprehensive findings from two known mouse models of autism, obtained at different developmental stages, using a systematic behavioral test battery combining standard tests as well as novel, quantitative, computer-vision based systems. The first mouse model recapitulates a deletion in human chromosome 16p11.2, found in 1% of individuals with autism. The second mouse model harbors homozygous null mutations in Cntnap2, associated with autism and Pitt-Hopkins-like syndrome. Consistent with previous results, 16p11.2 heterozygous null mice, also known as Del(7Slx1b-Sept1)4Aam weighed less than wild type littermates displayed hyperactivity and no social deficits. Cntnap2 homozygous null mice were also hyperactive, froze less during testing, showed a mild gait phenotype and deficits in the three-chamber social preference test, although less robust than previously published. In the open field test with exposure to urine of an estrous female, however, the Cntnap2 null mice showed reduced vocalizations. In addition, Cntnap2 null mice performed slightly better in a cognitive procedural learning test. Although finding and replicating robust behavioral phenotypes in animal models is a challenging task, such functional readouts remain important in the development of therapeutics and we anticipate both our positive and negative findings will be utilized as a resource for the broader scientific community

UvA-DARE (Digital Academic Repository) Dissociable roles of mGlu5 and dopamine receptors in the rewarding and sensitizing properties of morphine and cocaine

General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Results MTEP attenuated the development of morphinebut not cocaine-induced CPP. In contrast, MTEP suppressed the development of cocaine-but not morphineinduced psychomotor sensitization. α-Flupenthixol blocked the development of both cocaine-and morphine-induced CPP but did not affect the development of sensitization to either drug. Conclusion Dopamine receptor stimulation mediates cocaine and morphine reward but not sensitization. In contrast, the role of mGlu5 receptors in reward and sensitization is drug-specific

Carbohydrate Intake in the Etiology of Crohn's Disease and Ulcerative Colitis

Background: Diet may have a role in the etiology of inflammatory bowel disease. In previous studies, the associations between increased intakes of carbohydrates, sugar, starch, and inflammatory bowel disease are inconsistent. However, few prospective studies have investigated the associations between these macronutrients and incident Crohn's disease (CD) or ulcerative colitis (UC). Methods: A total of 401,326 men and women were recruited between 1991 and 1998. At recruitment, dietary intakes of carbohydrate, sugar, and starch were measured using validated food frequency questionnaires. The cohort was monitored identifying participants who developed incident CD or UC. Cases were matched with 4 controls, and odds ratios were calculated for quintiles of total carbohydrate, sugar, and starch intakes adjusted for total energy intake, body mass index, and smoking. Results: One hundred ten participants developed CD, and 244 participants developed UC during follow-up. The adjusted odds ratio for the highest versus the lowest quintiles of total carbohydrate intake for CD was 0.87, 95% CI = 0.24 to 3.12 and for UC 1.46, 95% CI = 0.62 to 3.46, with no significant trends across quintiles for either (CD, Ptrend = 0.70; UC, Ptrend = 0.41). Similarly, no associations were observed with intakes of total sugar (CD, Ptrend = 0.50; UC, Ptrend = 0.71) or starch (CD, Ptrend = 0.69; UC, Ptrend = 0.17). Conclusions: The lack of associations with these nutrients is in agreement with many case–control studies that have not identified associations with CD or UC. As there is biological plausibility for how specific carbohydrates could have an etiological role in inflammatory bowel disease, future epidemiological work should assess individual carbohydrates, although there does not seem to be a macronutrient effect

Social brain activation during mentalizing in a large autism cohort: The Longitudinal European Autism Project

Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition with key deficits in social functioning. It is widely assumed that the biological underpinnings of social impairment are neurofunctional alterations in the "social brain," a neural circuitry involved in inferring the mental state of a social partner. However, previous evidence comes from small-scale studies and findings have been mixed. We therefore carried out the to-date largest study on neural correlates of mentalizing in ASD. Methods: As part of the Longitudinal European Autism Project, we performed functional magnetic resonance imaging at six European sites in a large, well-powered, and deeply phenotyped sample of individuals with ASD (N = 205) and typically developing (TD) individuals (N = 189) aged 6 to 30 years. We presented an animated shapes task to assess and comprehensively characterize social brain activation during mentalizing. We tested for effects of age, diagnosis, and their association with symptom measures, including a continuous measure of autistic traits. Results: We observed robust effects of task. Within the ASD sample, autistic traits were moderately associated with functional activation in one of the key regions of the social brain, the dorsomedial prefrontal cortex. However, there were no significant effects of diagnosis on task performance and no effects of age and diagnosis on social brain responses. Besides a lack of mean group differences, our data provide no evidence for meaningful differences in the distribution of brain response measures. Extensive control analyses suggest that the lack of case-control differences was not due to a variety of potential confounders. Conclusions: Contrary to prior reports, this large-scale study does not support the assumption that altered social brain activation during mentalizing forms a common neural marker of ASD, at least with the paradigm we employed. Yet, autistic individuals show socio-behavioral deficits. Our work therefore highlights the need to interrogate social brain function with other brain measures, such as connectivity and network-based approaches, using other paradigms, or applying complementary analysis approaches to assess individual differences in this heterogeneous condition

Imbalanced social-communicative and restricted repetitive behavior subtypes of autism spectrum disorder exhibit different neural circuitry

Social-communication (SC) and restricted repetitive behaviors (RRB) are autism diagnostic symptom domains. SC and RRB severity can markedly differ within and between individuals and may be underpinned by different neural circuitry and genetic mechanisms. Modeling SC-RRB balance could help identify how neural circuitry and genetic mechanisms map onto such phenotypic heterogeneity. Here, we developed a phenotypic stratification model that makes highly accurate (97-99%) out-of-sample SC = RRB, SC > RRB, and RRB > SC subtype predictions. Applying this model to resting state fMRI data from the EU-AIMS LEAP dataset (n = 509), we find that while the phenotypic subtypes share many commonalities in terms of intrinsic functional connectivity, they also show replicable differences within some networks compared to a typically-developing group (TD). Specifically, the somatomotor network is hypoconnected with perisylvian circuitry in SC > RRB and visual association circuitry in SC = RRB. The SC = RRB subtype show hyperconnectivity between medial motor and anterior salience circuitry. Genes that are highly expressed within these networks show a differential enrichment pattern with known autism-associated genes, indicating that such circuits are affected by differing autism-associated genomic mechanisms. These results suggest that SC-RRB imbalance subtypes share many commonalities, but also express subtle differences in functional neural circuitry and the genomic underpinnings behind such circuitry

Behavioral Characterization of the Novel GABA B Receptor- Positive Modulator GS39783 (N,NЈ-Dicyclopentyl-2- methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): Anxiolytic-Like Activity without Side Effects Associated with Baclofen or Benzodiazepines

ABSTRACT The role of GABA B receptors in various behavioral processes has been largely defined using the prototypical GABA B receptor agonist baclofen. However, baclofen induces sedation, hypothermia and muscle relaxation, which may interfere with its use in behavioral paradigms. Although there is much evidence for a role of the inhibitory neurotransmitter GABA in the pathophysiology of anxiety, the role of GABA B receptors in these disorders is largely unclear. We recently identified GS39783 (N,NЈ-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine) as a selective allosteric positive modulator at GABA B receptors. The aim of the present study was to broadly characterize the effects of GS39783 in well-validated rodent models for motor activity, cognition, and anxiety. The following tests were included: locomotor activity in rats and mice, rotarod and traction tests (including determinations of core temperature) in mice, passive avoidance in mice and rats, elevated plus maze in rats, elevated zero maze in mice and rats, stress-induced hyperthermia in mice, and pentobarbital-and ethanol-induced sleep in mice. Unlike baclofen and/or the benzodiazepine chlordiazepoxide, GS39783 had no effect in any of the tests for locomotion, cognition, temperature, or narcosis. Most interestingly, GS39783 had anxiolytic-like effects in all the tests used. Overall, the data obtained here suggest that positive modulation of GABA B receptors may serve as a novel therapeutic strategy for the development of anxiolytics, with a superior side effect profile to both baclofen and benzodiazepines

Fibre intake and the development of inflammatory bowel disease – a European prospective multi-centre cohort study (EPIC-IBD)

Background and Aims: Population-based prospective cohort studies investigating fibre intake and development of inflammatory bowel disease (IBD) are lacking. Our aim was to investigate the association between fibre intake and the development of Crohn’s disease (CD) and ulcerative colitis (UC) in a large European population. Methods: 401 326 participants, aged 20–80 years, were recruited in 8 countries in Europe between 1991 and 1998. At baseline, fibre intake (total fibres, fibres from fruit, vegetables and cereals) was recorded using food frequency questionnaires. The cohort was monitored for the development of IBD. Each case was matched with four controls and odds ratios (ORs) for the exposures were calculated using conditional logistic regression. Sensitivity analyses according to smoking status were computed. Results: In total, 104 and 221 participants developed incident CD and UC, respectively. For both CD and UC, there were no statistically significant associations with either quartiles, or trends across quartiles, for total fibre, or any of the individual sources. The associations were not affected by adjusting for smoking and energy intake. Stratification according to smoking status showed null findings apart from an inverse association with cereal fibre and CD in non-smokers (Quartile 4 vs 1 OR=0.12, 95% CI=0.02–0.75, P=0.023, OR trend across quartiles=0.50, 95% CI=0.29–0.86, P=0.017). Conclusion: The results do not support the hypothesis that dietary fibre is involved in the aetiology of UC, although future work should investigate whether there may be a protective effect of specific types of fibre according to smoking status in CD