Pubmed du 28/05/20

jeudi 28 mai 2020

1. Baranova J, Dragunas G, Botellho MCS, Ayub ALP, Bueno-Alves R, Alencar RR, Papaiz DD, Sogayar MC, Ulrich H, Correa RG. Autism Spectrum Disorder : Signaling Pathways and Prospective Therapeutic Targets. Cell Mol Neurobiol ;2020 (May 28)

The Autism Spectrum Disorder (ASD) consists of a prevalent and heterogeneous group of neurodevelopmental diseases representing a severe burden to affected individuals and their caretakers. Despite substantial improvement towards understanding of ASD etiology and pathogenesis, as well as increased social awareness and more intensive research, no effective drugs have been successfully developed to resolve the main and most cumbersome ASD symptoms. Hence, finding better treatments, which may act as "disease-modifying" agents, and novel biomarkers for earlier ASD diagnosis and disease stage determination are needed. Diverse mutations of core components and consequent malfunctions of several cell signaling pathways have already been found in ASD by a series of experimental platforms, including genetic associations analyses and studies utilizing pre-clinical animal models and patient samples. These signaling cascades govern a broad range of neurological features such as neuronal development, neurotransmission, metabolism, and homeostasis, as well as immune regulation and inflammation. Here, we review the current knowledge on signaling pathways which are commonly disrupted in ASD and autism-related conditions. As such, we further propose ways to translate these findings into the development of genetic and biochemical clinical tests for early autism detection. Moreover, we highlight some putative druggable targets along these pathways, which, upon further research efforts, may evolve into novel therapeutic interventions for certain ASD conditions. Lastly, we also refer to the crosstalk among these major signaling cascades as well as their putative implications in therapeutics. Based on this collective information, we believe that a timely and accurate modulation of these prominent pathways may shape the neurodevelopment and neuro-immune regulation of homeostatic patterns and, hopefully, rescue some (if not all) ASD phenotypes.

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2. Brandalise F, Kalmbach BE, Mehta P, Thornton O, Johnston D, Zemelman BV, Brager DH. Fragile X Mental Retardation Protein bidirectionally controls dendritic I(h) in a cell-type specific manner between mouse hippocampus and prefrontal cortex. J Neurosci ;2020 (May 28)

Channelopathies are implicated in Fragile X syndrome (FXS), yet the dysfunction of a particular ion channel varies with cell type. We previously showed that HCN channel function is elevated in CA1 dendrites of the fmr1 (-/y) mouse model of FXS, but reduced in L5 prefrontal cortex (PFC) dendrites. Using male mice, we tested whether FMRP, the protein whose absence causes FXS, differentially modulates HCN channels in CA1 versus L5 PFC dendrites. Using a combination of viral tools, intracellular peptide, and dendritic electrophysiology we found that FMRP regulates HCN channels via a cell-autonomous protein-protein interaction. Virally expressed FMRP restored wild type HCN-channel-related dendritic properties in both CA1 and L5 neurons. Rapid intracellular perfusion of the non-mRNA binding N-terminal fragment, FMRP(1-298), similarly restored dendritic function. In support of a protein-protein interaction, we found that FMRP associated with HCN-TRIP8b complexes in both hippocampus and PFC. Finally, voltage-clamp recordings showed that FMRP modulated I(h) by regulating the number of functional dendritic HCN channels rather than individual channel properties. Together these represent three novel findings as to the nature of the changes in dendritic function in CA1 and PFC neurons based on the presence or absence of FMRP. Moreover, our findings provide evidence that FMRP can regulate its targets in opposite directions depending upon the cellular milieu.Significance StatementChanges in dendritic function, and voltage-gated ion channels in particular, are increasingly the focus of neurological disorders. We, and others, previously identified cell-type specific channelopathies in a mouse of model of Fragile X syndrome (FXS). The present study shows that replacing Fragile X Mental Retardation Protein (FMRP), which is absent in FXS, in adult CA1 and L5 PFC neurons regulates the number of functional dendritic HCN channels in a cell type specific manner. These results suggest that FMRP regulates dendritic HCN channels via a cell autonomous protein-protein mechanism.

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3. Burrows E, Koyama L, May C, Hill-Yardin EL, Hannan AJ. Environmental enrichment modulates affiliative and aggressive social behaviour in the neuroligin-3 R451C mouse model of autism spectrum disorder. Pharmacol Biochem Behav ;2020 (May 28):172955.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by impairments in social communication and the presence of restrictive and repetitive behaviours. A mouse model expressing an autism-associated R451C mutation in the gene encoding the synaptic adhesion protein neuroligin-3 (NL3) has been extensively characterised and shows altered behaviour relevant to core traits observed in ASD. Reported impairments in social behaviours in NL3(R451C) mice however remain controversial due to inconsistent findings in various assays across different laboratories. Such inconsistencies could plausibly be explained by an increased susceptibility of the NL3(R451C) mouse social phenotype to environmental modulation. To address this, NL3(R451C) mice were housed in standard or enriched housing from 4 weeks of age prior to behavioural testing. Enrichment rearing enhanced direct interactions with the stranger mouse in all mice in the three-chamber social interaction test however, NL3(R451C) mice did not show impairment in social interaction in the three-chamber test, in contrast with previous reports. Environmental enrichment enhanced aggressive behaviour in all mice, and did not specifically alter the heightened aggressive phenotype previously described in NL3(R451C) mice. Specific genotype effects of enrichment included reduced anxiety-like behaviour in WT mice, and lower locomotor activity levels in NL3 mice. While genotype-specific effects of enrichment were not seen on social behaviour, the general increase in affiliative social interaction and aggression seen in all mice, indicates that these behaviours, are vulnerable to change based on housing condition. Mouse models expressing ASD-associated mutations have great utility in elucidating the neurobiology underling development of core traits and it is crucial that efforts are focussed on those models exhibiting robust phenotypes. In light of the findings in the present study, we suggest approaches to improve replicability and reproducibility in mouse models of ASD.

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4. Capriola-Hall NN, Brewe AM, Golt J, White SW. Anxiety and Depression Reduction as Distal Outcomes of a College Transition Readiness Program for Adults with Autism. J Autism Dev Disord ;2020 (May 28)

Young adults with autism spectrum disorder (ASD) experience increased rates of anxiety and depression which can impact academic success. The Stepped Transition in Education Program for Students with ASD (STEPS) applies cognitive-behavioral principles to help young adults with ASD improve their adjustment to postsecondary education. We aimed to determine if STEPS had an effect on anxiety and depression. Treatment-seeking adults with ASD (n = 32 ; Mage = 19.74) were randomized to STEPS or transition as usual (TAU ; i.e., waitlist control group). STEPS participants evinced significantly greater declines in depressive symptoms from pre-treatment to post-treatment compared to the waitlist. Anxiety symptoms did not significantly change. Results suggest that transition support for young people with ASD may improve mental health.

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5. Griesi-Oliveira K, Passos-Bueno MR. Reply to Lombardo, 2020 : An additional route of investigation : what are the mechanisms controlling ribosomal protein genes dysregulation in autistic neuronal cells ?. Mol Psychiatry ;2020 (May 28)

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6. Hall DA, Nag S, Ouyang B, Bennett DA, Liu Y, Ali A, Zhou L, Berry-Kravis E. Fragile X Gray Zone Alleles Are Associated With Signs of Parkinsonism and Earlier Death. Mov Disord ;2020 (May 28)

BACKGROUND : Premutation size (55-199 CGG repeats) in the fragile X mental retardation 1 (FMR1) gene cause fragile X-associated tremor/ataxia syndrome, but it is unclear whether smaller "gray" zone expansions of 41-54 repeats are also associated with movement disorders. The objectives of this study were to determine the association between the FMR1 gene gray zone expansions, AGG interspersions, and the presence of parkinsonism and motor and cognitive function in an elderly community-based population. METHODS : Automated FMR1 polymerase chain reaction was performed on existing samples from 2 longitudinal aging studies whose subjects agreed to brain donation. A detailed clinical evaluation including a modified Unified Parkinson’s Disease Rating Scale score, a composite score of global motor function, 17 cognitive tests summarized as a global measure of cognition, and neuropathological examination were obtained for genotyped participants. RESULTS : The average age of the population (n = 2362) was 85.9 ± 7.3 years, and average age at death was 88.6 ± 6.4 years (n = 1326), with 72% women. The prevalence of FMR1 gray zone alleles was 5.2% (122 of 2362). There was no difference between participants with gray zone expansions or those lacking AGG interspersions compared with normal participants in global cognition, global motor function, clinical diagnosis, or pathological changes. Gray zone alleles were associated with signs of parkinsonism in men (P = 0.01), and gray zone carrier men were more likely to die (hazard ratio, 2.34 ; 95% confidence interval, 1.31-4.16). CONCLUSIONS : This is the largest study to investigate gray zone alleles in a community population. The key findings are that in men, the gray zone allele is associated with signs of parkinsonism and higher risk of death, but not with intranuclear neuronal inclusions. © 2020 International Parkinson and Movement Disorder Society.

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7. Hancock CL. We don’t play that way, we play this way : Functional Play Behaviours of Children with Autism and Severe Learning Difficulties. Res Dev Disabil ;2020 (May 24) ;103:103688.

BACKGROUND : Research on play for children with autism and severe learning difficulties (SLD) has been limited ; instead, much of the research focuses on higher levels of play, such as symbolic play. Those studies that present details regarding functional play are focused on examining the extent of the play deficit and limited in depth with respect to the precision of the categories presented. Therefore, the current understanding, the tools available to support, plan and measure play are not sufficiently detailed or focused on children with autism and SLD. AIMS : The aim of the research was to analyse the functional play actions and establish precise functional play categories though direct observations of children aged 3-11 diagnosed with a combination of autism and SLD. METHODS : Free-play observations of children diagnosed with autism and SLD (N-27) were conducted in a natural play situation across three special schools in England. OUTCOMES AND RESULTS : The results reveal four key areas of functional play : interacting with one object ; interacting with two (or more) objects ; interacting with self ; and interacting with the environment. In addition, seven subcategories were established as additional components related to functional play. CONCLUSIONS AND IMPLICATIONS : The results suggest that functional play for children with autism and SLD is far more complex than currently recognised. Through the depth and detail established, the categories provide greater understanding of the play characteristics and the most detailed account of the functional play characteristics for this group of children. The analysis provides sensitive measurement scales to support accuracy and precision when planning, supporting and measuring small increments of progress in play.

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8. Hatila S, Solanki G. Co-Occurrence of Autistic Spectrum Disorder and Childhood-Onset Schizophrenia. Prim Care Companion CNS Disord ;2020 (May 28) ;22(3)

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9. Huang Y, Zhang B, Cao J, Yu S, Wilson G, Park J, Kong J. Potential Locations for Noninvasive Brain Stimulation in Treating Autism Spectrum Disorders-A Functional Connectivity Study. Front Psychiatry ;2020 ;11:388.

OBJECTIVES : Noninvasive brain stimulation (NIBS) is an emerging tool for treating autism spectrum disorder (ASD). Exploring new stimulation targets may improve the efficacy of NIBS for ASD. MATERIALS AND METHODS : We first conducted a meta-analysis on 170 functional magnetic resonance imaging studies to identify ASD-associated brain regions. We then performed resting state functional connectivity analysis on 70 individuals with ASD to investigate brain surface regions correlated with these ASD-associated regions and identify potential NIBS targets for ASD. RESULTS : We found that the medial prefrontal cortex, angular gyrus, dorsal lateral prefrontal cortex, inferior frontal gyrus, superior parietal lobe, postcentral gyrus, precentral gyrus, middle temporal gyrus, superior temporal sulcus, lateral occipital cortex, and supplementary motor area/paracentral gyrus are potential locations for NIBS in ASD. CONCLUSION : Our findings may shed light on the development of new NIBS targets for ASD.

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10. Kayarian FB, Jannati A, Rotenberg A, Santarnecchi E. Targeting Gamma-Related Pathophysiology in Autism Spectrum Disorder Using Transcranial Electrical Stimulation : Opportunities and Challenges. Autism Res ;2020 (May 28)

A range of scalp electroencephalogram (EEG) abnormalities correlates with the core symptoms of autism spectrum disorder (ASD). Among these are alterations of brain oscillations in the gamma-frequency EEG band in adults and children with ASD, whose origin has been linked to dysfunctions of inhibitory interneuron signaling. While therapeutic interventions aimed to modulate gamma oscillations are being tested for neuropsychiatric disorders such as schizophrenia, Alzheimer’s disease, and frontotemporal dementia, the prospects for therapeutic gamma modulation in ASD have not been extensively studied. Accordingly, we discuss gamma-related alterations in the setting of ASD pathophysiology, as well as potential interventions that can enhance gamma oscillations in patients with ASD. Ultimately, we argue that transcranial electrical stimulation modalities capable of entraining gamma oscillations, and thereby potentially modulating inhibitory interneuron circuitry, are promising methods to study and mitigate gamma alterations in ASD. LAY SUMMARY : Brain functions are mediated by various oscillatory waves of neuronal activity, ranging in amplitude and frequency. In certain neuropsychiatric disorders, such as schizophrenia and Alzheimer’s disease, reduced high-frequency oscillations in the "gamma" band have been observed, and therapeutic interventions to enhance such activity are being explored. Here, we review and comment on evidence of reduced gamma activity in ASD, arguing that modalities used in other disorders may benefit individuals with ASD as well.

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11. Leader G, Murray M, O’Súilleabháin PS, Maher L, Naughton K, Arndt S, White K, Traina I, Mannion A. Relationship between parent-reported gastrointestinal symptoms, sleep problems, autism spectrum disorder symptoms, and behavior problems in children and adolescents with 22q11.2 deletion syndrome. Res Dev Disabil ;2020 (May 28) ;104:103698.

BACKGROUND : 22q11.2 deletion syndrome (22q) is a chromosome disorder, where a segment of chromosome 22, located at q11.2, is missing. This study aims to investigate the relationship between a number of parent-reported comorbid conditions including gastrointestinal symptoms, sleep problems, autism spectrum disorder (ASD) symptoms and behavior problems in children and adolescents with 22q deletion syndrome. METHOD : The Gastrointestinal Symptom Inventory, Children’s Sleep Habits Questionnaire, Behavior Problem Inventory-Short Form and the Social Communication Questionnaire were completed by parents of 149 children and adolescents aged 3-18 years with a diagnosis of 22q. RESULTS : A series of correlations and hierarchical multiple regressions were conducted to examine the relationships between GI symptoms, sleep problems and behavior problems in children and adolescents with 22q deletion syndrome. A significant moderate relationship was found between GI symptoms and sleep problems. Gender and ASD symptoms predicted GI symptoms. Significant small relationships were found between GI symptoms and self-injurious behavior. Significant small to moderate relationships were found between sleep problems and self-injurious behavior, aggressive/destructive behavior, and sterotyped behavior. Sleep problems predicted challenging behavior. CONCLUSIONS : This research demonstrated the importance of studying the relationship between comorbidities, including gastrointestinal symptoms, sleep problems, and behavior problems and how they shape the phenotype of 22q deletion syndrome.

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12. Major S, Campbell K, Espinosa S, Baker JP, Carpenter KL, Sapiro G, Vermeer S, Dawson G. Impact of a digital Modified Checklist for Autism in Toddlers-Revised on likelihood and age of autism diagnosis and referral for developmental evaluation. Autism ;2020 (May 28):1362361320916656.

This was a project in primary care for young children (1-2 years old). We tested a parent questionnaire on a tablet. This tablet questionnaire asked questions to see whether the child may have autism. We compared the paper and pencil version of the questionnaire to the tablet questionnaire. We read the medical charts for the children until they were 4 years old to see whether they ended up having autism. We found that doctors were more likely to recommend an autism evaluation when a parent used the tablet questionnaire. We think that the tablet’s automatic scoring feature helped the doctors. We also think that the doctors benefited from the advice the tablet gave them.

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13. Nyström P, Jones E, Darki F, Bölte S, Falck-Ytter T. Atypical Topographical Organization of Global Form and Motion Processing in 5-Month-Old Infants at Risk for Autism. J Autism Dev Disord ;2020 (May 26)

Research indicates that individuals with autism spectrum disorder (ASD) are superior at local processing while the integration of local features to global percepts is reduced. Here, we compared infants at familiar risk for ASD to typically developing infants in terms of global coherence processing at 5 months of age, using steady state visually evoked potentials (SSVEP). We found a different topographical organization for global form and motion processing in infants at risk (n = 50) than in controls (n = 23). In contrast, activation patterns for local visual change were strikingly similar between groups. Although preliminary, the results represent the first neurophysiological evidence supporting the view that basic atypicalities in perception may play a role in the developmental pathways leading to ASD.

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14. Ongono JS, Béranger R, Baghdadli A, Mortamais M. Pesticides used in Europe and autism spectrum disorder risk : can novel exposure hypotheses be formulated beyond organophosphates, organochlorines, pyrethroids and carbamates ? - A systematic review. Environ Res ;2020 (May 12) ;187:109646.

BACKGROUND : A growing body of evidences suggests an association between early exposure to organophosphates (OPs), organochlorines (OCs), pyrethroids or carbamates and autism spectrum disorder (ASD). However, there are limited data about the other pesticide groups, especially in Europe. OBJECTIVES : Based on a systematic review, we aimed to assess the influence of neuro- and thyrotoxic agricultural and domestic pesticides (other than OPs, OCs, pyrethroids and carbamates) authorized in Europe on risk of ASD in children or ASD behavioral phenotypes in rodents. METHODS : Pesticides were initially identified in the Hazardous Substances Data Bank. 20 currently used (10 pesticide groups) were retained based on the higher exposure potential. Epidemiological (children) and in vivo (rodents) studies were identified through PubMed, Web of Science and TOXLINE, without restriction of publication date or country (last update : November 2019). The risk of bias and level of evidence were also assessed. This systematic review is registered at the International Prospective Register of Systematic Reviews (PROSPERO, registration number CRD42019145384). RESULTS : In total, two epidemiological and 15 in vivo studies were retained, focusing on the azole, neonicotinoid, phenylpyrazole and phosphonoglycine pesticide groups. No study was conducted in Europe. Glyphosate, imidacloprid, clothianidin, myclobutanil, acetamiprid, tebuconazole, thiabendazole and fipronil, globally reported an association with an increased risk of ASD in children and/or ASD behavioral phenotypes in rodents. In children, glyphosate and myclobutanil showed a "moderate level of evidence" in their association with ASD, whereas imidacloprid showed an "inadequate level of evidence". In rodents, clothianidin, imidacloprid and glyphosate showed a "high level of evidence" in their association with altered behavioral, learning and memory skills. CONCLUSION : In the framework of environmental risk factors of ASD, novel hypotheses can be formulated about early exposure to eight pesticides. Glyphosate presented the most salient level of evidence. Given their neuro- and thyrotoxic properties, additional studies are needed for the 12 other pesticides not yet studied as potential ASD risk factors according to our inclusion criteria.

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15. Payne K, Maras KL, Russell AJ, Brosnan MJ, Mills R. Self-reported motivations for engaging or declining to engage in cyber-dependent offending and the role of autistic traits. Res Dev Disabil ;2020 (May 28) ;104:103681.

Cyber-dependent offending, i.e. criminal behaviour reliant on computing and the online domain, has been reportedly associated with particular characteristics and motivations such as being young, male, autistic and motivated by challenge. These associations are anecdotal however and empirical evidence is limited. The present study investigated reasons for engaging or declining to commit cyber-dependent offending in cyber-skilled non-offenders (n = 175) and offenders (n = 7) via an online survey measuring cyber-dependent criminality. The potential role of autism and autistic traits was also considered. Qualitative interviews about motivations for offending were carried out with the offenders. The cyber-dependent offenders reported seven main reasons for engaging in cyber-dependent offending : (1) lack of understanding ; (2) entertainment ; (3) peer influence ; (4) experience and career ; (5) anonymity and risk perception ; (6) life events ; and (7) morals. Twenty-nine (approximately 17 %) of the non-offenders had been asked to engage in cyber-dependent offending but had declined. Their reasons and motivations for declining to commit cyber-dependent offences were compared with the cyber-dependent offenders reasons and motivations for engaging in cybercrime. Seven main reasons for declining to offend were identified : (1) moral principles ; (2) perception of risk ; (3) fear of consequences ; (4) not wanting to ; (5) wanting to adhere to the law ; (6) behaviour being too complicated ; and (7) price being too low. Implications for practise are discussed.

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16. Raulston TJ, Bhana N, McIntyre LL, Ousley C. Brief Report : Collateral Joint Engagement During a Playdate Intervention for Children with and at Risk for Autism. J Autism Dev Disord ;2020 (May 28)

Joint engagement involves a child coordinating their attention between a person and a shared event. Children with autism present with impaired joint engagement. Playdates are a common way that children socially engage yet have been largely overlooked in the social skills literature. Requesting skills have been conceptualized as pivotal, producing collateral effects. In the current study, we conducted a secondary analysis of a single-case design that evaluated a parent-implemented playdate intervention focused on supporting children and peers to request and respond to one another during games. We examined the collateral effects of the playdate intervention on joint engagement. Two children demonstrated gains in joint engagement with a peer, and the third exhibited variable changes. Implications for future research are discussed.

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17. Santiesteban I, Gibbard C, Drucks H, Clayton N, Banissy MJ, Bird G. Individuals with Autism Share Others’ Emotions : Evidence from the Continuous Affective Rating and Empathic Responses (CARER) Task. J Autism Dev Disord ;2020 (May 28)

A new task (’CARER’) was used to test claims of reduced empathy in autistic adults. CARER measures emotion identification (ability to identify another’s affective state), affective empathy (degree to which another’s affective state causes a matching state in the Empathiser) and affect sharing (degree to which the Empathiser’s state matches the state they attribute to another). After controlling for alexithymia, autistic individuals showed intact affect sharing, emotion identification and affective empathy. Results suggested reduced retrospective socio-emotional processing, likely due to a failure to infer neurotypical mental states. Thus, autism may be associated with difficulties inferring another’s affective state retrospectively, but not with sharing that state. Therefore, when appropriate measures are used, autistic individuals do not show a lack of empathy.

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18. Toczylowska B, Zieminska E, Senator P, Lazarewicz JW. Hippocampal Metabolite Profiles in Two Rat Models of Autism : NMR-Based Metabolomics Studies. Mol Neurobiol ;2020 (May 28)

Autism spectrum disorders (ASDs) are increasingly being diagnosed. Hypotheses link ASD to genetic, epigenetic, or environmental factors. The role of oxidative stress and the imbalance between excitatory and inhibitory neurotransmission in the pathogenesis of ASD has been suggested. Rats in which ASD symptoms are induced by valproate (VPA) or thalidomide (THAL) application in utero are useful models in ASD studies. Our study investigated whether rats in ASD models show changes in metabolite levels in the brain consistent with the hypothetical pathomechanisms of ASD. Female rats were fed one dose of 800 mg/kg VPA or 500 mg/kg THAL orally on the 11th day of gestation, and 1-month offspring were used for the experiments. Metabolic profiles from proton nuclear magnetic resonance spectroscopy of hydrophilic and hydrophobic extracts of rat hippocampi were subjected to OPLS-DA statistical analysis. Large differences between both models in the content of several metabolites in the rat hippocampus were noticed. The following metabolic pathways were identified as being disturbed in both ASD models : steroid hormone biosynthesis ; fatty acid biosynthesis ; the synthesis and degradation of ketone bodies ; glycerophospholipid metabolism ; cholesterol metabolism ; purine metabolism ; arginine and proline metabolism ; valine, leucine, and isoleucine biosynthesis and degradation. These results indicate disorders of energy metabolism, altered structure of cell membranes, changes in neurotransmission, and the induction of oxidative stress in the hippocampus. Our data, consistent with hypotheses of ASD pathomechanisms, may be useful in future ASD studies, especially for the interpretation of the results of metabolomics analysis of body fluids in rat ASD models.

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19. Tubul-Lavy G, Jokel A, Leon-Attia O, Gabis LV. Content Words in Child-Directed Speech of Mothers Toward Children With Autism Spectrum Disorder. Am J Speech Lang Pathol ;2020 (May 28):1-14.

Purpose Our study aimed to analyze the characteristics of content word usage in mother’s child-directed speech ( CDS) toward children with autism spectrum disorder compared to mother’s CDS toward typically developing children. Method We analyzed the lexical characteristics of CDS of mothers of children with autism (16 dyads) and compared them from a language developmental perspective to mothers of 20 typical children at the same level of expressive language development. Results Results suggest that mothers of children with autism use equal amounts of content words at the same language level, but the content consists of significantly more concrete nouns and active verbs and rarely the use of abstract nouns, stative verbs, adjectives, and adverbs. Conclusion This study suggests that professionals and parents of children with autism should be aware of the importance of varying their language use of content words.

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