Facteurs de risque environnementaux de l'autisme: examen fondé sur des données probantes des revues systématiques et des méta-analyses

Aperçu: G.M. 

Les données actuelles suggèrent que plusieurs facteurs environnementaux, dont la vaccination, le tabagisme maternel, l'exposition au thimérosal et les techniques de reproduction assistée les plus probables, ne sont pas liés au risque de TSA. Au contraire, l'âge avancé des parents est associé à un risque accru de TSA. Les complications liées à la naissance associées au traumatisme ou à l'ischémie et à l'hypoxie ont également montré des liens forts avec les TSA, alors que d'autres facteurs liés à la grossesse tels que l'obésité maternelle, le diabète maternel et la césarienne ont montré une association moins forte (mais significative) .  

Les revues sur les éléments nutritionnels n'ont pas été concluantes sur les effets néfastes de la carence en acide folique et oméga 3, mais la vitamine D semble être déficiente chez les patients avec un diagnostic de TSA. Les études sur les éléments toxiques ont été largement limitées par leur conception, mais il y a suffisamment de preuves pour l'association entre certains métaux lourds (le mercure inorganique le plus important et le plomb) et le TSA pour mériter une enquête plus approfondie.

Mol Autism. 2017 Mar 17;8:13. doi: 10.1186/s13229-017-0121-4. eCollection 2017.

Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses

Modabbernia A¹, Velthorst E², Reichenberg A³.

Author information

1

0000 0001 0670 2351grid.59734.3cDepartment of Psychiatry and Seaver Autism Center, Icahn School of Medicine at Mount Sinai, New York, USA.

2

0000 0001 0670 2351grid.59734.3cDepartment of Psychiatry and Seaver Autism Center, Icahn School of Medicine at Mount Sinai, New York, USA ; 0000 0001 0670 2351grid.59734.3cDepartment of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, USA.

3

0000 0001 0670 2351grid.59734.3cDepartment of Psychiatry and Seaver Autism Center, Icahn School of Medicine at Mount Sinai, New York, USA ; 0000 0001 0670 2351grid.59734.3cDepartment of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, USA ; 0000 0001 0670 2351grid.59734.3cFriedman Brain Institute, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA ; 0000 0001 0670 2351grid.59734.3cSeaver Autism Center, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA.

Abstract

BACKGROUND:

According to recent evidence, up to 40-50% of variance in autism spectrum disorder (ASD) liability might be determined by environmental factors. In the present paper, we conducted a review of systematic reviews and meta-analyses of environmental risk factors for ASD. We assessed each review for quality of evidence and provided a brief overview of putative mechanisms of environmental risk factors for ASD.

FINDINGS:

Current evidence suggests that several environmental factors including vaccination, maternal smoking, thimerosal exposure, and most likely assisted reproductive technologies are unrelated to risk of ASD. On the contrary, advanced parental age is associated with higher risk of ASD. Birth complications that are associated with trauma or ischemia and hypoxia have also shown strong links to ASD, whereas other pregnancy-related factors such as maternal obesity, maternal diabetes, and caesarian section have shown a less strong (but significant) association with risk of ASD. The reviews on nutritional elements have been inconclusive about the detrimental effects of deficiency in folic acid and omega 3, but vitamin D seems to be deficient in patients with ASD. The studies on toxic elements have been largely limited by their design, but there is enough evidence for the association between some heavy metals (most important inorganic mercury and lead) and ASD that warrants further investigation. Mechanisms of the association between environmental factors and ASD are debated but might include non-causative association (including confounding), gene-related effect, oxidative stress, inflammation, hypoxia/ischemia, endocrine disruption, neurotransmitter alterations, and interference with signaling pathways.

CONCLUSIONS:

Compared to genetic studies of ASD, studies of environmental risk factors are in their infancy and have significant methodological limitations. Future studies of ASD risk factors would benefit from a developmental psychopathology approach, prospective design, precise exposure measurement, reliable timing of exposure in relation to critical developmental periods and should take into account the dynamic interplay between gene and environment by using genetically informed designs.

PMID: 28331572

PMCID: PMC5356236

DOI: 10.1186/s13229-017-0121-4

Évaluation clinique des symptômes autistiques chez les femmes avec anorexie mentale

Aperçu: G.M.

Les symptômes de TSA sont surreprésentés chez les femmes atteintes d'une AN sévère et semblent être associés à d'autres symptômes psychiatriques, ce qui justifie d'autres investigations.

Mol Autism. 2017 Mar 16;8:12. doi: 10.1186/s13229-017-0128-x. eCollection 2017.

Clinical evaluation of autistic symptoms in women with anorexia nervosa

Westwood H¹, Mandy W², Tchanturia K³.

Author information

1

0000 0001 2322 6764grid.13097.3cPsychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

2

0000000121901201grid.83440.3bResearch Department of Clinical, Educational and Health Psychology, University College London, 103 Denmark Hill, London, SE5 8AF UK.

3

0000 0001 2322 6764grid.13097.3cPsychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK ; 0000 0000 9489 2441grid.428923.6Ilia State University, Tbilisi, Georgia ; 0000 0000 9439 0839grid.37640.36Psychological Medicine Clinical Academic Group, South London and Maudsley NHS Foundation Trust National Eating Disorders Service, London, UK.

Abstract

BACKGROUND:

Despite a suggested link between anorexia nervosa (AN) and autism spectrum disorder (ASD), previous studies have used self-report or diagnostic criteria to assess for ASD in AN populations, rather than direct observation of symptom characteristic of ASD. The aim of this study was to use a standardised, clinical assessment of ASD, the Autism Diagnostic Observation Schedule, 2nd Edition (ADOS-2), to investigate the presence of autistic symptoms in a cross-sectional sample of women with AN.

METHODS:

Sixty women were recruited from inpatient or day-patient specialist eating disorder services. Each participant underwent the ADOS-2 assessment and completed a set of self-report questionnaires assessing eating disorder pathology and other psychiatric symptoms. IQ was also assessed.

RESULTS:

Fourteen women (23.3%) scored above clinical cutoff for ASD on the ADOS-2. Only eight of these women displayed repetitive or restrictive behaviours, while all 14 had difficulties with social affect. Elevated ASD symptoms were associated with increased alexithymia and obsessive-compulsive symptoms, but not specific eating disorder pathology.

CONCLUSIONS:

ASD symptoms are over-represented in women with severe AN and appear to be associated with other psychiatric symptoms, which warrant further investigation and consideration in treatment.

PMID 28331571

PMCID: PMC5356303

DOI: 10.1186/s13229-017-0128-x

Conditionnement classique pour préserver les effets du traitement à la mélatonine courte chez les enfants ayant un retard de sommeil: une étude pilote

Aperçu: G.M.

Le traitement à la mélatonine est efficace dans le traitement des troubles du sommeil chez les enfants  mais les effets disparaissent généralement lorsque le traitement est interrompu. L'étude
vérifie si le conditionnement classique peut aider à préserver les effets du traitement de la mélatonine chez les enfants souffrant de troubles du sommeil, avec ou sans déficit de l'attention avec hyperactivité (TDAH) ou autisme. Le conditionnement classique a été appliqué en ayant des enfants boivent la limonade organique tout en prenant la mélatonine et en employant une lampe de lumière rouge foncée qui a été allumée quand les enfants sont allés se coucher. Le traitement à la mélatonine a été efficace pour faire avancer l'apparition de la mélatonine à faible luminosité et réduire les problèmes d'apparition du sommeil, et des effets positifs ont été constatés sur les problèmes de santé et de comportement. Après arrêt de la mélatonine, le sommeil est revenu aux niveaux de référence.Nous avons constaté que pour les enfants sans comorbidité dans le groupe expérimental, la latence du sommeil et le début du sommeil retardé moins dans la semaine d'arrêt, ce qui suggère un effet de conditionnement classique. Cependant, le conditionnement classique semble contre-productif chez les enfants atteints du TDAH ou de l'autisme.

Nat Sci Sleep. 2017 Mar 9;9:67-79. doi: 10.2147/NSS.S129203. eCollection 2017.

Classical conditioning for preserving the effects of short melatonin treatment in children with delayed sleep: a pilot study

van Maanen A¹, Meijer AM¹, Smits MG², Oort FJ¹.

Author information

1

Research Institute Child Development and Education, University of Amsterdam, Amsterdam.

2

Centre for Sleep-Wake Disorders and Chronobiology, Hospital Gelderse Vallei, Ede, the Netherlands.

Abstract

Melatonin treatment is effective in treating sleep onset problems in children with delayed melatonin onset, but effects usually disappear when treatment is discontinued. In this pilot study, we investigated whether classical conditioning might help in preserving treatment effects of melatonin in children with sleep onset problems, with and without comorbid attention deficit hyperactivity disorder (ADHD) or autism. After a baseline week, 16 children (mean age: 9.92 years, 31% ADHD/autism) received melatonin treatment for 3 weeks and then gradually discontinued the treatment. Classical conditioning was applied by having children drink organic lemonade while taking melatonin and by using a dim red light lamp that was turned on when children went to bed. Results were compared with a group of 41 children (mean age: 9.43 years, 34% ADHD/autism) who received melatonin without classical conditioning. Melatonin treatment was effective in advancing dim light melatonin onset and reducing sleep onset problems, and positive effects were found on health and behavior problems. After stopping melatonin, sleep returned to baseline levels. We found that for children without comorbidity in the experimental group, sleep latency and sleep start delayed less in the stop week, which suggests an effect of classical conditioning. However, classical conditioning seems counterproductive in children with ADHD or autism. Further research is needed to establish these results and to examine other ways to preserve melatonin treatment effects, for example, by applying morning light.

PMID: 28331380

PMCID: PMC5352231

DOI: 10.2147/NSS.S129203

*Résultats du diagnostic par séquençage de l'exome chez des patients avec troubles du spectre de l'autisme diagnostiqués ou suspectés

Aperçu: G.M.

L'étude sur le diagnostic par séquençage de l'exome une cohorte de 163 personnes avec troubles du spectre de l'autisme (66,3%) ou des caractéristiques autistiques (33,7%) suggère que ce protocole  serait une méthode de diagnostic primaire efficace. De plus, les données recueillies peuvent aider les cliniciens à mieux déterminer quel sous-ensemble de personnes avec troubles du spectre de l'autisme  avec des caractéristiques cliniques supplémentaires bénéficieront le plus du diagnostic par séquençage de l'exome.

Pediatr Neurol. 2017 Feb 8. pii: S0887-8994(16)30572-0. doi: 10.1016/j.pediatrneurol.2017.01.033.

Outcomes of Diagnostic Exome Sequencing in Patients With Diagnosed or Suspected Autism Spectrum Disorders

Rossi M¹, El-Khechen D², Black MH², Farwell Hagman KD², Tang S², Powis Z².

Author information

1

Clinical Genomics Department, Ambry Genetics, Aliso Viejo, California. Electronic address: mrossi@ambrygen.com

2

Clinical Genomics Department, Ambry Genetics, Aliso Viejo, California.

Abstract

BACKGROUND:

Exome sequencing has recently been proved to be a successful diagnostic method for complex neurodevelopmental disorders. However, the diagnostic yield of exome sequencing for autism spectrum disorders has not been extensively evaluated in large cohorts to date.

MATERIALS AND METHODS:

We performed diagnostic exome sequencing in a cohort of 163 individuals with autism spectrum disorder (66.3%) or autistic features (33.7%).

RESULTS:

The diagnostic yield observed in patients in our cohort was 25.8% (42 of 163) for positive or likely positive findings in characterized disease genes, while a candidate genetic etiology was reported for an additional 3.3% (4 of 120) of patients. Among the positive findings in the patients with autism spectrum disorder or autistic features, 61.9% were the result of de novo mutations. Patients presenting with psychiatric conditions or ataxia or paraplegia in addition to autism spectrum disorder or autistic features were significantly more likely to receive positive results compared with patients without these clinical features (95.6% vs 27.1%, P < 0.0001; 83.3% vs 21.2%, P < 0.0001, respectively). The majority of the positive findings were in recently identified autism spectrum disorder genes, supporting the importance of diagnostic exome sequencing for patients with autism spectrum disorder or autistic features as the causative genes might evade traditional sequential or panel testing.

CONCLUSIONS:

These results suggest that diagnostic exome sequencing would be an efficient primary diagnostic method for patients with autism spectrum disorders or autistic features. Moreover, our data may aid clinicians to better determine which subset of patients with autism spectrum disorder with additional clinical features would benefit the most from diagnostic exome sequencing.

Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

PMID: 28330790

DOI: 10.1016/j.pediatrneurol.2017.01.033

Diagnostic de l'autisme par EEG traité par des algorithmes de calcul avancés: Une étude pilote

Traduction partielle : G.M.

Comput Methods Programs Biomed. 2017 Apr;142:73-79. doi: 10.1016/j.cmpb.2017.02.002. Epub 2017 Feb 20.

Diagnosis of autism through EEG processed by advanced computational algorithms: A pilot study

Grossi E¹, Olivieri C², Buscema M³.

Author information

1

Autism Research Unit, Villa Santa Maria Institute, Italy, Via IV Novembre 22038 Tavernerio (CO). Electronic address: enzo.grossi@bracco.com.

2

Autism Research Unit, Villa Santa Maria Institute, Italy, Via IV Novembre 22038 Tavernerio (CO). Electronic address: chiara.olivieri.co@gmail.com.

3

Semeion Research Centre of Sciences of Communication, Via Sersale 117, Rome, 00128, Italy. Electronic address: m.buscema@semeion.it

Abstract

BACKGROUND:

(MS-ROM / I-FAST) est un nouveau système complexe basé sur les réseaux neuronaux artificiels (ANNs) capable d'extraire des caractéristiques d'intérêt dans l'EEG informatisé par l'analyse de quelques minutes de leur EEG sans prétraitement préliminaire. Une étude de preuve de concept publiée précédemment a montré des valeurs de précision allant de 94% à 98% chez des sujets concernés ayant une déficience cognitive légère et / ou une maladie d'Alzheimer chez des personnes âgées en bonne santé. La présence de schémas déviants dans les enregistrements simples de l'EEG de l'autisme, en cohérence avec l'organisation atypique du cortex cérébral, nous a incités à appliquer ces puissants systèmes analytiques à la recherche d'une signature EEG du trouble
Multi-Scale Ranked Organizing Map coupled with Implicit Function as Squashing Time algorithm(MS-ROM/I-FAST) is a new, complex system based on Artificial Neural networks (ANNs) able to extract features of interest in computerized EEG through the analysis of few minutes of their EEG without any preliminary pre-processing. A proof of concept study previously published showed accuracy values ranging from 94%-98% in discerning subjects with Mild Cognitive Impairment and/or Alzheimer's Disease from healthy elderly people. The presence of deviant patterns in simple resting state EEG recordings in autism, consistent with the atypical organization of the cerebral cortex present, prompted us in applying this potent analytical systems in search of a EEG signature of the disease.

AIM OF THE STUDY:

The aim of the study is to assess how effectively this methodology distinguishes subjects with autism from typically developing ones.

METHODS:

Fifteen definite ASD subjects (13 males; 2 females; age range 7-14; mean value = 10.4) and ten typically developing subjects (4 males; 6 females; age range 7-12; mean value 9.2) were included in the study. Patients received Autism diagnoses according to DSM-V criteria, subsequently confirmed by the ADOS scale. A segment of artefact-free EEG lasting 60 seconds was used to compute input values for subsequent analyses. MS-ROM/I-FAST coupled with a well-documented evolutionary system able to select predictive features (TWIST) created an invariant features vector input of EEG on which supervised machine learning systems acted as blind classifiers.

RESULTS:

La capacité prédictive globale du système d'apprentissage automatique pour trier les cas autistes du groupe contrôle sans autisme s'est élevée de façon constante à 100% avec tous les types de systèmes utilisés en utilisant le protocole d'essai et à 84% - 92,8% en utilisant le protocole Leave One Out. Les similitudes entre les matrices de poids ANN mesurées avec des algorithmes approchés n'ont pas été affectées par l'âge des sujets. Cela suggère que les ANN ne lisent pas les modèles d'EEG liés à l'âge, mais plutôt des caractéristiques invariantes liées à la signature de déconnexion sous-jacente du cerveau.
The overall predictive capability of machine learning system in sorting out autistic cases from normal control amounted consistently to 100% with all kind of systems employed using training-testing protocol and to 84% - 92.8% using Leave One Out protocol. The similarities among the ANN weight matrixes measured with apposite algorithms were not affected by the age of the subjects. This suggests that the ANNs do not read age-related EEG patterns, but rather invariant features related to the brain's underlying disconnection signature.

CONCLUSION:

This pilot study seems to open up new avenues for the development of non-invasive diagnostic testing for the early detection of ASD.

Copyright © 2017 Elsevier B.V. All rights reserved.

 

PMID: 28325448

DOI: 10.1016/j.cmpb.2017.02.002

Relation entre le sélénium, le plomb et le mercure dans les globules rouges des enfants autistes saoudiens

Aperçu: G.M.

Les données obtenues démontrent une élévation significative du Hg et du Pb ainsi qu'une diminution significative des taux de Se dans les globules rouges des patients avec TSA par rapport aux témoins sans TSA.

Metab Brain Dis. 2017 Mar 21. doi: 10.1007/s11011-017-9996-1.

Relationship between selenium, lead, and mercury in red blood cells of Saudi autistic children

El-Ansary A^1,2,3, Bjørklund G⁴, Tinkov AA^5,6,7, Skalny AV^6,7,8,9, Al Dera H^10,11.

Author information

1

Central Laboratory, Center for Female Scientific and Medical Colleges, King Saud University, Riyadh, Saudi Arabia.

2

Autism Research and Treatment Center, Riyadh, Saudi Arabia.

3

Medicinal Chemistry Department, National Research Centre, Dokki, Cairo, Egypt.

4

Council for Nutritional and Environmental Medicine, Toften 24, 8610, Mo i Rana, Norway. bjorklund@conem.org.

5

Orenburg State University, Orenburg, Russia.

6

Orenburg State Medical University, Orenburg, Russia.

7

Yaroslavl State University, Yaroslavl, Russia.

8

RUDN University, Moscow, Russia.

9

All-Russian Research Institute of Medicinal and Aromatic Plants, Moscow, Russia.

10

Basic Medical Science Department, College of Medicine, King Saud bin Abdul Aziz University for Health Sciences, Riyadh, Saudi Arabia.

11

King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia.

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that can cause significant social, communication and behavioral challenges. Environmental contribution to ASD is due in large part to the sensitivity of the developing brain to external exposures such as lead (Pb), and mercury (Hg) as toxic heavy metals or due to a poor detoxification ability as the phenotype of this disorder. Selenium (Se) as an antioxidant element that counteracts the neurotoxicity of Hg, and Pb, presumably through the formation of nontoxic complexes. In the present study, Pb, Hg, and Se were measured in red blood cells (RBCs) of 35 children with ASD and 30 age- and gender-matched healthy control children using atomic absorption spectrometry. Receiver Operating Characteristics (ROC) analysis of the obtained data was performed to measure the predictive value of their absolute and relative concentrations. The obtained data demonstrates a significant elevation of Hg and Pb together with a significant decrease in the Se levels in RBCs of patients with ASD when compared to the healthy controls. The ratios of Se to both Pb and Hg were remarkably altered, being indicative of heavy metal neurotoxicity in patients with ASD. In conclusion, the present study indicates the importance of Se for prevention and/or therapy of heavy metal neurotoxicity.

PMID: 28326463

DOI: 10.1007/s11011-017-9996-1

«J'étais juste tellement différent»: Les expériences de femmes diagnostiquées avec un trouble du spectre de l'autisme à l'âge adulte en relation avec le genre et les relations sociales

Aperçu: G.M.

Un nombre limité d'études qualitatives à petite échelle ont exploré les expériences des adolescentes avec troubles du spectre de l'autisme , mais pas les femmes adultes.Sept entretiens semi-structurés avec des femmes ayant reçu un diagnostic à l'âge adulte ont été réalisés. Le recrutement a porté sur les services communautaires de santé mentale, les services aux patients hospitalisés et un groupe de soutien communautaire. Des expériences et des histoires diverses des femmes ont émergé de deux grandes catégories liées à l'identité de genre et aux relations sociales.

Autism. 2017 Mar 1:1362361316687987. doi: 10.1177/1362361316687987.

'I was just so different': The experiences of women diagnosed with an autism spectrum disorder in adulthood in relation to gender and social relationships

Kanfiszer L^1,2, Davies F¹, Collins S¹.

Author information

1

1 University of Essex, UK.

2

2 Great Ormond Street Hospital for Children NHS Foundation Trust, UK.

Abstract

Existing literature exploring autism spectrum disorders within female populations predominantly utilises quantitative methodology. A limited number of small-scale, qualitative studies have explored the experiences of adolescent girls with autism spectrum disorder, but adult women have remained largely unheard. This study aims to broaden the stories told within autobiographical literature and empower those within the wider community of women with autism spectrum disorder. In doing so, it seeks to extend existing conceptualisations of experience to include socially and culturally located factors. A qualitative methodology was adopted, utilising multi-stage narrative analysis. Seven semi-structured interviews with women who received a diagnosis in adulthood were conducted. Recruitment spanned community mental health services, an inpatient service and a community support group. From the women's diverse experiences and stories emerged two broad categories related to gender identity and social relationships. The findings are discussed in relation to existing constructs of autism in women.

PMID: 28326792

DOI: 10.1177/1362361316687987

Les échanges sociaux positifs et négatifs vécus par les pères et les mères d'enfants autistes

Aperçu: G.M.

Cette étude a examiné les types et les sources d'échanges sociaux positifs et négatifs signalés par les mères et les pères d'enfants autistes et leur association avec les symptômes dépressifs parentaux.
Les pères ont signalé moins d'échanges sociaux positifs et moins de négatifs avec la famille, les amis et les professionnels de santé que les mères. Les échanges sociaux positifs et négatifs avec le conjoint étaient les plus fortement associés aux symptômes dépressifs.

Autism. 2017 Mar 1:1362361316687117. doi: 10.1177/1362361316687117.

Positive and negative social exchanges experienced by fathers and mothers of children with autism

Hickey EJ¹, Dubois L², Hartley SL¹.

Author information

1

1 University of Wisconsin-Madison, USA.

2

2 Special Olympics, USA.

Abstract

When faced with child-related challenges associated with autism spectrum disorder, positive and negative social exchanges may be critical to parents' psychological well-being. This study examined the types and sources of positive and negative social exchanges reported by mothers and fathers of children with autism spectrum disorder and their association with parental depressive symptoms in 176 families of children (5-12 years; 85% male) with autism spectrum disorder. One-way repeated measure multivariate analyses of variance and multilevel modeling were used. Results indicated that informational was the most frequent type, and one's spouse was the primary source, of both positive and negative social exchanges. Fathers reported fewer positive, and also fewer negative, social exchanges with family, friends, and health professionals than mothers. Positive and negative social exchanges with one's spouse were most strongly associated with depressive symptoms. Findings have implications for interventions designed to foster optimal outcomes in families of children with autism spectrum disorder.

PMID: 28326797

DOI: 10.1177/1362361316687117

Un rôle critique des protéines Shank2 spinales dans l'hypersensibilité à la douleur induite par NMDA

Aperçu: G.M.

Les comportements d'auto-mutilations (SIB) sont des traits dévastateurs du trouble du spectre de l"autisme (TSA). Bien que les déficits de la sensation de douleur puissent être l'un des facteurs qui sous-tendent le développement des SIB, les mécanismes n'ont pas encore été abordés.

La protéine synaptique Shank2 a été considérée comme un composant clé dans le TSA, et les mutations du gène SHANK2 induisent le dysfonctionnement des récepteurs N-méthyl-D-aspartate (NMDA), suggérant un lien entre les récepteurs Shank2 et NMDA dans les TSA, récepteurs qui jouent un rôle central dans l'hypersensibilité à la douleur.La protéine Shank2 est impliquée dans la douleur médiée par le récepteur NMDA spinale, et les mutations de Shank2 peuvent supprimer la signalisation NMDA-ERK dans la transmission de la douleur spinale.

Mol Pain. 2017 Jan;13:1744806916688902. doi: 10.1177/1744806916688902.

A critical role of spinal Shank2 proteins in NMDA-induced pain hypersensitivity

Yoon SY^1,2, Kwon SG³, Kim YH^1,2,4, Yeo JH³, Ko HG⁵, Roh DH³, Kaang BK^5,6, Beitz AJ⁷, Lee JH^8,9, Oh SB^1,2.

Author information

Abstract

Background Self-injurious behaviors (SIBs) are devastating traits in autism spectrum disorder (ASD). Although deficits in pain sensation might be one of the contributing factors underlying the development of SIBs, the mechanisms have yet to be addressed. Recently, the Shank2 synaptic protein has been considered to be a key component in ASD, and mutations of SHANK2 gene induce the dysfunction of N-methyl-D-aspartate (NMDA) receptors, suggesting a link between Shank2 and NMDA receptors in ASD. Given that spinal NMDA receptors play a pivotal role in pain hypersensitivity, we investigated the possible role of Shank2 in nociceptive hypersensitivity by examining changes in spontaneous pain following intrathecal NMDA injection in S hank2-/- ( Shank2 knock-out, KO) mice. Results Intrathecal NMDA injection evoked spontaneous nociceptive behaviors. These NMDA-induced nociceptive responses were significantly reduced in Shank2 KO mice. We also observed a significant decrease of NMDA currents in the spinal dorsal horn of Shank2 KO mice. Subsequently, we examined whether mitogen-activated protein kinase or AKT signaling is involved in this reduced pain behavior in Shank2 KO mice because the NMDA receptor is closely related to these signaling molecules. Western blotting and immunohistochemistry revealed that spinally administered NMDA increased the expression of a phosphorylated form of extracellular signal-regulated kinase (p-ERK) which was significantly reduced in Shank2 KO mice. However, p38, JNK, or AKT were not changed by NMDA administration. The ERK inhibitor, PD98059, decreased NMDA-induced spontaneous pain behaviors in a dose-dependent manner in wild-type mice. Moreover, it was found that the NMDA-induced increase in p-ERK was primarily colocalized with Shank2 proteins in the spinal cord dorsal horn. Conclusion Shank2 protein is involved in spinal NMDA receptor-mediated pain, and mutations of Shank2 may suppress NMDA-ERK signaling in spinal pain transmission. This study provides new clues into the mechanisms underlying pain deficits associated with SIB and deserves further study in patients with ASD.

PMID: 28326932

DOI: 10.1177/1744806916688902

*SIGUEME: Intervention technologique pour l'autisme "à bas niveau de fonctionnement" pour développer des compétences pour travailler avec des signifiants et des concepts visuels

Traduction partielle: G.M.

Res Dev Disabil. 2017 Mar 16;64:25-36. doi: 10.1016/j.ridd.2017.02.008.

SIGUEME: Technology-based intervention for low-functioning autism to train skills to work with visual signifiers and concepts

Vélez-Coto M¹, Rodríguez-Fórtiz MJ², Rodriguez-Almendros ML³, Cabrera-Cuevas M³, Rodríguez-Domínguez C³, Ruiz-López T⁴, Burgos-Pulido Á⁵, Garrido-Jiménez I⁵, Martos-Pérez J⁶.

Author information

1

Mind, Brain, and Behaviour Research Centre (CIMCYC), University of Granada, Spain.

2

Research Centre for Information and Communications Technologies of the University of Granada, Spain. Electronic address: mjfortiz@ugr.es.

3

Research Centre for Information and Communications Technologies of the University of Granada, Spain.

4

Everyware Technologies.

5

Special Education School Fundación Purísima Concepción, Granada, Spain.

6

Director Centro Deletrea, Madrid, Spain.

Abstract

BACKGROUND:

Les personnes avec TSA à "faible niveau de fonctionnement" et handicaps associés ont souvent du mal à comprendre les symboles traditionnellement utilisés dans les documents éducatifs pendant le processus d'apprentissage. Les interventions axées sur la technologie sont de plus en plus courantes, aidant les enfants avec des déficiences cognitives à accomplir des tâches universitaires et à améliorer leurs capacités et leurs connaissances. Ces enfants ont souvent de la difficulté à exécuter certaines tâches contenues dans les matériels pédagogiques car ils manquent de compétences nécessaires, comme le raisonnement abstrait. Afin d'aider ces enfants, les auteurs ont conçu et créé SIGUEME pour former l'attention et les compétences cognitives perceptuelles et visuelles nécessaires pour travailler avec et comprendre les matériaux graphiques et les objets.
 People with low-functioning ASD and other disabilities often find it difficult to understand the symbols traditionally used in educational materials during the learning process. Technology-based interventions are becoming increasingly common, helping children with cognitive disabilities to perform academic tasks and improve their abilities and knowledge. Such children often find it difficult to perform certain tasks contained in educational materials since they lack necessary skills such as abstract reasoning. In order to help these children, the authors designed and created SIGUEME to train attention and the perceptual and visual cognitive skills required to work with and understand graphic materials and objects.

METHODS:

A pre-test/post-test design was implemented to test SIGUEME. Seventy-four children with low-functioning ASD (age=13.47, SD=8.74) were trained with SIGUEME over twenty-five sessions and compared with twenty-eight children (age=12.61, SD=2.85) who had not received any intervention.

RESULTS:

Il y a eu une amélioration statistiquement significative dans le groupe expérimental dans l'attention (W = -5,497, p <0,001). Il y a également eu un changement significatif dans l'association et la catégorisation (W = 2,721, p = 0,007) et l'interaction (W = -3,287, p = 0,001). 
There was a statistically significant improvement in the experimental group in Attention (W=-5.497, p<0.001). There was also a significant change in Association and Categorization (W=2.721, p=0.007) and Interaction (W=-3.287, p=0.001).

CONCLUSIONS:

SIGUEME est un outil efficace pour améliorer l'attention, la catégorisation et l'interaction chez les enfants qui fonctionnent peu avec le TSA. Il est également un instrument utile et puissant pour les enseignants, les parents et les éducateurs en augmentant la motivation et l'autonomie de l'enfant

SIGUEME is an effective tool for improving attention, categorization and interaction in low-functioning children with ASD. It is also a useful and powerful instrument for teachers, parents and educators by increasing the child's motivation and autonomy.

Copyright © 2017 Elsevier Ltd. All rights reserved.

PMID:28327383

DOI: 10.1016/j.ridd.2017.02.008

Le β-Arrestin2 associe le récepteur 5 au glutamate métabotrope à la synthèse des protéines neuronales et est une cible potentielle pour traiter le X fragile

Aperçu: G.M.

La synthèse des protéines synaptiques est essentielle pour la modification du cerveau par l'expérience et est aberrante dans plusieurs désordres génétiquement définis, notamment le syndrome de l'X fragile (FX), une cause héréditaire de l'autisme et de la déficience intellectuelle. 

La β-arrestine2 favorise la synthèse de protéines stimulées par mGlu5 dans l'hippocampe et montre que la réduction génétique de β-arrestine2 corrige la plasticité et la cognition synaptique aberrante dans le modèle de souris Fmr1- / y de FX. 

En plus d'identifier une condition clé pour la synthèse de protéines stimulées par mGlu5, ces données suggèrent que les modulateurs négatifs polarisés par ß-arrestine2 de mGlu5 offrent des avantages significatifs par rapport aux inhibiteurs de première génération pour le traitement de FX et des troubles apparentés.

Cell Rep. 2017 Mar 21;18(12):2807-2814. doi: 10.1016/j.celrep.2017.02.075.

β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X

Stoppel LJ¹, Auerbach BD², Senter RK¹, Preza AR¹, Lefkowitz RJ³, Bear MF⁴.

Author information

1

The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

2

The Center for Hearing and Deafness, Department of Communicative Disorders and Sciences, The State University of New York at Buffalo, Buffalo, NY 14214, USA.

3

Departments of Medicine and Biochemistry, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.

4

The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: mbear@mit.edu

Abstract

Synaptic protein synthesis is essential for modification of the brain by experience and is aberrant in several genetically defined disorders, notably fragile X (FX), a heritable cause of autism and intellectual disability. Neural activity directs local protein synthesis via activation of metabotropic glutamate receptor 5 (mGlu₅), yet how mGlu₅ couples to the intracellular signaling pathways that regulate mRNA translation is poorly understood. Here, we provide evidence that β-arrestin2 mediates mGlu₅-stimulated protein synthesis in the hippocampus and show that genetic reduction of β-arrestin2 corrects aberrant synaptic plasticity and cognition in the Fmr1^-/y mouse model of FX. Importantly, reducing β-arrestin2 does not induce psychotomimetic activity associated with full mGlu₅ inhibitors and does not affect G_q signaling. Thus, in addition to identifying a key requirement for mGlu₅-stimulated protein synthesis, these data suggest that β-arrestin2-biased negative modulators of mGlu₅ offer significant advantages over first-generation inhibitors for the treatment of FX and related disorders.

Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

PMID: 28329674

DOI: 10.1016/j.celrep.2017.02.075