1. Alonazi M, Ben Bacha A, Al Suhaibani A, Almnaizel AT, Aloudah HS, El-Ansary A. Psychobiotics improve propionic acid-induced neuroinflammation in juvenile rats, rodent model of autism. Transl Neurosci;2022 (Jan 1);13(1):292-300.

This study aimed to evaluate the protective and therapeutic potency of bee pollen and probiotic mixture on brain intoxication caused by propionic acid (PPA) in juvenile rats. Five groups of six animals each, were used: the control group only receiving phosphate-buffered saline; the bee pollen and probiotic-treated group receiving a combination of an equal quantity of bee pollen and probiotic (0.2 kg/kg body weight); the PPA group being treated for 3 days with an oral neurotoxic dose of PPA (0.25 kg/kg body weight); the protective and therapeutic groups receiving bee pollen and probiotic mixture treatment right before and after the neurotoxic dose of PPA, respectively. The levels of interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-12, tumor necrosis factor α, and interferon γ (IFN-γ) were investigated to evaluate the neuroinflammatory responses in brain tissues from different animal groups. The much higher IL-1β, IL-8, and IFN-γ, as pro-inflammatory cytokines (P < 0.001), together with much lower IL-10, as anti-inflammatory cytokine (P < 0.001) compared to controls clearly demonstrated the neurotoxic effects of PPA. Interestingly, the mixture of bee pollen and probiotics was effective in alleviating PPA neurotoxic effects in both therapeutic and protective groups demonstrating highly significant changes in IL-1β, IL-8, IL-10, and IFN-γ levels together with non-significant reduction in IL-6 levels compared to PPA-treated rats. Overall, our findings demonstrated a new approach to the beneficial use of psychobiotics presenting as bee pollen and probiotic combination in neuroinflammation through cytokine changes as a possible role of glial cells in gut-brain axis.

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2. Angrand L, Masson JD, Rubio-Casillas A, Nosten-Bertrand M, Crépeaux G. Inflammation and Autophagy: A Convergent Point between Autism Spectrum Disorder (ASD)-Related Genetic and Environmental Factors: Focus on Aluminum Adjuvants. Toxics;2022 (Aug 31);10(9)

Autism spectrum disorder (ASD), schizophrenia, and bipolar disorder are genetically complex and heterogeneous neurodevelopmental disorders (NDDs) resulting from genetic factors and gene-environment (GxE) interactions for which onset occurs in early brain development. Recent progress highlights the link between ASD and (i) immunogenetics, neurodevelopment, and inflammation, and (ii) impairments of autophagy, a crucial neurodevelopmental process involved in synaptic pruning. Among various environmental factors causing risk for ASD, aluminum (Al)-containing vaccines injected during critical periods have received special attention and triggered relevant scientific questions. The aim of this review is to discuss the current knowledge on the role of early inflammation, immune and autophagy dysfunction in ASD as well as preclinical studies which question Al adjuvant impacts on brain and immune maturation. We highlight the most recent breakthroughs and the lack of epidemiological, pharmacokinetic and pharmacodynamic data constituting a « scientific gap ». We propose additional research, such as genetic studies that could contribute to identify populations at genetic risk, improving diagnosis, and potentially the development of new therapeutic tools.

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3. Chakravarty MM. Variation in Neuroanatomy in Autism Spectrum Disorder. Biol Psychiatry;2022 (Oct 15);92(8):612-613.

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4. Cicinelli G, Nobile E, Brighenti S, Bari S, Tonella E, Aresi A, Attanasio M, Mazza M, Valenti M, Keller R. Wechsler Intelligence Scale for Adults – Fourth Edition profiles of adults with autism spectrum disorder. Epidemiol Psychiatr Sci;2022 (Sep 23);31:e67.

AIM: In this study, we have compared 229 Wechsler Adults Intelligence Scale – Fourth Edition (WAIS-IV) cognitive profiles of different severity adults with autism spectrum disorder to verify the impact of several variables including sex, age, level of education and autism severity level in an Italian sample. Moreover, we wanted to find out the optimal cut points for the major intelligence quotients in order to discriminate autism severity levels. METHODS: Participants were recruited from two National Health System Center in two different Italian regions and were assessed with gold-standard instruments as a part of their clinical evaluation. According to DSM-5, cognitive domains were also measured with multi-componential tests. We used the Italian adaptation of WAIS-IV. We checked our hypotheses using linear regression models and receiver operating characteristics (ROC) curves. RESULTS: Our results showed that age and level of education have a strong impact on Verbal Comprehension (VCI) and Working Memory Indexes (WMI). Gender differences are relevant when considering the VCI and Processing Speed index (PSI) in which women obtained the best performance. These differences are still relevant when considering cut points of ROC because 69 resulted to be the optimal cut point for women, 65 for men. CONCLUSIONS: Few conclusions can be assumed only examining Full Scale Intelligence Quotient (FSIQ) scores as it includes many different information about broader cognitive abilities. Looking deeper at main indexes and their subtests findings are consistent with previous research on the disorder (moderate correlations of FSIQ, Perceptual Reasoning index, WMI and PSI with the participants’ age), while other results are unforeseen (no effect of sex found on FSIQ score) or novel (significant effect of education on VCI and WMI). Using an algorithm predicting optimal cut point for discriminating through autism severity levels can help clinicians to better label and quantify the required help a person may need, a test cannot replace diagnostic and clinical evaluation by experienced clinicians.

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5. Danis E, Nader AM, Degré-Pelletier J, Soulières I. Semantic and Visuospatial Fluid Reasoning in School-Aged Autistic Children. J Autism Dev Disord;2022 (Sep 22)

In light of the known visuoperceptual strengths and altered language skills in autism, we investigated the impact of problem content (semantic/visuospatial) combined with complexity and presence of lures on fluid reasoning in 43 autistic and 41 typical children (6-13 years old). Increased complexity and presence of lures diminished performance, but less so as the children’s age increased. Typical children were slightly more accurate overall, whereas autistic children were faster at solving complex visuospatial problems. Thus, reasoning could rely more extensively on visuospatial strategies in autistic versus typical children. A combined speed-accuracy measure revealed similar performance in both groups, suggesting a similar pace in fluid reasoning development. Visual presentation of conceptual information seems to suit the reasoning processes of autistic children.

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6. Gaines AG. The Grief Experiences of Children with Developmental Disabilities: A Narrative Literature Review. Omega (Westport);2022 (Sep 22):302228221124520.

BACKGROUND: Children with developmental disabilities have wide-ranging social, developmental, and communication challenges impacting their grieving process. This narrative review examined the literature relating to the grief experiences of children with developmental disabilities to identify implications for practice and areas for future research. METHODS: The literature review was conducted using five databases, and a hand search of dissertations with original research, due to the sparse body of published works. RESULTS: Nine works were included in the review, which were thematically synthesized into three categories: (1) Understanding of death concepts, (2) Social-emotional responses to loss, and (3) Disenfranchised grief. CONCLUSIONS: Children with developmental disabilities are affected by loss, even if their comprehension of death concepts is impacted by their level of disability. They may experience challenges due to changes in routines and concrete thinking, and are at risk of disenfranchised grief. Future research is needed to inform developmentally appropriate grief interventions.

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7. Hwang G. Autism Spectrum Disorder: Time to Notice the Individuals More Than the Group. Biol Psychiatry;2022 (Oct 15);92(8):606-608.

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8. Krakowski A. Balanced Sex Ratios and the Autism Continuum. Biol Psychiatry;2022 (Oct 15);92(8):e35-e36.

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9. Kulsirichawaroj P, Likasitwattanakul S, Boonsimma P, Prangphan K, Chanvanichtrakool M. Neuronal Ceroid Lipofuscinoses Presenting as Rett-like Phenotype: A Two-Case Report From Thailand. Pediatr Neurol;2022 (Aug 17);136:50-55.

BACKGROUND: Neuronal ceroid lipofuscinoses (NCLs) (hereafter described as CLN disease) comprise a rare and life-limiting set of genetically inherited neurodegenerative disorders that are characterized by abnormal lysosomal storage. The NCL disorders are, collectively, the most common group of degenerative brain disorders in children. PATIENT DESCRIPTIONS: We report two cases of CLN disease that were diagnosed and treated at the Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Both cases of CLN disease (CLN1 and CLN6 diagnosed in 2016 and 2017, respectively) profiled in this report presented with clinical features of Rett syndrome. In the first case, a 2-year-old girl presented with Rett-like clinical features, including global developmental regression and hand-wringing action. Single-gene analysis of the MECP2 gene was negative. However, PPT1 gene sequencing revealed a novel homozygous frameshift mutation, c.629_630dupGT (p.Ile211Valfs∗10). In the second case, a 7.5-year-old girl presented with ataxia, progressive myoclonic epilepsy, and Rett-like hand-wringing. A c.794_796delCCT variant in the CLN6 gene was identified by whole-exome sequencing. Fingerprint bodies from electron microscopy of the skin also supported a diagnosis of CLN disease in our second case. DISCUSSION: Presentation with clinical features of Rett syndrome has only been reported in patients diagnosed with CLN1 and CLN7 disease, and never in those with CLN6. CONCLUSIONS: Physicians should suspect and investigate for CLN disease in patients with Rett-like phenotype who are negative for MECP2 mutation, especially in patients with visual impairment and early prominent brain atrophy.

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10. Laidi C, Floris DL, Tillmann J, Elandaloussi Y, Zabihi M, Charman T, Wolfers T, Durston S, Moessnang C, Dell’Acqua F, Ecker C, Loth E, Murphy D, Baron-Cohen S, Buitelaar JK, Marquand AF, Beckmann CF, Frouin V, Leboyer M, Duchesnay E, Coupé P, Houenou J. Cerebellar Atypicalities in Autism?. Biol Psychiatry;2022 (Oct 15);92(8):674-682.

BACKGROUND: The cerebellum contains more than 50% of the brain’s neurons and is involved in social cognition. Cerebellar anatomical atypicalities have repeatedly been reported in individuals with autism. However, studies have yielded inconsistent findings, likely because of a lack of statistical power, and did not capture the clinical and neuroanatomical diversity of autism. Our aim was to better understand cerebellar anatomy and its diversity in autism. METHODS: We studied cerebellar gray matter morphology in 274 individuals with autism and 219 control subjects of a multicenter European cohort, EU-AIMS LEAP (European Autism Interventions-A Multicentre Study for Developing New Medications; Longitudinal European Autism Project). To ensure the robustness of our results, we conducted lobular parcellation of the cerebellum with 2 different pipelines in addition to voxel-based morphometry. We performed statistical analyses with linear, multivariate (including normative modeling), and meta-analytic approaches to capture the diversity of cerebellar anatomy in individuals with autism and control subjects. Finally, we performed a dimensional analysis of cerebellar anatomy in an independent cohort of 352 individuals with autism-related symptoms. RESULTS: We did not find any significant difference in the cerebellum when comparing individuals with autism and control subjects using linear models. In addition, there were no significant deviations in our normative models in the cerebellum in individuals with autism. Finally, we found no evidence of cerebellar atypicalities related to age, IQ, sex, or social functioning in individuals with autism. CONCLUSIONS: Despite positive results published in the last decade from relatively small samples, our results suggest that there is no striking difference in cerebellar anatomy of individuals with autism.

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11. Losada-Puente L, Baña M. Assessment of Adaptive Behavior in People with Autism Spectrum Disorders through the ICAP. Behav Sci (Basel);2022 (Sep 15);12(9)

Evaluating adaptive behavior in people with Autism Spectrum Disorder (ASD) requires attending to a set of cognitive processes associated with social interaction skills and functional communication that are altered. This paper presents the analysis of an instrument to assess and diagnose adaptive behavior in people with Autism Spectrum Disorder (ASD), given the need for rigorous, standardized, and statistically reliable tools to address this dimension, incorporated into the diagnosis since 1992. The Inventory for Service Planning and Individual Programming (ICAP) was applied to n = 209 children with ASD. Its psychometric properties were studied to provide statistical criteria for its usefulness in assessing adaptive behavior. Results highlighted variations in its original structure, reducing the number of items from 77 to 60 by eliminating those with little discriminative power, and of dimensions from four to three given their greater congruence with the results of the exploratory analysis: daily life skills (α = 0.892-0.935), communication and linguistic skills (α = 0.860-0.931), and motor skills (α = 0.828-0.857). This again raises questions about the use of instruments similar in their dimensions, and about the interaction between variables and items, a frequent issue in the field of mind, social, and health sciences.

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12. McArthur GE, Lee E, Laycock R. Autism Traits and Cognitive Performance: Mediating Roles of Sleep Disturbance, Anxiety and Depression. J Autism Dev Disord;2022 (Sep 22)

Theories about autism spectrum disorder (ASD) have addressed cognitive deficits however few have examined how comorbid diagnoses, including sleep disturbance, anxiety and depression contribute to the underlying deficits. We investigated potential mediations of common ASD comorbidities in the relationship between sub-clinical autism traits and cognitive performance using an international community sample. Cognitive tasks assessed working memory [executive functioning (EF) theory], mental state attribution [theory of mind (ToM)], and global/local visual processing [weak central coherence (WCC) theory]. Structural equation modelling (SEM) demonstrated sleep disturbance and anxiety mediated the relationship of autism traits on measures of EF, but not WCC and ToM. This suggests that treating the symptoms of sleep disturbance and anxiety may lead to improvements in working memory.

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13. Punt AM, Judson MC, Sidorov MS, Williams BN, Johnson NS, Belder S, den Hertog D, Davis CR, Feygin MS, Lang PF, Jolfaei MA, Curran PJ, van IWF, Elgersma Y, Philpot BD. Molecular and behavioral consequences of Ube3a gene overdosage in mice. JCI Insight;2022 (Sep 22);7(18)

Chromosome 15q11.2-q13.1 duplication syndrome (Dup15q syndrome) is a severe neurodevelopmental disorder characterized by intellectual disability, impaired motor coordination, and autism spectrum disorder. Chromosomal multiplication of the UBE3A gene is presumed to be the primary driver of Dup15q pathophysiology, given that UBE3A exhibits maternal monoallelic expression in neurons and that maternal duplications typically yield far more severe neurodevelopmental outcomes than paternal duplications. However, studies into the pathogenic effects of UBE3A overexpression in mice have yielded conflicting results. Here, we investigated the neurodevelopmental impact of Ube3a gene overdosage using bacterial artificial chromosome-based transgenic mouse models (Ube3aOE) that recapitulate the increases in Ube3a copy number most often observed in Dup15q. In contrast to previously published Ube3a overexpression models, Ube3aOE mice were indistinguishable from wild-type controls on a number of molecular and behavioral measures, despite suffering increased mortality when challenged with seizures, a phenotype reminiscent of sudden unexpected death in epilepsy. Collectively, our data support a model wherein pathogenic synergy between UBE3A and other overexpressed 15q11.2-q13.1 genes is required for full penetrance of Dup15q syndrome phenotypes.

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14. Riccioni A, Siracusano M, Arturi L, Marcovecchio C, Postorino V, Gialloreti LE, Mazzone L. Developmental and Intelligence Quotient in Autism: A Brief Report on the Possible Long-Term Relation. Behav Sci (Basel);2022 (Aug 25);12(9)

Developmental level and cognitive skills assessment represents a crucial aspect in the delineation of the clinical phenotype and long-term outcomes of individuals with autism spectrum disorder (ASD). Nevertheless, the evaluation of cognitive development trajectory across a lifespan ranging from birth to school age appears challenging for clinicians and researchers, because of the lack of measures that coherently cover this timeframe. Thus, the main goal of this community-based study was to investigate within a sample of ASD children if the developmental quotient (DQ), evaluated through the Griffiths Mental Development Scales Extended Revised (GMDS-ER) scale, predicts the non-verbal brief intelligence quotient (IQ), measured through the Leiter-R at follow-up. The main observation of our study was a positive correlation between the level of DQ and nonverbal IQ at follow-up evaluations, highlighting that ASD children characterized by a greater developmental profile will later present higher non-verbal IQ.

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15. Smith J, Rabba AS, Cong L, Datta P, Dresens E, Hall G, Heyworth M, Lawson W, Lee P, Lilley R, Syeda N, Ma E, Wang J, Wang R, Yeow C, Pellicano E. They were Saying that I was a ‘typical Chinese mum’: Chinese Parents’ Experiences of Parent-Teacher Partnerships for Their Autistic Children. J Autism Dev Disord;2022 (Sep 23)

Effective parent-teacher partnerships improve outcomes for autistic students. Yet, we know little about what effective partnerships look like for parents of autistic children from different backgrounds. We conducted interviews with 17 Chinese parents of autistic children attending Australian kindergartens/schools to understand their experiences. Parents appreciated the acceptance, opportunities and supports they received in Australia. They had high expectations of children; expectations not often shared by educators. Parents were respectful of teachers’ expertise and polite and undemanding in interactions. Nevertheless, parents were frustrated by inconsistent teaching quality and inadequate communication. Navigating systems was also challenging and parents faced discrimination from teachers and their community. Recommendations include fostering open home-school communication, proactively seeking parents’ expertise about children and explicitly scaffolding parents’ self-advocacy.

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16. Sparaci L, Formica D, Lasorsa FR, Raiano L, Venuti P, Capirci O. New Methods for Unraveling Imitation Accuracy Differences Between Children with Autism and Typically Developing Peers. Percept Mot Skills;2022 (Sep 23):315125221126215.

This study applies methods used in sign language and gesture research to better understand reduced imitation accuracy (IA) of actions and gestures in children with autism spectrum disorder (ASD), and we addressed contrasting theories on IA in ASD and the role of objects and meanings in imitation. Eight male children with ASD with a mean chronological age (CA) of 86.76 months (SD = 10.74, range 70.5-104.4) and 22 male and female peers with typical development (TD) and a mean CA of 85.44 months (SD = 7.95, range 73.4-96.7) imitated videos of an adult performing actions with objects, representational gestures, conventional gestures and meaningless gestures. We measured accuracy as ability to effectively reproduce features (handshape, palm orientation, location, movement direction and type) and timing (speed) of observed actions/gestures, after ruling out cases of specular (i.e., mirror-like) versus anatomical imitation. Results highlighted significantly lower feature and timing accuracy in children with ASD with respect to the TD group across tasks, and these findings supported sensory-motor theories of IA in ASD. Our data also showed the different impact of objects and meanings within groups. Overall, these results suggest validity to our assessment method and suggested the importance of considering both discreet variables (i.e., variables describing action/gesture feature accuracy, e.g. handshape, movement direction) and continuous variables (i.e., kinematic variables, e.g. speed) in evaluating IA in autism.

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17. Streatch E, Bruno N, Latimer-Cheung AE. Investigating Strategies Used to Foster Quality Participation in Recreational Sport Programs for Children With Autism Spectrum Disorder and Their Perceived Importance. Adapt Phys Activ Q;2022 (Sep 22):1-19.

Quality experiences in sport programming for children with autism spectrum disorder (ASD) can promote physical and psychosocial benefits and long-term quality participation (QP). Unfortunately, children with ASD often experience sport participation barriers and, consequently, participate less in sport compared with children without disabilities. This study investigated QP priorities and strategies that could foster QP for children with ASD. Caregivers (n = 13), volunteers (n = 26), and staff (n = 14) involved in sport programming for children with ASD rated experiential elements of QP using the Measure of Experiential Aspects of Participation. In addition , a two-round Delphi survey with staff (Round 1: n = 11; Round 2: n = 13) generated 22 strategies for promoting QP-each rated highly with regard to importance (5.69-6.85 on a 7-point scale). Strategies were substantiated with published research evidence. Findings informed the development of a QP tool designed to help instructors implement identified strategies in hopes of improving sport experiences for children with ASD.

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18. Wang X, Carroll X, Zhang P, du Prel JB, Wang H, Xu H, Leeper-Woodford S. Exploring brainstem auditory evoked potentials and mental development index as early indicators of autism spectrum disorders in high-risk infants. Autism Res;2022 (Sep 22)

This study of infants from Hubei Province, China examined brainstem auditory evoked potentials (BAEP) and mental development index (MDI) as possible early indicators associated with autism spectrum disorders (ASD). The 34 ASD cases and 102 controls who had recovered from perinatal conditions were matched for age, sex, gestational age, birth weight and maternal age. BAEP absolute latencies (AL) I, III, V and interpeak latencies (IPL) I-III, III-V, I-V were compared in ASD cases and controls at ages 1, 3 and 6 months. MDI scores were compared in these infants from 1 month to 2 years old. Multiple logistic regression analysis was performed to test associations among ASD, BAEP and MDI. Results showed BAEP AL I, V and IPL III-V prolonged in the ASD group (p < 0.001), and MDI scores in ASD cases sharply declining from 12 to 24 months (p < 0.001). Regression analysis revealed odds ratios (OR) indicating that ASD was likely associated with abnormal values of BAEP AL I at 1 and 3 months (OR(AL I) : 4.27; OR(AL I) : 4.13), and AL V at 6 months (OR(AL V) : 7.85). Lower MDI scores (MDI < 80) in infants at 1, 3, and 6 months were likely associated with ASD (OR(MDI) : 2.58; OR(MDI) : 3.83; OR(MDI) : 4.87). These data show that abnormal BAEP values and low MDI scores are independent factors associated with ASD, and that monitoring of BAEP and MDI during infancy might facilitate screening for ASD development. LAY SUMMARY: The relationship between ASD and BAEP as well as MDI has been investigated in a sample of children from birth to 2 years of age in Hubei Province, China. Abnormal BAEP values from 1 to 6 months of age and lower MDI scores observed in these infants were associated with later diagnosis of ASD. Using this simple, non-invasive BAEP and MDI testing strategy might be a valuable tool for clinicians to identify early development of ASD.

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19. Zhang Y, Zhang K, Chen J, Liu L, Luo M, Chen Q, Zeng X, Wang G. Eye Tracking Study of Social Intensity on Social Orientation of Autistic Children. Behav Sci (Basel);2022 (Sep 5);12(9)

Some previous studies indicate that impaired social attention mainly results in social disorders in autistic children. In the social attention mode of autistic children, social orientation and joint attention are particularly important. The influence of different social intensity and ecological validity on them are worthy of further study. This study used realistic paintings with moderate ecological validity as experimental materials, to design isolated individual scene and social interaction scene, and to explore the impact of social interaction on the social orientation of autistic children. It found that in the scenes without social interaction, the attention patterns of autistic children and typical developing children were the same, while the attention patterns of autistic children were abnormal in the scenes with social interaction. From the eye tracking data, it was shown that the gaze processing process of autistic children was not as smooth as that of typical developing children. Compared with cartoons and other social scenes with low ecological validity, realistic painting could better restore the proportion of real scenes. Moreover, it could reduce the complexity of information which could not be done in real scenes. The findings of this study provide support for training and education of autistic children. Intervention with realistic paintings is conducive to the migration of autistic children.

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20. Zhou HY, Lai IYS, Hung KSY, Chan MKM, Ho ZTY, Lam JPH, Lui SSY, Chan RCK. Audiovisual temporal processing in adult patients with first-episode schizophrenia and high-functioning autism. Schizophrenia (Heidelb);2022 (Sep 22);8(1):75.

Schizophrenia and autism spectrum disorder (ASD) are both neurodevelopmental disorders with altered sensory processing. Widened temporal binding window (TBW) signifies reduced sensitivity to detect stimulus asynchrony, and may be a shared feature in schizophrenia and ASD. Few studies directly compared audiovisual temporal processing ability in the two disorders. We recruited 43 adult patients with first-episode schizophrenia (FES), 35 average intelligent and verbally-fluent adult patients with high-functioning ASD and 48 controls. We employed two unisensory Temporal Order Judgement (TOJ) tasks within visual or auditory modalities, and two audiovisual Simultaneity Judgement (SJ) tasks with flash-beeps and videos of syllable utterance as stimuli. Participants with FES exhibited widened TBW affecting both speech and non-speech processing, which were not attributable to altered unisensory sensory acuity because they had normal visual and auditory TOJ thresholds. However, adults with ASD exhibited intact unisensory and audiovisual temporal processing. Lower non-verbal IQ was correlated with larger TBW width across the three groups. Taking our findings with earlier evidence in chronic samples, widened TBW is associated with schizophrenia regardless illness stage. The altered audiovisual temporal processing in ASD may ameliorate after reaching adulthood.

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21. Zoodsma JD, Keegan EJ, Moody GR, Bhandiwad AA, Napoli AJ, Burgess HA, Wollmuth LP, Sirotkin HI. Disruption of grin2B, an ASD-associated gene, produces social deficits in zebrafish. Mol Autism;2022 (Sep 22);13(1):38.

BACKGROUND: Autism spectrum disorder (ASD), like many neurodevelopmental disorders, has complex and varied etiologies. Advances in genome sequencing have identified multiple candidate genes associated with ASD, including dozens of missense and nonsense mutations in the NMDAR subunit GluN2B, encoded by GRIN2B. NMDARs are glutamate-gated ion channels with key synaptic functions in excitatory neurotransmission. How alterations in these proteins impact neurodevelopment is poorly understood, in part because knockouts of GluN2B in rodents are lethal. METHODS: Here, we use CRISPR-Cas9 to generate zebrafish lacking GluN2B (grin2B(-/-)). Using these fish, we run an array of behavioral tests and perform whole-brain larval imaging to assay developmental roles and functions of GluN2B. RESULTS: We demonstrate that zebrafish GluN2B displays similar structural and functional properties to human GluN2B. Zebrafish lacking GluN2B (grin2B(-/-)) surprisingly survive into adulthood. Given the prevalence of social deficits in ASD, we assayed social preference in the grin2B(-/-) fish. Wild-type fish develop a strong social preference by 3 weeks post fertilization. In contrast, grin2B(-/-) fish at this age exhibit significantly reduced social preference. Notably, the lack of GluN2B does not result in a broad disruption of neurodevelopment, as grin2B(-/-) larvae do not show alterations in spontaneous or photic-evoked movements, are capable of prey capture, and exhibit learning. Whole-brain imaging of grin2B(-/-) larvae revealed reduction of an inhibitory neuron marker in the subpallium, a region linked to ASD in humans, but showed that overall brain size and E/I balance in grin2B(-/-) is comparable to wild type. LIMITATIONS: Zebrafish lacking GluN2B, while useful in studying developmental roles of GluN2B, are unlikely to model nuanced functional alterations of human missense mutations that are not complete loss of function. Additionally, detailed mammalian homologies for larval zebrafish brain subdivisions at the age of whole-brain imaging are not fully resolved. CONCLUSIONS: We demonstrate that zebrafish completely lacking the GluN2B subunit of the NMDAR, unlike rodent models, are viable into adulthood. Notably, they exhibit a highly specific deficit in social behavior. As such, this zebrafish model affords a unique opportunity to study the roles of GluN2B in ASD etiologies and establish a disease-relevant in vivo model for future studies.

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