1. Blanco B, Lloyd-Fox S, Begum-Ali J, Pirazzoli L, Goodwin A, Mason L, Pasco G, Charman T, Jones EJH, Johnson MH. Cortical responses to social stimuli in infants at elevated likelihood of ASD and/or ADHD: A prospective cross-condition fNIRS study. Cortex; a journal devoted to the study of the nervous system and behavior. 2023; 169: 18-34.

Autism spectrum disorders (ASD) and attention-deficit hyperactivity disorder (ADHD) are highly prevalent neurodevelopmental conditions that often co-occur and present both common and distinct neurodevelopmental profiles. Studying the developmental pathways leading to the emergence of ASD and/or ADHD symptomatology is crucial in understanding neurodiversity and discovering the mechanisms that underpin it. This study used functional near-infrared spectroscopy (fNIRS) to investigate differences in cortical specialization to social stimuli between 4- to 6-month-old infants at typical and elevated likelihood of ASD and/or ADHD. Results showed that infants at both elevated likelihood of ASD and ADHD had reduced selectivity to vocal sounds in left middle and superior temporal gyrus. Furthermore, infants at elevated likelihood of ASD showed attenuated responses to visual social stimuli in several cortical regions compared to infants at typical likelihood. Individual brain responses to visual social stimuli were associated with later autism traits, but not ADHD traits. These outcomes support our previous observations showing atypical social brain responses in infants at elevated likelihood of ASD and align with later atypical brain responses to social stimuli observed in children and adults with ASD. These findings highlight the importance of characterizing antecedent biomarkers of atypicalities in processing socially relevant information that might contribute to both phenotypic overlap and divergence across ASD and ADHD conditions and their association with the later emergence of behavioural symptoms.

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2. Camia M, Scorza M, Lipparini A, Martorana L, Nardocci F, Padovani R, Rubichi S, Benassi E. Psychological health of mothers and siblings of children with autism spectrum disorders during COVID-19 pandemic: new evidence in Italian families. Acta bio-medica : Atenei Parmensis. 2023; 94(5): e2023199.

BACKGROUND AND AIM: Psychological challenges are well recognized in families with a child with Autism Spectrum Disorders (ASD). Instead, less is known about the effects of traumatic scenarios, such as COVID-19, on the psychological health of these families. The main aim of this research was to study the psychological health of both mothers and typically developing (TD) siblings of children with ASD during the COVID-19 pandemic. Second, we investigated the relationship between the mothers’ psychological resources and their children psychological well-being. METHODS: The sample included 52 mothers and their children: 15 with one child with ASD and at least one TD child (aged 4-14) (ASD-siblings group) and 37 with one or more TD child (aged 4-14) (TD control group). The data were collected through an online platform; four standardized questionnaires (GAD-7, BDI-II, CD-RISC 25 and CBCL) were administered. RESULTS: The analyses revealed more internalizing and total behavioral symptoms in the siblings of children with ASD, compared to TD control group. Regarding the mothers, we did not find differences in depression and anxious symptoms between the two groups. However, the results reported a lower level of resilience in the mothers of children with ASD relative to mothers of TD children. Finally, the psychological well-being of the TD children was associated with the level of mothers’ anxiety only in the ASD-siblings group. CONCLUSIONS: Overall, our data show that the COVID-19 outbreak may had been particularly challenging for families of children with ASD, and highlight the importance of intensifying psychological support to families.

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3. Chen K, Zhuang W, Zhang Y, Yin S, Liu Y, Chen Y, Kang X, Ma H, Zhang T. Alteration of the large-scale white-matter functional networks in autism spectrum disorder. Cerebral cortex (New York, NY : 1991). 2023.

Autism spectrum disorder is a neurodevelopmental disorder whose core deficit is social dysfunction. Previous studies have indicated that structural changes in white matter are associated with autism spectrum disorder. However, few studies have explored the alteration of the large-scale white-matter functional networks in autism spectrum disorder. Here, we identified ten white-matter functional networks on resting-state functional magnetic resonance imaging data using the K-means clustering algorithm. Compared with the white matter and white-matter functional network connectivity of the healthy controls group, we found significantly decreased white matter and white-matter functional network connectivity mainly located within the Occipital network, Middle temporo-frontal network, and Deep network in autism spectrum disorder. Compared with healthy controls, findings from white-matter gray-matter functional network connectivity showed the decreased white-matter gray-matter functional network connectivity mainly distributing in the Occipital network and Deep network. Moreover, we compared the spontaneous activity of white-matter functional networks between the two groups. We found that the spontaneous activity of Middle temporo-frontal and Deep network was significantly decreased in autism spectrum disorder. Finally, the correlation analysis showed that the white matter and white-matter functional network connectivity between the Middle temporo-frontal network and others networks and the spontaneous activity of the Deep network were significantly correlated with the Social Responsiveness Scale scores of autism spectrum disorder. Together, our findings indicate that changes in the white-matter functional networks are associated behavioral deficits in autism spectrum disorder.

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4. Cooper C, Meso AI. Cognitive-perceptual traits associated with autism and schizotypy influence use of physics during predictive visual tracking. The European journal of neuroscience. 2023.

Schizophrenia and autism spectrum disorder (ASD) can disrupt cognition and consequently behaviour. Traits of ASD and the subclinical manifestation of schizophrenia called schizotypy have been studied in healthy populations with overlap found in trait profiles linking ASD social deficits to negative schizotypy and ASD attention to detail to positive schizotypy. Here, we probed the relationship between subtrait profiles, cognition and behaviour, using a predictive tracking task to measure individuals’ eye movements under three gravity conditions. A total of 48 healthy participants tracked an on-screen projected ball under familiar gravity, inverted upward acceleration (against gravity) and horizontal gravity control conditions while eye movements were recorded and dynamic performance quantified. Participants completed ASD and schizotypy inventories generating highly correlated scores, r = 0.73. All tracked best under the gravity condition, producing anticipatory downward responses from stimulus onset which were delayed under upward inverted gravity. Tracking performance was not associated with overall ASD or schizotypy trait levels. Combining measures using principal components analysis (PCA), we decomposed the inventories into subtraits unveiling interesting patterns. Positive schizotypy was associated with ASD dimensions of rigidity, odd behaviour and face processing, which all linked to anticipatory tracking responses under inverted gravity. In contrast, negative schizotypy was associated with ASD dimensions of social interactions and rigidity and to early stimulus-driven tracking under gravity. There was also substantial nonspecific overlap between ASD and schizotypy dissociated from tracking. Our work links positive-odd traits with anticipatory tracking when physics rules are violated and negative-social traits with exploitation of physics laws of motion.

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5. Ellul P, Maruani A, Vantalon V, Humeau E, Amestoy A, Anchordoqui A, Atzori P, Baleyte JM, Benmansour S, Bonnot O, Bouvard M, Cartigny A, Coulon N, Coutelle R, Da Fonseca D, Demily C, Givaudan M, Gollier-Briant F, Guénolé F, Koch A, Leboyer M, Lefebvre A, Lejuste F, Levy C, Mendes E, Robert N, Schroder CM, Speranza M, Zante E, Peyre H, Rosenzwajg M, Klatzmann D, Tchitchek N, Delorme R. Maternal immune activation during pregnancy is associated with more difficulties in socio-adaptive behaviors in autism spectrum disorder. Scientific reports. 2023; 13(1): 17687.

Autism spectrum disorder (ASD) are neurodevelopmental conditions characterised by deficits in social communication and interaction and repetitive behaviours. Maternal immune activation (MIA) during the mid-pregnancy is a known risk factor for ASD. Although reported in 15% of affected individuals, little is known about the specificity of their clinical profiles. Adaptive skills represent a holistic approach to a person’s competencies and reflect specifically in ASD, their strengths and difficulties. In this study, we hypothesised that ASD individual with a history of MIA (MIA(+)) could be more severely socio-adaptively impaired than those without MIA during pregnancy (MIA(-)). To answer this question, we considered two independent cohorts of individuals with ASD (PARIS study and FACE ASD) screened for pregnancy history, and used supervised and unsupervised machine learning algorithms. We included 295 mother-child dyads with 14% of them with MIA(+). We found that ASD-MIA(+) individuals displayed more severe maladaptive behaviors, specifically in their socialization abilities. MIA(+) directly influenced individual’s socio-adaptive skills, independent of other covariates, including ASD severity. Interestingly, MIA(+) affect persistently the socio-adaptive behavioral trajectories of individuals with ASD. The current study has a retrospective design with possible recall bias regarding the MIA event and, even if pooled from two cohorts, has a relatively small population. In addition, we were limited by the number of covariables available potentially impacted socio-adaptive behaviors. Larger prospective study with additional dimensions related to ASD is needed to confirm our results. Specific pathophysiological pathways may explain these clinical peculiarities of ASD- MIA(+) individuals, and may open the way to new perspectives in deciphering the phenotypic complexity of ASD and for the development of specific immunomodulatory strategies.

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6. Huang Q, Velthuis H, Pereira AC, Ahmad J, Cooke SF, Ellis CL, Ponteduro FM, Puts NAJ, Dimitrov M, Batalle D, Wong NML, Kowalewski L, Ivin G, Daly E, Murphy DGM, McAlonan GM. Exploratory evidence for differences in GABAergic regulation of auditory processing in autism spectrum disorder. Translational psychiatry. 2023; 13(1): 320.

Altered reactivity and responses to auditory input are core to the diagnosis of autism spectrum disorder (ASD). Preclinical models implicate ϒ-aminobutyric acid (GABA) in this process. However, the link between GABA and auditory processing in humans (with or without ASD) is largely correlational. As part of a study of potential biosignatures of GABA function in ASD to inform future clinical trials, we evaluated the role of GABA in auditory repetition suppression in 66 adults (n = 28 with ASD). Neurophysiological responses (temporal and frequency domains) to repetitive standard tones and novel deviants presented in an oddball paradigm were compared after double-blind, randomized administration of placebo, 15 or 30 mg of arbaclofen (STX209), a GABA type B (GABA(B)) receptor agonist. We first established that temporal mismatch negativity was comparable between participants with ASD and those with typical development (TD). Next, we showed that temporal and spectral responses to repetitive standards were suppressed relative to responses to deviants in the two groups, but suppression was significantly weaker in individuals with ASD at baseline. Arbaclofen reversed weaker suppression of spectral responses in ASD but disrupted suppression in TD. A post hoc analysis showed that arbaclofen-elicited shift in suppression was correlated with autistic symptomatology measured using the Autism Quotient across the entire group, though not in the smaller sample of the ASD and TD group when examined separately. Thus, our results confirm: GABAergic dysfunction contributes to the neurophysiology of auditory sensory processing alterations in ASD, and can be modulated by targeting GABA(B) activity. These GABA-dependent sensory differences may be upstream of more complex autistic phenotypes.

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7. Itani KN, Elfaki S. A Rare Case of Hao-Fountain Syndrome Mimicking Fragile X Syndrome. Cureus. 2023; 15(9): e45332.

Hao-Fountain syndrome (HAFOUS) is a rare neurodevelopmental disorder caused by mutations in the ubiquitin-specific protease 7 (USP7) gene for endosomal recycling. The diagnosis is often challenging due to the nonspecific presentation of intellectual disability and developmental delay, often accompanied by dysmorphic facies. In this case, we present an 18-year-old female with intellectual disability (ID), attention-deficit/hyperactivity disorder (ADHD), and dysmorphic facies who had undergone single nucleotide polymorphism (SNP) microarray and fragile X polymerase chain reaction (PCR) testing five years prior to diagnosis, both returning with negative results for genetic anomalies. The patient was managed symptomatically for ADHD until recently when the topic of a possible genetic condition was reintroduced to the family, who were agreeable to a referral to a medical geneticist and repeat genetic testing. Repeat testing, but now with whole-exome sequence (WES) analysis, revealed a pathogenic variant of the USP7 gene, prompting the diagnosis of Hao-Fountain syndrome. Our patient continues to be symptomatically managed for ADHD and intellectual disability. Educational resources and support group information were also shared and discussed with the patient and her family in the wake of this rare diagnosis.

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8. Mori T, Tsuchiya KJ, Harada T, Nakayasu C, Okumura A, Nishimura T, Katayama T, Endo M. Autism symptoms, functional impairments, and gaze fixation measured using an eye-tracker in 6-year-old children. Frontiers in psychiatry. 2023; 14: 1250763.

INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental disorder clinically characterized by abnormalities in eye contact during social exchanges. We aimed to clarify whether the amount of gaze fixation, measured at the age of 6 years using Gazefinder, which is an established eye-tracking device, is associated with ASD symptoms and functioning. METHODS: The current study included 742 participants from the Hamamatsu Birth Cohort Study. Autistic symptoms were evaluated according to the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), and the functioning of the participating children in real life was assessed using the Japanese version of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II). The Gazefinder system was used for gaze fixation rates; two areas of interest (eyes and mouth) were defined in a talking movie clip, and eye gaze positions were calculated through corneal reflection techniques. RESULTS: The participants had an average age of 6.06 ± 0.14 years (males: 384; 52%). According to ADOS, 617 (83%) children were assessed as having none/mild ASD and 51 (7%) as severe. The average VABS-II scores were approximately 100 (standard deviation = 12). A higher gaze fixation rate on the eyes was associated with a significantly lower likelihood of the child being assigned to the severe ADOS group after controlling for covariates (odds ratio [OR], 0.02; 95% confidence interval [CI], 0.002-0.38). The gaze fixation rate on the mouth was not associated with ASD symptoms. A higher gaze fixation rate on the mouth was associated with a significantly lower likelihood of the child being assigned to the low score group in VABS-II socialization after controlling for covariates (OR, 0.18; 95% CI, 0.04-0.85). The gaze fixation rate on the eyes was not associated with functioning. CONCLUSION: We found that children with low gaze fixation rates on the eyes were likely to have more ASD symptoms, and children with low gaze fixation rates on the mouth were likely to demonstrate poorer functioning in socialization. Hence, preschool children could be independently assessed in the general population for clinically relevant endophenotypes predictive of ASD symptoms and functional impairments.

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9. Muhammad T, Pastore SF, Good K, Ausió J, Vincent JB. Chromatin gatekeeper and modifier CHD proteins in development, and in autism and other neurological disorders. Psychiatric genetics. 2023.

Chromatin, a protein-DNA complex, is a dynamic structure that stores genetic information within the nucleus and adapts to molecular/cellular changes in its structure, providing conditional access to the genetic machinery. ATP-dependent chromatin modifiers regulate access of transcription factors and RNA polymerases to DNA by either « opening » or « closing » the structure of chromatin, and its aberrant regulation leads to a variety of neurodevelopmental disorders. The chromodomain helicase DNA-binding (CHD) proteins are ATP-dependent chromatin modifiers involved in the organization of chromatin structure, act as gatekeepers of genomic access, and deposit histone variants required for gene regulation. In this review, we first discuss the structural and functional domains of the CHD proteins, and their binding sites, and phosphorylation, acetylation, and methylation sites. The conservation of important amino acids in SWItch/sucrose non-fermenting (SWI/SNF) domains, and their protein and mRNA tissue expression profiles are discussed. Next, we convey the important binding partners of CHD proteins, their protein complexes and activities, and their involvements in epigenetic regulation. We also show the ChIP-seq binding dynamics for CHD1, CHD2, CHD4, and CHD7 proteins at promoter regions of histone genes, as well as several genes that are critical for neurodevelopment. The role of CHD proteins in development is also discussed. Finally, this review provides information about CHD protein mutations reported in autism and neurodevelopmental disorders, and their pathogenicity. Overall, this review provides information on the progress of research into CHD proteins, their structural and functional domains, epigenetics, and their role in stem cell, development, and neurological disorders.

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10. Pham LNH, Lee AK, Estes A, Dager S, Hemingway SJA, Thorne JC, Lau BK. Comparing narrative storytelling ability in individuals with autism and fetal alcohol spectrum disorders. International journal of language & communication disorders. 2023.

BACKGROUND: Narrative discourse, or storytelling, is used in daily conversation and requires higher-level language and social communication skills that are not always captured by standardised assessments of language. Many autistic individuals and individuals with fetal alcohol spectrum disorders (FASD) have difficulties with both social communication and language skills, and narrative discourse analysis offers an ecologically relevant approach to assessing those challenges. AIMS: This study investigated narrative discourse in individuals with autism and FASD, as well as an age- and sex-matched comparison group. METHODS AND PROCEDURES: Narratives from 45 adolescents and adults, 11 with autism, 11 with FASD and 23 age- and sex-matched comparison participants were elicited using a wordless storybook. They were then transcribed orthographically, formatted to the Systematic Analyses of Language Transcript (SALT) convention and scored based on the SALT Narrative Scoring Scheme (NSS), a standardised language analysis protocol. In addition to the NSS total score, which assesses the overall structure and cohesion of the narratives produced, local and global measures of language ability were also employed. The local language measures included the number of mental state and temporal relation terms produced, while the global language measures included mean length of utterance, total different words, total words, total utterances, rate of speech, the number of mazes (e.g., repetitions, ‘um’, ‘uh’ or self-corrections) per total word and the NSS total score. OUTCOMES AND RESULTS: Using the SALT Language Sample Analysis tool, our results revealed that on global language measures, group differences were found on rate of speech, number of mazes per total words and the description of conflict/resolution in the narratives produced. The autism group produced significantly more mazes per total word and scored higher on the NSS conflict/resolution category score compared to the FASD and comparison groups. Both the autism and FASD groups spoke at a lower rate than the comparison group. On local language measures of narrative production, all groups were comparable, on average. CONCLUSIONS AND IMPLICATIONS: While many aspects of narrative discourse in the autism and FASD groups were similar to each other and to the comparison group, we observed group differences on global measures of narrative production and significant individual variability within groups, suggesting that narrative abilities considered at an individual level may provide important clinical information for intervention planning. Future research should also consider additional variables that influence narrative discourse, such as motivation, distractibility or decision-making of individual participants. WHAT THIS PAPER ADDS: What is already known on the subject Narrative discourse, or storytelling, is used in daily conversational interactions and reveals higher-level language skills that may not be well captured by standardised assessments of language. Many autistic individuals and individuals with fetal alcohol spectrum disorders (FASD) show difficulty with pragmatic and expressive language skills. What this paper adds to existing knowledge We found that many aspects of the narratives produced by the adolescents/young adults in the autism and FASD groups were comparable to each other and to the neurotypical group. However, the groups differed on three global measures of narrative production: rate of speech, number of mazes per total words and the description of conflict/resolution in the narratives produced. Also, significant variability was observed within groups, suggesting that narrative abilities should be considered at an individual level as opposed to their clinical groups. What are the potential or actual clinical implications of this work? This study showed that narrative discourse is an appropriate task that can be added to routine clinical assessments of language abilities in autistic adolescents/young adults as well as those with FASD or typical development and has the potential to reveal higher-level, real-world language skills. An important clinical implication of this study is that narrative language abilities should be considered at an individual level and individual-tailored interventions based on ability level due to the variability observed across individuals.

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11. Posar A, Visconti P. Autism Spectrum Disorder in 2023: A Challenge Still Open. Turkish archives of pediatrics. 2023.

In this paper, we provide an update on autism spectrum disorder (ASD), including epidemiology, etiopathogenesis, clinical presentation, instrumental investigations, early signs, onset patterns, neuropsychological hypotheses, treatments, and long-term outcome. The prevalence of this condition has increased enormously over the last few decades. This increase prompted a search for possible environmental factors whose effects would add up to a genetic predisposition leading to the development of autism. But the genetic and environmental variables involved are extremely numerous, and conclusive data regarding the etiopathogenesis are still far away. Assuming that a well-defined etiology is still found today only in a minority of cases, numerous pathogenetic mechanisms have been hypothesized. Among these, we mention oxidative stress, mitochondrial dysfunction, alteration of the intestinal microbiota, immune dysregulation, and neuroinflammation. These pathogenetic mechanisms could alter epigenetic status and gene expression, finally leading to ASD. Inherent in the term spectrum is the great clinical heterogeneity of this condition, mainly due to the frequent comorbidity that characterizes it. The earlier the diagnosis is made and the earlier psychoeducational treatment begins, the better the prognosis. In this sense, the role of pediatricians can be decisive in making children with signs suggestive of autism undergo a specialist diagnostic course. The development of increasingly advanced cognitive-behavioral educational techniques has considerably improved the prognosis of affected individuals, even though only a small minority of them come off the autistic spectrum. Pharmacological therapies are used to treat comorbidities. During childhood, the most important prognostic factor for long-term outcome seems to be intellectual functioning.

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12. Schnitzler T, Fuchs T. Autism as a Disorder of Affective Empathy. Psychopathology. 2023: 1-10.

Since the first description by Leo Kanner, individuals with autism spectrum disorder (ASD) have been attributed a reduced empathy. However, it has not yet been clarified how empathy is specifically impaired in autism. Typically, scholars distinguish between the affective and the cognitive dimensions of empathy. The latter largely overlaps with the concept of the theory of mind (ToM), according to which we need internal inferences or simulations for gaining access to the hidden mental states of others. Since a deficit in ToM is a widely accepted explanation for difficulties of individuals with ASD in social interactions, limitations in cognitive empathy are accordingly assumed. Regarding affective empathy, there are contradictory results using various methods, showing an impaired affective empathy. The main aim of the paper is to present ASD primarily as a disorder of shared interpersonal and interaffective experiences and thus of affective empathy by means of a phenomenological analysis considering empirical studies. In this framework, a deficit of the ToM is accepted but criticized as a central explanatory approach for ASD since (1) it assumes a fundamental inaccessibility of other people, which does not correspond to our everyday social situations, and (2) it manifests developmentally long after the first signs of ASD, which means that its deficit cannot explain the basic autistic difficulties in social interactions.

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13. Sivayokan B, Sivayokan S, Kumanan T, Sathiadas G, Sreeharan N. Establishing a novel partnership model to deploy health services for children with autism in a low-resource setting – experience from Sri Lanka. The Lancet regional health Southeast Asia. 2023; 17: 100255.

Sri Lanka is representative of challenges faced by low-income and middle-income countries, including the rise in the prevalence of autism and the lack of sufficient autism-specific services in the state sectors. The experience in establishing a Center to provide services for children with autism in Northern Sri Lanka is described. Funding and resourcing were accessed through an innovative partnership-based public/non-governmental organisation/charity model, where service-based outcomes were the main objectives. This model, incorporating state institutions, local and international charity organisations, and volunteers, devised a bespoke approach to care provision using the available resources under the clinical supervision of a consultant psychiatrist and the administrative purview of the Regional Director of Health Services. The evolution of this Center into a Learning Health System is described, reflecting how a minimalistic partnership approach focused on the integration of existing organisations and services could be a feasible model for the delivery of high-quality healthcare in low-resource settings.

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14. Tian R, Li Y, Zhao H, Lyu W, Zhao J, Wang X, Lu H, Xu H, Ren W, Tan QQ, Shi Q, Wang GD, Zhang YP, Lai L, Mi J, Jiang YH, Zhang YQ. Modeling SHANK3-associated autism spectrum disorder in Beagle dogs via CRISPR/Cas9 gene editing. Molecular psychiatry. 2023.

Despite intensive studies in modeling neuropsychiatric disorders especially autism spectrum disorder (ASD) in animals, many challenges remain. Genetic mutant mice have contributed substantially to the current understanding of the molecular and neural circuit mechanisms underlying ASD. However, the translational value of ASD mouse models in preclinical studies is limited to certain aspects of the disease due to the apparent differences in brain and behavior between rodents and humans. Non-human primates have been used to model ASD in recent years. However, a low reproduction rate due to a long reproductive cycle and a single birth per pregnancy, and an extremely high cost prohibit a wide use of them in preclinical studies. Canine model is an appealing alternative because of its complex and effective dog-human social interactions. In contrast to non-human primates, dog has comparable drug metabolism as humans and a high reproduction rate. In this study, we aimed to model ASD in experimental dogs by manipulating the Shank3 gene as SHANK3 mutations are one of most replicated genetic defects identified from ASD patients. Using CRISPR/Cas9 gene editing, we successfully generated and characterized multiple lines of Beagle Shank3 (bShank3) mutants that have been propagated for a few generations. We developed and validated a battery of behavioral assays that can be used in controlled experimental setting for mutant dogs. bShank3 mutants exhibited distinct and robust social behavior deficits including social withdrawal and reduced social interactions with humans, and heightened anxiety in different experimental settings (n = 27 for wild-type controls and n = 44 for mutants). We demonstrate the feasibility of producing a large number of mutant animals in a reasonable time frame. The robust and unique behavioral findings support the validity and value of a canine model to investigate the pathophysiology and develop treatments for ASD and potentially other psychiatric disorders.

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