1. Chowdhury TA, Luy DA, Farache D, Lee AS, Quinn CC. Autism candidate gene rbm-26 ( RBM26/27 ) regulates MALSU-1 to protect against mitochondrial dysfunction during axon development. bioRxiv;2023 (Oct 14)

Mitochondrial dysfunction is thought to be a key component of neurodevelopmental disorders such as autism, intellectual disability, and ADHD. However, little is known about the molecular mechanisms that protect against mitochondrial dysfunction during neurodevelopment. Here, we address this question through the investigation of rbm-26 , the C. elegans ortholog of the RBM27 autism candidate gene, which encodes an RNA-binding protein whose role in neurons is unknown. We report that RBM-26 (RBM26/27) protects against neurodevelopmental defects by negatively regulating expression of the MALSU-1 mitoribosomal assembly factor. Autism-associated missense variants in RBM-26 cause a sharp decrease in RBM-26 protein expression along with neurodevelopmental defects, including errors in axon targeting and axon degeneration. Using an unbiased screen, we identified the mRNA for the MALSU-1 mitoribosomal assembly factor as a binding partner for RBM-26. RBM-26 negatively regulates the expression of malsu-1 mRNA and MALSU-1 protein, and genetic analysis indicates that this interaction is required to protect against neurodevelopmental defects. Moreover, biochemical evidence suggests that excess levels of MALSU-1 disrupt the biogenesis of mitoribosomes in rbm-26 mutants. These observations reveal a mechanism that can protect mitochochondrial function to prevent neurodevelopmental defects and suggest that disruptions in this process can cause neurodevelopmental disorders.

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2. Cuomo M, Coretti L, Costabile D, Della Monica R, De Riso G, Buonaiuto M, Trio F, Bravaccio C, Visconti R, Berni Canani R, Chiariotti L, Lembo F. Host fecal DNA specific methylation signatures mark gut dysbiosis and inflammation in children affected by autism spectrum disorder. Sci Rep;2023 (Oct 24);13(1):18197.

The gut-brain axis involves several bidirectional pathway communications including microbiome, bacterial metabolites, neurotransmitters as well as immune system and is perturbed both in brain and in gastrointestinal disorders. Consistently, microbiota-gut-brain axis has been found altered in autism spectrum disorder (ASD). We reasoned that such alterations occurring in ASD may impact both on methylation signatures of human host fecal DNA (HFD) and possibly on the types of human cells shed in the stools from intestinal tract giving origin to HFD. To test this hypothesis, we have performed whole genome methylation analysis of HFD from an age-restricted cohort of young children with ASD (N = 8) and healthy controls (N = 7). In the same cohort we have previously investigated the fecal microbiota composition and here we refined such analysis and searched for eventual associations with data derived from HFD methylome analysis. Our results showed that specific epigenetic signatures in human fecal DNA, especially at genes related to inflammation, associated with the disease. By applying methylation-based deconvolution algorithm, we found that the HFD derived mainly from immune cells and the relative abundance of those differed between patients and controls. Consistently, most of differentially methylated regions fitted with genes involved in inflammatory response. Interestingly, using Horvath epigenetic clock, we found that ASD affected children showed both epigenetic and microbiota age accelerated. We believe that the present unprecedented approach may be useful for the identification of the ASD associated HFD epigenetic signatures and may be potentially extended to other brain disorders and intestinal inflammatory diseases.

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3. Galvin J, Howes A, Richards G. Longitudinal Associations Between Autistic Traits, Self-compassion, Anxiety and Depression in Autistic and Non-autistic Adults Without Intellectual Disability. J Autism Dev Disord;2023 (Oct 24)

PURPOSE: Previous cross-sectional research suggests self-compassion may mediate associations between autistic traits and mental health in autistic and non-autistic adults. However, no research to date has examined these relationships longitudinally. In this study, we used a cross-lagged panel analysis to examine correlations over time between autistic traits, self-compassion, and anxiety/depression. METHODS: Participants were from the UK and included autistic (n = 228 at T1, n = 156 at T2, and n = 165 at T3) and non-autistic adults (n = 228 at T1, n = 122 at T2, and n = 124 at T3) without intellectual disability. Participants were recruited through an online participation platform and completed demographics, the Autism Spectrum Quotient (AQ), the Self-Compassion Scale (SCS), and the Hospital Anxiety and Depression Scale (HADS) at baseline (T1), 6 months (T2), and 12 months (T3). RESULTS: In the autistic sample, negative correlations were observed between self-compassion and subsequent anxiety/depression across all models and timepoints, and these relationships were not reciprocal (i.e., earlier depression and anxiety did not predict future self-compassion). In the non-autistic sample, the findings generally suggested bi-directional relationships between self-compassion and anxiety/depression. In both groups, an indirect pathway between T1 autistic traits and T3 anxiety/depression via T2 self-compassion was confirmed. CONCLUSION: Considering the high prevalence of anxiety and depression among autistic people, and that self-compassion can be cultivated through practice, these findings suggest that self-compassion could be a useful therapeutic target to promote mental health in the autistic population.

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4. Gibson MT, Schmidt-Kassow M, Paulmann S. How neurotypical listeners recognize emotions expressed through vocal cues by speakers with high-functioning autism. PLoS One;2023;18(10):e0293233.

We conducted an investigation to explore how neurotypical (NT) listeners perceive the emotional tone of voice in sentences spoken by individuals with high-functioning autism spectrum disorders (ASD) and NT speakers. The investigation included both male and female speakers from both groups. In Study 1, NT listeners were asked to identify the emotional prosody (anger, fear, happiness, surprise or neutral) conveyed by the speakers. Results revealed that emotional expressions produced by male ASD speakers were generally less accurately recognized compared to male NT speakers. In contrast, emotions expressed by female ASD speakers were more accurately categorized compared to female NT speakers, except when expressing fear. This suggests that female ASD speakers may not express emotional prosody in the same way as their male counterparts. In Study 2, a subset of produced materials was rated for valence, voice modulation, and voice control to supplement Study 1 results: Female ASD speakers sounded less negative when expressing fear compared to female NT speakers. Male ASD speakers were perceived as less positive than NT speakers when expressing happiness. Voice modulation also differed between groups, showing a tendency for ASD speakers to follow different display rules for both positive emotions (happiness and surprise) tested. Finally, male ASD speakers were rated to use voice cues less appropriately compared to NT male speakers, an effect less pronounced for female ASD speakers. Together, the results imply that difficulties in social interactions among individuals with high-functioning ASD could be due to non-prototypical voice use of male ASD speakers and emphasize that female individuals do not show the same effects.

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5. Kim H, Kim SA, Lee H, Dodds R. Korean Immigrant Mothers and the Journey to Autism Diagnosis and Services for Their Child in the United States. J Autism Dev Disord;2023 (Oct 24)

Since autism diagnosis is directly linked to the availability of supportive services, identifying best practices for early diagnosis of autism has long been a concern of professionals and families. Meanwhile, studies show persistent racial disparities in autism diagnosis. Although numerous clinical diagnostic guidelines have been published, there is not enough discussion of diagnostic procedures through the lens of culturally diverse families. PURPOSE: This study focuses on the autism diagnostic experiences that Korean immigrant mothers had with their children. METHODS: Eleven first-generation Korean-American mothers of children with autism were included in the study. The data was collected using semi-structured interviews in Korean. RESULTS: The main five factors (i.e., cultural beliefs and values, language barriers, complex emotions, immigration and navigating systems, and facilitators and assets) that mainly influence the diagnosis process were identified through thematic analysis. CONCLUSION: Dynamics are interactive within and between the factors, influencing the entire diagnostic process by either delaying or facilitating the identification of a child’s autism and the provision of treatment.

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6. Larson C, Eigsti IM, Spaulding T, Parish-Morris J. Language is a critical mediator of autistic experiences within the criminal justice system. Autism Res;2023 (Oct 23)

Autism spectrum disorder is characterized by social communication challenges and restricted and repetitive behaviors and interests, but also by highly heterogeneous language skills. The recent International Society of Autism Research (INSAR) policy statement, Autism and the Criminal Justice System: Policy opportunities and challenges (INSAR, 2022), aims to prevent, reduce, and improve interactions between autistic individuals and the criminal justice system. This policy statement provides a foundation for considering how to include language in these important aims. In this commentary, we outline the centrality of language skills to these interactions and provide specific recommendations that can inform future research and provide guidance for autistic individuals, community partners, and individuals working within the criminal justice system. Considering language as a part of justice system policy for autistic individuals will result in greater equity and inclusion, particularly for autistic individuals with co-occurring language deficits and those who are linguistically diverse. Moreover, it will allow autistic individuals to combat other barriers to effectively navigating interactions with the criminal justice system, such as those related to the core features of autism. We advocate for a greater role for service providers who can assess challenges in language skills, and identify the specific accommodations each autistic individual will need to prevent, reduce, and improve interactions with the criminal justice system.

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7. Oberman LM, Francis SM, Lisanby SH. The use of noninvasive brain stimulation techniques in autism spectrum disorder. Autism Res;2023 (Oct 23)

Noninvasive brain stimulation (NIBS) techniques, including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), have recently emerged as alternative, nonpharmacological interventions for a variety of psychiatric, neurological, and neurodevelopmental conditions. NIBS is beginning to be applied in both research and clinical settings for the treatment of core and associated symptoms of autism spectrum disorder (ASD) including social communication deficits, restricted and repetitive behaviors, irritability, hyperactivity, depression and impairments in executive functioning and sensorimotor integration. Though there is much promise for these targeted device-based interventions, in other disorders (including adult major depressive disorder (MDD) and obsessive compulsive disorder (OCD) where rTMS is FDA cleared), data on the safety and efficacy of these interventions in individuals with ASD is limited especially in younger children when neurodevelopmental interventions typically begin. Most studies are open-label, small scale, and/or focused on a restricted subgroup of individuals with ASD. There is a need for larger, randomized controlled trials that incorporate neuroimaging in order to develop predictive biomarkers of treatment response and optimize treatment parameters. We contend that until such studies are conducted, we do not have adequate estimates of the safety and efficacy of NIBS interventions in children across the spectrum. Thus, broad off-label use of these techniques in this population is not supported by currently available evidence. Here we discuss the existing data on the use of NIBS to treat symptoms related to ASD and discuss future directions for the field.

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8. Shakhawat AM, Foltz JG, Nance AB, Bhateja J, Raymond JL. Systemic pharmacological suppression of neural activity reverses learning impairment in a mouse model of Fragile X syndrome. bioRxiv;2023 (Oct 5)

The enhancement of associative synaptic plasticity often results in impaired rather than enhanced learning. Previously, we proposed that such learning impairments may result from saturation of the plasticity mechanism making it unavailable to be recruited at the appropriate synapses to support learning (Nguyen-Vu et al., 2017). This hypothesis was based on experimental results from mice lacking two class I major histocompatibility molecules, MHCI H2-K (b) and H2-D (b) (MHCI K (b) D (b-/-) ), which have enhanced associative long-term depression at the parallel fiber-Purkinje cell synapses in the cerebellum (PF-Purkinje cell LTD). Here we extend this work by testing predictions of the saturation hypothesis in a second mouse line with enhanced PF-Purkinje cell LTD, the Fmr1 knockout mouse model of Fragile X syndrome (FXS). Mice lacking Fmr1 gene expression in cerebellar Purkinje cells (L7- Fmr1 KO) were selectively impaired on an oculomotor learning task in which PF-Purkinje cell LTD has been implicated, with no impairment on an LTD-independent oculomotor learning task. Consistent with the saturation hypothesis, behavioral pre-training designed to reverse LTD at the PF-Purkinje cell synapses eliminated the oculomotor learning deficit in the L7- Fmr1 KO mice, as previously reported in MHCI K (b) D (b-/-) mice. In addition, diazepam treatment to suppress neural activity and thereby limit the induction of associative LTD during the pre-training period also eliminated the learning deficit in L7- Fmr1 KO mice. These results support the hypothesis that the enhancement of synaptic plasticity can lead to its saturation in vivo and inability to support learning, providing a novel mechanistic perspective that could inform the development of new clinical approaches for autism and other disorders of the nervous system.

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9. Yan H. Artificial neural networks based multimodal device for autism spectrum disorder. Bratisl Lek Listy;2023;124(11):862-869.

The neuro developmental condition known as Autism Spectrum Disorder (ASD) affects people on a lifetime basis and exhibits itself in a wide range of ways. In this research work a brand-new semi-supervised training method for the recognition of discrete multi-modal autism spectrum disorder is proposed. At the coarse-grained level, we consider that various methodologies are anticipated to explore equivalent information about child autism. To build DC AlexNet, this combines two small network branches and a large network (trunk network). The network trunk is programmed just to become familiar with the distinguishing characteristics shared by face images at different resolutions. It is built using recently suggested residential components. To project images to a place where their ranges are as little as possible, two branch networks are programmed to learn coupled-mappings (CMs) that are particular to a given resolution. The suggested technique is properly assessed utilizing the databases for the OMEGE and DIAEMO datasets by evaluating it to state-of-the-art techniques in terms of many parameters. Deep Coupled AlexNet is developed to obtain 98.13 % of accuracy, 95.1 % of precision, 94.3 % of recall and 95.4 of F1-score for OMEGE dataset. Moreover, 98.6 % of accuracy, 97.2 % of precision, 98.5 of recall and 97.5 % of F1-score for DIAEMO dataset (Tab. 8, Fig. 10, Ref. 16). Keywords: autism spectrum disorder, artificial neural networks, emotion recognition, interaction design, multimodal factors.

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10. Zarate-Lopez D, Torres-Chávez AL, Gálvez-Contreras AY, Gonzalez-Perez O. Three Decades of Valproate: A Current Model for Studying Autism Spectrum Disorder. Curr Neuropharmacol;2023 (Oct 16)

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with increased prevalence and incidence in recent decades. Its etiology remains largely unclear, but it seems to involve a strong genetic component and environmental factors that, in turn, induce epigenetic changes during embryonic and postnatal brain development. In recent decades, clinical studies have shown that inutero exposure to valproic acid (VPA), a commonly prescribed antiepileptic drug, is an environmental factor associated with an increased risk of ASD. Subsequently, prenatal VPA exposure in rodents has been established as a reliable translational model to study the pathophysiology of ASD, which has helped demonstrate neurobiological changes in rodents, non-human primates, and brain organoids from human pluripotent stem cells. This evidence supports the notion that prenatal VPA exposure is a valid and current model to replicate an idiopathic ASD-like disorder in experimental animals. This review summarizes and describes the current features reported with this animal model of autism and the main neurobiological findings and correlates that help elucidate the pathophysiology of ASD. Finally, we discuss the general framework of the VPA model in comparison to other environmental and genetic ASD models.

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