1. Bajikar SS, Anderson AG, Zhou J, Durham MA, Trostle AJ, Wan YW, Liu Z, Zoghbi HY. MeCP2 regulates Gdf11, a dosage-sensitive gene critical for neurological function. Elife;2023 (Feb 27);12

Loss- and gain-of-function of MeCP2 causes Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), respectively. MeCP2 binds methyl-cytosines to finely tune gene expression in the brain, but identifying genes robustly regulated by MeCP2 has been difficult. By integrating multiple transcriptomics datasets, we revealed that MeCP2 finely regulates growth differentiation factor 11 (Gdf11). Gdf11 is down-regulated in RTT mouse models and, conversely, up-regulated in MDS mouse models. Strikingly, genetically normalizing Gdf11 dosage levels improved several behavioral deficits in a mouse model of MDS. Next, we discovered that losing one copy of Gdf11 alone was sufficient to cause multiple neurobehavioral deficits in mice, most notably hyperactivity and decreased learning and memory. This decrease in learning and memory was not due to changes in proliferation or numbers of progenitor cells in the hippocampus. Lastly, loss of one copy of Gdf11 decreased survival in mice, corroborating its putative role in aging. Our data demonstrate that Gdf11 dosage is important for brain function.

Lien vers le texte intégral (Open Access ou abonnement)

2. Czech H. Response to Tatzer et al: Their paper on what Asperger knew about Nazi « child euthanasia » does not provide a rigorous assessment of the available evidence. Acta Paediatr;2023 (Feb 27)

Lien vers le texte intégral (Open Access ou abonnement)

3. Fuselier MN, Guzick AG, Bakhshaie J, Wood JJ, Kendall PC, Kerns CM, Small BJ, Goodman WK, Storch EA. Examining the Relationship Between Anxiety Severity and Autism-Related Challenges During Cognitive Behavioral Therapy for Children with Autism. J Autism Dev Disord;2023 (Feb 27)

PURPOSE: Using data from a randomized clinical trial evaluating cognitive behavioral therapy (CBT) for children with autism and co-occurring anxiety, this study examined the relationship between autism features and anxiety symptoms throughout CBT. METHODS: Two multilevel mediation analyses were run which examined the mediating role of changes in anxiety for changes in two core features of autism, (a) repetitive and restrictive behaviors (RRBs) and (b) social communication/interaction impairments, between pre- and post-treatment. RESULTS: Indirect effects between time and autism characteristics were significant for both models, indicating that as anxiety changes, so do RRBs and social communication/interaction as the outcomes respectively. CONCLUSION: Findings suggest a bidirectional relationship between anxiety and autism features. Implications of these findings are discussed.

Lien vers le texte intégral (Open Access ou abonnement)

4. Garcia Torres M, Magaña S, Balcazar F. Brief report: Evaluation of an adapted youth version of Parents Taking Action for parents of pre/adolescents with autism spectrum disorder in Colombia. Autism;2023 (Feb 27):13623613231155773.

We evaluated the efficacy of the youth version of the program Parents Taking Action in Bogota, Colombia. This program aims to provide information, resources, and strategies about topics of puberty, sexuality, and adolescence for parents of preadolescents with autism spectrum disorder. We examined whether parents in the treatment groups would improve in levels of knowledge, empowerment, self-efficacy, and use of strategies compared to the control group. We recruited two groups of Colombian parents of pre/adolescent with autism spectrum disorder between the ages of 10 and 17 in the city of Bogota, Colombia, through a community-based organization. One of the groups received the intervention and the other served as a control group. Parents in the control group received the intervention after the 4-month follow-up. The intervention included four 3-h weekly sessions in which the curriculum with nine topic areas was delivered providing parents with a space to practice strategies, learn from others, and set goals. Parents in the intervention group reported significantly greater knowledge, self-efficacy, use of strategies, and empowerment compared to the control/waitlist group. Parents were also highly satisfied with the content, materials, and peer connections that the program offered. The program has potential for high impact as information is scarce and parents do not have resources related to the complicated developmental stages of pre/adolescence. The program shows promise as an efficacious tool for community organizations and health providers to provide extra support to families of youth with autism spectrum disorder.

Lien vers le texte intégral (Open Access ou abonnement)

5. Giuliani A, Sabbatinelli J, Amatori S, Graciotti L, Silvestrini A, Matacchione G, Ramini D, Mensà E, Prattichizzo F, Babini L, Mattiucci D, Busilacchi EM, Bacalini MG, Espinosa E, Lattanzio F, Procopio AD, Olivieri F, Poloni A, Fanelli M, Rippo MR. MiR-422a promotes adipogenesis via MeCP2 downregulation in human bone marrow mesenchymal stem cells. Cell Mol Life Sci;2023 (Feb 27);80(3):75.

Methyl-CpG binding protein 2 (MeCP2) is a ubiquitous transcriptional regulator. The study of this protein has been mainly focused on the central nervous system because alterations of its expression are associated with neurological disorders such as Rett syndrome. However, young patients with Rett syndrome also suffer from osteoporosis, suggesting a role of MeCP2 in the differentiation of human bone marrow mesenchymal stromal cells (hBMSCs), the precursors of osteoblasts and adipocytes. Here, we report an in vitro downregulation of MeCP2 in hBMSCs undergoing adipogenic differentiation (AD) and in adipocytes of human and rat bone marrow tissue samples. This modulation does not depend on MeCP2 DNA methylation nor on mRNA levels but on differentially expressed miRNAs during AD. MiRNA profiling revealed that miR-422a and miR-483-5p are upregulated in hBMSC-derived adipocytes compared to their precursors. MiR-483-5p, but not miR-422a, is also up-regulated in hBMSC-derived osteoblasts, suggesting a specific role of the latter in the adipogenic process. Experimental modulation of intracellular levels of miR-422a and miR-483-5p affected MeCP2 expression through direct interaction with its 3′ UTR elements, and the adipogenic process. Accordingly, the knockdown of MeCP2 in hBMSCs through MeCP2-targeting shRNA lentiviral vectors increased the levels of adipogenesis-related genes. Finally, since adipocytes released a higher amount of miR-422a in culture medium compared to hBMSCs we analyzed the levels of circulating miR-422a in patients with osteoporosis-a condition characterized by increased marrow adiposity-demonstrating that its levels are negatively correlated with T- and Z-scores. Overall, our findings suggest that miR-422a has a role in hBMSC adipogenesis by downregulating MeCP2 and its circulating levels are associated with bone mass loss in primary osteoporosis.

Lien vers le texte intégral (Open Access ou abonnement)

6. Grönniger B, Fritschka E, Fahrig I, Danzer A, Sadowski G. Water Sorption in Rubbery and Glassy Polymers, Nifedipine, and Their ASDs. Mol Pharm;2023 (Feb 27)

Polymers like poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) or hydroxypropyl methylcellulose acetate succinate (HPMCAS) are commonly used as a matrix for amorphous solid dispersions (ASDs) to enhance the bioavailability of the active pharmaceutical ingredients (APIs). The stability of ASDs is strongly influenced by the water sorption in the ASD from the surrounding air. In this work, the water sorption in the neat polymers PVPVA and HPMCAS, in the neat API nifedipine (NIF), and in their ASDs of different drug loads was measured above and below the glass-transition temperature. The equilibrium water sorption was predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) combined with the Non-Equilibrium Thermodynamics of Glassy Polymers (NET-GP).The water-sorption kinetics were modeled using the Maxwell-Stefan approach whereas the thermodynamic driving force was calculated using PC-SAFT and NET-GP. The water diffusion coefficients in the polymers, NIF, or ASDs were determined using the Free-Volume Theory. Using the water-sorption kinetics of the pure polymers and of NIF, the water-sorption kinetics of the ASDs were successfully predicted, thus providing the water diffusion coefficients in the ASD as a function of relative humidity and of the water concentration in polymers or ASDs.

Lien vers le texte intégral (Open Access ou abonnement)

7. Haegele JA, Sun F, Li C, Ng K, Lee J, Chee Ang SH, Alves MLT, Yang H, Wu Y, Tan JSY, Rintala P, Huang WY, Healy S, Dos Santos Alves I, Schliemann AL, Maeng H, Karna E, Ding D. Environmental Correlates of Physical Activity and Screen-Time in Youth with Autism Spectrum Disorder: A Seven-Country Observational Study. J Autism Dev Disord;2023 (Feb 27):1-9.

This cross-sectional observational study sought to examine the environmental correlates of physical activity and screen-time among youth with autism spectrum disorder (ASD). Parents of youth with ASD (n = 1,165) from seven countries/regions provided responses to an online survey form measuring environmental correlates (i.e., physical activity neighborhood environment, social network, social trust and cohesion, bedroom media, social home environment) and outcomes (i.e., physical activity, screen-time). Multiple linear regression analyses were conducted to determine environmental predictors of the outcomes. Physical activity neighborhood environment (B = 0.15, p = 0.047), social network (B = 0.16, p = 0.02), and social home environment (B = 1.07, p < 0.001) were significantly associated with physical activity, whereas social trust and cohesion and bedroom media were not. Further, social trust and cohesion (B = -0.14, p = 0.001), bedroom media (B = 0.10, p = 0.001), and social home environment (B = -0.16, p < 0.001) were significantly associated with screen-time while neighborhood environment and social network were not. The identified environmental attributes of physical activity and screen-time behaviors should be targeted for health promotion among youth with ASD.

Lien vers le texte intégral (Open Access ou abonnement)

8. Hudson M, Santavirta S, Putkinen V, Seppälä K, Sun L, Karjalainen T, Karlsson HK, Hirvonen J, Nummenmaa L. Neural responses to biological motion distinguish autistic and schizotypal traits. Soc Cogn Affect Neurosci;2023 (Feb 27)

Difficulties in social interactions characterize both autism and schizophrenia, and are correlated in the neurotypical population. It is unknown whether this represents a shared etiology or superficial phenotypic overlap. Both conditions exhibit atypical neural activity in response to the perception of social stimuli and decreased neural synchronization between individuals. This study investigated if neural activity and neural synchronization associated with biological motion perception are differentially associated with autistic and schizotypal traits in the neurotypical population. Participants viewed naturalistic social interactions whilst hemodynamic brain activity was measured with fMRI, which was modelled against a continuous measure of the extent of biological motion. General Linear Model analysis revealed that biological motion perception was associated with neural activity across the action-observation network. However, inter-subject phase synchronization analysis revealed neural activity to be synchronized between individuals in occipital and parietal areas, but de-synchronized in temporal and frontal regions. Autistic traits were associated with decreased neural activity (precuneus, middle cingulate gyrus) and schizotypal traits were associated with decreased neural synchronization (middle and inferior frontal gyri). Biological motion perception elicits divergent patterns of neural activity and synchronization, which dissociate autistic and schizotypal traits in the general population, suggesting they originate from different neural mechanisms.

Lien vers le texte intégral (Open Access ou abonnement)

9. Karjalainen S, Aro T, Parviainen T. Coactivation of Autonomic and Central Nervous Systems During Processing of Socially Relevant Information in Autism Spectrum Disorder: A Systematic Review. Neuropsychol Rev;2023 (Feb 27)

Body-brain interaction provides a novel approach to understand neurodevelopmental conditions such as autism spectrum disorder (ASD). In this systematic review, we analyse the empirical evidence regarding coexisting differences in autonomic (ANS) and central nervous system (CNS) responses to social stimuli between individuals with ASD and typically developing individuals. Moreover, we review evidence of deviations in body-brain interaction during processing of socially relevant information in ASD. We conducted systematic literature searches in PubMed, Medline, PsychInfo, PsychArticles, and Cinahl databases (until 12.1.2022). Studies were included if individuals with ASD were compared with typically developing individuals, study design included processing of social information, and ANS and CNS activity were measured simultaneously. Out of 1892 studies identified based on the titles and abstracts, only six fulfilled the eligibility criteria to be included in synthesis. The quality of these studies was assessed using a quality assessment checklist. The results indicated that individuals with ASD demonstrate atypicalities in ANS and CNS signalling which, however, are context dependent. There were also indications for altered contribution of ANS-CNS interaction in processing of social information in ASD. However, the findings must be considered in the context of several limitations, such as small sample sizes and high variability in (neuro)physiological measures. Indeed, the methodological choices varied considerably, calling for a need for unified guidelines to improve the interpretability of results. We summarize the current experimentally supported understanding of the role of socially relevant body-brain interaction in ASD. Furthermore, we propose developments for future studies to improve incremental knowledge building across studies of ANS-CNS interaction involving individuals with ASD.

Lien vers le texte intégral (Open Access ou abonnement)

10. Knight EJ, Freedman EG, Myers EJ, Berruti AS, Oakes LA, Cao CZ, Molholm S, Foxe JJ. Severely attenuated visual feedback processing in children on the autism spectrum. J Neurosci;2023 (Feb 27)

Individuals on the autism spectrum often exhibit atypicality in their sensory perception, but the neural underpinnings of these perceptual differences remain incompletely understood. One proposed mechanism is an imbalance in higher-order feedback re-entrant inputs to early sensory cortices during sensory perception, leading to increased propensity to focus on local object features over global context. We explored this theory by measuring visual evoked potentials during contour integration as considerable work has revealed that these processes are largely driven by feedback inputs from higher-order ventral visual stream regions. We tested the hypothesis that autistic individuals would have attenuated evoked responses to illusory contours compared to neurotypical controls. Electrophysiology was acquired while 29 autistic and 31 neurotypical children (7-17 years-old, inclusive of both males and females) passively viewed a random series of Kanizsa figure stimuli, each consisting of four inducers that were aligned either at random rotational angles or such that contour integration would form an illusory square. Autistic children demonstrated attenuated automatic contour integration over lateral occipital regions relative to neurotypical controls. The data are discussed in terms of the role of predictive feedback processes on perception of global stimulus features and the notion that weakened « priors » may play a role in the visual processing anomalies seen in autism.SIGNIFICANCE STATEMENT:Children on the autism spectrum differ from typically developing children in many aspects of their processing of sensory stimuli. One proposed mechanism for these differences is an imbalance in higher order feedback to primary sensory regions, leading to an increased focus on local object features rather than global context. However, systematic investigation of these feedback mechanisms remains limited. Using electroencephalography (EEG) and a visual illusion paradigm that is highly dependent on intact feedback processing, we demonstrated significantly disruptions to visual feedback processing in children with autism. This provides much needed experimental evidence that advances our understanding of the contribution of feedback processing to visual perception in autism spectrum disorder.

Lien vers le texte intégral (Open Access ou abonnement)

11. Palmer M, Chandler S, Carter Leno V, Mgaieth F, Yorke I, Hollocks M, Pickles A, Slonims V, Scott S, Charman T, Simonoff E. Factors associated with mental health symptoms among UK autistic children and young people and their parents during the COVID-19 pandemic. Autism;2023 (Feb 27):13623613231153694.

What is already known about the topic: The COVID-19 pandemic and the associated restrictions impacted all of society. There is emerging evidence showing a range of impacts on autistic children and young people and their families. Further research that looks at how individuals coped during the pandemic while considering how they were doing before the pandemic is needed.What this paper adds: This article explores whether how well autistic youth were doing before the pandemic influenced how they coped during the pandemic. It also looked at how well their parents were doing during the pandemic and whether any pre-pandemic factors influenced how they coped. Samples of both primary-school-aged autistic children and autistic teenagers and their parents were surveyed to answer these questions. More engagement and enjoyment in education provision during the pandemic and getting outside more were linked with better child and parental mental health during the pandemic. More attention deficit hyperactivity disorder before the pandemic was linked with more attention deficit hyperactivity disorder and behavioural problems during the pandemic in primary-school-aged autistic children, and more emotional problems during the pandemic in autistic teenagers. Parents with more mental health problems during the pandemic had more mental health problems before the pandemic.Implications for practice, research or policy: Encouraging engagement and enjoyment in education and promoting physical exercise are key intervention targets. Ensuring access to attention deficit hyperactivity disorder medication and support is important, especially if this is managed jointly across school and home.

Lien vers le texte intégral (Open Access ou abonnement)

12. Saha S, Chatterjee M, Dutta N, Sinha S, Mukhopadhyay K. Analysis of neurotransmitters validates the importance of the dopaminergic system in autism spectrum disorder. World J Pediatr;2023 (Feb 27)

BACKGROUND: The reasons behind the cardinal symptoms of communication deficits and repetitive, stereotyped behaviors that characterize autism spectrum disorder (ASD) remain unknown. The dopamine (DA) system, which regulates motor activity, goal-directed behaviors, and reward function, is believed to play a crucial role in ASD, although the exact mechanism is still unclear. Investigations have shown an association of the dopamine receptor D4 (DRD4) with various neurobehavioral disorders. METHODS: We analyzed the association between ASD and four DRD4 genetic polymorphisms, 5′ flanking 120-bp duplication (rs4646984), rs1800955 in the promoter, exon 1 12 bp duplication (rs4646983), and exon 3 48 bp repeats. We also examined plasma DA and its metabolite levels, DRD4 mRNA expression, and correlations of the studied polymorphisms with these parameters by case-control comparative analyses. The expression of DA transporter (DAT), which is important in regulating the circulating DA level, was also evaluated. RESULTS: A significantly higher occurrence of rs1800955 « T/TT » was observed in the probands. ASD traits were affected by rs1800955 « T » and the higher repeat alleles of the exon 3 48 bp repeats, rs4646983 and rs4646984. ASD probands exhibited lower DA and norepinephrine levels together with higher homovanillic acid levels than the control subjects. DAT and DRD4 mRNA expression were down-regulated in the probands, especially in the presence of DAT rs3836790 « 6R » and rs27072 « CC » and DRD4 rs4646984 higher repeat allele and rs1800955 « T ». CONCLUSION: This pioneering investigation revealed a positive correlation between genetic variants, hypodopaminergic state, and impairment in socio-emotional and communication reciprocity in Indian subjects with ASD, warranting further in-depth analysis.

Lien vers le texte intégral (Open Access ou abonnement)

13. Wu SH, Li X, Qin DD, Zhang LH, Cheng TL, Chen ZF, Nie BB, Ren XF, Wu J, Wang WC, Hu YZ, Gu YL, Lv LB, Yin Y, Hu XT, Qiu ZL. Corrigendum to « Induction of core symptoms of autism spectrum disorders by in vivo CRISPR/Cas9-based gene editing in the brain of adolescent rhesus monkeys » [Sci. Bull. 66(9) (2021) 937-946. Sci Bull (Beijing);2023 (Feb 20)

Lien vers le texte intégral (Open Access ou abonnement)

14. Xiong Y, Chen J, Lv M, Wang F, Zhang H, Tang B, Li Y. Thymol improves autism-like behaviour in VPA-induced ASD rats through the Pin1/p38 MAPK pathway. Int Immunopharmacol;2023 (Feb 27);117:109885.

Inflammation plays an essential role in the pathogenesis of autism spectrum disorder (ASD). Thymol is a bioactive monoterpene isolated from Thymus vulgaris that has anti-inflammatory properties and is helpful in neurodevelopmental disorders. The purpose of this study was to investigate the effects of thymol on autism-like behaviours in rats with VPA-induced ASD and to assess the related molecular mechanisms. In the prefrontal cortex (PFC) of the valproic acid (VPA)-exposed rat model, the levels of Pin1, phosphorylated p38 MAPK, interleukin-1β (IL-1β) and tumour necrosis factor (TNF)-α, were increased, and the levels of PSD95 and synaptophysin (SYP) decreased. After thymol treatment (30 mg/kg), the VPA-induced autism-like behaviours were alleviated. Moreover, thymol also rescued the dysregulated levels of Pin1, phosphorylated p38 MAPK, IL-1β, TNF-α, PSD95, and SYP. In addition, immunofluorescence experiments showed that thymol treatment decreased the correlation between Pin1 and phosphorylated p38 MAPK. Mechanistically, Pin1 knockdown by RNA interference confirmed that Pin1 promotes inflammation via phosphorylation of p38 MAPK in the VPA exposure rat model. In conclusion, thymol improved autism-like behaviours in VPA-induced ASD rats by reducing inflammation and improving neurodevelopment. This effect was mediated by the Pin1/p38 MAPK pathway. These results experimentally provide the potential for thymol in new therapeutic avenues for autism.

Lien vers le texte intégral (Open Access ou abonnement)

15. Xu B, Ho Y, Fasolino M, Medina J, O’Brien WT, Lamonica JM, Nugent E, Brodkin ES, Fuccillo MV, Bucan M, Zhou Z. Allelic contribution of Nrxn1α to autism-relevant behavioral phenotypes in mice. PLoS Genet;2023 (Feb 27);19(2):e1010659.

Copy number variations (CNVs) in the Neurexin 1 (NRXN1) gene, which encodes a presynaptic protein involved in neurotransmitter release, are some of the most frequently observed single-gene variants associated with autism spectrum disorder (ASD). To address the functional contribution of NRXN1 CNVs to behavioral phenotypes relevant to ASD, we carried out systematic behavioral phenotyping of an allelic series of Nrxn1 mouse models: one carrying promoter and exon 1 deletion abolishing Nrxn1α transcription, one carrying exon 9 deletion disrupting Nrxn1α protein translation, and one carrying an intronic deletion with no observable effect on Nrxn1α expression. We found that homozygous loss of Nrxn1α resulted in enhanced aggression in males, reduced affiliative social behaviors in females, and significantly altered circadian activities in both sexes. Heterozygous or homozygous loss of Nrxn1α affected the preference for social novelty in male mice, and notably, enhanced repetitive motor skills and motor coordination in both sexes. In contrast, mice bearing an intronic deletion of Nrxn1 did not display alterations in any of the behaviors assessed. These findings demonstrate the importance of Nrxn1α gene dosage in regulating social, circadian, and motor functions, and the variables of sex and genomic positioning of CNVs in the expression of autism-related phenotypes. Importantly, mice with heterozygous loss of Nrxn1, as found in numerous autistic individuals, show an elevated propensity to manifest autism-related phenotypes, supporting the use of models with this genomic architecture to study ASD etiology and assess additional genetic variants associated with autism.

Lien vers le texte intégral (Open Access ou abonnement)