1. Bäckström F, Ahl M, Wickham J, Ekdahl CT. Reduced epilepsy development in synapsin 2 knockout mice with autistic behavior following early systemic treatment with interleukin-6 receptor antibody. Epilepsy Res;2023 (Feb 26);191:107114.

BACKGROUND: Individuals with autism spectrum disorder (ASD) have an increased risk of developing epilepsy. Both ASD and epilepsy have been associated with increased levels of immune factors in the blood, including the proinflammatory cytokine interleukin 6 (IL-6). Mice lacking the synapsin 2 gene (Syn2 KO) exhibit ASD-like behavior and develop epileptic seizures. Their brains display neuroinflammatory changes including elevated IL-6 levels. We aimed to investigate the effect of systemic IL-6 receptor antibody (IL-6R ab) treatment on seizure development and frequency in Syn2 KO mice. MATERIAL AND METHODS: Weekly systemic (i.p.) injections of IL-6R ab or saline were given to Syn2 KO mice starting either early in life at 1 month of age, before seizure debut or at 3 months of age, directly after seizure debut and continued for 4 or 2 months, respectively. Seizures were provoked by handling the mice three times per week. The neuroinflammatory response and synaptic protein levels in the brain were determined by ELISA, immunohistochemistry and western blots. In an additional group of Syn2 KO mice, with IL-6R ab treatment early in life, ASD-related behavioral tests including social interaction and repetitive self-grooming, as well as cognitive memory and depressive-/anxiety-like tests, and actigraphy measurements of circadian sleep-awake rhythm were analyzed. RESULTS: The IL-6R ab treatment reduced seizure development and frequency in Syn2 KO mice when initiated before, but not after, seizure debut. However, early treatment did not reverse the neuroinflammatory response or the imbalance in synaptic protein levels in the brain previously reported in Syn2 KO mice. The treatment did not affect social interaction, performance in memory, depressive-/anxiety-like tests or the sleep-awake rhythm of Syn2 KO mice. CONCLUSION: These findings suggest the involvement of IL-6 receptor signaling during epilepsy development in Syn2 KO mice, without significant alterations of the immune reaction in the brain, and independently of cognitive performance, mood and circadian sleep-awake rhythm.

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2. Bircan E, Politis MD, Gokun Y, Luo C, Leonard H, Bourke J, Bower C, Nembhard WN. Intellectual disabilities and autism among children with congenital heart defects, Western Australia, 1983-2010. BMC Pediatr;2023 (Mar 4);23(1):106.

BACKGROUND: Children with congenital heart defects (CHDs) are at higher risk of developing an intellectual disability. However, severity of intellectual disabilities among this group of children are largely unknown. Our objective was to determine the risk of intellectual disability (ID), ID severity, and autism among children with CHDs. METHODS: We conducted a retrospective cohort study of singleton live births in Western Australia (n = 20,592) between 1983 and 2010. Children with CHDs were identified from the Western Australian Register for Developmental Anomalies (n = 6563) and infants without CHDs were randomly selected from state birth records (n = 14,029). Children diagnosed with ID before 18 years were identified by linkage to statewide Intellectual Disability Exploring Answers database. Odds ratios (OR) and 95% confidence intervals (CI) were calculated from logistic regression models for all CHDs combined and by CHD severity adjusting for potential confounders. RESULTS: Of 20,592 children, 466 (7.1%) with CHDs and 187 (1.3%) without CHDs had an ID. Compared to children without CHDs, children with any CHD had 5.26 times (95% CI 4.42, 6.26) the odds of having an ID and 4.76 times (95% CI 3.98, 5.70) the odds of having mild/moderate ID. Children with any CHD had 1.76 times the odds of having autism (95% CI 1.07, 2.88), and 3.27 times the odds of having an unknown cause of ID (95% CI 2.65, 4.05) compared to children without CHD. The risk of having autism (aOR 3.23, 95% CI 1.11, 9.38), and unknown cause of ID (aOR 3.45, 95% CI 2.09, 5.70) was greatest for children with mild CHD. CONCLUSIONS: Children with CHDs were more likely to have an ID or autism. Future research should elucidate underlying etiology of ID in children with CHDs.

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3. Gehdu BK, Tsantani M, Press C, Gray K, Cook R. EXPRESS: Recognition of facial expressions in autism: effects of face masks and alexithymia. Q J Exp Psychol (Hove);2023 (Mar 5):17470218231163007.

It is often assumed that the recognition of facial expressions is impaired in autism. However, recent evidence suggests that reports of expression recognition difficulties in autistic participants may be attributable to co-occurring alexithymia – a trait associated with difficulties interpreting interoceptive and emotional states – not autism per se. Due to problems fixating on the eye-region, autistic individuals may be more reliant on information from the mouth region when judging facial expressions. As such, it may be easier to detect expression recognition deficits attributable to autism, not alexithymia, when participants are forced to base expression judgements on the eye-region alone. To test this possibility, we compared the ability of autistic participants (with and without high levels of alexithymia) and non-autistic controls to categorize facial expressions i) when the whole face was visible, and ii) when the lower portion of the face was covered with a surgical mask. High-alexithymic autistic participants showed clear evidence of expression recognition difficulties: they correctly categorised fewer expressions than non-autistic controls. In contrast, low-alexithymic autistic participants were unimpaired relative to non-autistic controls. The same pattern of results was seen when judging masked and unmasked expression stimuli. In sum, we find no evidence for an expression recognition deficit attributable to autism, in the absence of high levels of co-occurring alexithymia, either when participants judge whole-face stimuli or just the eye-region. These findings underscore the influence of co-occurring alexithymia on expression recognition in autism.

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4. Jiang T, Yang Y, Wu C, Qu C, Chen JG, Cao H. MicroRNA-218 regulates neuronal radial migration and morphogenesis by targeting Satb2 in developing neocortex. Biochem Biophys Res Commun;2023 (Mar 5);647:9-15.

Neuronal migration and morphogenesis are fundamental processes for cortical development. Their defects may cause abnormities in neural circuit formation and even neuropsychiatric disorders. Many proteins, especially layer-specific transcription factors and adhesion molecules, have been reported to regulate the processes. However, the involvement of non-coding RNAs in cortical development has not been extensively studied. Here, we identified microRNA-218 (miR-218) as a layer V-specific microRNA in mouse brains. Expression of miR-218 was elevated in patients with autism spectrum disorder (ASD) and schizophrenia. We found in this study that miR-218 overexpression in developing mouse cortex led to severe defects in radial migration, morphogenesis, and spatial distribution of the cortical neurons. Moreover, we identified Satb2, an upper-layer marker, as a molecular target repressed by miR-218. These results suggest an underlying mechanism of miR-218 involvement in neuropsychiatric disorders, and the interactions of layer-specific non-coding RNAs and proteins in regulating cortical development.

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5. Luo L, Chen J, Wu Q, Yuan B, Hu C, Yang T, Wei H, Li T. Prenatally VPA exposure is likely to cause autistic-like behavior in the rats offspring via TREM2 down-regulation to affect the microglial activation and synapse alterations. Environ Toxicol Pharmacol;2023 (Mar 2):104090.

Microglial dysfunction has been reported in the valproic acid (VPA)-induced autism spectrum disorder (ASD) rat models. However, how does prenatal VPA exposure affect microglia remains to be elucidated. The triggering receptor expressed on myeloid cells 2 (TREM2) is revealed to be implicated in a range of microglia functions. However, reports on the association between TREM2 and VPA-induced ASD rat models are scarce. Our results showed that prenatal VPA exposure induced autistic-like behaviors, downregulated the levels of TREM2, up-regulated microglial activation, dysregulated microglial polarization, and altered synapse in offspring. TREM2 overexpression partly ameliorated microglia dysfunction and autistic-like behaviors in prenatal VPA-exposed rats. Our findings demonstrated that prenatally VPA exposure is likely to cause autistic-like behavior in the rat offspring via TREM2 down-regulation to affect the microglial activation, microglial polarization and synaptic pruning of microglia for the first time.

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6. Martinez-Cayuelas E, Gavela-Pérez T, Rodrigo-Moreno M, Losada-Del Pozo R, Moreno-Vinues B, Garces C, Soriano-Guillén L. Sleep Problems, Circadian Rhythms, and Their Relation to Behavioral Difficulties in Children and Adolescents with Autism Spectrum Disorder. J Autism Dev Disord;2023 (Mar 4)

This was an exploratory cross-sectional study comparing 45 children with ASD to 24 typically developing drug-naïve controls, group-matched on age, sex, and body mass index. Objective data was obtained using the following: an ambulatory circadian monitoring device; saliva samples to determine dim light melatonin onset (DLMO): and three parent-completed measures: the Child Behavior Checklist (CBCL); the Repetitive Behavior Scale-Revised (RBS-R); and the General Health Questionnaire (GHQ28). The CBCL and RBS-R scales showed the highest scores amongst poor sleepers with ASD. Sleep fragmentation was associated with somatic complaints and self-injury, leading to a higher impact on family life. Sleep onset difficulties were associated with withdrawal, anxiety, and depression. Those with phase advanced DLMO had lower scores for « somatic complaints »; « anxious/depressed » state; and « social problems », suggesting that this phenomenon has a protective role.

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7. Mattern H, Cola M, Tena KG, Knox A, Russell A, Pelella MR, Hauptmann A, Covello M, Parish-Morris J, McCleery JP. Sex differences in social and emotional insight in youth with and without autism. Mol Autism;2023 (Mar 4);14(1):10.

Autism was formally recognized by the medical community in the first half of the twentieth century. Almost 100 years later, a small but growing literature has reported sex differences in the behavioral expression of autism. Recent research has also begun to explore the internal experiences of individuals with autism, including social and emotional insight. The current study examines sex differences in language-based markers of social and emotional insight in girls and boys with autism and non-autistic peers during semi-structured clinical interviews. Sixty-four participants aged 5 to 17 years were individually matched on chronological age and full-scale IQ to form four groups: autistic girls, autistic boys, non-autistic girls, and non-autistic boys. Transcribed interviews were scored using four scales that index aspects of social and emotional insight. Results revealed the main effects of diagnosis, such that youth with autism exhibited lower insight than non-autistic youth on scales indexing social cognition and object relations, emotional investment, and social causality. With regards to sex differences, across diagnoses, girls were rated higher than boys on the social cognition and object relations, emotional investment, and social causality scales. Examined within each diagnosis separately, clear sex differences emerged: both autistic and non-autistic girls demonstrated better social cognition and understanding of social causality than boys in their respective diagnostic groups. No within-diagnosis sex differences were found on the emotional insight scales, however. These results suggest that relatively enhanced social cognition and understanding of social causality in girls may be a population-level sex difference that is preserved in autism, despite the core social challenges that characterize this condition. The current findings reveal critical new information about insight into social and emotional thinking and relationships in autistic girls versus boys that have important implications for improving identification and designing effective interventions.

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8. Siafis S, Leucht S. Clinician- versus caregiver-rated scales as outcome measures of repetitive-restricted behaviors in clinical trials of autism: A systematic review and meta-analysis. Eur Neuropsychopharmacol;2023 (Mar 2);70:56-62.

The agreement between treatment effects measured by clinician- and caregiver-ratings of repetitive-restricted behaviors (RRBs) is important for clinical practice and research but is still unclear. Therefore, we conducted a post-hoc meta-analysis of placebo-controlled randomized-controlled trials (RCTs) investigating pharmacological and dietary-supplement treatments for autism that reported both clinician- and caregiver-ratings of RRBs. Treatment effects between medications and placebo were quantified with standardized mean differences (SMDs). The agreement between clinician- and caregiver-rated SMDs was investigated with an intraclass correlation coefficient (ICC) and random-effects meta-analysis of their difference (Δg). A meta-regression investigated the association between clinician (dependent) and caregiver-rated SMDs (independent variable). Certainty in the evidence was evaluated using the GRADE approach. We identified 15 eligible placebo-controlled RCTs with 1567 participants, from which 13 included children/adolescents and 9 reported data for the pair of the clinician-rated Yale-Brown Obsessive Compulsive Scale (YBOCS) and the caregiver-rated Aberrant Behavior Checklist-Stereotypic Behavior (ABC-S). There was on average a good agreement between clinician- and caregiver-rated SMDs (ICC=0.84, 95% confidence intervals [0.55, 0.95]), no clear difference between them (Δg=0.08, 95%CI[-0.06, 0.21], 95% prediction intervals [-0.16, 0.31]), and the beta of the meta-regression was 0.62, 95%CI[0.27, 0.97]. The certainty of the evidence was low due to concerns in imprecision and inconsistency. Our analysis showed on average a good agreement between clinician- and caregiver-rated treatment effects in RRBs, yet discordance could be expected in future RCTs, given the wide prediction intervals. It is also not certain that these results could be generalizable to other rating scales and intervention modalities. Ethics committee approval: Not applicable as a meta-analysis of previously published studies..

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9. Udhnani MD, Miller JS, Lecavalier L. Development and Preliminary Validation of the Accommodations & Impact Scale for Developmental Disabilities. J Autism Dev Disord;2023 (Mar 5)

The lives of caregivers can be deeply impacted by having a child with a developmental disability (DD). To offset those impacts, caregivers may engage in accommodations, or strategies to bolster everyday functioning. The nature and extent of these accommodations can provide insight into how the family is doing and what supports are needed from a family-centered perspective. This paper presents the development and preliminary validation of the Accommodations & Impact Scale for Developmental Disabilities (AISDD). The AISDD is a rating scale that measures day-to-day accommodations and impacts of raising a child with a DD. A sample of 407 caregivers of youth with DDs (M(age) = 11.7 years; 63% males) completed the AISDD, along with measures of caregiver strain, daily challenges, child adaptive behavior, and behavior and emotional regulation. The AISDD is a unidimensional, 19-item scale with excellent internal consistency (ordinal alpha = .93) and test-retest (ICC = .95) reliability. Scores were normally distributed and sensitive to age (r = – .19), diagnosis (ASD + ID > ASD > ID), adaptive functioning (r = – .35), and challenging behaviors (r = .57). Finally, the AISDD showed excellent convergent validity with similar measures of accommodations and impacts. These findings support the use of the AISDD as a valid and reliable tool for measuring accommodations among caregivers of individuals with DDs. This measure shows promise in its ability to identify which families may need additional support for their children.

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10. Zhao T, Shen L, Ye X, Bai G, Liao C, Chen Z, Peng T, Li X, Kang X, An G. Prenatal and postnatal exposure to polystyrene microplastics induces testis developmental disorder and affects male fertility in mice. J Hazard Mater;2023 (Mar 5);445:130544.

Polystyrene microplastics (PS-MPs) can threaten human health, especially male fertility. However, most existing studies have focused on the adulthood stage of male reproduction toxicity caused by relatively short-term PS-MP exposure. This study aimed to investigate the toxic effect of PS-MPs on testicular development and reproductive function upon prenatal and postnatal exposure. Pregnant mice and their offspring were exposed to 0, 0.5 mg/L, 5 mg/L, and 50 mg/L PS-MPs through their daily drinking water from gestational day 1 to postnatal day (PND) 35 or PND70. We found that PS-MP exposure induced testis development disorder by PND35 and spermatogenesis dysfunction by PND70. By combining RNA sequencing results and bioinformatics analysis, the hormone-mediated signaling pathway, G1/S transition of the mitotic cell cycle, coregulation of androgen receptor activity, and Hippo signaling pathway were shown to be involved in testis development on PND35. The meiotic cell cycle, regulation of the immune effector process, neutrophil degranulation, and inflammation mediated by chemokine and cytokine signaling pathways were associated with disturbed spermatogenesis on PND70. These findings show that prenatal and postnatal exposure to PS-MPs resulted in testis development disorder and male subfertility, which may be regulated by the Hippo signaling pathway and involve an immune reaction.

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