1. Ahlfors SP, Graham S, Bharadwaj H, Mamashli F, Khan S, Joseph RM, Losh A, Pawlyszyn S, McGuiggan NM, Vangel M, Hämäläinen MS, Kenet T. No Differences in Auditory Steady-State Responses in Children with Autism Spectrum Disorder and Typically Developing Children. J Autism Dev Disord;2023 (Mar 17)

Auditory steady-state response (ASSR) has been studied as a potential biomarker for abnormal auditory sensory processing in autism spectrum disorder (ASD), with mixed results. Motivated by prior somatosensory findings of group differences in inter-trial coherence (ITC) between ASD and typically developing (TD) individuals at twice the steady-state stimulation frequency, we examined ASSR at 25 and 50 as well as 43 and 86 Hz in response to 25-Hz and 43-Hz auditory stimuli, respectively, using magnetoencephalography. Data were recorded from 22 ASD and 31 TD children, ages 6-17 years. ITC measures showed prominent ASSRs at the stimulation and double frequencies, without significant group differences. These results do not support ASSR as a robust ASD biomarker of abnormal auditory processing in ASD. Furthermore, the previously observed atypical double-frequency somatosensory response in ASD did not generalize to the auditory modality. Thus, the hypothesis about modality-independent abnormal local connectivity in ASD was not supported.

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2. Arenella M, Mota NR, Teunissen MWA, Brunner HG, Bralten J. Autism spectrum disorder and brain volume link through a set of mTOR-related genes. J Child Psychol Psychiatry;2023 (Mar 15)

BACKGROUND: Larger than average head and brain sizes are often observed in individuals with autism spectrum disorders (ASDs). ASD and brain volume are both highly heritable, with multiple genetic variants contributing. However, it is unclear whether ASD and brain volume share any genetic mechanisms. Genes from the mammalian target of rapamycin (mTOR) pathway influence brain volume, and variants are found in rare genetic syndromes that include ASD features. Here we investigated whether variants in mTOR-related genes are also associated with ASD and if they constitute a genetic link between large brains and ASD. METHODS: We extended our analyses between large heads (macrocephaly) and rare de novo mTOR-related variants in an intellectual disability cohort (N = 2,258). Subsequently using Fisher’s exact tests we investigated the co-occurrence of mTOR-related de novo variants and ASD in the de-novo-db database (N = 23,098). We next selected common genetic variants within a set of 96 mTOR-related genes in genome-wide genetic association data of ASD (N = 46,350) to test gene-set association using MAGMA. Lastly, we tested genetic correlation between genome-wide genetic association data of ASD (N = 46,350) and intracranial volume (N = 25,974) globally using linkage disequilibrium score regression as well as mTOR specific by restricting the genetic correlation to the mTOR-related genes using GNOVA. RESULTS: Our results show that both macrocephaly and ASD occur above chance level in individuals carrying rare de novo variants in mTOR-related genes. We found a significant mTOR gene-set association with ASD (p = .0029) and an mTOR-stratified positive genetic correlation between ASD and intracranial volume (p = .027), despite the absence of a significant genome-wide correlation (p = .81). CONCLUSIONS: This work indicates that both rare and common variants in mTOR-related genes are associated with brain volume and ASD and genetically correlate them in the expected direction. We demonstrate that genes involved in mTOR signalling are potential mediators of the relationship between having a large brain and having ASD.

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3. Ding Z, Huang G, Wang T, Duan W, Li H, Wang Y, Jia H, Yang Z, Wang K, Chu X, Kurtz-Nelson EC, Ahlers K, Earl RK, Han Y, Feliciano P, Chung WK, Eichler EE, Jiang M, Xiong B. Genetic ablation of GIGYF1, associated with autism, causes behavioral and neurodevelopmental defects in zebrafish and mice. Biol Psychiatry;2023 (Mar 14)

BACKGROUND: Autism spectrum disorder (ASD) is characterized by deficits in social communication and restricted or repetitive behaviors. Due to the extremely high genetic and phenotypic heterogeneity, it is critical to pinpoint the genetic factors for the understanding of the pathology of these disorders. METHODS: We analyzed the exomes generated by the SPARK project and performed a meta-analysis with previous data. We then generated a zebrafish knockout model and three mouse Gigyf1 knockout models to examine the function of GIGYF1 in neurodevelopment and behavior. Finally, we performed whole tissue and single-nuclei transcriptome analysis to explore the molecular and cellular function of GIGYF1. RESULTS: GIGYF1 variants are significantly associated with various NDD phenotypes including autism, global developmental delay, intellectual disability, sleep disturbance. Loss of GIGYF1 causes similar behavioral effects in zebrafish and mice, including elevated levels of anxiety and reduced social engagements, which is reminiscent of the behavioral deficits in human patients carrying GIGYF1 mutations. Moreover, excitatory neuron-specific Gigyf1 knockout mice recapitulate the increased repetitive behaviors and impaired social memory, suggesting a crucial role of Gigyf1 in excitatory neurons, which correlates with the observations in single nuclei RNAseq. We also identified a series of downstream target genes of GIGYF1 that affects many aspects of the nervous system especially synaptic transmission. CONCLUSION: De novo variants (DNVs) of GIGYF1 are associated with NDDs including ASD. GIGYF1 is involved in neurodevelopment and animal behavior, potentially through regulating hippocampal CA2 neuronal numbers and disturbing synaptic transmission.

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4. Ilioska I, Oldehinkel M, Llera A, Chopra S, Looden T, Chauvin R, Van Rooij D, Floris DL, Tillmann J, Moessnang C, Banaschewski T, Holt RJ, Loth E, Charman T, Murphy DGM, Ecker C, Mennes M, Beckmann CF, Fornito A, Buitelaar JK. Connectome-wide Mega-analysis Reveals Robust Patterns of Atypical Functional Connectivity in Autism. Biol Psychiatry;2022 (Dec 23)

BACKGROUND: Neuroimaging studies of functional connectivity (FC) in autism have been hampered by small sample sizes and inconsistent findings with regard to whether connectivity is increased or decreased in individuals with autism, whether these alterations affect focal systems or reflect a brain-wide pattern, and whether these are age and/or sex dependent. METHODS: The study included resting-state functional magnetic resonance imaging and clinical data from the EU-AIMS LEAP (European Autism Interventions Longitudinal European Autism Project) and the ABIDE (Autism Brain Imaging Data Exchange) 1 and 2 initiatives of 1824 (796 with autism) participants with an age range of 5-58 years. Between-group differences in FC were assessed, and associations between FC and clinical symptom ratings were investigated through canonical correlation analysis. RESULTS: Autism was associated with a brainwide pattern of hypo- and hyperconnectivity. Hypoconnectivity predominantly affected sensory and higher-order attentional networks and correlated with social impairments, restrictive and repetitive behavior, and sensory processing. Hyperconnectivity was observed primarily between the default mode network and the rest of the brain and between cortical and subcortical systems. This pattern was strongly associated with social impairments and sensory processing. Interactions between diagnosis and age or sex were not statistically significant. CONCLUSIONS: The FC alterations observed, which primarily involve hypoconnectivity of primary sensory and attention networks and hyperconnectivity of the default mode network and subcortex with the rest of the brain, do not appear to be age or sex dependent and correlate with clinical dimensions of social difficulties, restrictive and repetitive behaviors, and alterations in sensory processing. These findings suggest that the observed connectivity alterations are stable, trait-like features of autism that are related to the main symptom domains of the condition.

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5. Morimoto M, Hashimoto T, Tsuda Y, Suenaga M, Nakamura T, Katoh S. Study on oxidative stress and inflammatory/antioxidant substance levels in autism spectrum disorder. J Chin Med Assoc;2023 (Mar 17)

BACKGROUND: The etiology of autism spectrum disorder (ASD) includes oxidative stress and brain inflammation. We investigated the relationship among oxidative stress markers, in vivo inflammatory substances, and antioxidants that can be easily measured in the clinic and compared them between children with ASD and those with typical development (TD). METHODS: Sixty-one children with TD and 199 with untreated ASD were investigated. They were Japanese children aged 2-15 years and were divided into those aged <7 and ≥7 years. Serum levels of reactive oxygen metabolites (ROMs), high-sensitivity C-reactive protein (hsCRP), prolactin (PRL), albumin (Alb), total bilirubin (T-Bil), and uric acid (UA) were measured. These measurements were compared between TD and ASD, and the relationship between oxidative stress and relevant laboratory parameters was analyzed. RESULTS: The hsCRP and PRL levels were significantly higher in patients with ASD than in those with TD. Among those aged <7 years, hsCRP and PRL were significantly higher in those with ASD than in those with TD. Among those aged ≥7 years, ROMs, hsCRP, and PRL were significantly higher in those with ASD than in those with TD. In ASD, ROMs were significantly correlated with hsCRP, Alb, T-Bil, and PRL. In contrast, no significant correlations were found in the TD group except for the relationship between ROMs and hsCRP in those aged <7 years. CONCLUSION: The results suggest that serum levels of in vivo inflammatory substances, stress-related substances, and antioxidants are altered in ASD under oxidative stress.

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6. Paynter J, O’Leary K, Westerveld M. Pre-school Skills and School-Age Reading Comprehension in Children on the Autism Spectrum: A Preliminary Investigation. J Autism Dev Disord;2023 (Mar 17)

We explored reading comprehension development in children on the spectrum from pre-school to the first (YOS1) and third year of schooling (YOS3). Children were first assessed on meaning-related skills in pre-school. Forty-one children completed follow-up assessments of reading comprehension, reading accuracy, and listening comprehension in YOS1. Nineteen returned for assessments of reading accuracy, reading comprehension, and listening comprehension in YOS3. Children showed poorer reading comprehension than reading accuracy at both timepoints. Reading comprehension, reading accuracy, and listening comprehension were significantly concurrently correlated. Pre-school receptive vocabulary was a significant predictor of YOS3 reading comprehension. Results from this preliminary investigation highlight the potential for early identification of children on the spectrum at risk for reading comprehension difficulties.

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7. Schaeffer J, Abd El-Raziq M, Castroviejo E, Durrleman S, Ferré S, Grama I, Hendriks P, Kissine M, Manenti M, Marinis T, Meir N, Novogrodsky R, Perovic A, Panzeri F, Silleresi S, Sukenik N, Vicente A, Zebib R, Prévost P, Tuller L. Language in autism: domains, profiles and co-occurring conditions. J Neural Transm (Vienna);2023 (Mar 16)

This article reviews the current knowledge state on pragmatic and structural language abilities in autism and their potential relation to extralinguistic abilities and autistic traits. The focus is on questions regarding autism language profiles with varying degrees of (selective) impairment and with respect to potential comorbidity of autism and language impairment: Is language impairment in autism the co-occurrence of two distinct conditions (comorbidity), a consequence of autism itself (no comorbidity), or one possible combination from a series of neurodevelopmental properties (dimensional approach)? As for language profiles in autism, three main groups are identified, namely, (i) verbal autistic individuals without structural language impairment, (ii) verbal autistic individuals with structural language impairment, and (iii) minimally verbal autistic individuals. However, this tripartite distinction hides enormous linguistic heterogeneity. Regarding the nature of language impairment in autism, there is currently no model of how language difficulties may interact with autism characteristics and with various extralinguistic cognitive abilities. Building such a model requires carefully designed explorations that address specific aspects of language and extralinguistic cognition. This should lead to a fundamental increase in our understanding of language impairment in autism, thereby paving the way for a substantial contribution to the question of how to best characterize neurodevelopmental disorders.

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8. Shen G, Green HL, Franzen RE, Berman JI, Dipiero M, Mowad TG, Bloy L, Liu S, Airey M, Goldin S, Ku M, McBride E, Blaskey L, Kuschner ES, Kim M, Konka K, Roberts TPL, Edgar JC. Resting-State Activity in Children: Replicating and Extending Findings of Early Maturation of Alpha Rhythms in Autism Spectrum Disorder. J Autism Dev Disord;2023 (Mar 17)

Resting-state alpha brain rhythms provide a foundation for basic as well as higher-order brain processes. Research suggests atypical maturation of the peak frequency of resting-state alpha activity (= PAF) in autism spectrum disorder (ASD). The present study examined resting-state alpha activity in young school-aged children, obtaining magnetoencephalographic (MEG) eyes-closed resting-state data from 47 typically developing (TD) males and 45 ASD males 6.0 to 9.3 years old. Results confirmed a higher PAF in ASD versus TD, and demonstrated that alpha power differences between groups were linked to the shift of PAF in ASD. Additionally, a higher PAF was associated with better cognitive performance in TD but not ASD. Finding thus suggested functional consequences of group differences in resting-state alpha activity.

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9. Vellingiri B, Venkatesan D, Iyer M, Mohan G, Krishnan P, Sai Krishna K, R S, Narayanasamy A, Gopalakrishnan AV, Kumar NS, Subramaniam MD. Concurrent Assessment of Oxidative Stress and MT-ATP6 Gene Profiling to Facilitate Diagnosis of Autism Spectrum Disorder (ASD) in Tamil Nadu Population. J Mol Neurosci;2023 (Mar 17)

Autism spectrum disorder (ASD) is a neurodevelopmental disability that causes social impairment, debilitated verbal or nonverbal conversation, and restricted/repeated behavior. Recent research reveals that mitochondrial dysfunction and oxidative stress might play a pivotal role in ASD condition. The goal of this case-control study was to investigate oxidative stress and related alterations in ASD patients. In addition, the impact of mitochondrial DNA (mtDNA) mutations, particularly MT-ATP6, and its link with oxidative stress in ASD was studied. We found that ASD patient’s plasma had lower superoxide dismutase (SOD) and higher catalase (CAT) activity, resulting in lower SOD/CAT ratio. MT-ATP6 mutation analysis revealed that four variations, 8865 G>A, 8684 C>T, 8697 G>A, and 8836 A>G, have a frequency of more than 10% with missense and synonymous (silent) mutations. It was observed that abnormalities in mitochondrial complexes (I, III, V) are more common in ASD, and it may have resulted in MT-ATP6 changes or vice versa. In conclusion, our findings authenticate that oxidative stress and genetics both have an equal and potential role behind ASD and we recommend to conduct more such concurrent research to understand their unique mechanism for better diagnosis and therapeutic for ASD.

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10. Newell V, Phillips L, Jones C, Townsend E, Richards C, Cassidy S. A systematic review and meta-analysis of suicidality in autistic and possibly autistic people without co-occurring intellectual disability. Mol Autism;2023 (Mar 15);14(1):12.

BACKGROUND: Suicidality is highly prevalent in autistic people without co-occurring intellectual disabilities, and high autistic traits are found in adults who have attempted suicide. However, prevalence rates for both autistic and possibly autistic people have not been synthesised meta-analytically. AIMS: To (1) calculate pooled prevalence estimates of suicidality in autistic people and possibly autistic people without co-occurring intellectual disability; (2) evaluate the influence of participant and study level characteristics on heterogeneity; and (3) determine the quality of evidence. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were followed. PsycINFO, Embase, MEDLINE and Web of Science were systematically searched from 1992 to January 25, 2022. Empirical quantitative studies reporting prevalence of suicidal ideation, suicide plans, or suicide attempts and behaviours were considered for inclusion. Random effects models were used to estimate pooled prevalence of each suicidality outcome with 95% confidence intervals. Heterogeneity was explored using sensitivity and moderator analyses. RESULTS: Data from 48,186 autistic and possibly autistic participants in 36 primary studies were meta-analysed. Pooled prevalence of suicidal ideation was 34.2% (95% CI 27.9-40.5), suicide plans 21.9% (13.4-30.4), and suicidal attempts and behaviours 24.3% (18.9-29.6). High levels of heterogeneity (I(2) > 75) were observed in all three analyses. Estimates did not differ between autistic or possibly autistic samples. Geographical location (p = 0.005), transgender or gender non-conforming samples (p < 0.001) and type of report (p < 0.001) significantly moderated suicidal ideation, whereas age group (p = 0.001) and measure of suicidality (p = 0.001) significantly moderated suicide plans. There was a significant association between the proportion of male participants and prevalence of suicide plans, with a decrease in the proportion of males for every unit change of suicide plan prevalence (p = 0.013). No variables were found to moderate estimates of suicide attempts and behaviours. CONCLUSIONS: The results confirm suicidality is highly prevalent in both autistic and possibly autistic people without co-occurring intellectual disability and highlights potential moderators. Possibly autistic individuals require more attention in clinical and research considerations going forward to further understand and prevent suicide in both groups.

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11. Wang X, Chang Z, Wang R. Opposite effects of positive and negative symptoms on resting-state brain networks in schizophrenia. Commun Biol;2023 (Mar 17);6(1):279.

Schizophrenia is a severe psychotic disorder characterized by positive and negative symptoms, but their neural bases remain poorly understood. Here, we utilized a nested-spectral partition (NSP) approach to detect hierarchical modules in resting-state brain functional networks in schizophrenia patients and healthy controls, and we studied dynamic transitions of segregation and integration as well as their relationships with clinical symptoms. Schizophrenia brains showed a more stable integrating process and a more variable segregating process, thus maintaining higher segregation, especially in the limbic system. Hallucinations were associated with higher integration in attention systems, and avolition was related to a more variable segregating process in default-mode network (DMN) and control systems. In a machine-learning model, NSP-based features outperformed graph measures at predicting positive and negative symptoms. Multivariate analysis confirmed that positive and negative symptoms had opposite effects on dynamic segregation and integration of brain networks. Gene ontology analysis revealed that the effect of negative symptoms was related to autistic, aggressive and violent behavior; the effect of positive symptoms was associated with hyperammonemia and acidosis; and the interaction effect was correlated with abnormal motor function. Our findings could contribute to the development of more accurate diagnostic criteria for positive and negative symptoms in schizophrenia.

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12. Sabzevari F, Amelirad O, Moradi Z, Habibi M. Artificial intelligence evaluation of COVID-19 restrictions and speech therapy effects on the autistic children’s behavior. Sci Rep;2023 (Mar 15);13(1):4312.

In the present study, we aimed to quantify the effects of COVID-19 restrictions and speech treatment approaches during lockdowns on autistic children using CBCL and neuro-fuzzy artificial intelligence method. In this regard, a survey including CBCL questionnaire is prepared using online forms. In total, 87 children with diagnosed Autism spectrum disorders (ASD) participated in the survey. The influences of three treatment approaches of in-person, telehealth and public services along with no-treatment condition during lockdown were the main factors of the investigation. The main output factors were internalized and externalized problems in general and their eight subcategory syndromes. We examined the reports by parents/caregivers to find correlation between treatments and CBCL listed problems. Moreover, comparison of the eight syndromes rating scores from pre-lockdown to post-lockdown periods were performed. In addition, artificial intelligence method were engaged to find the influence of speech treatment during restrictions on the level of internalizing and externalizing problems. In this regard, a fully connected adaptive neuro fuzzy inference system is employed with type and duration of treatments as input and T-scores of the syndromes are the output of the network. The results indicate that restrictions alleviate externalizing problems while intensifying internalizing problems. In addition, it is concluded that in-person speech therapy is the most effective and satisfactory approach to deal with ASD children during stay-at-home periods.

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13. Embon I, Cukier S, Iorio A, Barttfeld P, Solovey G. Is visual metacognition associated with autistic traits? A regression analysis shows no link between visual metacognition and Autism-Spectrum Quotient scores. Conscious Cogn;2023 (Mar 17);110:103502.

Metacognition -the human ability to recognize correct decisions- is a key cognitive process linked to learning and development. Several recent studies investigated the relationship between metacognition and autism. However, the evidence is still inconsistent. While some studies reported autistic people having lower levels of metacognitive sensitivity, others did not. Leveraging the fact that autistic traits are present in the general population, our study investigated the relationship between visual metacognition and autistic traits in a sample of 360 neurotypical participants. We measured metacognition as the correspondence between confidence and accuracy in a visual two alternative forced choice task. Autistic-traits were assessed through the Autism-spectrum Quotient (AQ) score. A regression analysis revealed no statistically significant association between autistic traits and metacognition or confidence. Furthermore, we found no link between AQ sub-scales and metacognition. We do not find support for the hypothesis that autistic traits are associated with metacognition in the general population.

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14. Loan A, Leung JW, Cook DP, Ko C, Vanderhyden BC, Wang J, Chan HM. Prenatal low-dose methylmercury exposure causes premature neuronal differentiation and autism-like behaviors in a rodent model. iScience;2023 (Mar 17);26(3):106093.

Aberrant neurodevelopment is a core deficit of autism spectrum disorder (ASD). Here we ask whether a non-genetic factor, prenatal exposure to the environmental pollutant methylmercury (MeHg), is a contributing factor in ASD onset. We showed that adult mice prenatally exposed to non-apoptotic MeHg exhibited key ASD characteristics, including impaired communication, reduced sociability, and increased restrictive repetitive behaviors, whereas in the embryonic cortex, prenatal MeHg exposure caused premature neuronal differentiation. Further single-cell RNA sequencing (scRNA-seq) analysis disclosed that prenatal exposure to MeHg resulted in cortical radial glial precursors (RGPs) favoring asymmetric differentiation to directly generate cortical neurons, omitting the intermediate progenitor stage. In addition, MeHg exposure in cultured RGPs increased CREB phosphorylation and enhanced the interaction between CREB and CREB binding protein (CBP). Intriguingly, metformin, an FDA-approved drug, can reverse MeHg-induced premature neuronal differentiation via CREB/CBP repulsion. These findings provide insights into ASD etiology, its underlying mechanism, and a potential therapeutic strategy.

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15. Dumitriu D, Baldwin E, Coenen RJJ, Hammond LA, Peterka DS, Heilbrun L, Frye RE, Palmer R, Norrman HN, Fridell A, Remnelius KL, Isaksson J, Austin C, Curtin P, Bölte S, Arora M. Deciduous tooth biomarkers reveal atypical fetal inflammatory regulation in autism spectrum disorder. iScience;2023 (Mar 17);26(3):106247.

Atypical regulation of inflammation has been proposed in the etiology of autism spectrum disorder (ASD); however, measuring the temporal profile of fetal inflammation associated with future ASD diagnosis has not been possible. Here, we present a method to generate approximately daily profiles of prenatal and early childhood inflammation as measured by developmentally archived C-reactive protein (CRP) in incremental layers of deciduous tooth dentin. In our discovery population, a group of Swedish twins, we found heightened inflammation in the third trimester in children with future ASD diagnosis relative to controls (n = 66; 14 ASD cases; critical window: -90 to -50 days before birth). In our replication study, in the US, we observed a similar increase in CRP in ASD cases during the third trimester (n = 47; 23 ASD cases; -128 to -21 days before birth). Our results indicate that the third trimester is a critical period of atypical fetal inflammatory regulation in ASD.

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16. Luo L, Li T, Wu Q, Yuan B, Hu C, Yang T, Wei H, Chen J. Retinoic acid administration normalizes aberrant microglial activation via regulating TREM2 transcription in the PFC of valproic acid induced autism rat. Neurosci Lett;2023 (Mar 15);803:137193.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disease with an unclear underlying pathogenesis. Disruption of retinoic acid (RA)-retinoic acid receptor α (RARα) signaling and aberrant microglial activation were reported to be involved in the pathogenesis of ASD. However, the effect of RA-RARα signaling on microglial activation in ASD and the underlying mechanisms are unknown. Herein, we found inhibited RA-RARα signaling and increased microglial activation in valproic acid (VPA)-induced autism rats. Furthermore, we administered RA to VPA rats and found that RA ameliorated autism-like behaviors, inhibited microglial activation and normalized microglial polarization in VPA rats. Additionally, the expression levels of RARα and triggering receptor expressed on myeloid cells 2 (TREM2) were increased in the prefrontal cortex (PFC) of VPA rats given RA. Chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays confirmed that RARα can regulate the transcriptional activity of the TREM2 gene by binding to its promoter. We conclude that RA administration ameliorates autism-like behaviors in VPA rats by inhibiting microglial activation and normalizing microglial polarization through the regulation of TREM2 transcription by RARα.

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17. Khoja S, Haile MT, Chen LY. Advances in neurexin studies and the emerging role of neurexin-2 in autism spectrum disorder. Front Mol Neurosci;2023;16:1125087.

Over the past 3 decades, the prevalence of autism spectrum disorder (ASD) has increased globally from 20 to 28 million cases making ASD the fastest-growing developmental disability in the world. Neurexins are a family of presynaptic cell adhesion molecules that have been increasingly implicated in ASD, as evidenced by genetic mutations in the clinical population. Neurexins function as context-dependent specifiers of synapse properties and critical modulators in maintaining the balance between excitatory and inhibitory transmission (E/I balance). Disrupted E/I balance has long been established as a hallmark of ASD making neurexins excellent starting points for understanding the etiology of ASD. Herein we review neurexin mutations that have been discovered in ASD patients. Further, we discuss distinct synaptic mechanisms underlying the aberrant neurotransmission and behavioral deficits observed in different neurexin mouse models, with focus on recent discoveries from the previously overlooked neurexin-2 gene (Nrxn2 in mice and NRXN2 in humans). Hence, the aim of this review is to provide a summary of new synaptic insights into the molecular underpinnings of ASD.

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18. Mukherjee S, Beresford B. Factors influencing the mental health of autistic children and teenagers: Parents’ observations and experiences. Autism;2023 (Mar 15):13623613231158959.

Autistic people are more likely to experience mental health difficulties compared to neurotypical people. It is very important that we understand what increases the risk for mental health difficulties, and what helps to protect against them. So far, research on this for children and young people has only investigated a small number of factors and these have been chosen by researchers and clinicians. This study took a different approach in which parents’ expertise in their children was recognised. Parents were asked to tell the story of their autistic teenagers’ mental health from diagnosis in early childhood through to the present, and to explain the ‘theories’ they developed about what affected their child’s mental health – positively and negatively – and how. Parents believed a wide range of factors played a role. These include: (1) aspects of their child (e.g. their autistic traits, intelligence); (2) aspects of their surroundings (e.g. the efforts parents make to prevent and respond to their child’s difficulties, features of the school they attend, availability of social activities); (3) changes their child experienced growing up (e.g. puberty, awareness of being autistic); and (4) life events involving loss and separation. Many of the factors parents identified as important have received little or no research attention to date. The findings suggest issues that should be considered in future research and reveal ways that support for parents and autistic children and teenagers can be improved.

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19. Guthrie W, Wetherby AM, Woods J, Schatschneider C, Holland RD, Morgan L, Lord CE. The earlier the better: An RCT of treatment timing effects for toddlers on the autism spectrum. Autism;2023 (Mar 15):13623613231159153.

Behavioral interventions that incorporate naturalistic, developmental strategies have been shown to improve outcomes for young children who receive an autism spectrum disorder (ASD) diagnosis. Although there is broad consensus that children on the spectrum should begin supports as soon as possible, the empirical evidence for this is relatively limited and little is known about the optimal age to start autism-specific interventions. Our team conducted a randomized controlled trial (RCT) to test the effects of starting intervention at different ages, using the Early Social Interaction (ESI) model, a parent-implemented intervention for toddlers on the spectrum. Participants included 82 autistic toddlers and their caregiver(s) who received 9 months of Individual-ESI and 9 months of Group-ESI, with the timing/order of these two treatment conditions randomized. Thus, families received the more intensive and individualized Individual-ESI at either 18 or 27 months of age. Results revealed that children who received Individual-ESI earlier showed greater treatment gains than those who received this intervention later. Gains were demonstrated in several areas, which included the use and understanding of language, social use of communication skills, and self-help skills. Importantly, these findings were specific to the intensive and individualized parent coaching model compared to group-based treatment, allowing us to rule out the possibility that these timing effects were due to children getting older rather than the treatment itself. Our results suggest that even a narrow window of 18 versus 27 months may have an impact on outcomes and underscore the importance of screening and evaluation as young as possible.

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20. Yew RY, Hooley M, Stokes MA. Factors of relationship satisfaction for autistic and non-autistic partners in long-term relationships. Autism;2023 (Mar 16):13623613231160244.

Previous research has found that autistic people report lower satisfaction in their romantic relationships compared to non-autistic people. However, the majority of this research has focused on autistic traits as barriers to relationship satisfaction, while overlooking the role of their partners in these relationships. Our study explored a range of factors in both autistic people and non-autistic partners of autistic people and how they may be linked to long-term relationship satisfaction. These factors included social and communication skills, personality traits, social loneliness, partner responsiveness, and sexual satisfaction. We found that partner responsiveness was a strong predictor of relationship satisfaction for both autistic and non-autistic partners, suggesting that rather than focusing intervention solely on the autistic person, the role of their partner should also be considered. Service providers who work with couples involving an autistic person to enhance their relationship satisfaction could focus on assisting their clients to identify each other’s needs and how best to meet them.

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21. Ma D, Huang JL, Xiong T. Association between congenital heart disease and autism spectrum disorders: A protocol for a systematic review and meta-analysis. Medicine (Baltimore);2023 (Mar 17);102(11):e33247.

BACKGROUND: Congenital heart disease (CHD), the most common heart defect in children, refers to congenital disease with abnormal development of the heart or large blood vessels during the fetal period. The researchers suggest that children with CHD show more obvious neurodevelopmental disorders than children with normal development, and children with CHD may have a higher risk of social interaction and communication disorders. This is similar to the characteristics of children with autism spectrum disorder (ASD). However, the association between type of CHD and ASD is not well understood. This systematic review and meta-analysis will reveal the relationship between type of CHD and ASD. METHODS: We will search the Cochrane Library, Embase, PubMed, China National Knowledge Infrastructure, Wanfang, Chinese Scientific Journals Full text, and China Biology Medicine disc databases using relevant subject terms and free words. We will use a fixed effects model or random effects model for meta-analysis. The risk of bias will be assessed by the Newcastle-Ottawa Scale and the agency for health care research and quality. Heterogeneity will be tested by Q statistics and I² values. Publication bias will be detected by funnel plots and Egger test. Subgroup analyses and sensitivity analyses will also be used to explore and interpret the heterogeneity. RESULTS: The study will afford additional insight into the investigation the association between type of CHD and ASD. CONCLUSIONS: The results will provide evidence for the early identification and early intervention of ASD in children with CHD, which may contribute to improving the neurodevelopmental outcome of children with CHD.

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22. Yi J, Zhao X, Noell CR, Helmer P, Solmaz SR, Vallee RB. Role of Nesprin-2 and RanBP2 in BICD2-associated brain developmental disorders. PLoS Genet;2023 (Mar);19(3):e1010642.

Bicaudal D2 (BICD2) is responsible for recruiting cytoplasmic dynein to diverse forms of subcellular cargo for their intracellular transport. Mutations in the human BICD2 gene have been found to cause an autosomal dominant form of spinal muscular atrophy (SMA-LED2), and brain developmental defects. Whether and how the latter mutations are related to roles we and others have identified for BICD2 in brain development remains little understood. BICD2 interacts with the nucleoporin RanBP2 to recruit dynein to the nuclear envelope (NE) of Radial Glial Progenitor cells (RGPs) to mediate their well-known but mysterious cell-cycle-regulated interkinetic nuclear migration (INM) behavior, and their subsequent differentiation to form cortical neurons. We more recently found that BICD2 also mediates NE dynein recruitment in migrating post-mitotic neurons, though via a different interactor, Nesprin-2. Here, we report that Nesprin-2 and RanBP2 compete for BICD2-binding in vitro. To test the physiological implications of this behavior, we examined the effects of known BICD2 mutations using in vitro biochemical and in vivo electroporation-mediated brain developmental assays. We find a clear relationship between the ability of BICD2 to bind RanBP2 vs. Nesprin-2 in controlling of nuclear migration and neuronal migration behavior. We propose that mutually exclusive RanBP2-BICD2 vs. Nesprin-2-BICD2 interactions at the NE play successive, critical roles in INM behavior in RGPs and in post-mitotic neuronal migration and errors in these processes contribute to specific human brain malformations.

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