1. Alehagen L, Bölte S, Black MH. Application of the international classification of functioning, disability, and health in autism and attention-deficit hyperactivity disorder: A scoping review. Autism;2024 (Aug 25):13623613241272044.

The International Classification of Functioning, Disability, and Health (ICF) is a framework designed by the World Health Organization (WHO) to help different sectors, such as healthcare, social services, education, and policy, understand how people with health-related issues function (do the things they want to and need to do) in their daily lives. This framework has also been used to guide clinical practice and research in autism and attention-deficit hyperactivity disorder (ADHD). To make it more practical, shorter versions of the ICF called Core Sets have been developed. We wanted to explore how the ICF and the ICF Core Sets have been used in research relating to autism and ADHD. We looked at the research that had been previously published on this topic by conducting a systematic search and review. Seventy-eight studies meeting our criteria were included in our review. Results show that the ICF has been applied in many ways across various contexts. However, most of the research has focused on autism, mainly involving children. The review highlights that although the ICF was used in some studies, the underlying philosophies of the framework were not always followed. The medical perspective still influenced the way research was done and interpreted. Nevertheless, using the ICF in the right way can help shift research on neurodevelopmental conditions like autism and ADHD toward a more holistic approach, moving away from solely focusing on medical aspects.

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2. Cerda-Aedo B. Relationship between stress levels and coping techniques in caregivers of children with autism spectrum disorder in Chile, 2021. Dement Neuropsychol;2024;18:e20220112.

Today, talking about autism spectrum disorder (ASD) is the same as talking about cases that occur in one in 160 births worldwide. Some of them will be able to live independently when they grow up while others will have less autonomy and will be more dependent, requiring the support of caregivers throughout their lives. OBJECTIVE: Understanding the emotional burden that this could generate on parents, we sought to analyze the level of stress and coping techniques in caregivers of children with ASD in Chile, 2021. METHODS: Interview with a sample composed of 61 parents or guardians of people with ASD. RESULTS: After data analysis, it was possible to perform a statistically significant correlation (p=0.002) between the level of stress and the coping strategies (problem-solving, self-criticism, emotional expression, wishful thinking, social support, cognitive restructuring, problem avoidance, and social withdrawal). In addition, positive strategies that reduce stress levels in parents or caregivers of children with ASD were identified (problem resolution, cognitive restructuring, social support, and emotional expression). CONCLUSION: Through this research, it was possible to respond to each of the stated objectives, managing to determine what were the characteristics of caregivers and their main difficulties. It was also observed that the majority lost the possibility of working to dedicate themselves to the care of the diagnosed person.

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3. Duan X, Shan X, Uddin LQ, Chen H. The future of disentangling the heterogeneity of autism with neuroimaging studies. Biol Psychiatry;2024 (Aug 22)

Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition. Over the past decade, a considerable number of approaches have been developed to identify potential neuroimaging-based biomarkers of ASD and have uncovered specific neural mechanisms underlying behaviors associated with ASD. However, the substantial heterogeneity among those diagnosed with ASD hinders the development of biomarkers. Disentangling the heterogeneity of ASD is pivotal to improve quality of life for individuals with ASD by facilitating early diagnosis and individualized interventions for those who need support. In this Review, we discuss recent advances in neuroimaging that have facilitated the characterization of the heterogeneity of this condition from three frameworks: neurosubtyping, dimensional models, and normative models. In addition, we discuss the challenges, possible solutions, and clinical utility of these three frameworks. We argue that several factors need to be considered when parsing heterogeneity using neuroimaging, including co-occurring conditions, neurodevelopment, heredity and environment, and multi-site and multi-modality data. We close with a discussion of future directions for achieving a better understanding of the neural mechanisms underlying neurodevelopmental heterogeneity and the future of precision medicine in ASD.

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4. Dumont C, Belenger M, Eigsti IM, Kissine M. Enhanced pitch discrimination in autistic children with unexpected bilingualism. Autism Res;2024 (Aug 26)

Some autistic children acquire foreign languages from exposure to screens. Such unexpected bilingualism (UB) is therefore not driven by social interaction, rather, language acquisition appears to rely on less socially mediated learning and other cognitive processes. We hypothesize that UB children may rely on other cues, such as acoustic cues, of the linguistic input. Previous research indicates enhanced pitch processing in some autistic children, often associated with language delays and difficulties in forming stable phonological categories due to sensitivity to subtle linguistic variations. We propose that repetitive screen-based input simplifies linguistic complexity, allowing focus on individual cues. This study hypothesizes that autistic UB children exhibit superior pitch discrimination compared with both autistic and non-autistic peers. From a sample of 46 autistic French-speaking children aged 9 to 16, 12 were considered as UB. These children, along with 45 non-autistic children, participated in a two-alternative forced-choice pitch discrimination task. They listened to pairs of pure tones, 50% of which differed by 3% (easy), 2% (medium), or 1% (hard). A stringent comparison of performance revealed that only the autistic UB group performed above chance for tone pairs that differed, across all conditions. This group demonstrated superior pitch discrimination relative to autistic and non-autistic peers. This study establishes the phenomenon of UB in autism and provides evidence for enhanced pitch discrimination in this group. Acute perception of auditory information, combined with repeated language content, may facilitate UB children’s focus on phonetic features, and help acquire a language with no communicative support or motivation.

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5. Huang WA, Engelhard M, Coffman M, Hill ED, Weng Q, Scheer A, Maslow G, Henao R, Dawson G, Goldstein BA. A conditional multi-label model to improve prediction of a rare outcome: An illustration predicting autism diagnosis. J Biomed Inform;2024 (Aug 30);157:104711.

OBJECTIVE: This study aimed to develop a novel approach using routinely collected electronic health records (EHRs) data to improve the prediction of a rare event. We illustrated this using an example of improving early prediction of an autism diagnosis, given its low prevalence, by leveraging correlations between autism and other neurodevelopmental conditions (NDCs). METHODS: To achieve this, we introduced a conditional multi-label model by merging conditional learning and multi-label methodologies. The conditional learning approach breaks a hard task into more manageable pieces in each stage, and the multi-label approach utilizes information from related neurodevelopmental conditions to learn predictive latent features. The study involved forecasting autism diagnosis by age 5.5 years, utilizing data from the first 18 months of life, and the analysis of feature importance correlations to explore the alignment within the feature space across different conditions. RESULTS: Upon analysis of health records from 18,156 children, we are able to generate a model that predicts a future autism diagnosis with moderate performance (AUROC=0.76). The proposed conditional multi-label method significantly improves predictive performance with an AUROC of 0.80 (p < 0.001). Further examination shows that both the conditional and multi-label approach alone provided marginal lift to the model performance compared to a one-stage one-label approach. We also demonstrated the generalizability and applicability of this method using simulated data with high correlation between feature vectors for different labels. CONCLUSION: Our findings underscore the effectiveness of the developed conditional multi-label model for early prediction of an autism diagnosis. The study introduces a versatile strategy applicable to prediction tasks involving limited target populations but sharing underlying features or etiology among related groups.

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6. Jensen de López KM, Thirup Møller H. Prevalence of Autism in Scandinavian Countries (Denmark, Norway, Sweden), and Nordic Countries (Finland, Iceland, the Faroe Islands, and Greenland). Neuropsychiatr Dis Treat;2024;20:1597-1612.

AIM: This study aims to identify and describe prevalence rates for ASD in the Scandinavian countries (Denmark, Norway, Sweden), as well as the Nordic countries (Finland, Iceland, the Faroe Islands, and Greenland). METHODS: A systematic review was conducted following PRISMA (2009) guidelines and based on the two databases: APA PsycINFO and MEDLINE (PubMed). RESULTS: A total of 13 studies were included in the analyses. It was not possible to identify ASD prevalence studies for Greenland. However, for the remaining countries descriptive increases in ASD prevalence figures were observed. Increases were evident both in relation to age and birth cohort. Studies varied regarding which age group and cohort prevalence figures were reported. The most reported age group was the 7-12-year-olds. In this group, recent prevalence figures for Denmark ranged from 0.26% to 1.47%, in Norway 0.6%, in Sweden 0.23-0.68%, in Finland 0.22-0.86%, and in Iceland 2.40-3.13%. Iceland stood out in terms of higher prevalence figures compared to the other Scandinavian and Nordic countries. Two studies from the Faroe Islands reported ASD prevalence rates between 0.50% and 0.94% for 7-24-year-olds. These studies were based on nationwide figures, but not from national or official registers. DISCUSSION AND CONCLUSION: This study documented increasing prevalence of ASD in Scandinavian and Nordic countries. Several explanations of aspects that may contribute to the increases were discussed, eg, heightened awareness of ASD and earlier diagnosis. The importance of considering differences in data sources was discussed, with an emphasis on the importance of using national registries when available as this source is the most reliable and valid. The absence of prevalence figures for Greenland may be attributed to structural as well as cultural aspects, eg, two parallel systems assessing ASD, cultural taboos as well as lack of awareness of ASD. Suggestions or how to gain knowledge on ASD prevalence in Greenland is presented.

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7. Kamensek T, Iarocci G, Oruc I. Atypical daily visual exposure to faces in adults with autism spectrum disorder. Curr Biol;2024 (Aug 20)

Expert face processes are refined and tuned through a protracted development. Exposure statistics of the daily visual experience of neurotypical adults (the face diet) show substantial exposure to familiar faces. People with autism spectrum disorder (ASD) do not show the same expertise with faces as their non-autistic counterparts. This may be due to an impoverished visual experience with faces, according to experiential models of autism. Here, we present the first empirical report on the day-to-day visual experience of the faces of adults with ASD. Our results, based on over 360 h of first-person perspective footage of daily exposure, show striking qualitative and quantitative differences in the ASD face diet compared with those of neurotypical observers, which is best characterized by a pattern of reduced and atypical exposure to familiar faces in ASD. Specifically, duration of exposure to familiar faces was lower in ASD, and faces were viewed from farther distances and from viewpoints that were biased toward profile pose. Our results provide strong evidence that individuals with ASD may not be getting the experience needed for the typical development of expert face processes.

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8. Litman A, Sauerwald N, Snyder LG, Foss-Feig J, Park CY, Hao Y, Dinstein I, Theesfeld CL, Troyanskaya OG. Decomposition of phenotypic heterogeneity in autism reveals distinct and coherent genetic programs. medRxiv;2024 (Aug 16)

Unraveling the phenotypic and genetic complexity of autism is extremely challenging yet critical for understanding the biology, inheritance, trajectory, and clinical manifestations of the many forms of the condition. Here, we leveraged broad phenotypic data from a large cohort with matched genetics to characterize classes of autism and their patterns of core, associated, and co-occurring traits, ultimately demonstrating that phenotypic patterns are associated with distinct genetic and molecular programs. We used a generative mixture modeling approach to identify robust, clinically-relevant classes of autism which we validate and replicate in a large independent cohort. We link the phenotypic findings to distinct patterns of de novo and inherited variation which emerge from the deconvolution of these genetic signals, and demonstrate that class-specific common variant scores strongly align with clinical outcomes. We further provide insights into the distinct biological pathways and processes disrupted by the sets of mutations in each class. Remarkably, we discover class-specific differences in the developmental timing of genes that are dysregulated, and these temporal patterns correspond to clinical milestone and outcome differences between the classes. These analyses embrace the phenotypic complexity of children with autism, unraveling genetic and molecular programs underlying their heterogeneity and suggesting specific biological dysregulation patterns and mechanistic hypotheses.

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9. Martin JC, Clark SR, Hartmann S, Schubert KO. A Tale of Three Spectra: Basic Symptoms in Clinical-High-Risk of Psychosis Vary Across Autism Spectrum Disorder, Schizotypal Personality Disorder, and Borderline Personality Disorder. Schizophr Bull Open;2024 (Jan);5(1):sgae017.

BACKGROUND AND HYPOTHESIS: The clinical-high-risk (CHR) approach was developed to prevent psychosis through the detection of psychosis risk. CHR services are transdiagnostic in nature, therefore the appropriate management of comorbidity is a central part of care. Differential diagnosis is particularly challenging across 3 common comorbidities, schizotypal personality disorder (SPD), autism spectrum disorder (ASD), and borderline personality disorder (BPD). Phenomenological research indicates a disturbance of « basic self » may differentiate between these commonly comorbid disorders and can be captured by Huber’s basic symptoms (BS) concept. We investigated whether BS vary across these disorders and may inform differential diagnosis in young person’s meeting CHR criteria. STUDY DESIGN: A total of 685 participants meeting CHR criteria from the NAPLS-3 cohort completed the COGDIS items of the schizophrenia proneness instrument, a measure of BS, as well as the structured interview for DSM-5 (SCID-5). A logistic regression model was used to investigate the variation of COGDIS across SPD, ASD, and BPD, while controlling for age and SIPs positive severity. STUDY RESULTS: Meeting COGDIS criteria was positively associated with SPD (OR = 1.72, CI = [1.31-2.28], P = .001) but not ASD nor BPD. CONCLUSIONS: Our results indicate that « basic self-disturbance » as indicated by COGDIS differs across SPD, ASD, and BPD. COGDIS may be useful to inform the management of comorbidities in CHR services, by providing insight into subtle subjective experiences that may benefit from disorder-specific interventions.

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10. Patel NR, Rehmani N, Utter R, Gracious B. Refractory Homicidal Ideation in a Young Adult Male With High-Functioning Autism Spectrum Disorder and Schizophrenia. Cureus;2024 (Jul);16(7):e65436.

Persistent homicidal ideation (HI), while not common among psychiatric disorders, can occur within multiple diagnoses in the Diagnostic and Statistical Manual of Mental Disorders. There is a growing global and national concern for homicide and homicide-related deaths. In this case report, we discuss refractory homicidal ideation in an 18-year-old male with the diagnoses of autism spectrum disorder (ASD) and schizophrenia and a history of Tourette’s syndrome and highlight the interplay of comorbidities and challenges in effective management and treatment.

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11. Qu L, Wang J. Comment on « Associations between neonatal jaundice and autism spectrum disorder or attention deficit hyperactivity disorder: Nationwide population based cohort study »: Neonatal jaundice and autism spectrum disorder or attention deficit hyperactivity disorder. J Formos Med Assoc;2024 (Aug 23)

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12. Sane S, Ebrahimi V, Shirvani Farsani Z, Ghafouri-Fard S. Assessment of Expression of lncRNAs in Autistic Patients. J Mol Neurosci;2024 (Aug 26);74(3):81.

Autism is a severe neurodevelopmental condition with unknown pathobiology. Nevertheless, multiple pieces of evidence suggest long non-coding RNA (lncRNA) dysregulation may be a contributing factor to this disorder. We investigated the association between the expression of five specific lncRNAs and autism. Peripheral blood was collected from 30 children with autism and 41 healthy children. The expression levels of PCAT-29, lincRNA-ROR, LINC-PINT, lincRNA-p21, and PCAT-1 were calculated. Then, their significance as biomarkers was also evaluated. The expression of LincRNA-ROR (27 times), LINC-PINT (5.26 times), LincRNA-p21 (4.54 times), PCAT-29 (16.66 times), and PCAT-1 (25 times) genes was significantly decreased in patients compared to the control group (p values < 0.05). According to the ROC curve analysis for each lncRNA, LincRNA-ROR, LINC-PINT, LincRNA-p21, PCAT-29, and PCAT-1 lncRNAs with diagnostic power of 0.85, 0.67, 0.64, 0.74, and 0.84, respectively, could be used as diagnostic biomarkers for autism. Additionally, significant positive correlations were reported between expression levels of PCAT-1 and PCAT-29 genes. Moreover, a positive correlation was detected between expression levels of lincRNA-ROR and patients' age. The current study shows further pieces of evidence for deregulation of lncRNAs in autistic patients that show these lncRNAs may play an important part in the pathogenesis of ASD. However, the role of lncRNA in the neurobiology of autism needs to be investigated further.

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13. Sgadò P, Pross A, Lamanna J, Adiletta A. Face processing in animal models: implications for autism spectrum disorder. Front Neurosci;2024;18:1462272.

Processing facial features is crucial to identify social partners (prey, predators, or conspecifics) and recognize and accurately interpret emotional expressions. Numerous studies in both human and non-human primates provided evidence promoting the notion of inherent mechanisms for detecting facial features. These mechanisms support a representation of faces independent of prior experiences and are vital for subsequent development in social and language domains. Moreover, deficits in processing faces are a reliable biomarker of autism spectrum disorder, appearing early and correlating with symptom severity. Face processing, however, is not only a prerogative of humans: other species also show remarkable face detection abilities. In this review, we present an overview of the current literature on face detection in vertebrate models that could be relevant to the study of autism.

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14. Shaw E, Pennington L, Andrew M, Taylor H, Cadwgan J, Sellers D, Morris C, Garland D, Parr J. Informing creation of the FEEDS Toolkit to support parent-delivered interventions for eating, drinking and swallowing difficulties in young children with neurodisability: intervention use by neurodevelopmental diagnosis and healthcare professional role. BMJ Paediatr Open;2024 (Aug 24);8(1)

BACKGROUND: The FEEDS (Focus on Early Eating, Drinking and Swallowing) study focused on interventions used to improve feeding for children with neurodisability and eating, drinking and swallowing difficulties (EDSD), and the outcomes viewed as important by healthcare professionals (HPs) and parent carers. The FEEDS Toolkit was created subsequently as an intervention decision aid to be used collaboratively by parent carers and HPs. This study aimed to inform on current intervention practices and influence toolkit design by ascertaining whether specific intervention use varied by a child’s main diagnosis and by specific HP role. METHODS: FEEDS survey data were grouped by child’s main diagnosis and HP role. Main diagnoses included autism spectrum disorder (ASD) n=183; Down syndrome (DS) n=69; cerebral palsy (CP) n=30). HPs included were speech and language therapists (SLT) n=131; occupational therapists (OT) n=63; physiotherapists (PT) n=57; paediatricians n=50; dieticians n=40; nurses n=32 and health visitors n=14. RESULTS: Most interventions were used commonly across diagnoses. However, some interventions were used more commonly with specific conditions, for example, positioning (CP 85%, DS 70%, ASD 23%, strategies/programmes aimed at changing behaviour at mealtimes (ASD 52%, CP 8%, DS 11%); visual supports (ASD 58%, CP 0%, DS 21%). HPs reported using a broad range of interventions, SLTs (mean=13.9), dieticians (12.3), OTs (12.7) and paediatricians (11.1). There was overlap between intervention use and HP role, for example, positioning (100% PT, 97% SLT, 94% OT, 73% paediatricians and 69% nurses). CONCLUSIONS: Interdisciplinary working is common when managing EDSD, with all HP types using multiple interventions. A child’s main diagnosis does not substantially influence intervention use, and the individual context of each child requires consideration in intervention selection. Study findings have supported development of the FEEDS Toolkit for use in feeding services.

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15. Shin YS, Christensen D, Wang J, Shirley DJ, Orlando AM, Romero RA, Wilkes BJ, Vaillancourt DE, Coombes S, Wang Z. Transcallosal white matter and cortical gray matter variations in autistic adults ages 30-73 years: A bi-tensor free water imaging approach. Res Sq;2024 (Aug 16)

Background: Autism spectrum disorder (ASD) has long been recognized as a lifelong condition, but brain aging studies in autistic adults aged >30 years are limited. Free water, a novel brain imaging marker derived from diffusion MRI (dMRI), has shown promise in differentiating typical and pathological aging and monitoring brain degeneration. We aimed to examine free water and free water corrected dMRI measures to assess white and gray matter microstructure and their associations with age in autistic adults. Methods: Forty-three autistic adults ages 30-73 years and 43 age, sex, and IQ matched neurotypical controls participated in this cross-sectional study. We quantified fractional anisotropy (FA), free water, and free water-corrected FA (fwcFA) across 32 transcallosal white matter tracts and 94 gray matter areas in autistic adults and neurotypical controls. Follow-up analyses assessed age effect on dMRI metrics of the whole brain for both groups and the relationship between dMRI metrics and clinical measures of ASD in regions that significantly differentiated autistic adults from controls. Results: We found globally elevated free water in 24 transcallosal tracts in autistic adults. We identified negligible differences in dMRI metrics in gray matter between the two groups. Age-associated FA reductions and free water increases were featured in neurotypical controls; however, this brain aging profile was largely absent in autistic adults. Additionally, greater autism quotient (AQ) total raw score was associated with increased free water in the inferior frontal gyrus pars orbitalis and lateral orbital gyrus in autistic adults. Limitations: All autistic adults were cognitively capable individuals, minimizing the generalizability of the research findings across the spectrum. This study also involved a cross-sectional design, which limited inferences about the longitudinal microstructural changes of white and gray matter in ASD. Conclusions: We identified differential microstructural configurations between white and gray matter in autistic adults and that autistic individuals present more heterogeneous brain aging profiles compared to controls. Our clinical correlation analysis offered new evidence that elevated free water in some localized white matter tracts may critically contribute to autistic traits in ASD. Our findings underscored the importance of quantifying free water in dMRI studies of ASD.

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16. Wang L, Clark EA, Hanratty L, Koblan KS, Foley A, Dedic N, Bristow LJ. TAAR1 and 5-HT(1B) receptor agonists attenuate autism-like irritability and aggression in rats prenatally exposed to valproic acid. Pharmacol Biochem Behav;2024 (Aug 26):173862.

Despite the rising prevalence of autism spectrum disorder (ASD), there remains a significant unmet need for pharmacotherapies addressing its core and associative symptoms. While some atypical antipsychotics have been approved for managing associated irritability and aggression, their use is constrained by substantial side effects. This study aimed firstly to develop behavioral measures to explore frustration, irritability and aggression phenotypes in the rat prenatal valproic acid (VPA) model of ASD. Additionally, we investigated the potential of two novel mechanisms, 5-HT(1B) and TAAR1 agonism, to alleviate these behaviors. Male offspring exposed to prenatal VPA were trained to achieve stable performance on a cued operant task, followed by pharmacological assessment in an operant frustration test, bottle brush test and resident intruder test. VPA exposed rats demonstrated behaviors indicative of frustration and irritability, as well as increased aggression compared to controls. The irritability-like behavior and aggression were further exacerbated in animals previously experiencing a frustrative event during the operant test. Single administration of the 5-HT(1B) agonist CP-94253 or TAAR1 agonist RO5263397 attenuated the frustration-like behavior compared to vehicle. Additionally, both agonists reduced irritability-like behavior under both normal and frustrative conditions. While CP-94253 reduced aggression in the resident intruder test under both conditions, RO5263397 only produced effects in rats that previously experienced a frustrative event. Our study describes previously uncharacterized phenotypes of frustration, irritability, and aggression in the rat prenatal VPA model of ASD. Administration of selective TAAR1 or 5-HT(1B) receptor agonists alleviated these deficits, warranting further exploration of both targets in ASD treatment.

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17. Zandam H, Moura I, Akobirshoev I, Mitra M. Non-COVID Respiratory Infections Emergency Room Visits Among Autistic in the United States. Am J Prev Med;2024 (Aug 22)

INTRODUCTION: This is a retrospective study to examine the risk of non-COVID-19 respiratory infection (RI) related emergency department (ED) visits and hospitalizations among autistic adults compared to non-autistic adults using the 2018 Healthcare Cost and Utilization Project Nationwide Emergency Department Sample (HCUP-NEDS). METHODS: The data were analyzed in 2022 using the ICD-10-CM codes to extract about 46,996 autistic case records that were matched by age and sex with non-autistic records (140,997) in a 1:3 case-control ratio. Respiratory infections were also identified using the ICD-10-CM codes and classified by type. Logistic regression models were conducted for the likelihood of presenting with RI infections to the ED and subsequent hospitalization. All models were adjusted for covariates. RESULTS: Autistics were more likely to present with any type of respiratory infection at the emergency department (AOR = 1.83: CI= 1.69-2.42), lower respiratory infections (AOR=1.37: CI=1.09-1.50), and pneumonia (AOR=2.42: CI=1.98-2.47) compared to non-autistics. They are also more likely to be hospitalized from RIs during ED visits (AOR=3.87: CI=3.21-4.30), including upper and lower RIs, pneumonia, and bronchitis. CONCLUSIONS: Autistic individuals were more likely to experience emergency department visits and hospitalizations due to respiratory infections compared to non-autistic individuals. Amid growing evidence of the disproportionate impact of COVID-19 on the autistic population, our findings highlight a broader, pre-existing burden of respiratory infections among autistic adults in the US that extends beyond the recent pandemic.

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18. Zeng X, Fan L, Qin Q, Zheng D, Wang H, Li M, Jiang Y, Wang H, Liu H, Liang S, Wu L, Liang S. Exogenous PD-L1 binds to PD-1 to alleviate and prevent autism-like behaviors in maternal immune activation-induced male offspring mice. Brain Behav Immun;2024 (Aug 23);122:527-546.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder caused by the interaction of multiple pathogenic factors. Epidemiological studies and animal experiments indicate that maternal immune activation (MIA) is closely related to the development of ASD in offspring. A large number of pro-inflammatory cytokines are transferred from the placenta to the fetal brain during MIA, which impedes fetal neurodevelopment and is accompanied by activation of immune cells and microglia. Programmed cell death protein 1 (PD-1) can be highly expressed on the surface of various activated immune cells, when combined with programmed cell death-ligand 1 (PD-L1), it can activate the PD-1/PD-L1 pathway and exert powerful immunosuppressive effects, suggesting that this immune checkpoint may have the potential to treat MIA-induced ASD. This study combined bioinformatics analysis and experimental validation to explore the efficacy of Fc-fused PD-L1 (PD-L1-Fc) in treating MIA-induced ASD. Bioinformatics analysis results showed that in human placental inflammation, IL-6 was upregulated, T cells proliferated significantly, and the PD-1/PD-L1 pathway was significantly enriched. The experimental results showed that intraperitoneal injection of poly(I:C) induced MIA in pregnant mice resulted in significant expression of IL-6 in their serum, placenta, and fetal brain. At the same time, the expression of PD-1 and PD-L1 in the placenta and fetal brain increased, CD4(+) T cells in the spleen were significantly activated, and PD-1 expression increased. Their offspring mice exhibited typical ASD-like behaviors. In vitro experiments on primary microglia of offspring mice have confirmed that the expression of IL-6, PD-1, and PD-L1 is significantly increased, and PD-L1-Fc effectively reduced their expression levels. In the prefrontal cortex of MIA offspring mice, there was an increase in the expression of IL-6, PD-1, and PD-L1; activation of microglial cells, and colocalization with PD-1. Then we administered brain stereotaxic injections of PD-L1-Fc to MIA offspring mice and intraperitoneal injections to MIA pregnant mice. The results indicated that PD-L1-Fc effectively suppressed neuroinflammation in the frontal cortex of offspring mice and partially ameliorated ASD-like behaviors; MIA in pregnant mice was significantly alleviated, and the offspring mice they produced did not exhibit neuroinflammation or ASD-like behaviors. In summary, we have demonstrated the therapeutic ability of PD-L1-Fc for MIA-induced ASD, aiming to provide new strategies and insights for the treatment of ASD.

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