Pathogenesis Of Autism Spectrum Disorder Research Articles

Causal effects of 731 immune cell phenotypes on autism spectrum disorder: a Mendelian randomization study

ObjectiveThe role of different immune cells in autism spectrum disorders (ASD) is still controversial. The purpose of this study was to evaluate the causal effects of different immune cell phenotypes on ASD via Mendelian randomization (MR).MethodsDatasets of immune cell phenotypes were obtained from the European Bioinformatics Institute, and datasets of ASD were obtained from the IEU Open GWAS project. Single nucleotide polymorphisms were selected based on the assumptions of association, independence, and exclusivity. Inverse variance weighted was utilized as the main method for MR analysis. MR-Egger was employed to assess the horizontal pleiotropy of the results. Cochran’s Q and leave-one-out method were used for heterogeneity analysis and sensitivity analysis of the results, respectively.ResultsMR analysis showed that TD CD8br AC [odds ratio (OR), 1.137; 95% confidence interval (CI), 1.031–1.254; p = 0.010], CD8br %leukocyte (OR, 1.142; 95% CI, 1.067–1.223; p < 0.001), CD8br and CD8dim %leukocyte (OR, 1.117; 95% CI, 1.032–1.210; p = 0.006), naive CD8br %T cell (OR, 1.052; 95% CI, 1.004–1.104; p = 0.035), CD28− CD8dim %T cell (OR, 1.097; 95% CI, 1.038–1.158; p < 0.001), CD127− CD8br AC (OR, 1.086; 95% CI, 1.006–1.171; p = 0.034), CD45 on CD8br (OR, 1.059; 95% CI, 1.021–1.099; p = 0.002), CD3 on HLA DR+ CD8br (OR, 1.098; 95% CI, 1.041–1.158; p < 0.001), CD4 on activated Treg (OR, 1.048; 95% CI, 1.001–1.096; p = 0.046), CD3 on CD39+ resting Treg (OR, 1.070; 95% CI, 1.012–1.131; p = 0.018), IgD+ CD38− %lymphocyte (OR, 1.103; 95% CI, 1.023–1.190; p = 0.011), CD62L− plasmacytoid DC %DC (OR, 1.046; 95% CI, 1.001–1.093; p = 0.046), and FSC-A on plasmacytoid DC (OR, 1.075; 95% CI, 1.003–1.153; p = 0.042) were associated with increased genetic susceptibility to ASD. MR-Egger displayed no horizontal pleiotropy (p ≥ 0.05). Cochran’s Q revealed no heterogeneity of results (p ≥ 0.05). Sensitivity analysis indicated that the results were robust.ConclusionThis MR analysis revealed 13 immune cell phenotypes associated with increased genetic susceptibility to ASD and emphasized the importance of CD8 T cells and Tregs, which provides new directions for the pathogenesis and drug research of ASD.

Short tandem repeat expansions in cortical layer-specific genes implicate in phenotypic severity and adaptability of autism spectrum disorder.

Short tandem repeats (STRs) are repetitive DNA sequences and highly mutable in various human disorders. While the involvement of STRs in various genetic disorders has been extensively studied, their role in autism spectrum disorder (ASD) remains largely unexplored. In this study, we aimed to investigate genetic association of STR expansions with ASD using whole genome sequencing (WGS) and identify risk loci associated with ASD phenotypes. We analyzed WGS data of 634 ASD families and performed genome-wide evaluation for 12,929 STR loci. We found rare STR expansions that exceeded normal repeat lengths in autism cases compared to unaffected controls. By integrating single cell RNA and ATAC sequencing datasets of human postmortem brains, we prioritized STR loci in genes specifically expressed in cortical development stages. A deep learning method was used to predict functionality of ASD-associated STR loci. In ASD cases, rare STR expansions predominantly occurred in early cortical layer-specific genes involved in neurodevelopment, highlighting the cellular specificity of STR-associated genes in ASD risk. Leveraging deep learning prediction models, we demonstrated that these STR expansions disrupted the regulatory activity of enhancers and promoters, suggesting a potential mechanism through which they contribute to ASD pathogenesis. We found that individuals with ASD-associated STR expansions exhibited more severe ASD phenotypes and diminished adaptability compared to non-carriers. Short tandem repeat expansions in cortical layer-specific genes are associated with ASD and could potentially be a risk genetic factor for ASD. Our study is the first to show evidence of STR expansion associated with ASD in an under-investigated population.

Hippocampal proteome comparison of infant and adult Fmr1 deficiency mice reveals adult-related changes associated with postsynaptic density

Deficiency in fragile X mental retardation 1 (Fmr1) leads to loss of its encoded protein FMRP and causes fragile X syndrome (FXS) by dysregulating its target gene expression in an age-related fashion. Using comparative proteomic analysis, this study identified 105 differentially expressed proteins (DEPs) in the hippocampus of postnatal day 7 (P7) Fmr1−/y mice and 306 DEPs of P90 Fmr1−/y mice. We found that most DEPs in P90 hippocampus were not changed in P7 hippocampus upon FMRP absence, and some P90 DEPs exhibited diverse proteophenotypes with abnormal expression of protein isoform or allele variants. Bioinformatic analyses showed that the P7 DEPs were mainly enriched in fatty acid metabolism and oxidoreductase activity and nutrient responses; whereas the P90 PEPs (especially down-regulated DEPs) were primarily enriched in postsynaptic density (PSD), neuronal projection development and synaptic plasticity. Interestingly, 25 of 30 down-regulated PSD proteins present in the most enriched protein to protein interaction network, and 6 of them (ANK3, ATP2B2, DST, GRIN1, SHANK2 and SYNGAP1) are both FMRP targets and autism candidates. Therefore, this study suggests age-dependent alterations in hippocampal proteomes upon loss of FMRP that may be associated with the pathogenesis of FXS and its related disorders. SignificanceIt is well known that loss of FMRP resulted from Fmr1 deficiency leads to fragile X syndrome (FXS), a common neurodevelopmental disorder accompanied by intellectual disability and autism spectrum disorder (ASD). FMRP exhibits distinctly spatiotemporal patterns in the hippocampus between early development and adulthood, which lead to distinct dysregulations of gene expression upon loss of FMRP at the two age stages potentially linked to age-related phenotypes. Therefore, comparison of hippocampal proteomes between infancy and adulthood is valuable to provide insights into the early causations and adult-dependent consequences for FXS and ASD. Using a comparative proteomic analysis, this study identified 105 and 306 differentially expressed proteins (DEPs) in the hippocampi of postnatal day 7 (P7) and P90 Fmr1−/y mice, respectively. Few overlapping DEPs were identified between P7 and P90 stages, and the P7 DEPs were mainly enriched in the regulation of fatty acid metabolism and oxidoreduction, whereas the P90 DEPs were preferentially enriched in the regulation of synaptic formation and plasticity. Particularly, the up-regulated P90 proteins are primarily involved in immune responses and neurodegeneration, and the down-regulated P90 proteins are associated with postsynaptic density, neuron projection and synaptic plasticity. Our findings suggest that distinctly changed proteins in FMRP-absence hippocampus between infancy and adulthood may contribute to age-dependent pathogenesis of FXS and ASD.

Exploring the Neurogenetic Landscape of Autism Spectrum Disorder: The Role of Brain-Derived Neurotrophic Factor (BDNF) Gene in the Complex Web of Neurodevelopment

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with varied manifestations including altered metabolic profiles. Recent research highlights the potential role of Brain-Derived Neurotrophic Factor (BDNF), a hormone derived from adipose tissue, in the pathology of ASD. BDNF levels are reportedly correlated with the severity of autism symptoms, suggesting a link between metabolic dysfunction and the disorder. Objective: This study aims to deepen the understanding of BDNF levels in individuals with ASD and to explore the implications for diagnosis, treatment, and management of the disorder. It seeks to elucidate the relationship between low BDNF levels and increased autism severity, and to identify potential therapeutic interventions targeting BDNF dysregulation. Methods: EDTA blood samples (5ml each) from 140 participants (108 with ASD and 32 healthy controls) were collected across various hospitals in Karachi. Plasma serum levels of BDNF were analyzed following a six-month follow-up. A comprehensive statistical analysis was performed, focusing on the relationship between BDNF levels and autism severity, and evaluating diagnostic and therapeutic implications of BDNF dysregulation. Results: Analysis revealed that lower BDNF serum levels were consistently associated with higher autism severity. Specifically, 60-70% of participants with ASD scored below 8 on the Mini-Mental State Examination (MMSE), indicating significant cognitive impairment. The statistical significance of these findings was confirmed with p-values <0.05. Conclusion: The study confirms that low BDNF levels are significantly associated with greater severity of autism symptoms, underscoring the importance of metabolic factors in the pathogenesis of ASD. BDNF stands out as a potential biomarker for early ASD diagnosis and personalized treatment strategies. Future Prospects: Future research should aim to delineate the mechanistic relationship between BDNF dysregulation and ASD pathology. Longitudinal studies are needed to assess the long-term effects of BDNF modulation on ASD outcomes and to validate its effectiveness as both a diagnostic and prognostic marker.

Systematic Review: Autism Spectrum Disorder and the Gut Microbiota.

Autism spectrum disorders (ASD) are a varying group of disorders characterized by deficiency in social interaction and restrictive patterns of behavior and interests. While there are several studies focusing on the neuro-psychiatric pathogenesis of ASD, its etiology remains unclear. The role of gut-brain-axis in ASD has been studied increasingly and a correlation between symptoms and the composition of gut microbiota has been documented in various works. Despite this, the significance of individual microbes and their function is still widely unknown. This work aims to elucidate the current knowledge of the interrelations between ASD and the gut microbiota in children based on scientific evidence. This is a systematic review done by a literature search focusing on the main findings concerning the gut microbiota composition, interventions targeting the gut microbiota, and possible mechanisms explaining the results in children aged between 2 and 18 years of age. Most studies in this review found significant differences between microbial communities, while there was notable variation in results regarding diversity indices or taxonomic level abundance. The most consistent results regarding taxa differences in ASD children's gut microbiota were higher levels of Proteobacteria, Actinobacteria and Sutterella compared to controls. These results show that the gut microbiota of children with ASD is altered compared to one of neurotypically developed children. More research is needed to discover whether some of these features could be used as potential biomarkers for ASD and how the gut microbiota could be targeted in therapeutical interventions.Appeared originally in Acta Psychiatr Scand 2023;148:242-254.

The gut metabolite indole-3-propionic acid activates ERK1 to restore social function and hippocampal inhibitory synaptic transmission in a 16p11.2 microdeletion mouse model

BackgroundMicrodeletion of the human chromosomal region 16p11.2 (16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document}) is a prevalent genetic factor associated with autism spectrum disorder (ASD) and other neurodevelopmental disorders. However its pathogenic mechanism remains unclear, and effective treatments for 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document} syndrome are lacking. Emerging evidence suggests that the gut microbiota and its metabolites are inextricably linked to host behavior through the gut-brain axis and are therefore implicated in ASD development. Despite this, the functional roles of microbial metabolites in the context of 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document} are yet to be elucidated. This study aims to investigate the therapeutic potential of indole-3-propionic acid (IPA), a gut microbiota metabolite, in addressing behavioral and neural deficits associated with 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document}, as well as the underlying molecular mechanisms.ResultsMice with the 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document} showed dysbiosis of the gut microbiota and a significant decrease in IPA levels in feces and blood circulation. Further, these mice exhibited significant social and cognitive memory impairments, along with hyperactivation of hippocampal dentate gyrus neurons and reduced inhibitory synaptic transmission in this region. However, oral administration of IPA effectively mitigated the histological and electrophysiological alterations, thereby ameliorating the social and cognitive deficits of the mice. Remarkably, IPA treatment significantly increased the phosphorylation level of ERK1, a protein encoded by the Mapk3 gene in the 16p11.2 region, without affecting the transcription and translation of the Mapk3 gene.ConclusionsOur study reveals that 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document} leads to a decline in gut metabolite IPA levels; however, IPA supplementation notably reverses the behavioral and neural phenotypes of 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document} mice. These findings provide new insights into the critical role of gut microbial metabolites in ASD pathogenesis and present a promising treatment strategy for social and cognitive memory deficit disorders, such as 16p11.2 microdeletion syndrome.92Bbfs5rK2Gd_SbL4an2CwVideo

Personalized repetitive transcranial magnetic stimulation guided by the spectral electroencephalogram may enhance and democratize therapy for autism spectrum disorder

Autism spectrum disorder (ASD) is a genetically heterogeneous group of neurodevelopmental disorders that affect 1 in 36 children (CDC data) and have recognizable core deficits in common, including repetitive stereotyped behaviors and difficulties in social interaction and communication. Pharmacological interventions moderate some ASD comorbidities, but do not alleviate core deficits and have significant side effects. While many behavioral therapies are inadequate, a very intensive form called applied behavioral analysis (ABA) is demonstrably effective. ABA is based on graded progression and immediate feedback. ABA has raised concerns over its intensive nature and has triggered unease about being too harsh. One solution may derive from a widespread hypothesis of ASD pathogenesis, which posits that the brain in ASD is overexcited, i.e., excitation dominates over inhibition, and electroencephalographic (EEG) alpha band oscillatory activity is altered, which degrades sensory input and task management. This may also disrupt the brain mesolimbic dopaminergic reward cascade causing social interactions to be unrewarding, leading to deleterious social behavior and poor communication. We hypothesize that a comprehensive, personalized form of spectral EEG guided repetitive transcranial magnetic stimulation that we term PrTMS, can normalize alpha EEG oscillations, E/I balance, and dopaminergic reward signaling, to facilitate improved psychosocial behavior. The goal is for PrTMS to synergize with behavioral interventions, so that ABA for example, could be less intensive. This may hold the promise of making self-determination more readily attainable for ASD persons, and could also democratize ASD therapy by rendering it more affordable.

Cerebellar phenotypes in germline PTEN mutation carriers.

PTEN hamartoma tumour syndrome (PHTS) comprises different hereditary conditions caused by germline PTEN mutations, predisposing to the development of multiple hamartomas in many body tissues and also increasing the risk of some types of cancer. Cerebellar involvement in PHTS patients has been long known due to the development of a pathognomonic cerebellar hamartoma (known as dysplastic gangliocytoma of the cerebellum or Lhermitte-Duclos disease). Recently, a crucial role of the cerebellum has been highlighted in the pathogenesis of autism spectrum disorders, now recognised as a phenotype expressed in a variable percentage of PHTS children. In addition, rare PTEN variants are indeed identified in medulloblastoma as well, even if they are less frequent than other germline gene mutations. The importance of PTEN and its downstream signalling enzymatic pathways, PI3K/AKT/mTOR, has been studied at different levels in both human clinical settings and animal models, not only leading to a better understanding of the pathogenesis of different disorders but, most importantly, to identify potential targets for specific therapies. In particular, PTEN integrity makes an important contribution to the normal development of tissue architecture in the nervous system, including the cerebellum. Thus, in patients with PTEN germline mutations, the cerebellum is an affected organ that is increasingly recognised in different disorders, whereas, in animal models, cerebellar Pten loss causes a variety of functional and histological alterations. In this review, we summarise the range of cerebellar involvement observed in PHTS and its relationships with germline PTEN mutations, along with the phenotypes expressed by murine models with PTEN deficiency in cerebellar tissue.

NASP gene contributes to autism by epigenetic dysregulation of neural and immune pathways

BackgroundEpigenetics makes substantial contribution to the aetiology of autism spectrum disorder (ASD) and may harbour a unique opportunity to prevent the development of ASD. We aimed to identify novel epigenetic...

The complex etiology of autism spectrum disorder due to missense mutations of CHD8.

CHD8 is an ATP-dependent chromatin-remodeling factor encoded by the most frequently mutated gene in individuals with autism spectrum disorder (ASD). Although many studies have examined the consequences of CHD8 haploinsufficiency in cells and mice, few have focused on missense mutations, the most common type of CHD8 alteration in ASD patients. We here characterized CHD8 missense mutations in ASD patients according to six prediction scores and experimentally examined the effects of such mutations on the biochemical activities of CHD8, neural differentiation of embryonic stem cells, and mouse behavior. Only mutations with high prediction scores gave rise to ASD-like phenotypes in mice, suggesting that not all CHD8 missense mutations detected in ASD patients are directly responsible for the development of ASD. Furthermore, we found that mutations with high scores cause ASD by mechanisms either dependent on or independent of loss of chromatin-remodeling function. Our results thus provide insight into the molecular underpinnings of ASD pathogenesis caused by missense mutations of CHD8.

Vitamin D and Autism Spectrum Disorder: An Intriguing Association

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects the overall cognitive, emotional, social, and physical health of the affected individual. It is characterised by challenges in social communication and interaction, repetitive and stereotyped behaviours, and narrow interests. The pathogenesis of ASD is thought to involve a combination of genetic and environmental factors. Increasing evidence suggests that vitamin D deficiency during pregnancy and early childhood may contribute to the development of ASD. While studies have indicated that vitamin D supplementation can significantly improve symptoms of ASD, the underlying mechanism remains elusive. This review summarises the association between vitamin D levels and ASD, explores potential mechanisms underlying vitamin D's role in ASD, and examines the effect of vitamin D supplementation on ASD symptoms.

The mast cells - Cytokines axis in Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a neurodevelopmental disturbance, diagnosed in early childhood. It is associated with varying degrees of dysfunctional communication and social skills, repetitive and stereotypic behaviors. Regardless of the constant increase in the number of diagnosed patients, there are still no established treatment schemes in global practice. Many children with ASD have allergic symptoms, often in the absence of mast cell (MC) positive tests. Activation of MCs may release molecules related to inflammation and neurotoxicity, which contribute to the pathogenesis of ASD. The aim of the present paper is to enrich the current knowledge regarding the relationship between MCs and ASD by providing PPI network analysis-based data that reveal key molecules and immune pathways associated with MCs in the pathogenesis of autism. Network and enrichment analyzes were performed using receptor information and secreted molecules from activated MCs identified in ASD patients. Our analyses revealed cytokines and key marker molecules for MCs degranulation, molecular pathways of key mediators released during cell degranulation, as well as various receptors. Understanding the relationship between ASD and the activation of MCs, as well as the involved molecules and interactions, is important for elucidating the pathogenesis of ASD and developing effective future treatments for autistic patients by discovering new therapeutic target molecules.

Contactin-associated protein-like 2 (CNTNAP2) mutations impair the essential α-secretase cleavages, leading to autism-like phenotypes

Mutations in the Contactin-associated protein-like 2 (CNTNAP2) gene are associated with autism spectrum disorder (ASD), and ectodomain shedding of the CNTNAP2 protein plays a role in its function. However, key enzymes involved in the C-terminal cleavage of CNTNAP2 remain largely unknown, and the effect of ASD-associated mutations on this process and its role in ASD pathogenesis remain elusive. In this report we showed that CNTNAP2 undergoes sequential cleavages by furin, ADAM10/17-dependent α-secretase and presenilin-dependent γ-secretase. We identified that the cleavage sites of ADAM10 and ADAM17 in CNTNAP2 locate at its C-terminal residue I79 and L96, and the main α-cleavage product C79 by ADAM10 is required for the subsequent γ-secretase cleavage to generate CNTNAP2 intracellular domain (CICD). ASD-associated CNTNAP2 mutations impair the α-cleavage to generate C79, and the inhibition leads to ASD-like repetitive and social behavior abnormalities in the Cntnap2-I1254T knock-in mice. Finally, exogenous expression of C79 improves autism-like phenotypes in the Cntnap2-I1254T knock-in and Cntnap2−/− knockout mice. This data demonstrates that the α-secretase is essential for CNTNAP2 processing and its function. Our study indicates that inhibition of the cleavage by pathogenic mutations underlies ASD pathogenesis, and upregulation of its C-terminal fragments could have therapeutical potentials for ASD treatment.

The spectrum of pre-mRNA splicing in autism.

Disruptions in spatiotemporal gene expression can result in atypical brain function. Specifically, autism spectrum disorder (ASD) is characterized by abnormalities in pre-mRNA splicing. Abnormal splicing patterns have been identified in the brains of individuals with ASD, and mutations in splicing factors have been found to contribute to neurodevelopmental delays associated with ASD. Here we review studies that shed light on the importance of splicing observed in ASD and that explored the intricate relationship between splicing factors and ASD, revealing how disruptions in pre-mRNA splicing may underlie ASD pathogenesis. We provide an overview of the research regarding all splicing factors associated with ASD and place a special emphasis on five specific splicing factors-HNRNPH2, NOVA2, WBP4, SRRM2, and RBFOX1-known to impact the splicing of ASD-related genes. In the discussion of the molecular mechanisms influenced by these splicing factors, we lay the groundwork for a deeper understanding of ASD's complex etiology. Finally, we discuss the potential benefit of unraveling the connection between splicing and ASD for the development of more precise diagnostic tools and targeted therapeutic interventions. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution RNA Evolution and Genomics > Computational Analyses of RNA RNA-Based Catalysis > RNA Catalysis in Splicing and Translation.

Exploratory Analysis of MicroRNA Alterations in a Neurodevelopmental Mouse Model for Autism Spectrum Disorder and Schizophrenia.

MicroRNAs (miRNAs) play a crucial role in the regulation of gene expression levels and have been implicated in the pathogenesis of autism spectrum disorder (ASD) and schizophrenia (SCZ). In this study, we examined the adult expression profiles of specific miRNAs in the prefrontal cortex (PFC) of a neurodevelopmental mouse model for ASD and SCZ that mimics perinatal pathology, such as NMDA receptor hypofunction, and exhibits behavioral and neurophysiological phenotypes related to these disorders during adulthood. To model the early neuropathogenesis of the disorders, mouse pups were administered subcutaneously with ketamine (30 mg/Kg) at postnatal days 7, 9, and 11. We focused on a set of miRNAs most frequently altered in ASD (miR-451a and miR-486-3p) and in SCZ (miR-132-3p and miR-137-3p) according to human studies. Additionally, we explored miRNAs whose alterations have been identified in both disorders (miR-21-5p, miR-92a-2-5p, miR-144-3p, and miR-146a-5p). We placed particular emphasis on studying the sexual dimorphism in the dynamics of these miRNAs. Our findings revealed significant alterations in the PFC of this ASD- and SCZ-like mouse model. Specifically, we observed upregulated miR-451a and downregulated miR-137-3p. Furthermore, we identified sexual dimorphism in the expression of miR-132-3p, miR-137-3p, and miR-92a-2-5p. From a translational perspective, our results emphasize the potential involvement of miR-92a-2-5p, miR-132-3p, miR-137-3p, and miR-451a in the pathophysiology of ASD and SCZ and strengthen their potential as biomarkers and therapeutic targets of such disorders.

Gut microbiome and serum amino acid metabolome alterations in autism spectrum disorder

Gut microbiota and their metabolic products might play important roles in regulating the pathogenesis of autism spectrum disorder (ASD). The purpose of this study was to characterize gut microbiota and serum amino acid metabolome profiles in children with ASD. A non-randomized controlled study was carried out to analyze the alterations in the intestinal microbiota and their metabolites in patients with ASD (n = 30) compared with neurotypical controls (NC) (n = 30) by metagenomic sequencing to define the gut microbiota community and liquid chromatography/mass spectrometry (LC/MS) analysis to characterize the metabolite profiles. Compared with children in the NC group, those in the ASD group showed lower richness, higher evenness, and an altered microbial community structure. At the class level, Deinococci and Holophagae were significantly lower in children with ASD compared with TD. At the phylum level, Deinococcus-Thermus was significantly lower in children with ASD compared with TD. In addition, the functional properties (such as galactose metabolism) displayed significant differences between the ASD and NC groups. Five dominant altered species were identified and analyzed (LDA score > 2.0, P < 0.05), including Subdoligranulum, Faecalibacterium_praushitzii, Faecalibacterium, Veillonellaceae, and Rumminococcaceae. The peptides/nickel transport system was the main metabolic pathway involved in the differential species in the ASD group. Decreased ornithine levels and elevated valine levels may increase the risk of ASD through a metabolic pathway known as the nickel transport system. The microbial metabolism in diverse environments was negatively correlated with phascolarctobacterium succinatutens. Our study provides novel insights into compositional and functional alterations in the gut microbiome and metabolite profiles in ASD and the underlying mechanisms between metabolite and ASD.

Between Dysbiosis, Maternal Immune Activation and Autism: Is There a Common Pathway?

Autism spectrum disorder (ASD) is a neuropsychiatric condition characterized by impaired social interactions and repetitive stereotyped behaviors. Growing evidence highlights an important role of the gut-brain-microbiome axis in the pathogenesis of ASD. Research indicates an abnormal composition of the gut microbiome and the potential involvement of bacterial molecules in neuroinflammation and brain development disruptions. Concurrently, attention is directed towards the role of short-chain fatty acids (SCFAs) and impaired intestinal tightness. This comprehensive review emphasizes the potential impact of maternal gut microbiota changes on the development of autism in children, especially considering maternal immune activation (MIA). The following paper evaluates the impact of the birth route on the colonization of the child with bacteria in the first weeks of life. Furthermore, it explores the role of pro-inflammatory cytokines, such as IL-6 and IL-17a and mother's obesity as potentially environmental factors of ASD. The purpose of this review is to advance our understanding of ASD pathogenesis, while also searching for the positive implications of the latest therapies, such as probiotics, prebiotics or fecal microbiota transplantation, targeting the gut microbiota and reducing inflammation. This review aims to provide valuable insights that could instruct future studies and treatments for individuals affected by ASD.

Identification and Analysis of ZIC-Related Genes in Cerebellum of Autism Spectrum Disorders.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with significant genetic heterogeneity. The ZIC gene family can regulate neurodevelopment, especially in the cerebellum, and has been implicated in ASD-like behaviors in mice. We performed bioinformatic analysis to identify the ZIC gene family in the ASD cerebellum. We explored the roles of ZIC family genes in ASD by investigating (i) the association of ZIC genes with ASD risk genes from the Simons Foundation Autism Research Initiative (SFARI) database and ZIC genes in the brain regions of the Human Protein Atlas (HPA) database; (ii) co-expressed gene networks of genes positively and negatively correlated with ZIC1, ZIC2, and ZIC3, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and receiver operating characteristic (ROC) curve analysis of genes in these networks; and (iii) the relationship between ZIC1, ZIC2, ZIC3, and their related genes with cerebellar immune cells and stromal cells in ASD patients. (i) ZIC1, ZIC2, and ZIC3 were associated with neurodevelopmental disorders and risk genes related to ASD in the human cerebellum and (ii) ZIC1, ZIC2, and ZIC3 were highly expressed in the cerebellum, which may play a pathogenic role by affecting neuronal development and the cerebellar internal environment in patients with ASD, including immune cells, astrocytes, and endothelial cells. (iii) OLFM3, SLC27A4, GRB2, TMED1, NR2F1, and STRBP are closely related to ZIC1, ZIC2, and ZIC3 in ASD cerebellum and have good diagnostic accuracy. (iv) ASD mice in the maternal immune activation model demonstrated that Zic3 and Nr2f1 levels were decreased in the immune-activated cerebellum. Our study supports the role of ZIC1, ZIC2, and ZIC3 in ASD pathogenesis and provides potential targets for early and accurate prediction of ASD.

Primitive reflexes in very low birth weight infants later diagnosed with autism spectrum disorder.

As early screening and diagnosis is very important in treatment and intervention of autism spectrum disorder (ASD), we investigated the relationship between primitive reflexes and ASD. Of 88 very low birth weight infants (<1500 g) born from April 2010 to March 2012, subjects comprised 38 examined for 18 primitive reflexes between age 38 and 45 weeks corrected age and followed-up over 6 years. ASD was diagnosed using Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) and Autism Diagnostic Observation Schedule Second Edition (ADOS-2). We compared the number of abnormal primitive reflexes between two groups (11 children with and 19 without ASD) after excluding eight children with cerebral palsy in this case-control study. Twenty cases showed one to four hypoactive reflex(es) and two showed one hyperactive reflex together with hypoactive reflex(es). Ten out of 11 cases with ASD had one to four abnormal reflex(es). The number of abnormal hypoactive primitive reflexes was significantly higher in the ASD group (P=0.002). The result suggests primitive reflexes can be one of the key elements in very early infancy to identify ASD in low-birth-weight infants. Abnormal hypoactive primitive reflex of low-birth-weight infants with ASD may inform future research of the pathogenesis of ASD.

Yigansan ameliorates maternal immune activation-induced autism-like behaviours by regulating the IL-17A/TRAF6/MMP9 pathway: Network analysis and experimental validation

BackgroundMaternal immune activation (MIA) is a significant factor inducing to autism spectrum disorder (ASD) in offspring. The fundamental principle underlying MIA is that inflammation during pregnancy impedes fetal brain development and triggers behavioural alterations in offspring. The intricate pathogenesis of ASD renders drug treatment effects unsatisfactory. Traditional Chinese medicine has strong potential due to its multiple therapeutic targets. Yigansan, composed of seven herbs, is one of the few that has been proven to be effective in treating neuro-psychiatric disorders among numerous traditional Chinese medicine compounds, but its therapeutic effect on ASD remains unknown. HypothesisYigansan improves MIA-induced ASD-like behaviours in offspring by regulating the IL-17 signalling pathway. MethodsPregnant C57BL/6J mice were intraperitoneally injected with poly(I:C) to construct MIA models and offspring ASD models. Network analysis identified that the IL-17A/TRAF6/MMP9 pathway is a crucial pathway, and molecular docking confirmed the binding affinity between the monomer of Yigansan and target proteins. qRT-PCR and Western blot were used to detect the expression levels of inflammatory factors and pathway proteins, immunofluorescence was used to detect the distribution of IL-17A, and behavioural tests were used to evaluate the ASD-like behaviours of offspring. ResultsWe demonstrated that Yigansan can effectively alleviate MIA-induced neuroinflammation of adult offspring by regulating the IL-17A/TRAF6/MMP9 pathway, and the expression of IL-17A was reduced in the prefrontal cortex. Importantly, ASD-like behaviours have been significantly improved. Moreover, we identified that quercetin is the effective monomer for Yigansan to exert therapeutic effects. ConclusionOverall, this study was firstly to corroborate the positive therapeutic effect of Yigansan in the treatment of ASD. We elucidated the relevant molecular mechanism and regulatory pathway involved, determined the optimal therapeutic dose and effective monomer, providing new solutions for the challenges of drug therapy for ASD.