Etiology Of Autism Research Articles

Anti-ableism and scientific accuracy in autism research: a false dichotomy.

It was recently argued that autism researchers committed to rejecting ableist frameworks in their research may sacrifice "scientifically accurate" conceptualizations of autism. In this perspective piece, we argue that: (a) anti-ableism vs. scientific accuracy is a false dichotomy, (b) there is no ideology-free science that has claim to scientific accuracy, and (c) autism science has a history of false leads in part because of unexamined ableist ideologies that undergird researcher framings and interpretations of evidence. To illustrate our claims, we discuss several avenues of autism research that were promoted as scientific advances, but were eventually debunked or shown to have much less explanatory value than initially proposed. These research programs have involved claims about autism etiology, the nature of autism and autistic characteristics, and autism intervention. Common to these false leads have been ableist assumptions about autism that inform researcher perspectives. Negative impacts of this work have been mitigated in some areas of autism research, but these perspectives continue to exert influence on the lives of autistic people, including the availability of services, discourses about autism, and sociocultural conceptualizations of autistic people. Examining these false leads may help current researchers better understand how ableism may negatively influence their areas of inquiry. We close with a positive argument that promoting anti-ableism can be done in tandem with increasing scientific accuracy.

Conceptualizing Epigenetics and the Environmental Landscape of Autism Spectrum Disorders.

Complex interactions between gene variants and environmental risk factors underlie the pathophysiological pathways in major psychiatric disorders. Autism Spectrum Disorder is a neuropsychiatric condition in which susceptible alleles along with epigenetic states contribute to the mutational landscape of the ailing brain. The present work reviews recent evolutionary, molecular, and epigenetic mechanisms potentially linked to the etiology of autism. First, we present a clinical vignette to describe clusters of maladaptive behaviors frequently diagnosed in autistic patients. Next, we microdissect brain regions pertinent to the nosology of autism, as well as cell networks from the bilateral body plan. Lastly, we catalog a number of pathogenic environments associated with disease risk factors. This set of perspectives provides emerging insights into the dynamic interplay between epigenetic and environmental variation in the development of Autism Spectrum Disorders.

Identification of potentially relevant metals for the etiology of autism by using a Bayesian multivariate approach for partially censored values

Heavy metals are known to be able to cross the placental and blood brain barriers to affect critical neurodevelopmental processes in the fetus. We measured metal levels (Al, Cd, Hg, Li, Pb and Zn) in the cord blood of newborns and in the serum of the same children at 5 years of age, and compared between individuals with or without (controls) autism spectrum disorder (ASD) diagnosis. The samples were from a biobank associated with the All Babies in Southeast Sweden (ABIS) registry. We proposed a Bayesian multivariate log-normal model for partially censored values to identify potentially relevant metals for the etiology of ASD. Our results in cord blood suggest prenatal Al levels could be indicative of later ASD incidence, which could also be related to an increased possibility of a high, potentially toxic, exposure to Al and Li during pregnancy. In addition, a larger possibility of a high, potentially beneficial, exposure to Zn could occur during pregnancy in controls. Finally, we found decisive evidence for an average increase of Hg in 5-year-old ASD children compared to only weak evidence for controls. This is concordant with previous research showing an impaired ability for eliminating Hg in the ASD group.

PCSK9 Involvement in Autism Etiology: Sequence Variations, Protein Concentration, and Promoter Methylation

Besides its main role in the control of blood cholesterol, PCSK9 has a role in the regulation of neuronal development and apoptosis. We suggest, for the first time, the possible involvement of PCSK9 in autism. In this case-control study, Sanger sequencing was used to analyze sequence variations in the PCSK9 gene exons and their flanking intronic sequences. ELISA assay was used to determine the plasma concentration of PCSK9. The methylation percentage of the PCSK9 gene promoter was assessed by methylation-specific PCR (MSP). Forty-three variants were found; out of them, seven showed differential frequency between patients and controls. rs.45448095, rs.45613943, rs.630431, rs.529500286, and rs.45439391 are risk factors for autism, while rs.11800231 and rs.483462 are protective variants. The concentration of plasma PCSK9 protein was significantly elevated and the methylation percentage of PCSK9 gene promoter was significantly lower in cases than in controls (P <0.001 and = 0.002, respectively). ROC curve analysis identified an area under the curve (AUC) of 0.915 for plasma protein concentration and 0.693 for percent gene promoter methylation. In addition, two new variants were identified (g.23809C>T in intron 11 and g.24071T>G in 3' UTR). This is the first study to investigate the correlation between PCSK9 protein and autism and suggests the potential involvement of PCSK9 as one of the susceptibility genes for autism. Further studies with a larger number of subjects are recommended.

Increased glutamate and glutamine levels and their relationship to astrocytes and dopaminergic transmissions in the brains of adults with autism

Increased excitatory neuronal tones have been implicated in autism, but its mechanism remains elusive. The amplified glutamate signals may arise from enhanced glutamatergic circuits, which can be affected by astrocyte activation and suppressive signaling of dopamine neurotransmission. We tested this hypothesis using magnetic resonance spectroscopy and positron emission tomography scan with 11C-SCH23390 for dopamine D1 receptors in the anterior cingulate cortex (ACC). We enrolled 18 male adults with high-functioning autism and 20 typically developed (TD) male subjects. The autism group showed elevated glutamate, glutamine, and myo-inositol (mI) levels compared with the TD group (p = 0.045, p = 0.044, p = 0.030, respectively) and a positive correlation between glutamine and mI levels in the ACC (r = 0.54, p = 0.020). In autism and TD groups, ACC D1 receptor radioligand binding was negatively correlated with ACC glutamine levels (r = − 0.55, p = 0.022; r = − 0.58, p = 0.008, respectively). The enhanced glutamate-glutamine metabolism might be due to astroglial activation and the consequent reinforcement of glutamine synthesis in autistic brains. Glutamine synthesis could underly the physiological inhibitory control of dopaminergic D1 receptor signals. Our findings suggest a high neuron excitation-inhibition ratio with astrocytic activation in the etiology of autism.

Generation of induced pluripotent stem cell lines from three individuals with autism spectrum disorder

Uncovering the molecular mechanisms of autism spectrum disorder (autism) necessitates development of relevant experimental models that are capable of recapitulating features of the clinical phenotype. Using non-integrative episomal vectors, peripheral blood mononuclear cells derived from three unrelated individuals diagnosed with autism were reprogrammed to induced pluripotent stem cells (iPSCs). The resultant lines exhibited the expected cellular morphology, karyotype, and evidence of pluripotency. These iPSCs constitute a valuable resource to support investigations of the underlying aetiology of autism.

Structural neuroimaging phenotypes and associated molecular and genomic underpinnings in autism: a review.

Autism has been associated with differences in the developmental trajectories of multiple neuroanatomical features, including cortical thickness, surface area, cortical volume, measures of gyrification, and the gray-white matter tissue contrast. These neuroimaging features have been proposed as intermediate phenotypes on the gradient from genomic variation to behavioral symptoms. Hence, examining what these proxy markers represent, i.e., disentangling their associated molecular and genomic underpinnings, could provide crucial insights into the etiology and pathophysiology of autism. In line with this, an increasing number of studies are exploring the association between neuroanatomical, cellular/molecular, and (epi)genetic variation in autism, both indirectly and directly in vivo and across age. In this review, we aim to summarize the existing literature in autism (and neurotypicals) to chart a putative pathway from (i) imaging-derived neuroanatomical cortical phenotypes to (ii) underlying (neuropathological) biological processes, and (iii) associated genomic variation.

Genus-Level Analysis of Gut Microbiota in Children with Autism Spectrum Disorder: A Mini Review.

Autism is a global health problem, probably due to a combination of genetic and environmental factors. There is emerging data that the gut microbiome of autistic children differs from the one of typically developing children and it is important to know which bacterial genera may be related to autism. We searched different databases using specific keywords and inclusion criteria and identified the top ten bacterial genera from the selected articles that were significantly different between the studied patients and control subjects studied. A total of 34 studies that met the inclusion criteria were identified. The genera Bacteroides, Bifidobacterium, Clostridium, Coprococcus, Faecalibacterium, Lachnospira, Prevotella, Ruminococcus, Streptococcus, and Blautia exhibited the most substantial data indicating that their fluctuations in the gastrointestinal tract could be linked to the etiology of autism. It is probable that autism symptoms are influenced by both increased levels of harmful bacteria and decreased levels of beneficial bacteria. Interestingly, these genera demonstrated varying patterns of increased or decreased levels across different articles. To validate and eliminate the sources of this fluctuation, further research is needed. Consequently, future investigations on the causes of autism should prioritize the examination of the bacterial genera discussed in this publication.

Differences in Intrinsic Gray Matter Connectivity and Their Genomic Underpinnings in Autism Spectrum Disorder

BackgroundAutism is a heterogeneous neurodevelopmental condition accompanied by differences in brain connectivity. Structural connectivity in autism has mainly been investigated within the white matter. However, many genetic variants associated with autism highlight genes related to synaptogenesis and axonal guidance, thus also implicating differences in intrinsic (i.e., gray matter) connections in autism. Intrinsic connections may be assessed in vivo via so-called intrinsic global and local wiring costs. MethodsHere, we examined intrinsic global and local wiring costs in the brain of 359 individuals with autism and 279 healthy control participants ages 6 to 30 years from the EU-AIMS LEAP (Longitudinal European Autism Project). FreeSurfer was used to derive surface mesh representations to compute the estimated length of connections required to wire the brain within the gray matter. Vertexwise between-group differences were assessed using a general linear model. A gene expression decoding analysis based on the Allen Human Brain Atlas was performed to link neuroanatomical differences to putative underpinnings. ResultsGroup differences in global and local wiring costs were predominantly observed in medial and lateral prefrontal brain regions, in inferior temporal regions, and at the left temporoparietal junction. The resulting neuroanatomical patterns were enriched for genes that had been previously implicated in the etiology of autism at genetic and transcriptomic levels. ConclusionsBased on intrinsic gray matter connectivity, the current study investigated the complex neuroanatomy of autism and linked between-group differences to putative genomic and/or molecular mechanisms to parse the heterogeneity of autism and provide targets for future subgrouping approaches.

Unveiling sex-based differences in developing propionic acid-induced features in mice as a rodent model of ASD.

Males are more likely to develop autism as a neurodevelopmental disorder than females are, although the mechanisms underlying male vulnerability are not fully understood. Therefore, studying the role of autism etiologies considering sex differences in the propionic acid (PPA) rodent model of autism would build greater understanding of how females are protected from autism spectrum disorder, which may be used as a treatment strategy for males with autism. This study aimed to investigate the sex differences in oxidative stress, glutamate excitotoxicity, neuroinflammation, and gut microbiota impairment as etiological mechanisms for many neurological diseases, with specific reference to autism. Forty albino mice were divided into four groups of 10 animals each with two control and two treated groups of both sexes received only phosphate-buffered saline or a neurotoxic dose of PPA (250 mg/kg body weight) for 3 days, respectively. Biochemical markers of energy metabolism, oxidative stress, neuroinflammation, and excitotoxicity were measured in mouse brain homogenates, whereas the presence of pathogenic bacteria was assessed in mouse stool samples. Furthermore, the repetitive behavior, cognitive ability, and physical-neural coordination of the animals were examined. Collectively, selected variables related to oxidative stress, glutamate excitotoxicity, neuroinflammation, and gut bacteria were impaired concomitantly with altered behavior in PPA-induced rodent model, with males being more susceptible than females. This study explains the role of sex in the higher vulnerability of males to develop autistic biochemical and behavioral features compared with females. Female sex hormones and the higher detoxification capacity and higher glycolytic flux in females serve as neuroprotective contributors in a rodent model of autism.

Epigenetic changes in sperm are associated with paternal and child quantitative autistic traits in an autism-enriched cohort.

There is a need to consider paternal contributions to autism spectrum disorder (ASD) more strongly. Autism etiology is complex, and heritability is not explained by genetics alone. Understanding paternal gametic epigenetic contributions to autism could help fill this knowledge gap. In the present study, we explored whether paternal autistic traits, and the sperm epigenome, were associated with autistic traits in children at 36 months enrolled in the Early Autism Risk Longitudinal Investigation (EARLI) cohort. EARLI is a pregnancy cohort that recruited and enrolled pregnant women in the first half of pregnancy who already had a child with ASD. After maternal enrollment, EARLI fathers were approached and asked to provide a semen specimen. Participants were included in the present study if they had genotyping, sperm methylation data, and Social Responsiveness Scale (SRS) score data available. Using the CHARM array, we performed genome-scale methylation analyses on DNA from semen samples contributed by EARLI fathers. The SRS-a 65-item questionnaire measuring social communication deficits on a quantitative scale-was used to evaluate autistic traits in EARLI fathers (n = 45) and children (n = 31). We identified 94 significant child SRS-associated differentially methylated regions (DMRs), and 14 significant paternal SRS-associated DMRs (fwer p < 0.05). Many child SRS-associated DMRs were annotated to genes implicated in ASD and neurodevelopment. Six DMRs overlapped across the two outcomes (fwer p < 0.1), and, 16 DMRs overlapped with previous child autistic trait findings at 12 months of age (fwer p < 0.05). Child SRS-associated DMRs contained CpG sites independently found to be differentially methylated in postmortem brains of individuals with and without autism. These findings suggest paternal germline methylation is associated with autistic traits in 3-year-old offspring. These prospective results for autism-associated traits, in a cohort with a family history of ASD, highlight the potential importance of sperm epigenetic mechanisms in autism.

Maternal and Early-Life Exposure to Antibiotics and the Risk of Autism and Attention-Deficit Hyperactivity Disorder in Childhood: a Swedish Population-Based Cohort Study.

Antibiotics represent the most common type of medication used during pregnancy and infancy. Antibiotics have been proposed as a possible factor in changes in microbiota composition, which may play a role in the aetiology of autism and attention deficit/hyperactivity disorder (ADHD). Our aim was to investigate the association between maternal and early-life antibiotic use and autism and ADHD in childhood. This Swedish nation-wide population-based cohort study included all first live singleton births (N = 483,459) between January 2006 and December 2016. The association of dispensed antibiotics with autism and ADHD in children aged ≤ 11 years was estimated by applying multivariable logistic regression and generalised estimating equations models. Of the mothers, 25.9% (n = 125,106) were dispensed ≥1 antibiotic during the exposure period (from 3 months pre-conception to delivery), and 41.6% (n = 201,040) of the children received ≥ 1 antibiotic in early life (aged ≤ 2 years). Penicillin was the most prescribed antibiotic class (17.9% of mothers, 38.2% of children). Maternal antibiotic use was associated with an increased risk of autism [odds ratio (OR) = 1.16, 95% confidence interval (CI) 1.09-1.23] and ADHD (OR = 1.29, 95% CI 1.21-1.36) in childhood. Early-life exposure to antibiotics showed an even stronger association [autism (OR = 1.46, 95% CI 1.38-1.55); ADHD (OR = 1.90, 95% CI 1.80-2.00)]. Both maternal and childhood-exposure sub-analyses suggested a dose-response relationship. Maternal and early-life antibiotic use was associated with an increased risk of autism and ADHD in childhood. However, differences were noted by exposure period and antibiotic classes.

Association of GABRG3, GABRB3, HTR2A gene variants with autism spectrum disorder

Autism spectrum disorder (ASD) is a neurodevelopmental and neurobehavioral disorder characterized by impaired social communication, repetitive and restricted patterns of behavior, activity, or interest, and altered emotional processing. Reported prevalence is 4 times higher in men and it has increased in recent years. Immunological, environmental, epigenetic, and genetic factors play a role in the pathophysiology of autism. Many neurochemical pathways and neuroanatomical events are effective in determining the disease. It is still unclear how the main symptoms of autism occur because of this complex and heterogeneous situation. In this study, we focused on gamma amino butyric acid (GABA) and serotonin, which are thought to contribute to the etiology of autism; it is aimed to elucidate the mechanism of the disease by investigating variant changes in the GABA receptor subunit genes GABRB3, GABRG3 and the HTR2A gene, which encodes one of the serotonin receptors.200 patients with ASD between the ages of 3–9 and 100 healthy volunteers were included in the study. Genomic DNA isolation was performed from peripheral blood samples taken from volunteers. Genotyping was performed using the RFLP method with PCR specific for specific variants. Data were analyzed with SPSS v25.0 program.According to the data obtained in our study; In terms of HTR2A (rs6313 T102C) genotypes, the homozygous C genotype carrying frequency in the patient group and the homozygous T genotype carrying frequency in the GABRG3 (rs140679 C/T) genotypes were found to be significantly higher in the patient group compared to the control group (*p: 0.0001, p: 0.0001). It was determined that the frequency of individuals with homozygous genotype was significantly higher in the patient group compared to the control group and having homozygous genotypes increased the disease risk approximately 1.8 times. In terms of GABRB3 (rs2081648 T/C) genotypes, it was determined that there was no statistically significant difference in the frequency of carrying homozygous C genotype in the patient group compared to the control group (p: 0.36).According to the results of our study, we think that the HTR2A (rs6313 T102C) polymorphism is effective in modulating the empathic and autistic characteristics of individuals, and that the HTR2A (rs6313 T102C) polymorphism is more distributed in the post-synaptic membranes in individuals with a higher number of C alleles. We believe that this situation can be attributed to the spontaneous stimulatory distribution of the HTR2A gene in the postsynaptic membranes because of T102C transformation.In genetically based autism cases, carrying the point mutation in the rs6313 variant of the HTR2A gene and the C allele and the point mutation in the rs140679 variant of the GABRG3 gene and accordingly carrying the T allele provide a predisposition to the disease.

Pyramidal neurons form active, transient, multilayered circuits perturbed by autism-associated mutations at the inception of neocortex

Cortical circuits are composed predominantly of pyramidal-to-pyramidal neuron connections, yet their assembly during embryonic development is not well understood. We show that mouse embryonic Rbp4-Cre cortical neurons, transcriptomically closest to layer 5 pyramidal neurons, display two phases of circuit assembly invivo. At E14.5, they form a multi-layered circuit motif, composed of only embryonic near-projecting-type neurons. By E17.5, this transitions to a second motif involving all three embryonic types, analogous to the three adult layer 5 types. Invivo patch clamp recordings and two-photon calcium imaging of embryonic Rbp4-Cre neurons reveal active somas and neurites, tetrodotoxin-sensitive voltage-gated conductances, and functional glutamatergic synapses, from E14.5 onwards. Embryonic Rbp4-Cre neurons strongly express autism-associated genes and perturbing these genes interferes with the switch between the two motifs. Hence, pyramidal neurons form active, transient, multi-layered pyramidal-to-pyramidal circuits at the inception of neocortex, and studying these circuits could yield insights into the etiology of autism.

Analysis of blood sodium level in autism spectrum disorder

Introduction A number of recent studies have brought attention to the involvement of dietary salt and blood sodium levels in the etiopathogenesis of autism. In our study, by comparing the blood sodium levels of children with autism spectrum disease (ASD) and healthy children, we aimed to shed light on the etiopathogenesis of ASD. Method We retrospectively analyzed the blood sodium levels obtained from the 4-year follow-up of 84 children (42 with ASD and 42 controls). Results According to the comparison of blood sodium levels obtained from the 4-year follow-up of children in the ASD and control groups, no significant difference was found between the blood sodium levels of both groups. Discussion The notion that blood sodium levels influence the progression of autism is novel, and the majority of material on this topic comes from animal trials. The results of the few human-focused studies are controversial. More studies are needed to elucidate the role of blood sodium levels and salt consumption in the etiology of autism.

NRF2, KEAP1 and GSK-3 levels in autism spectrum disorder: a case control study

Recent studies show that oxidative stress has an important role in the etiology of autism. In our study, Nrf2, which is the main regulator of cellular antioxidant response, and Keap1 and Gsk-3β, which are the main proteins that regulate this pathway, were compared between children with autism and healthy controls. To the best of our knowledge, our study is the first in which Nrf2, Keap1 and Gsk-3β levels were evaluated together in children with ASD. In our study, Nrf2 level was found to be lower and Keap1 level higher in children with autism. Although GSK-3β is increased in many psychiatric and neurodegenerative diseases, it was found to be low in the autistic group in accordance with the literature. In conclusion, considering the versatile modulation of the Nrf2 pathway, this article does not provide any mechanistic insight into the pathway, but it suggests that Nrf2, Keap1 and Gsk-3β, which have central roles in oxidative stress, may play a role in the pathophysiology of autism.

An old model with new insights: endogenous retroviruses drive the evolvement toward ASD susceptibility and hijack transcription machinery during development.

The BTBR T+Itpr3tf/J (BTBR/J) strain is one of the most valid models of idiopathic autism, serving as a potent forward genetics tool to dissect the complexity of autism. We found that a sister strain with an intact corpus callosum, BTBR TF/ArtRbrc (BTBR/R), showed more prominent autism core symptoms but moderate ultrasonic communication/normal hippocampus-dependent memory, which may mimic autism in the high functioning spectrum. Intriguingly, disturbed epigenetic silencing mechanism leads to hyperactive endogenous retrovirus (ERV), a mobile genetic element of ancient retroviral infection, which increases de novo copy number variation (CNV) formation in the two BTBR strains. This feature makes the BTBR strain a still evolving multiple-loci model toward higher ASD susceptibility. Furthermore, active ERV, analogous to virus infection, evades the integrated stress response (ISR) of host defense and hijacks the transcriptional machinery during embryonic development in the BTBR strains. These results suggest dual roles of ERV in the pathogenesis of ASD, driving host genome evolution at a long-term scale and managing cellular pathways in response to viral infection, which has immediate effects on embryonic development. The wild-type Draxin expression in BTBR/R also makes this substrain a more precise model to investigate the core etiology of autism without the interference of impaired forebrain bundles as in BTBR/J.

Immunotherapy In Autism Spectrum Disorder; A Case Series

IntroductionResearches has shown that a subset of the autism spectrum disorder (ASD) population presents with immune dysregulation. Based upon the immunological abnormalities, various treatment modalities have been applied to children with ASD. One immunomodulatory treatment that has been studied in ASD is intravenous immunoglobulins (IVIG).ObjectivesThis report is based upon two hypotheses: autism etiology may be closely related to neuroinflammation; and, an effective treatment should restore the individual’s comminication skills. In this report, we present two cases who were diagnosed with ASD and received IVIG treatment.MethodsCase A is a 5-year-old female patient who was diagnosed with ASD at the age of 3. The second case, B is a 9 -year-old male patient who is a 7th grade student and was also diagnosed with ASD at the age of 3. The first patient’s autism symptoms was noticed by her family at the age of 2. Although she had the ability to coordinate eye contact, understood simple commands, she was observed to lose all her acquired developmental skills one by one at around 18-24 months. Towards the age of 3, stereotypical movements such as turning around and flapping wings, started. Similarly, the second patient’s acquired skills were lost around at the age of 2-3, after having recurrent infections. Based on deficits in social‐emotional reciprocity, deficits in nonverbal communicative behaviors used for social interaction and restricted/repetitive patterns of behavior, both patients were diagnosed with ASD. Considering that autoimmune mechanisms may have been affected in ASD, IVIG treatment was initiated at 1 g/kg/month. Case A received IVIG once in a month, total 5 infusions had been applied. Case B received total 12 infusions with the same protocol. Treatment response was assessed with the Childhood Autism Rating Scale (CARS).ResultsIn these two ASD cases which were treated with IVIG ,a subjective partial reduction in autism symptoms and an objective decrease in CARS scores were detected. Current evidence suggests that there are various factors contributing to the development of autism and different combinations of these aspects give rise to different variations of some ASD subtypes. Recent studies in this field indicate a possible connection between the immune system impairments and ASD. This report, therefore, provide support for the notion that at least a subset of children with ASD might have immune abnormalities and may respond to the immune modulating effect of IVIG therapy.ConclusionsAlthough, autoimmune or inflammatory etiologies may not explain the majority of cases of autism, it might at least be useful to understand some. Further studies with larger number of patients should be conducted about the use of IVIG in selected patients with ASD.Disclosure of InterestNone Declared

Modelling the Interplay Between Neuron-Glia Cell Dysfunction and Glial Therapy in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complicated, interpersonally defined, static condition of the underdeveloped brain. Although the aetiology of autism remains unclear, disturbance of neuronglia interactions has lately been proposed as a significant event in the pathophysiology of ASD. In recent years, the contribution of glial cells to autism has been overlooked. In addition to neurons, glial cells play an essential role in mental activities, and a new strategy that emphasises neuron-glia interactions should be applied. Disturbance of neuron-glia connections has lately been proposed as a significant event in the pathophysiology of ASD because aberrant neuronal network formation and dysfunctional neurotransmission are fundamental to the pathology of the condition. In ASD, neuron and glial cell number changes cause brain circuits to malfunction and impact behaviour. A study revealed that reactive glial cells result in the loss of synaptic functioning and induce autism under inflammatory conditions. Recent discoveries also suggest that dysfunction or changes in the ability of microglia to carry out physiological and defensive functions (such as failure in synaptic elimination or aberrant microglial activation) may be crucial for developing brain diseases, especially autism. The cerebellum, white matter, and cortical regions of autistic patients showed significant microglial activation. Reactive glial cells result in the loss of synaptic functioning and induce autism under inflammatory conditions. Replacement of defective glial cells (Cell-replacement treatment), glial progenitor cell-based therapy, and medication therapy (inhibition of microglia activation) are all utilised to treat glial dysfunction. This review discusses the role of glial cells in ASD and the various potential approaches to treating glial cell dysfunction.

Role of SHANK3 in concentrated ambient PM2. 5 exposure induced autism-like phenotype

Perinatal air pollution plays an important role in the development of autism. However, research on the pathogenic mechanism remains limited. In this study, the model of systemic inhalation of concentrated approximately 8-fold the level (mean concentration was 224 μg/m3) reported in ambient outdoor air of PM2.5 (particulate matters that are 2.5 μm or less in diameter)in early-postnatal male Sprague-Dawley (SD) rats was established. Through a series of autism-related behavioral tests, it was identified that young rats (postnatal day 1-day21, named PND1-PND21) exposed to PM2.5 exhibited typical autistic phenotypes, such as impaired language communication, abnormal repetitive and stereotyped behaviors, and impaired social skills. Moreover, synaptic abnormalities have been found in the brain tissues of young rats exposed to PM2.5. In terms of the molecular mechanism, we found that the levels of SH3 and multiple ankyrin repeat domains 3 (SHANK3) expression and key molecular proteins in the downstream signaling pathways were decreased in the brain tissues of the exposed rats. Finally, at the epigenetic level, SHANK3 methylation levels were increased in young rats exposed to PM2.5. In conclusion, the study revealed that PM2.5 exposure might induce the early postnatal autism through the SHANK3 signaling pathway by affecting the SHANK3 methylation levels and reducing the SHANK3 expression levels. The study could provide new ideas for autism etiology and a theoretical basis for the prevention and treatment of autism in children.