Autism Genes Research Articles

Gene-Environment Interactions in Developmental Neurotoxicity: a Case Study of Synergy between Chlorpyrifos and CHD8 Knockout in Human BrainSpheres.

Background:Autism spectrum disorder (ASD) is a major public health concern caused by complex genetic and environmental components. Mechanisms of gene–environment () interactions and reliable biomarkers associated with ASD are mostly unknown or controversial. Induced pluripotent stem cells (iPSCs) from patients or with clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9)-introduced mutations in candidate ASD genes provide an opportunity to study () interactions.Objectives:In this study, we aimed to identify a potential synergy between mutation in the high-risk autism gene encoding chromodomain helicase DNA binding protein 8 (CHD8) and environmental exposure to an organophosphate pesticide (chlorpyrifos; CPF) in an iPSC-derived human three-dimensional (3D) brain model.Methods:This study employed human iPSC-derived 3D brain organoids (BrainSpheres) carrying a heterozygote CRISPR/Cas9-introduced inactivating mutation in CHD8 and exposed to CPF or its oxon-metabolite (CPO). Neural differentiation, viability, oxidative stress, and neurite outgrowth were assessed, and levels of main neurotransmitters and selected metabolites were validated against human data on ASD metabolic derangements.Results:Expression of CHD8 protein was significantly lower in CHD8 heterozygous knockout () BrainSpheres compared with ones. Exposure to CPF/CPO treatment further reduced CHD8 protein levels, showing the potential () interaction synergy. A novel approach for validation of the model was chosen: from the literature, we identified a panel of metabolic biomarkers in patients and assessed them by targeted metabolomics in vitro. A synergistic effect was observed on the cholinergic system, S-adenosylmethionine, S-adenosylhomocysteine, lactic acid, tryptophan, kynurenic acid, and acid levels. Neurite outgrowth was perturbed by CPF/CPO exposure. Heterozygous knockout of CHD8 in BrainSpheres led to an imbalance of excitatory/inhibitory neurotransmitters and lower levels of dopamine.Discussion:This study pioneered () interaction in iPSC-derived organoids. The experimental strategy enables biomonitoring and environmental risk assessment for ASD. Our findings reflected some metabolic perturbations and disruption of neurotransmitter systems involved in ASD. The increased susceptibility of BrainSpheres to chemical insult establishes a possibly broader role of () interaction in ASD. https://doi.org/10.1289/EHP8580

Risk homozygous haplotype regions for autism identifies population-specific ten genes for numerous pathways

BackgroundRecessive homozygous haplotype (rHH) mapping is a reliable tool for identifying recessive genes by detecting homozygous segments of identical haplotype structures. These are shared at a higher frequency amongst probands compared to parental controls. Finding out such rHH blocks in autism subjects can help in deciphering the disorder etiology.ObjectivesThe study aims to detect rHH segments of identical haplotype structure shared at a higher frequency in autism subjects than controls to identify recessive genes responsible for autism manifestation.MethodsIn the present study, 426 unrelated autism genotyped probands with 232 parents (116 trios) were obtained from Gene Expression Omnibus (GEO) Database. Homozygosity mapping analyses have been performed on the samples using standardized algorithms using the Affymetrix GeneChip® 500K SNP Nsp and Sty mapping arrays datasets.ResultsA total of 38 homozygous haplotype blocks were revealed across sample datasets. Upon downstream analysis, 10 autism genes were identified based on selected autism candidate genes criteria. Further, expressive Quantitative Trait Loci (QTL) analysis of SNPs revealed various binding sites for regulatory proteins BX3, FOS, BACH1, MYC, JUND, MAFK, POU2F2, RBBP5, RUNX3, and SMARCA4 impairing essential autism genes CEP290, KITLG, CHD8, and INS2. Pathways and processes such as adherens junction, dipeptidase activity, and platelet-derived growth factor—vital to autism manifestation were identified with varied protein-protein clustered interactions.ConclusionThese findings bring various population clusters with significant rHH genes. It is suggestive of the existence of common but population-specific risk alleles in related autism subjects.

Convergent and distributed effects of the 3q29 deletion on the human neural transcriptome

The 3q29 deletion (3q29Del) confers high risk for schizophrenia and other neurodevelopmental and psychiatric disorders. However, no single gene in this interval is definitively associated with disease, prompting the hypothesis that neuropsychiatric sequelae emerge upon loss of multiple functionally-connected genes. 3q29 genes are unevenly annotated and the impact of 3q29Del on the human neural transcriptome is unknown. To systematically formulate unbiased hypotheses about molecular mechanisms linking 3q29Del to neuropsychiatric illness, we conducted a systems-level network analysis of the non-pathological adult human cortical transcriptome and generated evidence-based predictions that relate 3q29 genes to novel functions and disease associations. The 21 protein-coding genes located in the interval segregated into seven clusters of highly co-expressed genes, demonstrating both convergent and distributed effects of 3q29Del across the interrogated transcriptomic landscape. Pathway analysis of these clusters indicated involvement in nervous-system functions, including synaptic signaling and organization, as well as core cellular functions, including transcriptional regulation, posttranslational modifications, chromatin remodeling, and mitochondrial metabolism. Top network-neighbors of 3q29 genes showed significant overlap with known schizophrenia, autism, and intellectual disability-risk genes, suggesting that 3q29Del biology is relevant to idiopathic disease. Leveraging “guilt by association”, we propose nine 3q29 genes, including one hub gene, as prioritized drivers of neuropsychiatric risk. These results provide testable hypotheses for experimental analysis on causal drivers and mechanisms of the largest known genetic risk factor for schizophrenia and highlight the study of normal function in non-pathological postmortem tissue to further our understanding of psychiatric genetics, especially for rare syndromes like 3q29Del, where access to neural tissue from carriers is unavailable or limited.

Transcriptome analysis of MBD5-associated neurodevelopmental disorder (MAND) neural progenitor cells reveals dysregulation of autism-associated genes

MBD5-associated neurodevelopmental disorder (MAND) is an autism spectrum disorder (ASD) characterized by intellectual disability, motor delay, speech impairment and behavioral problems; however, the biological role of methyl-CpG-binding domain 5, MBD5, in neurodevelopment and ASD remains largely undefined. Hence, we created neural progenitor cells (NPC) derived from individuals with chromosome 2q23.1 deletion and conducted RNA-seq to identify differentially expressed genes (DEGs) and the biological processes and pathways altered in MAND. Primary skin fibroblasts from three unrelated individuals with MAND and four unrelated controls were converted into induced pluripotent stem cell (iPSC) lines, followed by directed differentiation of iPSC to NPC. Transcriptome analysis of MAND NPC revealed 468 DEGs (q < 0.05), including 20 ASD-associated genes. Comparison of DEGs in MAND with SFARI syndromic autism genes revealed a striking significant overlap in biological processes commonly altered in neurodevelopmental phenotypes, with TGFβ, Hippo signaling, DNA replication, and cell cycle among the top enriched pathways. Overall, these transcriptome deviations provide potential connections to the overlapping neurocognitive and neuropsychiatric phenotypes associated with key high-risk ASD genes, including chromatin modifiers and epigenetic modulators, that play significant roles in these disease states.

Role of CNTNAP2 in autism manifestation outlines the regulation of signaling between neurons at the synapse

BackgroundAutism is characterized by high heritability and a complex genetic mutational landscape with restricted social behavior and impaired social communication. Whole-exome sequencing is a reliable tool to pinpoint variants for unraveling the disease pathophysiology. The present meta-analysis was performed using 222 whole-exome sequences deposited by Simons Simplex Collection (SSC) at the European Nucleotide Archive. This sample cohort was used to identify causal mutations in autism-specific genes to create a mutational landscape focusing on the CNTNAP2 gene.ResultsThe authors account for the identification of 15 high confidence genes with 24 variants for autism with Simons Foundation Autism Research Initiative (SFARI) gene scoring. These genes encompass critical autism pathways such as neuron development, synapse complexity, cytoskeleton, and microtubule activation. Among these 15 genes, overlapping variants were present across multiple samples: KMT2C in 167 cases, CNTNAP2 in 192 samples, CACNA1C in 152 cases, and SHANK3 in 124 cases. Pathway analysis identifies clustering and interplay of autism genes—WDFY3, SHANK2, CNTNAP2, HOMER1, SYNGAP1, and ANK2 with CNTNAP2. These genes coincide across autism-relevant pathways, namely abnormal social behavior and intellectual and cognitive impairment. Based on multiple layers of selection criteria, CNTNAP2 was chosen as the master gene for the study. It is an essential gene for autism with speech-language delays, a typical phenotype in most cases under study. It showcases nine variants across multiple samples with one damaging variant, T589P, with a GERP rank score range of 0.065–0.95. This unique variant was present across 86.5% of the samples impairing the epithelial growth factor (EGF) domain. Established microRNA (miRNA) genes hsa-mir-548aq and hsa-mir-548f were mutated within the CNTNAP2 region, adding to the severity. The mutated protein showed reduced stability by 0.25, increased solvent accessibility by 9%, and reduced depth by 0.2, which rendered the protein non-functional. Secondary physical interactors of CNTNAP2 through CNTN2 proteins were mutated in the samples, further intensifying the severity.ConclusionCNTNAP2 has been identified as a master gene in autism manifestation responsible for speech-language delay by impairing the EGF protein domain and downstream cascade. The decrease in EGF is correlated with vital autism symptoms, especially language disabilities.

Autism-linked gene FoxP1 selectively regulates the cultural transmission of learned vocalizations.

Autism spectrum disorders (ASDs) are characterized by impaired learning of social skills and language. Memories of how parents and other social models behave are used to guide behavioral learning. How ASD-linked genes affect the intertwined aspects of observational learning and behavioral imitation is not known. Here, we examine how disrupted expression of the ASD gene FOXP1, which causes severe impairments in speech and language learning, affects the cultural transmission of birdsong between adult and juvenile zebra finches. FoxP1 is widely expressed in striatal-projecting forebrain mirror neurons. Knockdown of FoxP1 in this circuit prevents juvenile birds from forming memories of an adult song model but does not interrupt learning how to vocally imitate a previously memorized song. This selective learning deficit is associated with potent disruptions to experience-dependent structural and synaptic plasticity in mirror neurons. Thus, FoxP1 regulates the ability to form memories essential to the cultural transmission of behavior.

Parallel in vivo analysis of large-effect autism genes implicates cortical neurogenesis and estrogen in risk and resilience

Gene Ontology analyses of autism spectrum disorders (ASD) risk genes have repeatedly highlighted synaptic function and transcriptional regulation as key points of convergence. However, these analyses rely on incomplete knowledge of gene function across brain development. Here we leverage Xenopus tropicalis to study invivo ten genes with the strongest statistical evidence for association with ASD. All genes are expressed in developing telencephalon at time points mapping to human mid-prenatal development, and mutations lead to an increase in the ratio of neural progenitor cells to maturing neurons, supporting previous in silico systems biological findings implicating cortical neurons in ASD vulnerability, but expanding the range of convergent functions to include neurogenesis. Systematic chemical screening identifies that estrogen, via Sonic hedgehog signaling, rescues this convergent phenotype in Xenopus and human models of brain development, suggesting a resilience factor that may mitigate a range of ASD genetic risks.

Multiplex gene and phenotype network to characterize shared genetic pathways of epilepsy and autism

It is well established that epilepsy and autism spectrum disorder (ASD) commonly co-occur; however, the underlying biological mechanisms of the co-occurence from their genetic susceptibility are not well understood. Our aim in this study is to characterize genetic modules of subgroups of epilepsy and autism genes that have similar phenotypic manifestations and biological functions. We first integrate a large number of expert-compiled and well-established epilepsy- and ASD-associated genes in a multiplex network, where one layer is connected through protein–protein interaction (PPI) and the other layer through gene-phenotype associations. We identify two modules in the multiplex network, which are significantly enriched in genes associated with both epilepsy and autism as well as genes highly expressed in brain tissues. We find that the first module, which represents the Gene Ontology category of ion transmembrane transport, is more epilepsy-focused, while the second module, representing synaptic signaling, is more ASD-focused. However, because of their enrichment in common genes and association with both epilepsy and ASD phenotypes, these modules point to genetic etiologies and biological processes shared between specific subtypes of epilepsy and ASD. Finally, we use our analysis to prioritize new candidate genes for epilepsy (i.e. ANK2, CACNA1E, CACNA2D3, GRIA2, DLG4) for further validation. The analytical approaches in our study can be applied to similar studies in the future to investigate the genetic connections between different human diseases.

How mutations in top autism gene could lead to seizures

How mutations in top autism gene could lead to seizures

Overlapped Pathways of Autism Genes and Cancer Genes are Targeted by Viruses

Overlapped Pathways of Autism Genes and Cancer Genes are Targeted by Viruses

Whole Exome Sequencing Identifies Novel De Novo Variants Interacting with Six Gene Networks in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a highly heritable condition caused by a combination of environmental and genetic factors such as de novo and inherited variants, as well as rare or common variants among hundreds of related genes. Previous genome-wide association studies have identified susceptibility genes; however, most ASD-associated genes remain undiscovered. This study aimed to examine rare de novo variants to identify genetic risk factors of ASD using whole exome sequencing (WES), functional characterization, and genetic network analyses of identified variants using Korean familial dataset. We recruited children with ASD and their biological parents. The clinical best estimate diagnosis of ASD was made according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5TM), using comprehensive diagnostic instruments. The final analyses included a total of 151 individuals from 51 families. Variants were identified and filtered using the GATK Best Practices for bioinformatics analysis, followed by genome alignments and annotation to the reference genome assembly GRCh37 (liftover to GRCh38), and further annotated using dbSNP 154 build databases. To evaluate allele frequencies of de novo variants, we used the dbSNP, gnomAD exome v2.1.1, and genome v3.0. We used Ingenuity Pathway Analysis (IPA, Qiagen) software to construct networks using all identified de novo variants with known autism-related genes to find probable relationships. We identified 36 de novo variants with potential relations to ASD; 27 missense, two silent, one nonsense, one splice region, one splice site, one 5′ UTR, and one intronic SNV and two frameshift deletions. We identified six networks with functional relationships. Among the interactions between de novo variants, the IPA assay found that the NF-κB signaling pathway and its interacting genes were commonly observed at two networks. The relatively small cohort size may affect the results of novel ASD genes with de novo variants described in our findings. We did not conduct functional experiments in this study. Because of the diversity and heterogeneity of ASD, the primary purpose of this study was to investigate probable causative relationships between novel de novo variants and known autism genes. Additionally, we based functional relationships with known genes on network analysis rather than on statistical analysis. We identified new variants that may underlie genetic factors contributing to ASD in Korean families using WES and genetic network analyses. We observed novel de novo variants that might be functionally linked to ASD, of which the variants interact with six genetic networks.

Coupling of autism genes to tissue-wide expression and dysfunction of synapse, calcium signalling and transcriptional regulation.

Autism Spectrum Disorder (ASD) is a heterogeneous disorder that is often accompanied with many co-morbidities. Recent genetic studies have identified various pathways from hundreds of candidate risk genes with varying levels of association to ASD. However, it is unknown which pathways are specific to the core symptoms or which are shared by the co-morbidities. We hypothesised that critical ASD candidates should appear widely across different scoring systems, and that comorbidity pathways should be constituted by genes expressed in the relevant tissues. We analysed the Simons Foundation for Autism Research Initiative (SFARI) database and four independently published scoring systems and identified 292 overlapping genes. We examined their mRNA expression using the Genotype-Tissue Expression (GTEx) database and validated protein expression levels using the human protein atlas (HPA) dataset. This led to clustering of the overlapping ASD genes into 2 groups; one with 91 genes primarily expressed in the central nervous system (CNS geneset) and another with 201 genes expressed in both CNS and peripheral tissues (CNS+PT geneset). Bioinformatic analyses showed a high enrichment of CNS development and synaptic transmission in the CNS geneset, and an enrichment of synapse, chromatin remodelling, gene regulation and endocrine signalling in the CNS+PT geneset. Calcium signalling and the glutamatergic synapse were found to be highly interconnected among pathways in the combined geneset. Our analyses demonstrate that 2/3 of ASD genes are expressed beyond the brain, which may impact peripheral function and involve in ASD co-morbidities, and relevant pathways may be explored for the treatment of ASD co-morbidities.

Identification of primary copy number variations reveal enrichment of Calcium, and MAPK pathways sensitizing secondary sites for autism

BackgroundAutism is a neurodevelopmental condition with genetic heterogeneity. It is characterized by difficulties in reciprocal social interactions with strong repetitive behaviors and stereotyped interests. Copy number variations (CNVs) are genomic structural variations altering the genomic structure either by duplication or deletion. De novo or inherited CNVs are found in 5–10% of autistic subjects with a size range of few kilobases to several megabases. CNVs predispose humans to various diseases by altering gene regulation, generation of chimeric genes, and disruption of the coding region or through position effect. Although, CNVs are not the initiating event in pathogenesis; additional preceding mutations might be essential for disease manifestation. The present study is aimed to identify the primary CNVs responsible for autism susceptibility in healthy cohorts to sensitize secondary-hits. In the current investigation, primary-hit autism gene CNVs are characterized in 1715 healthy cohorts of varying ethnicities across 12 populations using Affymetrix high-resolution array study. Thirty-eight individuals from twelve families residing in Karnataka, India, with the age group of 13–73 years are included for the comparative CNV analysis. The findings are validated against global 179 autism whole-exome sequence datasets derived from Simons Simplex Collection. These datasets are deposited at the Simons Foundation Autism Research Initiative (SFARI) database.ResultsThe study revealed that 34.8% of the subjects carried 2% primary-hit CNV burden with 73 singleton-autism genes in different clusters. Of these, three conserved CNV breakpoints were identified with ARHGAP11B, DUSP22, and CHRNA7 as the target genes across 12 populations. Enrichment analysis of the population-specific autism genes revealed two signaling pathways—calcium and mitogen-activated protein kinases (MAPK) in the CNV identified regions. These impaired pathways affected the downstream cascades of neuronal function and physiology, leading to autism behavior. The pathway analysis of enriched genes unravelled complex protein interaction networks, which sensitized secondary sites for autism. Further, the identification of miRNA targets associated with autism gene CNVs added severity to the condition.ConclusionThese findings contribute to an atlas of primary-hit genes to detect autism susceptibility in healthy cohorts, indicating their impact on secondary sites for manifestation.

Altered hippocampal-prefrontal communication during anxiety-related avoidance in mice deficient for the autism-associated gene Pogz.

Many genes have been linked to autism. However, it remains unclear what long-term changes in neural circuitry result from disruptions in these genes, and how these circuit changes might contribute to abnormal behaviors. To address these questions, we studied behavior and physiology in mice heterozygous for Pogz, a high confidence autism gene. Pogz+/- mice exhibit reduced anxiety-related avoidance in the elevated plus maze (EPM). Theta-frequency communication between the ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC) is known to be necessary for normal avoidance in the EPM. We found deficient theta-frequency synchronization between the vHPC and mPFC in vivo. When we examined vHPC-mPFC communication at higher resolution, vHPC input onto prefrontal GABAergic interneurons was specifically disrupted, whereas input onto pyramidal neurons remained intact. These findings illustrate how the loss of a high confidence autism gene can impair long-range communication by causing inhibitory circuit dysfunction within pathways important for specific behaviors.

Tauopathy in the young autistic brain: novel biomarker and therapeutic target

Given our recent discovery of somatic mutations in autism spectrum disorder (ASD)/intellectual disability (ID) genes in postmortem aged Alzheimer’s disease brains correlating with increasing tauopathy, it is important to decipher if tauopathy is underlying brain imaging results of atrophy in ASD/ID children. We concentrated on activity-dependent neuroprotective protein (ADNP), a prevalent autism gene. The unique availability of multiple postmortem brain sections of a 7-year-old male, heterozygous for ADNP de novo mutation c.2244Adup/p.His559Glnfs*3 allowed exploration of tauopathy, reflecting on a general unexplored mechanism. The tested subject exhibited autism, fine motor delays, severe intellectual disability and seizures. The patient died after multiple organ failure following liver transplantation. To compare to other ADNP syndrome mutations, immortalized lymphoblastoid cell lines from three different patients (including ADNP p.Arg216*, p.Lys408Valfs*31, and p.Tyr719* heterozygous dominant mutations) and a control were subjected to RNA-seq. Immunohistochemistry, high-throughput gene expression profiles in numerous postmortem tissues followed. Comparisons to a control brain and to extensive datasets were used. Live cell imaging investigated Tau-microtubule interaction, protecting against tauopathy. Extensive child brain tauopathy paralleled by multiple gene expression changes was discovered. Tauopathy was explained by direct mutation effects on Tau-microtubule interaction and correction by the ADNP active snippet NAP. Significant pathway changes (empirical P value < 0.05) included over 100 genes encompassing neuroactive ligand–receptor and cytokine–cytokine receptor interaction, MAPK and calcium signaling, axon guidance and Wnt signaling pathways. Changes were also seen in steroid biosynthesis genes, suggesting sex differences. Selecting the most affected genes by the ADNP mutations for gene expression analysis, in multiple postmortem tissues, identified Tau (MAPT)-gene-related expression changes compared with extensive normal gene expression (RNA-seq) databases. ADNP showed relatively reduced expression in the ADNP syndrome cerebellum, which was also observed for 25 additional genes (representing >50% of the tested genes), including NLGN1, NLGN2, PAX6, SMARCA4, and SNAP25, converging on nervous system development and tauopathy. NAP provided protection against mutated ADNP disrupted Tau-microtubule association. In conclusion, tauopathy may explain brain-imaging findings in ADNP syndrome children and may provide a new direction for the development of tauopathy protecting drug candidates like NAP in ASD/ID.

Homeostatic plasticity fails at the intersection of autism-gene mutations and a novel class of common genetic modifiers.

We identify a set of common phenotypic modifiers that interact with five independent autism gene orthologs (RIMS1, CHD8, CHD2, WDFY3, ASH1L) causing a common failure of presynaptic homeostatic plasticity (PHP) in Drosophila. Heterozygous null mutations in each autism gene are demonstrated to have normal baseline neurotransmission and PHP. However, PHP is sensitized and rendered prone to failure. A subsequent electrophysiology-based genetic screen identifies the first known heterozygous mutations that commonly genetically interact with multiple ASD gene orthologs, causing PHP to fail. Two phenotypic modifiers identified in the screen, PDPK1 and PPP2R5D, are characterized. Finally, transcriptomic, ultrastructural and electrophysiological analyses define one mechanism by which PHP fails; an unexpected, maladaptive up-regulation of CREG, a conserved, neuronally expressed, stress response gene and a novel repressor of PHP. Thus, we define a novel genetic landscape by which diverse, unrelated autism risk genes may converge to commonly affect the robustness of synaptic transmission.

Potential role of genomic imprinted genes and brain developmental related genes in autism

BackgroundAutism is a complex disease involving both environmental and genetic factors. Recent efforts have implicated the correlation of genomic imprinting and brain development in autism, however the pathogenesis of autism is not completely clear. Here, we used bioinformatic tools to provide a comprehensive analysis of the autism-related genes, genomic imprinted genes and the spatially and temporally differentially expressed genes of human brain, aiming to explore the relationship between autism, brain development and genomic imprinting.MethodsThis study analyzed the distribution correlation between autism-related genes and imprinted genes on chromosomes using sliding windows and statistical methods. The normal brains’ gene expression microarray data were reanalyzed to construct a spatio-temporal coordinate system of gene expression during brain development. Finally, we intersected the autism-related genes, imprinted genes and brain spatio-temporally differentially expressed genes for further analysis to find the major biological processes that these genes involved.ResultsWe found a positive correlation between the autism-related genes’ and imprinted genes’ distribution on chromosomes. Through the analysis of the normal brain microarray data, we constructed a spatio-temporal coordinate system of gene expression during human brain development, and obtained 13 genes that are differentially expressed in the process of brain development, which are both autism-related genes and imprinted genes. Furthermore, enrichment analysis illustrated that these genes are mainly involved in the biological processes, such as gamma-aminobutyric acid signaling pathway, neuron recognition, learning or memory, and regulation of synaptic transmission. Bioinformatic analysis implied that imprinted genes regulate the development and behavior of the brain. And its own mutation or changes in the epigenetic modification state of the imprinted control region could lead to some diseases, indicating that imprinted genes and brain development play an important role in diagnosis and prognosis of autism.ConclusionThis study systematically correlates brain development and genomic imprinting with autism, which provides a new perspective for the study of genetic mechanisms of autism, and selected the potential candidate biomarkers for early diagnosis of autism in clinic.

Sex Bias in Maternal Immune Activation-Induced Neurodevelopmental Disorder Begins at the Placenta

Systemic maternal inflammation during pregnancy is increasingly thought to be a risk factor for development of autism spectrum disorder (ASD), which is diagnosed at a rate 4-fold higher in males than in females. Administration of the viral mimic polyI:C to pregnant mice at mid-gestation leads to ASD-related phenotypes in offspring, consisting of deficits in communication and socialization, as well as repetitive behaviors. In this model of maternal immune activation (MIA), elevated production of maternal serum cytokines is known to promote alterations in fetal neurodevelopment. Although male and female littermates are exposed to the same maternal inflammation, we show that behavioral deficits can be elicited preferentially in the male offspring, mirroring the sex bias observed in human ASD. Because the placenta is partially derived from fetal cells and is the first site of fetal exposure to hematogenous maternal inflammation, we hypothesized that sex-specific reactions to MIA may originate at the placenta and that characterization of these sex differences may offer new insights into the orgins of neurodevelopmental disorders. To characterize responses to MIA at the maternal-fetal interface, we conducted bulk RNA sequencing of the placenta from polyI:C- and saline-treated embryos at several time points post-injection. We identified male-biased elevation in the expression of inflammatory signatures involving neutrophils, innate immune signaling, and antigen presentation. Placental transcriptomics analysis also identified male-specific downregulation of cholesterol and fatty acid synthesis as well as a gene signature suggesting failing placental health. Interestingly, we found that MIA induced the differential expression of a large percentage of high-risk autism genes at the placenta. These findings shed new light on how sex and maternal inflammation interface to shape placental responses and may help to reveal new molecular players underpinning sex differences in neurodevelopmental disorders.

Consecrate Recurrent Neural Network Classifier for Autism Classification

Most recent discoveries in Autism Spectrum Disorder (ASD) detection and classification studies reveal that there is a substantial relationship between Autism disorders and gene sequences. This work is indented to classify the autism spectrum disorder groups and sub-groups based on the gene sequences. The gene sequences are large data and perplexed for handling with conventional data mining or classification procedures. The Consecrate Recurrent Neural Network Classifier for Autism Classification (CRNNC-AC) work is introduced in this work to classify autism disorders using gene sequence data. A dedicated Elman [1] type Recurrent Neural Network (RNN) is introduced along with a legacy Long Short-Term Memory (LSTM) [2] in this classifier. The LSTM model is contrived to achieve memory optimization to eliminate memory overflows without affecting the classification accuracy. The classification quality metrics [3] such as Accuracy, Sensitivity, Specificity and F1-Score are concerned for optimization. The processing time of the proposed method is also measured to evaluate the pertinency.

Behavioral, circuitry, and molecular aberrations by region-specific deficiency of the high-risk autism gene Cul3.

Cullin 3 (Cul3) gene, which encodes a core component of the E3 ubiquitin ligase complex that mediates proteasomal degradation, has been identified as a true high-risk factor for autism. Here, by combining behavioral, electrophysiological, and proteomic approaches, we have examined how Cul3 deficiency contributes to the etiology of different aspects of autism. Heterozygous mice with forebrain Cul3 deletion displayed autism-like social interaction impairment and sensory-gating deficiency. Region-specific deletion of Cul3 leads to distinct phenotypes, with social deficits linked to the loss of Cul3 in prefrontal cortex (PFC), and stereotypic behaviors linked to the loss of Cul3 in striatum. Correlated with these behavioral alterations, Cul3 deficiency in forebrain or PFC induces NMDA receptor hypofunction, while Cul3 loss in striatum causes a cell type-specific alteration of neuronal excitability in striatal circuits. Large-scale profiling has identified sets of misregulated proteins resulting from Cul3 deficiency in different regions, including Smyd3, a histone methyltransferase involved in gene transcription. Inhibition or knockdown of Smyd3 in forebrain Cul3-deficient mice ameliorates social deficits and restores NMDAR function in PFC. These results have revealed for the first time a potential molecular mechanism underlying the manifestation of different autism-like behavioral deficits by Cul3 deletion in cortico-striatal circuits.