Gene expression data from the brain of adult autism model marmosets
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ABSTRACT:
ORGANISM(S): Callithrix jacchus
PROVIDER: GSE199560 | GEO | 2022/05/01
REPOSITORIES: GEO
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Project description:Autism spectrum disorder (ASD) affects gene expression in early postnatal development. We used valproic acid (VPA)-induced ASD model marmosets. Gene expression in VPA-exposed and unexposed (UE) marmosets were analyzed at 0, 3 and 6 months (M). We revealed three groups of differentially expressed genes based on the temporal patterns of modulation.
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Project description:Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder where patients have impaired social behavior, communication, repetitive behaviors, and restricted interest. Valproic acid (VPA) has been widely used to treat patients with epilepsy and bipolar disorder patients. However, VPA treatment during pregnancy has produced offspring with neurodevelopmental disorders, including ASD. To better understand the molecular function of ASD, we have used valproic acid, chemically induced ASD mice. We have performed LC-MS/MS analysis of VPA-induced offspring mice to the control to see the difference in their proteome difference. Our analysis showed that many neuronal network pathways were highly expressed in our differentially expressed proteins, and among them, Wnt/ β-catenin pathways showed clear enrichment. The RNF146 (E3 Ubiquitin-protein ligase) increase in VPA-exposed mice showed a highly significant effect on canonical Wnt/ β-catenin signaling pathways by disrupting the β-catenin destruction complex. The proteins like CREBBP, TCF4, and GSK3B also showed significant changes that indicate dysfunction of β-catenin destruction complex and activation of transcription factors.
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Project description:Developing cost-effective and disease-relevant animal models is essential for advancing biomedical research into human disorders. This study investigates the feasibility of a pig model for autism spectrum disorder (ASD) using embryonic exposure to valproic acid (VPA), an antiepileptic drug known to increase ASD risk. We established experimental paradigms to assess the behavioral characteristics of these pig models. Administration of VPA to Bama miniature pigs (Sus scrofa domestica) during critical embryonic stages resulted in abnormal gait, increased anxiety levels, reduced learning capabilities, and altered social patterns, while largely preserving social preference of treated piglets. Notably, we detected significant neuroanatomical changes in cortical regions associated with ASD in the VPA-treated pigs, including cortical malformation, increased neuronal soma size, decreased dendritic complexity, and reduced dendritic spine maturation. Transcriptome analysis of the prefrontal cortex of VPA-treated pigs further revealed substantial alterations in the expression of genes linked to ASD, especially genes of the dopamine signaling pathway, highlighting the model’s relevance and potential for shedding light on ASD’s underlying neuropathological and molecular mechanisms. These findings suggest that pig models could serve as a promising alternative to traditional rodent models and provide an ethical substitute for using primates in the translational research of neurodevelopmental disorders.
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Project description:Autism spectrum disorders (ASDs) are a neurodevelopmental disorder characterized by impairments in social interactions and stereotyped behaviors. While ASD has a strong genetic background, environmental factors including toxins, pesticides, infection and drugs are also known to confer autism susceptibility, likely by inducing epigenetic changes. Exposure to Valproic acid (VPA), a drug for epilepsy and bipolar disorders, during pregnancy is highly associated with the risk of ASD children. In rodents, in utero VPA exposure can precipitate behavioral phenotypes related to ASD in the offspring. Since VPA is an inhibitor of histone deacethytransferase (HDAC) activity, it thought to cause ASD with epigenetic modification. However, the core mechanism by which prenatal VPA exposure causes onset of ASD is still not fully uncovered. Here we revealed that prenatal VPA exposure strongly influences development of vasoactive intestinal peptide (VIP) - positive neurons, a subtype of cortical GABAergic interneurons. The number of VIP+ interneurons was severely reduced in somatosensory area of VPA-exposed ASD animals. We then found that the reduction in VIP+ interneurons is caused by the inhibition of HDAC3 activity upon prenatal VPA exposure. Importantly, prenatal HDAC3 inhibition caused not only the selective reduction in VIP+ interneurons but also the ASD-like behaviors in mice. We then demonstrated that the HDAC3 inhibition aberrantly activates Notch signaling, which influences the cell fate determination of VIP+ interneuron progenitors in caudal ganglionic eminence. Thus, this study uncovers the mechanism by which specific HDAC inhibition during development influences a specific type of GABAergic interneurons in the ASD model. The findings provide a novel insight into the understanding of ASD pathophysiology.
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Project description:Autism spectrum disorder (ASD) affects 1 in 44 children. Chromatin regulatory proteins are overrepresented among genes that contain high risk variants in ASD. Disruption of the chromatin environment leads to widespread dysregulation of gene expression, which is traditionally thought of as a mechanism of disease pathogenesis associated with ASD. Alternatively, alterations in chromatin dynamics could also lead to dysregulation of alternative splicing, which is understudied as a mechanism of ASD pathogenesis. The anticonvulsant valproic acid (VPA) is a well-known environmental risk factor for ASD that acts as a class I histone deacetylase (HDAC) inhibitor. However, the precise molecular mechanisms underlying defects in human neuronal development associated with exposure to VPA are understudied. To dissect how VPA exposure and subsequent chromatin hyperacetylation influence molecular signatures involved in ASD pathogenesis, we conducted RNA sequencing (RNA-seq) in human cortical neurons that were treated with VPA. We observed that differentially expressed genes (DEGs) were enriched for mRNA splicing, mRNA processing, histone modification, and metabolism related gene sets. Furthermore, we observed widespread increase in the number and the type of alternative splicing events. Analysis of differential transcript usage (DTU) showed that exposure to VPA induces extensive alterations in transcript isoform usage across neurodevelopmentally important genes. Finally, we find that DEGs and genes that display DTU overlap with known ASD-risk genes. Together, these findings suggest that, in addition to differential gene expression, changes in alternative splicing correlated with alterations in the chromatin environment could act as an additional mechanism of disease in ASD.
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Project description:Human forebrain organoids (day 42) derived from U1M and U2F iPS cell lines were exposed with or without 1 mM valproic acid (VPA) for 72h. Organoids were then randomly selected for RNA sequencing, we found that differentially expressed genes (DEGs) induced by VPA exposure that shared in both U1M and U2F were enriched with neural development, synaptic transmission, calcium and potassium signaling pathways. The DEGs were also significantly enriched with autism spectrum disorder (ASD)-associated genes, including genes dysregulated in brains or organoids derived from ASD patients, and known ASD risk genes, as well as genes in ASD risk-associated gene coexpression modules.
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Project description:Autism Spectrum Disorder (ASD) is a developmental disorder characterized by impaired social communication and repetitive behaviors. In recent years, a pharmacological mouse model of ASD involving maternal administration of valproic acid (VPA) has become widely used. Newborn pups in this model show an abnormal balance between excitatory and inhibitory (E/I) signaling in neurons and exhibit ASD-like behavior. To elucidate the molecular basis of this model, we analyzed secretome of primary neurons cultured from embryos maternally treated with or without VPA.
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Project description:In this study, we explored molecular alterations in the hippocampus of prenatal valproic acid (VPA)-exposed rats as a model of autism spectrum disorders (ASD). In addition, we assessed effects of chronic administration of intranasal oxytocin, a promising peptide for ASD treatment. Comparative analyses revealed that prenatal VPA exposure altered gene expression, a part of which is involved in key features including memory, developmental process, and epilepsy. Oxytocin partly improved these gene expression, which were predicted to interact with those involved in social behaviors and hippocampal-dependent memory. The present study documented molecular profiling in the hippocampus related to ASD and improvement by chronic treatment of oxytocin.
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Project description:Here we performed single-cell RNA sequencing to examine the transcriptomes of over 45,000 cells isolated from the hippocampus of an autistic mouse model. Each cell was assigned to one of twelve major cell types based on distinct expression profiles. Differential expression analysis identified cell type specific genes with altered expression after prenatal valproic acid exposure. The largest number of differentially expressed genes was detected in neurons, choroid plexus epithelial cells, and microglia. In microglia, there were more male-specific than female-specific inflammation-related pathways that were important to induce autistic-like behavior. Meanwhile, there were several X-linked genes among the male-specific DEGs of neurons, and the changes of those genes after prenatal VPA exposure may be another key reason why more male than female ASD patients are seen in clinic.
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