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Comparison of DEG between neonatal male and female mice age of P0 by CHD8 Asn2373LysfsX2 heterozygote mutation

ABSTRACT: CHD8, encoding a chromatin remodeling protein, is one of the most frequently mutated genes in autism spectrum disorders (ASDs) 1-8. However, whether and how such mutations cause autistic behaviors remain unclear. Here we show that a human CHD8 mutation causes autistic-like behaviors and enhanced excitatory drive specifically in male mice. We found that knockin mice carrying a heterozygous frame-shift mutation in the Chd8 gene (Asn2373LysfsX2) identified in human individuals with ASDs (Chd8+/N2373K mice) display male-specific autistic-like behaviors. Gene transcript analysis shows that male and female Chd8+/N2373K neurons exhibit largely opposite changes in the levels of 29 mRNAs, nine of which correspond to known ASD-risk genes. These results suggest that a human CHD8 mutation causes male-specific autistic-like behaviors in mice in association with gender-specific differential changes in gene transcripts and excitatory drive in the brain.

ORGANISM(S): Mus musculus

PROVIDER: GSE80803 | GEO | 2018/06/15

REPOSITORIES: GEO

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Hippocampus transcriptome analysis of CHD8 Asn2373LysfsX2 heterozygote mutation mice age of P25

Project description:CHD8, encoding a chromatin remodeling protein, is one of the most frequently mutated genes in autism spectrum disorders. However, how such mutations cause autistic behaviors remain unclear. In mice carrying a heterozygous frame-shift mutation in the Chd8 gene (Asn2373LysfsX2) identified in autistic human individuals, we observed autistic-like behaviors that are much stronger in males than in females, similar to human cases. These behaviors included enhanced mother-seeking ultrasonic vocalizations in pups, mother-attachment behaviors in juveniles, and isolation-induced self-grooming in adults. These behaviors were associated with opposite changes in synaptic excitation/inhibition and neuronal firing in male and female mice, but with strong changes in gene expression in female mice. Therefore, this CHD8 mutation may cause male-preponderant autistic-like behaviors in mice through differential synaptic/neuronal changes and gene expression

2018-06-15 | GSE103377 | GEO

Comparison of DEG between neonatal male and female mice age of P25 by CHD8 Asn2373LysfsX2 heterozygote mutation.

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Transcriptome analysis of Chd8 S62X heterozygote mutant and wild-type mice

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Prefrontal cortex transcriptome of Arid1b heterozygote mutation mice age of postnatal day 10

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Whole-brain transcriptome of Arid1b heterozygote mutation mice age of postnatal day 3

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Whole brain transcriptome analysis of Shank2 knock-out mice

Project description:Autism spectrum disorders (ASDs) are thought to involve neurodevelopmental dysregulations that lead to visible symptoms at early stages of life. Many ASD-related mechanisms suggested by animal studies are supported by demonstrated improvement in autistic-like phenotypes in adult animals following experimental reversal of dysregulated mechanisms. However, whether such mechanisms also act at earlier stages to cause autistic-like phenotypes is unclear. Here, we show that early correction of a dysregulated mechanism in young mice prevents manifestation of autistic-like phenotypes in adult mice. Shank2–/– mice, known to display N-methyl-D-aspartate receptor (NMDAR) hypofunction and autistic-like behaviors at post-weaning stages after postnatal day 21 (P21), show the opposite synaptic phenotype–NMDAR hyperfunction–at an earlier pre-weaning stage (~P14). Moreover, this NMDAR hyperfunction at P14 is rapidly shifted to NMDAR hypofunction after weaning (~P24). Chronic suppression of the early NMDAR hyperfunction by the NMDAR antagonist memantine (P7?21) prevents the NMDAR hypofunction and autistic-like behaviors from manifesting at later stages (~P28 and P56). These results suggest that early NMDAR hyperfunction leads to late NMDAR hypofunction and autistic-like behaviors in Shank2–/– mice, and that early correction of NMDAR function has the long-lasting effect of preventing autistic-like phenotypes from developing at later stages.

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Prefrontal cortex transcriptome of Arid1b heterozygote mutantation mice and drug treated-mice age of postnatal day 120

Project description:Arid1b is a chromatin remodeler implicated in neurodevelopmental disorders. Arid1b mutant mice with haploinsufficiency (Arid1b HT) displayed persistent excitatory synaptic dysfunction from juvenile to adult stage, decreased synaptic density and transmission. Moreover, they showed autistic-like behaviors in both of early and adult stages, decreased sociability in pup USV calling and adult social interaction, and adult repetitive grooming. We found that early chronic fluoxetine treatment could carry out long-lasting restoration in electrophysiological and behavioral deficits in Arid1b HT mice. Prefrontal cortex specific transcriptomic analysis with mice at postnatal day 120 which underwent chronic fluoxetine treatment from postnatal day 3 to postnatal day 21 via mammillary milk was done to investigate transcriptomic reprogramming which contributes to this restoration.

2022-07-21 | GSE203343 | GEO

Comparison of DEG between memantine-, vehicle-treated and naive Shank2 wild-type and knock-out mice

Project description:Autism spectrum disorders (ASDs) are thought to involve diverse neurodevelopmental dysregulations that lead to visible symptoms at early stages of life. Many ASD-related mechanisms suggested by animal studies are supported by demonstrated improvement in autistic-like phenotypes in adult animals following experimental reversal of dysregulated mechanisms. However, whether such mechanisms also act at earlier stages to play important roles in the development of autistic-like phenotypes is unclear. Here, we show that early correction of a dysregulated mechanism in young mice prevents manifestation of autistic-like phenotypes in adult mice. Shank2–/– mice, known to display N-methyl-D-aspartate receptor (NMDAR) hypofunction and autistic-like behaviors at post-weaning stages after postnatal day 21 (P21), show the opposite synaptic phenotype—NMDAR hyperfunction—at an earlier pre-weaning stage (~P14). Moreover, this NMDAR hyperfunction at P14 is rapidly shifted to NMDAR hypofunction after weaning (~P24). Chronic suppression of the early NMDAR hyperfunction in Shank2–/– mice by the NMDAR antagonist memantine before weaning (P7–21) prevents the NMDAR hypofunction and autistic-like behaviors from manifesting at later stages (~P28 and P56). In addition, early memantine treatment of Shank2–/– mice substantially alters transcription of numerous genes, driving gene expression patterns in a direction largely opposite that observed in drug-untreated Shank2–/– mice, which, interestingly, mimic those observed in autistic individuals. These results suggest that early NMDAR hyperfunction in Shank2–/– mice leads to late NMDAR hypofunction and autistic-like behaviors, and that early correction of NMDAR function has the long-lasting effect of preventing autistic-like phenotypes from developing at later stages. This SuperSeries is composed of the SubSeries listed below.

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Comparison of DEG between neonatal male and female mice by CHD8 Asn2373LysfsX2 heterozygote mutation

Project description:Comparison of DEG between neonatal male and female mice by CHD8 Asn2373LysfsX2 heterozygote mutation

| PRJNA344502 | ENA

Transcriptome of iPSC-derived Neural Cells with Heterozygous Knockout in CHD8

Project description:CHD8, encoding Chromodomain helicase DNA binding protein 8, is a top autism spectrum disorders (ASDs) risk gene. To better understanding the molecular links between CHD8 functions and ASD, we have applied the CRISPR/Cas9 technology to knockout one copy of CHD8 in induced pluripotent stem cells (iPSCs) to mimic the loss of function status that would exist in the developing human embryo prior to neuronal differentiation. Transcriptome profiling (RNA-seq) in neural progenitors and early differentiating neurons revealed that CHD8 hemizygosity (CHD8+/-) affected the expression of several thousands of genes, enriched for functions of neural development, Î²-catenin/Wnt signaling, extracellular matrix, and skeletal system development. Moreover, CHD8 regulates multiple genes implicated in ASD, schizophrenia and genes associated with brain volume. iPSCs derived from a healthy subject were transduced with CRISPR/Cas9 vectors with single guide RNA sequences to target the N-terminal of CHD8 protein to generate truncated mutation seach of the two target sequences. Two clones, one with a 2-bp (KO1) and the other with a 10-bp (KO2) heterozygous deletion were found.The CHD8+/- iPSC lines were used to generate NPCs and early differentiating neurons for RNA-seq analysis, together with samples prepared from the parental clones, for a total of 8 samples (two biological replicates of wild-type (WT) and CHD8+/- at two neurodevelopmental stages).

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