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Whole brain transcriptome analysis of Shank2 knock-out mice

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE82066 | GEO | 2021/04/20

REPOSITORIES: GEO

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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.

2021-04-20 | GSE97896 | GEO

Transcriptome analysis of memantine-treated Shank2 wild-type and knock-out mice

Project description:Shank2 is an excitatory postsynaptic scaffolding protein strongly implicated in autism spectrum disorders (ASD). Shank2-mutant mice with a homozygous deletion of exons 6 and 7 show decreased NMDA receptor (NMDAR) functions and autistic-like behaviors in juvenile (~postnatal day or P21) and adult (> P56) stages that are rescued by NMDAR activation. These mice, however, show an opposite change increased NMDAR functions—at ~P14, and NMDAR suppression by early and chronic memantine treatment during P7–21 prevents NMDAR hypofunction and autistic-like behaviors at juvenile (~P21) and adult (~P56) stages. To explore molecular mechanisms underlying the long-lasting effects of early memantine treatment, we performed RNA-Seq analysis of forebrains from wild-type and Shank2-mutant mice early and chronically treated with vehicle or memantine. Memantine-treated Shank2-mutant mice showed upregulations of chromatin-related genes and downregulations of mitochondria- and ribosome-related genes. In addition, vehicle-treated Shank2-mutant mice showed transcriptomic patterns that are largely opposite to those observed in ASD, as supported by the expression patterns of ASD-risk/related genes and cell-type-specific genes. These patterns, likely representing compensatory changes, were weakened by early memantine treatment. These results suggest that early chronic memantine treatment in Shank2-mutant mice alters chromatin- and mitochondria/ribosome-related gene expressions and weakens anti-ASD transcriptomic patterns.

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Dosage-dependent differential transcriptomic changes in the prefrontal cortex of heterozygous and homozygous Shank2-mutant mice

Project description:Shank2 is an abundant postsynaptic scaffolding protein known to regulate excitatory synaptic assembly and function and is implicated in autism spectrum disorders (ASD). Whereas patient Shank2 mutations in autistic individuals are heterozygous, Shank2 functions studied in mice have mainly relied on the results from homozygous mutant mice, largely because of relatively strong synaptic and behavioral phenotypes. Moreover, although synaptic changes at juvenile and adult Shank2-mutant mice seem to be largely similar, it remains unclear whether there are any age-dependent changes across these stages at the molecular level. To address these questions, we attempted RNA-Seq analyses of the transcriptomes in the prefrontal cortex of both heterozygous and homozygous Shank2-mutant mice lacking exons 6 and 7 at juvenile and adult stages. The results indicate that heterozygous, but not homozygous, juvenile Shank2-mutant mice show strong transcriptomic changes that promote excitatory synaptic transmission and suppress ASD-related gene expressions. In contrast, adult Shank2-mutant mice show largely similar and dosage-dependent transcriptomic changes.

2021-05-27 | GSE168211 | GEO

Effects of NMDAR on mouse hippocampal neuron (HT22) mRNA and lncRNA expression during hypoxia/reoxygenation injury

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2024-02-06 | PXD046944 | Pride

Transcriptome analysis of Shank2 mutant mice

Project description:Autism spectrum disorders (ASDs) are a group of developmental disorders that cause variable and heterogeneous phenotypes across three behavioral domains such as atypical social behavior, disrupted communications, and highly restricted and repetitive behaviors. In addition to these core symptoms, other neurological abnormalities are associated with ASD, including intellectual disability (ID). However, the molecular etiology underlying these behavioral heterogeneities in ASD is unclear. Mutations in SHANK2 genes are associated with ASD and ID. Interestingly, two lines of Shank2 knockout mice (e6-7 KO and e7 KO) showed shared and distinct phenotypes. Here, we found that the expression levels of Gabra2, as well as of GABA receptor-mediated inhibitory neurotransmission, are reduced in Shank2 e6-7, but not in e7 KO mice compared with their own wild type littermates. Furthermore, treatment of Shank2 e6-7 KO mice with an allosteric modulator for the GABAA receptor reverses spatial memory deficits, indicating that reduced inhibitory neurotransmission may cause memory deficits in Shank2 e6-7 KO mice. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.

2017-01-24 | GSE79824 | GEO

Human NMDAR autoantibodies disrupt excitatory-inhibitory balance leading to hippocampal network hypersynchrony

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2023-09-24 | PXD032055 | Pride

Alteration of PFC proteome in MK-801 induced schizophrenia-like adolescent mice

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2022-07-05 | PXD035089 | iProX

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

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