Transcriptome analysis of memantine-treated Shank2 wild-type and knock-out mice
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ABSTRACT:
PROVIDER: PRJNA721409 | ENA |
REPOSITORIES: ENA
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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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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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Project description:Comparison of DEG between memantine-, vehicle-treated and naive Shank2 wild-type and knock-out mice
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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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