Dosage-dependent differential transcriptomic changes in the prefrontal cortex of heterozygous and homozygous Shank2-mutant mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE168211 | GEO | 2021/05/27
REPOSITORIES: GEO
Similar Datasets
Project description:Shank2 is an abundant excitatory postsynaptic scaffolding protein implicated in neurodevelopmental disorders, including autism spectrum disorders (ASD), intellectual disability, developmental delay, and schizophrenia. Shank2-mutant mice with a homozygous deletion of exons 6 and 7 (Shank2-HM mice) show ASD-like behavioral deficits and altered synaptic functions, although little is known about how different brain regions contribute to Shank2-mutant phenotypes. Here we attempted transcriptomic analyses of the prefrontal cortex, hippocampus, and striatum in adult Shank2-heterozygous/HT and Shank2-homozygous/HM mice. The mutant cortex, hippocampus, and striatum displayed distinct sets of differentially expressed genes associated with neuronal and synaptic functions in a gene dosage-differential manner. Gene set enrichment analyses of cortical Shank2-HT transcripts revealed increased synaptic gene expression and transcriptomic changes that are opposite to those observed in ASD (reverse-ASD), whereas cortical Shank2-HM transcripts displayed decreased synaptic gene expression and ASD-like transcriptomic patterns. The hippocampal Shank2-HT transcripts displayed minimally altered synaptic gene expression and mixed ASD-like and reverse-ASD patterns, whereas the Shank2-HM-hippocampus showed increased synaptic gene expression and reverse-ASD patterns. The striatal Shank2-HT/HM transcriptomes were largely similar to the hippocampal transcriptomes, although the main changes were observed in cell-type-specific genes, unlike the hippocampal changes mainly involving ASD-related/risk genes. These results indicate that heterozygous and homozygous Shank2 deletions in mice lead to brain region- and gene dosage-differential transcriptomic changes.
2022-11-02 | GSE200439 | GEO
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.
2021-10-06 | GSE171931 | GEO
Project description:Shank3 is an abundant excitatory postsynaptic scaffolding proteins implicated in various neurodevelopmental and psychiatric disorders, including ASD, Phelan-McDermid syndrome, intellectual disability, and schizophrenia. Shank3-mutant mice with a homozygous deletion of exons 14-16 (Shank3-HM mice) show ASD-like behavioral deficits and altered synaptic and neuronal functions, but little is known about how different ages, brain regions, and gene dosages contribute to transcriptomic phenotypes in these mice. Here, we performed RNA-Seq-based transcriptomic analyses of the prefrontal cortex, hippocampus, and striatum in adult Shank3 heterozygous- and homozygous-mutant mice. In addition, juvenile and adult Shank3 homozygous-mutant forebrain transcriptomes were compared. Juvenile and adult forebrain transcriptomes from Shank3 homozygous-mutant mice showed the patterns that are opposite and similar to those observed in ASD: reverse-ASD and ASD-like patterns, respectively. Here, the juvenile reverse-ASD pattern involved synaptic gene upregulations and ribosomal and mitochondrial downregulations, whereas the adult ASD-like pattern involved opposite changes. Gene set enrichment analyses (GSEA) of brain regional transcripts in adult Shank3-HT and Shank3-HM mice revealed that the cortical, hippocampal, and striatal transcripts show distinctly altered biological functions and ASD-related/risk gene expressions. The cortex and striatum display ASD-like patterns whereas the hippocampus displays reverse-ASD patterns. The cortical ASD-like pattern more strongly involves ASD-risk genes whereas the striatal ASD-like pattern more strongly involves astrocyte/microglia genes. Shank3-HT and Shank3-HM transcripts in a given brain region display largely similar patterns in biological functions and ASD-related/risk gene expressions, suggestive of small gene dosage effects. These results suggest that heterozygous and homozygous Shank3 deletions in mice lead to age, brain region, and gene dosage-differential transcriptomic changes.
2022-11-02 | GSE201621 | GEO
Project description:Shank3 is an abundant excitatory postsynaptic scaffolding proteins implicated in various neurodevelopmental and psychiatric disorders, including ASD, Phelan-McDermid syndrome, intellectual disability, and schizophrenia. Shank3-mutant mice with a homozygous deletion of exons 14-16 (Shank3-HM mice) show ASD-like behavioral deficits and altered synaptic and neuronal functions, but little is known about how different ages, brain regions, and gene dosages contribute to transcriptomic phenotypes in these mice. Here, we performed RNA-Seq-based transcriptomic analyses of the prefrontal cortex, hippocampus, and striatum in adult Shank3 heterozygous- and homozygous-mutant mice. In addition, juvenile and adult Shank3 homozygous-mutant forebrain transcriptomes were compared. Juvenile and adult forebrain transcriptomes from Shank3 homozygous-mutant mice showed the patterns that are opposite and similar to those observed in ASD: reverse-ASD and ASD-like patterns, respectively. Here, the juvenile reverse-ASD pattern involved synaptic gene upregulations and ribosomal and mitochondrial downregulations, whereas the adult ASD-like pattern involved opposite changes. Gene set enrichment analyses (GSEA) of brain regional transcripts in adult Shank3-HT and Shank3-HM mice revealed that the cortical, hippocampal, and striatal transcripts show distinctly altered biological functions and ASD-related/risk gene expressions. The cortex and striatum display ASD-like patterns whereas the hippocampus displays reverse-ASD patterns. The cortical ASD-like pattern more strongly involves ASD-risk genes whereas the striatal ASD-like pattern more strongly involves astrocyte/microglia genes. Shank3-HT and Shank3-HM transcripts in a given brain region display largely similar patterns in biological functions and ASD-related/risk gene expressions, suggestive of small gene dosage effects. These results suggest that heterozygous and homozygous Shank3 deletions in mice lead to age, brain region, and gene dosage-differential transcriptomic changes.
2022-11-02 | GSE201853 | GEO
Project description:Heterozygous loss-of-function mutations in the synaptic scaffolding gene SHANK2 are strongly associated with autism spectrum disorder (ASD). To investigate their effect on synaptic connectivity, we generated cortical neurons from induced pluripotent stem cells (iPSC) derived from neurotypic and ASD-affected donors. We developed Sparse coculture for Connectivity (SparCon) assays where SHANK2 and control neurons were differentially labeled and sparsely seeded together on a lawn of unlabeled control neurons. We observed striking increases in total synapse number and dendrite complexity. Dendrite length increases were exacerbated by IGF1 or BDNF treatment. Increased excitatory synapse function in haploinsufficient SHANK2 neurons was phenocopied in gene-edited knockout SHANK2 neurons. Gene correction of an ASD SHANK2 mutation rescued excitatory synapse function supporting a role for SHANK2 as a negative regulator of connectivity in developing human neurons. The transcriptome in these isogenic SHANK2 neurons was deeply perturbed in synaptic and plasticity gene sets and ASD gene modules, and activity dependent dendrite extension was defective. Our unexpected findings provide evidence for hyperconnectivity and profoundly altered transcriptome in SHANK2 neurons derived from ASD subjects.
2019-02-04 | GSE122550 | GEO
Project description:Dyrk1A deficiency is linked to various neurodevelopmental disorders, including developmental delays and autism spectrum disorders (ASD). Haploinsufficiency of Dyrk1a in mice leads to ASD-related phenotypes, although key pathological mechanisms remain unclear. In addition, human DYRK1A mutations have not been characterized in mice. Here we report Dyrk1a-knockin mice carrying a human mutation (Ile48LysfsX2; Dyrk1a-I48K mice). These mice display severe microcephaly, social and cognitive deficits, dendritic shrinkage, excitatory synaptic deficits, and altered phospho-proteome patterns enriched for multiple signaling pathways and synaptic proteins. Early chronic lithium treatment of newborn mutant mice rescues brain volume, behavior, dendrite, synapse, and signaling/synapse phospho-proteome phenotypes at juvenile and adult stages. These results suggest that signaling/synaptic alterations contribute to phenotypic alterations in Dyrk1a-I48K mice, and that early correction of these alterations by lithium treatment has long-lasting effects of preventing juvenile and adult-stage phenotypes.
2024-12-04 | PXD050102 | Pride
Project description:Dyrk1A deficiency is linked to various neurodevelopmental disorders, including developmental delays and autism spectrum disorders (ASD). Haploinsufficiency of Dyrk1a in mice leads to ASD-related phenotypes, although key pathological mechanisms remain unclear. In addition, human DYRK1A mutations have not been characterized in mice. Here we report Dyrk1a-knockin mice carrying a human mutation (Ile48LysfsX2; Dyrk1a-I48K mice). These mice display severe microcephaly, social and cognitive deficits, dendritic shrinkage, excitatory synaptic deficits, and altered phospho-proteome patterns enriched for multiple signaling pathways and synaptic proteins. Early chronic lithium treatment of newborn mutant mice rescues brain volume, behavior, dendrite, synapse, and signaling/synapse phospho-proteome phenotypes at juvenile and adult stages. These results suggest that signaling/synaptic alterations contribute to phenotypic alterations in Dyrk1a-I48K mice, and that early correction of these alterations by lithium treatment has long-lasting effects of preventing juvenile and adult-stage phenotypes.
2024-12-04 | PXD050100 | Pride
Project description:Heterozygous loss-of-function mutations in the synaptic scaffolding gene SHANK2 are strongly associated with autism spectrum disorder (ASD). To investigate their effect on synaptic connectivity, we generated cortical neurons from induced pluripotent stem cells (iPSC) derived from neurotypic and ASD-affected donors. We developed Sparse coculture for Connectivity (SparCon) assays where SHANK2 and control neurons were differentially labeled and sparsely seeded together on a lawn of unlabeled control neurons. We observed striking increases in dendrite length, dendrite complexity, total synapse number, and frequency of spontaneous excitatory postsynaptic currents. These findings were phenocopied in gene-edited homozygous SHANK2 knockout cells and rescued by gene correction of an ASD SHANK2 muation, supporting a role for SHANK2 as a regulator of connectivity in developing human neurons. Dendrite length increases were exacerbated by IGF1, TG003, or BDNF, and suppressed by DHPG treatment. The transcriptome in these isogenic SHANK2 neurons was deeply perturbed in synapse, plasticity, and neuronal morphogenesis gene sets and ASD gene modules, and activity-dependent dendrite extension was impaired. Our unexpected findings provide evidence for hyperconnectivity and profoundly altered transcriptome in SHANK2 neurons derived from ASD subjects.
| EGAS00001003436 | EGA
Project description:Dyrk1A deficiency is linked to various neurodevelopmental disorders, including developmental delays and autism spectrum disorders (ASD). Haploinsufficiency of Dyrk1a in mice leads to ASD-related phenotypes, although key pathological mechanisms remain unclear. In addition, human DYRK1A mutations have not been characterized in mice. Here we report Dyrk1a-knockin mice carrying a human mutation (Ile48LysfsX2; Dyrk1a-I48K mice). These mice display severe microcephaly, social and cognitive deficits, dendritic shrinkage, excitatory synaptic deficits, and altered phospho-proteome patterns enriched for multiple signaling pathways and synaptic proteins. Early chronic lithium treatment of newborn mutant mice rescues brain volume, behavior, dendrite, synapse, and signaling/synapse phospho-proteome phenotypes at juvenile and adult stages. These results suggest that signaling/synaptic alterations contribute to phenotypic alterations in Dyrk1a-I48K mice, and that early correction of these alterations by lithium treatment has long-lasting effects of preventing juvenile and adult-stage phenotypes.
2024-07-02 | MSV000095221 | MassIVE
Project description:Dyrk1A deficiency is linked to various neurodevelopmental disorders, including developmental delays and autism spectrum disorders (ASD). Haploinsufficiency of Dyrk1a in mice leads to ASD-related phenotypes, although key pathological mechanisms remain unclear. In addition, human DYRK1A mutations have not been characterized in mice. Here we report Dyrk1a-knockin mice carrying a human mutation (Ile48LysfsX2; Dyrk1a-I48K mice). These mice display severe microcephaly, social and cognitive deficits, dendritic shrinkage, excitatory synaptic deficits, and altered phospho-proteome patterns enriched for multiple signaling pathways and synaptic proteins. Early chronic lithium treatment of newborn mutant mice rescues brain volume, behavior, dendrite, synapse, and signaling/synapse phospho-proteome phenotypes at juvenile and adult stages. These results suggest that signaling/synaptic alterations contribute to phenotypic alterations in Dyrk1a-I48K mice, and that early correction of these alterations by lithium treatment has long-lasting effects of preventing juvenile and adult-stage phenotypes.
2024-02-13 | MSV000094075 | MassIVE