Dosage-dependent differential transcriptomic changes in the prefrontal cortex of heterozygous and homozygous Shank2-mutant mice
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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: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:Autism spectrum disorders (ASD) are ~4-times more common in males than females, and CHD8 (a chromatin remodeler)-related ASD shows a strong male bias (~5:1), although the underlying mechanism remains unclear. Chd8-mutant mice with a C-terminal protein-truncating mutation (N2373X) display male-preponderant behavioral deficits as juveniles and adults, although whether this also applies to other Chd8 mutations remains unknown. Here we report that new Chd8-mutant mice with a stronger N-terminal protein-truncating mutation (S62X) display male-preponderant autistic-like behaviors at juvenile stages, but as adults, both males and females share behavioral deficits. Excitatory synaptic transmission is suppressed and enhanced in male and female juvenile Chd8+/S62X mice, respectively, but similarly enhanced in adults. ASD-like transcriptomic changes occur monophasically in newborn and juvenile (but not adult) males but biphasically in newborn and adult (not juvenile) females. Therefore, a strong CHD8 mutation induces early-onset ASD-like phenotypes in males but late-onset phenotypes in females after juvenile-stage female protection.
2023-03-08 | GSE167053 | GEO
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. To investigate early transcriptomic changes in Arid1b mutant mice, RNAseq analysis of prefrontal cortex from wild-type and Arid1b mutant mice at postnatal day 10 was done. Transcriptomic changes support these electrophysiological and behavioral deficits. Arid1b HT mice at postnatal day 10 showed alterations in genes implicated in synaptic functions and ASD.
2022-07-21 | GSE203249 | GEO
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. To investigate pup stage transcriptomic changes in Arid1b mutant mice, RNAseq analysis of whole brain from wild-type and Arid1b mutant mice at postnatal day 3 was done. Transcriptomic changes support these electrophysiological and behavioral deficits. Arid1b HT mice at postnatal day 3 showed alterations in genes implicated in synaptic functions and ASD.
2022-07-21 | GSE203214 | GEO
Project description:Autism spectrum disorders (ASD) represent neurodevelopmental disorders characterized by social deficits, repetitive behaviors, and various comorbidities, including epilepsy. ANK2, which encodes a neuronal scaffolding protein, is frequently mutated in ASD, but its in vivo functions and disease-related mechanisms are largely unknown. Here, we report that mice with Ank2 knockout restricted to cortical and hippocampal excitatory neurons (Ank2-cKO mice) show ASD-related behavioral abnormalities and juvenile seizure-related death. Ank2-cKO cortical neurons show abnormally increased excitability and firing rate. These changes accompanied decreases in the total level and function of the Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels and the density of these channels in the enlengthened axon initial segment. Importantly, the Kv7 agonist, retigabine, rescued neuronal excitability, juvenile seizure-related death, and hyperactivity in Ank2-cKO mice. These results suggest that Ank2 regulates neuronal excitability by regulating the length of and Kv7 density in the AIS and that Kv7 channelopathy is involved in Ank2-related brain dysfunctions.
2023-07-20 | PXD041769 | Pride