Striatal transcriptome analysis of Shank3-overexpressing mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE97544 | GEO | 2017/08/17
SECONDARY ACCESSION(S): PRJNA382260
REPOSITORIES: GEO
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Project description:Shank3 is a core excitatory postsynaptic protein expressed in multiple brain regions including the medial prefrontal cortex, striatum, and hippocampus. We have previously generated and characterized Shank3-overexpressing transgenic mice, and found that these mice exhibited manic-like behavioral phenotypes and increased food intake. To understand molecular mechanisms underlying the behavioral changes, we performed transcriptome (RNA-sequencing) analysis of the hypothalamic tissues from 10 to 12-week-old wild-type and Shank3 transgenic mice.
2018-12-03 | GSE120609 | GEO
Project description:Shank3 is a core excitatory postsynaptic protein expressed in multiple brain regions including the medial prefrontal cortex, striatum, and hippocampus. We have previously generated and characterized Shank3-overexpressing transgenic mice, and found that these mice exhibited manic-like behavioral phenotypes. To understand molecular mechanisms underlying the behavioral changes, we performed transcriptome (RNA-sequencing) analysis of the mPFC tissues from 10 to 12-week-old wild-type and Shank3 transgenic mice.
2018-12-25 | GSE113368 | GEO
Project description:Shank3 is a core excitatory postsynaptic protein expressed in multiple brain regions including the medial prefrontal cortex, striatum, and hippocampus. Shank3 knock-out mice display autism-like behaviors and synaptic dysfunction. To understand molecular mechanisms underlying the behavioral and synaptic changes, we performed transcriptome (RNA-sequencing) analysis of the striatum tissues from 10 to 12-week-old wild-type and Shank3 knock-out/heterozygous mice.
2019-09-11 | GSE124946 | GEO
Project description:Shank3 protein is a core organizer of the macromolecular complex in excitatory postsynapses, and its defects cause numerous synaptopathies including autism spectrum disorders. Although Shank3 function as a postsynaptic scaffold is well established, other potential mechanisms how Shank3 broadly modulates the postsynaptic proteome are relatively unexplored. To understand potential contribution of increased proteins synthesis to the proteomic change in TG striatal synaptosome, we performed RNA-seq analyses on both whole synaptosomal and synaptic polysome-enriched fractions. Comparative analyses showed a positive correlation only between polysome-associated transcriptome and up-regulated proteome in TG striatal synaptosome.
2023-12-18 | GSE163528 | 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.
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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.
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Project description:Disruption of the human SHANK3 gene can cause several neuropsychiatric disease entities including Phelan-McDermid syndrome (PMS), autism spectrum disorders (ASDs) and intellectual disability (ID). Although a wide array of neurobiological studies strongly supports a major role for SHANK3 in organizing the postsynaptic protein scaffold, the molecular processes at synapses of individuals harboring SHANK3 mutations are still far from being understood. In this study, we biochemically isolated the postsynaptic density (PSD) fraction from striatum and hippocampus of Shank3Δ11-/- mutant mice and performed ion-mobility enhanced data-independent label-free LC-MS/MS to obtain the corresponding PSD proteomes. This unbiased approach to identify molecular disturbances at PSDs devoid of major Shank3 isoforms revealed largely distinct molecular alterations in striatum and hippocampus. Being the first comprehensive analysis of brain region specific PSD proteomes from a Shank3 mutant line, our study provides crucial information on molecular alterations that could foster translational treatment studies for SHANK3 mutation-associated synaptopathies and possibly also ASD in general.
2017-03-08 | PXD005192 | Pride
Project description:Shank3 is a postsynaptic protein that complexes with group 1 metabotropic, AMPA-, and NMDA-type glutamate receptors. Mutations of Shank3 are causal for Phelan-McDermid syndrome (PMS) and associated autism phenotypes. Individuals with PMS often exhibit sensitivity to novelty or stress that can result in behavioral deterioration. Here we use a Shank3 mouse model with face-validity to PMS [Shank(3∆C/+)] and perform a transcriptomic analysis of principal neurons from neocortex of mice subjected to brief swim stress. Analysis reveals overrepresented pathways related to synapses accompanied by elevated expression of the immediate early gene Homer1a. In normal brain Homer1a is dynamically expressed in association with motivated behavior and mediates an essential step in sleep-related homeostatic down-scaling of synaptic proteins. This is consistent with observations that synaptic Shank3 expression requires Homer cross-linking, which is interrupted by Homer1a. Accentuated Homer 1a expression in Shank3(∆C/+) results in marked reductions of Shank3 expression, changes in synapse composition and NMDA-dependent synaptic plasticity, and disruption of social motivation. Deletion of Homer1a partially mitigates stress-induced phenotypes in Shank3(∆C/+) mice. Homer 1a is required for developmental plasticity, learning and memory, yet its enhanced expression in Shank3(∆C/+) may underlie a vulnerability of PMS patients that highlights the challenge of clinical management.
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Project description:The proteome of glutamatergic synapses is diverse across the mammalian brain and involved in neurodevelopmental disorders (NDDs). Among those is Fragile X syndrome (FXS), an NDD caused by the dysfunctional RNA binding protein FMRP. Here we demonstrate how the brain region-specific composition of post-synaptic density (PSD) contributes to FXS. The FXS mouse model shows, in the striatum, an altered association of the PSD with the actin cytoskeleton, reflecting immature dendritic spine morphology and reduced synaptic actin dynamics. Enhancing actin turnover with constitutively active RAC1 ameliorates these deficits. At the behavioral level, the FXS model displays striatal-driven inflexibility, a typical feature of FXS individuals, that is rescued by exogenous RAC1. Striatal ablation of Fmr1 is sufficient to recapitulate behavioral impairments observed in the FXS model. These results indicate that dysregulation of synaptic actin dynamics in the striatum, a region largely unexplored in FXS, contributes to the manifestation of FXS behavioral phenotypes.
2023-06-08 | PXD040331 | Pride
Project description:Dysregulation of the striatum is linked to multiple diseases including Huntington’s (HD), Parkinson’s, X-linked dystonia-parkinsonism (XDP), addiction, autism, and schizophrenia. Striatal medium spiny neurons (MSNs) make up 90% of the neuronal cell type in the striatum and are critical to motor control. The transcription factor Bcl11b (also known as CTIP2) is known to regulate of MSN differentiation, striatal striosome (patch) development and the architecture of the striatum during development. However, the function of Bcl11b adult striatal neurons in vivo has not been investigated. Therefore, we conditionally knocked out Bcl11b specifically in MSNs using D9-cre under the control of a regulatory elements of the mouse Ppp1r1b gene encoding DARPP-32 resulting in knockout around 5-6 weeks of age. Transcriptomic and behavioral analysis were performed on these mice.
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