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Multi-level profiling of the Fmr1 KO rat unveils altered behavioral traits along with aberrant glutamatergic function

ABSTRACT: Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disabilities and the most prevalent monogenic cause of autism. Although the knockout (KO) of the Fmr1 gene homolog in mice is primarily used for elucidating the neurobiological substrate of FXS, there is limited association of the experimental data with the pathophysiological condition in humans. The use of Fmr1 KO rats offers additional translational validity in this regard. Therefore, we employed a multi-level approach to study the behavioral profile and the glutamatergic and GABAergic neurotransmission status in pathophysiology-associated brain structures of Fmr1 KO rats, including the recordings of evoked and spontaneous field potentials from hippocampal slices, paralleled with next-generation RNA sequencing (RNA-seq). We found that these rats exhibit hyperactivity and cognitive deficits, along with characteristic bidirectional glutamatergic and GABAergic alterations in the prefrontal cortex and the hippocampus. These results are coupled to affected excitability and local inhibitory processes in the hippocampus, along with a specific transcriptional profile, highlighting dysregulated hippocampal network activity in KO rats. Overall, our data provide novel insights concerning the biobehavioral profile of FmR1 KO rats and translationally upscales our understanding on pathophysiology and symptomatology of FXS syndrome.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE248950 | GEO | 2023/12/31

REPOSITORIES: GEO

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Mass spectrometry analysis of synaptic proteome of adult Fmr1 KO and wild-type mice.

Project description:Fragile X syndrome (FXS) is the most common monogenetic cause of inherited intellectual disability and autism in humans. One of the well-characterized molecular phenotypes of Fmr1 KO mice, a model of FXS, is increased translation of synaptic proteins. Although this upregulation stabilizes in the adulthood, abnormalities during the critical period of plasticity have long-term effects on circuit formation and synaptic properties. Using high-resolution quantitative proteomics of synaptoneurosomes isolated from the adult, developed brains of Fmr1 KO mice, we show differential abundance of proteins regulating postsynaptic receptor activity of glutamatergic synapse. This work includes proteomic dataset that was acquired and analyzed to quantify changes in the abundance of proteins in synaptoneurosomes (basal state, unstimulated and in vitro NMDA-R stimulated) isolated from Fmr1 KO mice and their wild-type littermates.

2024-01-26 | PXD043700 | Pride

RNA sequencing data of Wild Type and Fmr1 KO hippocampal neuron

Project description:Fragile X syndrome (FXS), caused by mutations in fragile X mental retardation 1 gene (FMR1), is a prevailing genetic disorder of intellectual disability and autism. Analysis of transcriptome outcome (differentially expressed genes between WT and Fmr1 KO hippocampal neuron) associated with FXS reveal promising value of gene signature-based computation in repurposing drugs for potential practical treatment.

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Proteomic profiling of brain and testis reveals the diverse changes in ribosome proteins in fmr1 knockout mice

Project description:Fragile X syndrome (FXS), the leading cause of inherited form of mental retardation and autism, is caused by the transcriptional silencing of fmr1 encoding the protein of FMRP. FMRP, acting as an RNA binding protein, FMRP is a wide expressed protein, but primarily in the brain and testis and can regulate approximately 4% of transcripts. Macroorchidism is one of the common symptoms observed both in the FXS people and mice. Thus, we analyzed the protein profiles of cerebral cortex, hippocampus and testis from both the fmr1-KO and WT mouse using a quantitative proteomics. Proteins (FMRP, RS8, RL23A and MPZ) identified by MS/MS were also verified by Western blot. Among the identified proteins, most of the significant changed proteins were downregulated in the FMRP absence. The Gene Ontology and pathway analysis revealed that the changed proteins were clustered in polyribosome and RNA binding proteins in both cerebral cortex and hippocampus, but not the same in testis. Our results provide detailed insights to the ribosome protein profiles of cerebral cortex, hippocampus and testis in the absence of FMRP. Our studies also give a better understanding of protein profile changes and underling dysregulated pathways arising from the fmr1 silencing in the FXS.

2022-02-28 | PXD005089 | Pride

EB-mediated NPY expression and release.

Project description:Neuropeptide Y (NPY) is an endogenous modulator of neuronal activity by regulating GABA and glutamate release. Previously, we found that estradiol modulates NPY expression in the hippocampal dentate gyrus. Here we investigated which estrogen receptor type activation is required for the NPY expression. Further, we determined effects of estrogen receptor activation on NPY release. Finally, we determined the contribution of estrogen-mediated remodeling of the GABAergic and glutamatergic network in relation to changes in coupling with NPY in ovariectomized rats. We found that activation of either estrogen receptor type increases NPY expression as well as NPY release in the dentate gyrus. We also found that compared to OVX rats, estrogen replacement increases the likeness of synergistic/antagonistic coupling between the NPY and GABAergic synapse genes while the glutamatergic synapse genes are less likely coupled with NPY. The data together suggest that estrogen plays a critical role in regulation of activity of the NPY system and its coupling to GABAergic and glutamatergic synapses in female rat dentate gyrus. Two-conditions (E = beta-estradiol replacement vs O = oil) experiment. Biological replicates: 4E, 4O.

2014-08-02 | E-GEOD-60013 | biostudies-arrayexpress

Comparison of wildtype and Fmr1 knock-out adult mouse gene expression in the cochlear nucleus

Project description:Fragile X Syndrome (FXS) is a hereditary form of autism spectrum disorder. It is caused by a trinucleotide repeat expansion in the Fmr1 gene, leading to a loss of Fragile X Protein (FMRP) expression. The loss of FMRP causes auditory hypersensitivity: FXS patients display hyperacusis and the Fmr1- knock-out (KO) mouse model for FXS exhibits auditory seizures. FMRP is strongly expressed in the cochlear nucleus and other auditory brainstem nuclei. We hypothesize that the Fmr1-KO mouse has altered gene expression in the cochlear nucleus that may contribute to auditory hypersensitivity.

2023-08-01 | GSE236056 | GEO

Sustainedcorrection of hippocampal neurogenic and cognitive deficits after a brief treatment by Nutlin-3 in a mousemodel of Fragile X Syndrome.

Project description:We found that transient treatment with Nutlin-3 of 2-month-old young adult FMR1-deficient mice prevents the emergence of neurogenic and cognitive deficits in mature adult FXS mice at 6-month of age. We further found that the long-lasting restoration of neurogenesis and cognitive function might not be mediated by changing intrinsic properties of adult neural stem cells. Transcriptomic analysis of the hippocampal tissue demonstrated that transient Nultin-3 treatment leads to significant expression changes in genes related to extracellular matrix, secreted factors, and cell membrane proteins in FMR1-deficient hippocampus

2022-05-18 | GSE198403 | GEO

Genome-wide analysis identifies aberrant methylation in Fragile X syndrome is specific to the FMR1 locus

Project description:Fragile X syndrome (FXS) is a common form of inherited intellectual disability and is caused by an expansion of CGG repeats located in the 5Õ untranslated region (UTR) of the FMR1 gene, leading to hypermethylation and silencing of this locus. While the dramatic increase in DNA methylation (DNAm) of the FMR1 full mutation allele is well documented, the extent that these changes affect DNAm throughout the entire gene and the rest of the genome remains unexplored. Here, we examine the genome-wide methylation in peripheral blood (N = 9) as well as induced pluripotent stem cells (iPSCs; N = 10) from FXS individuals and controls (N = 53 and 9, respectively) and find the expected significant DNAm differences in the FMR1 promoter and 5Õ UTR, but also that these changes inversely persist throughout the FMR1 gene body. Importantly, we find there are no additional differential methylated loci (DML) throughout the remainder of the genome, indicating that the aberrant methylation of the FMR1 in FXS is locus-specific and does not change DNAm genome-wide. This study provides a comprehensive methylation profile of FXS and refines mechanistic considerations of FMR1 silencing. A total of 62 blood (53 controls + 9 Fragile X) samples analyzed using a linear regression model.

2013-04-15 | E-GEOD-41273 | biostudies-arrayexpress

Ribosome profiling and RNA-seq of Fragile X mouse brain cortex

Project description:Fragile X syndrome (FXS) is caused by inactivation of FMR1 gene and loss of its encoded product the RNA binding protein FMRP, which generally represses translation of its target transcripts in the brain. In mouse models of FXS (i.e., Fmr1 knockout animals; Fmr1 KO), deletion of Cpeb1, which encodes a translational activator, mitigates nearly all pathophysiologies associated with the disorder. Here we reveal unexpected wide-spread dys-regulation of RNA abundance in Fmr1 KO brain cortex and its rescue to normal levels in Fmr1/Cpeb1 double KO mice. Alteration and restoration of RNA levels are the dominant molecular events that drive the observed dys-regulation and rescue of translation as measured by whole transcriptome ribosome occupany in the brain. The RNAs down-regulated and rescued in these animal models are highly enriched for FMRP binding targets and have an optimal codon bias that would predict their stability in wild type and possible instability in FMRP knock-out brain. These results leads to a further study to profile RNA metabolism rates in Fragile X neurons.

2020-06-01 | GSE140565 | GEO

Uncovering the metabolic pleiotropy of FMR1-deficiency in Fragile X Syndrome

Project description:ene pleiotropy defines the capacity of a gene to impact multiple phenotypic characters. The Fragile X Mental Retardation 1 (FMR1) gene is a candidate for pleiotropy, as it controls protein synthesis through its product, the translational regulator FMRP. As FMR1 loss-of-function leads to neurodevelopmental defects and Fragile X Syndrome (FXS), intellectual disability and autism, FMR1 functions have been mostly studied in the brain. FMR1-deficiency could also have yet unexplored consequences in periphery and impact metabolism through translational repression in peripheral organs. We combined 1H NMR-based metabolic phenotyping and proteomics to reveal the pleiotropic metabolic effects associated with FMR1-deficiency in mouse and human. We demonstrate that Fmr1-deficiency in the mouse increases hepatic translation, improves glucose tolerance and insulin sensitivity and reduces adiposity, while enhancing -adrenergic driven lipolysis and utilization of lipid energetic substrates. Last, we provide converging evidences in FXS patients that the levels of glucose, insulin and free fatty acids are modified, suggesting that FMR1-deficiency also drives metabolic readjustments in human. As part of a larger study investigating the involvement of fmr in metabolic alteration in fmr1-KO mice, fmr1-KO mouse livers were analysed by MS.

2022-02-28 | PXD007241 | Pride

EB-mediated NPY expression and release

2014-08-02 | GSE60013 | GEO

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