Transcriptonal profiling of the hippocampus in the CA1 subfield in Fmr1 knockout mouse
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE106595 | GEO | 2018/08/03
REPOSITORIES: GEO
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Project description:Transcriptonal profiling of the hippocampus in the CA1 subfield in Fmr1 knockout mouse
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Project description:Impairment of synaptic plasticity is involved in a range of pathological conditions such as cognitive deficits. However, how synaptic efficacy is regulated is not fully understood. Here, we report that the epigenetic factor Jade family PHD finger 2 (JADE2), which is upregulated by neuronal activities, is critically involved in the maintenance of hippocampal synaptic plasticity and cognitive functions in mice. Knockdown or genetic deletion of JADE2 in hippocampal CA1 results in impaired structural and functional synaptic plasticity, leading to memory impairment, whereas overexpression of JADE2 in CA1 neurons facilitates hippocampal-dependent learning and memory. Mechanistically, we show that JADE2 modulates synaptic functions mainly by transcriptional activation of cytoskeletal protein RAC1, and this activity is dependent on its interaction with histone acetyltransferase HBO1. Together, our findings suggest JADE2 is a critical player for experience-dependent gene regulation in controlling synaptic plasticity and cognitive functions.
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Project description:While FMR1 is silenced in Fragile X syndrome (FXS), its expression is elevated (2-8 fold) in premutated individuals. These people may develop the Fragile X-associated Tremor Ataxia Syndrome (FXTAS), a late onset neurodegenerative disorder characterized by ataxia and parkinsonism. In addition, people carrying the premutation can be affected by a set of neurological and behavioural disorders during young age. Problems of memory have been detected in these patients as well in the mice model for FXTAS. To date little is known concerning the metabolism of FMR1 mRNA, notwithstanding the importance of the finely tuned regulation of the expression of this gene. In the present study we identified three microRNAs that specifically target the 3’UTR of FMR1 and can modulate its expression throughout the brain and, in particular, at the synaptic level. The expression level of miR-221 is reduced in brain and synaptosomal preparations of young FXTAS mice suggesting a general deregulation of transcripts located at the synapse of these mice. By transcriptome analysis we show here a robust deregulation of the expression levels of genes involved in learning, memory and autistic behavior, Parkinson disease and neurodegeneration. Interestingly, many of those deregulated mRNAs are target of the same miRNAs that modulate the expression of FMR1 at the synapse. Knock-In versus Wild Type, 3 replicates.
2013-03-07 | E-GEOD-43670 | biostudies-arrayexpress
Project description:TRAP (translating ribosome affinity purification) from CA1 pyramidal neurons and cerebellar granule cells in wildtype and Fmr1 KO littermate pairs. These data show a global downregulation of FMRP targets in Fmr1 KO mice in these cell types.
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Project description:Sequencing files from TRAP-seq samples isolated from DHPG-stimulated WT and Fmr1-/y hippocampal slices
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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.
2019-12-05 | GSE114015 | GEO
Project description:Using cell-free fetal RNA from amniotic fluid supernatant samples, the gene expression profiles of fetuses with varying FMR1 5’ UTR CGG repeat lengths were compared to gestational age- and sex-matched controls. Broad patterns of genome-wide expression changes were identified when comparing fetuses with expanded FMR1 alleles to those with normal length FMR1 alleles. Genes with altered expression include those related to ubiquitination, mitochondrial function and neuronal/synaptic architecture as well as genes previously linked to other intellectual disabilities and abnormalities of motor function.
2016-09-01 | GSE83556 | GEO
Project description:Hippocampal synaptic plasticity is important for learning and memory formation. Homeostatic synaptic plasticity is a specific form of synaptic plasticity that is induced upon prolonged changes in neuronal activity to maintain network homeostasis. While astrocytes are important regulators of synaptic transmission and plasticity, it is largely unclear how they interact with neurons to regulate synaptic plasticity at the circuit level. Here, we show that neuronal activity blockade selectively increases the expression and secretion of IL-33 (interleukin-33) by astrocytes in the hippocampal cornu ammonis 1 (CA1) subregion. This IL-33 stimulates an increase in excitatory synapses and neurotransmission through the activation of neuronal IL-33 receptor complex and synaptic recruitment of the scaffold protein PSD-95. We found that acute administration of tetrodotoxin in hippocampal slices or inhibition of hippocampal CA1 excitatory neurons by optogenetic manipulation increases IL-33 expression in CA1 astrocytes. Furthermore, IL-33 administration in vivo promotes the formation of functional excitatory synapses in hippocampal CA1 neurons, whereas conditional knockout of IL-33 in CA1 astrocytes decreases the number of excitatory synapses therein. Importantly, blockade of IL-33 and its receptor signaling in vivo by intracerebroventricular administration of its decoy receptor inhibits homeostatic synaptic plasticity in CA1 pyramidal neurons and impairs spatial memory formation in mice. These results collectively reveal an important role of astrocytic IL-33 in mediating the negative-feedback signaling mechanism in homeostatic synaptic plasticity, providing insights into how astrocytes maintain hippocampal network homeostasis.
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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
Project description:Fragile X syndrome and tuberous sclerosis are genetic syndromes that both have a high rate of co-morbidity with autism spectrum disorders. Several lines of evidences suggest that these two monogenic disorders may converge at a molecular level through the dysfunction of activity-dependent synaptic plasticity. We utilized mouse models of these monogenic disorders to identify genome-wide transcriptional changes in cerebellum and blood and characterize the (dis-)similarity of their molecular signatures. Differentially expressed genes and enriched pathways were distinct for the two mouse models examined, with the exception of immune system related pathways. In the cerebellum of the Fmr1 knockout (Fmr1-KO) model, the neuroactive ligand receptor interaction pathway and gene sets associated with synaptic plasticity such as long term potentiation, gap junction, and axon guidance were the most significantly perturbed pathways. The phosphatidylinositol signaling pathway was significantly dysregulated in both blood and brain of Fmr1-KO mice. In both the blood and brain of the Tsc2 heterozygous mouse model, immune system related pathways, genes encoding ribosomal proteins, and glycolipid metabolism pathways were significantly perturbed. Our data suggest that distinct molecular pathways may be involved in autism spectrum disorders with known but different genetic causes, and that blood gene expression profiles of Fmr1-knockout and Tsc2+/- mice mirror some, but not all, of the perturbed molecular pathways in the brain. For the Fmr1-KO model, 10 mice, consisting of 5 KO and 5 WT mice, were profiled. Thus, 10 pairs of blood and cerebella samples were profiled. Likewise, for the Tsc+/- model, 3 transgenic and 3 WT mice were sacrificed and paired blood and cerebella samples were prepared for gene expression profiling. All samples were profiled using the Affymetrix Mouse Gene ST 1.0 ST arrays. Three factors—tissue (i.e. blood vs. cerebellum), treatment (i.e. knockout vs. wildtype), and genetic background (Fmr1-KO vs. Tsc2+/-)—were analyzed with analysis of variance (ANOVA). Subsequently, we compared blood and brain gene expression changes in Fmr1 and Tsc2 knockout mice models using WT littermates as controls using t-tests with unequal variances. The false discovery rate (FDR) was calculated using Storey and Tibshirani’s method.
2012-09-06 | E-GEOD-40630 | biostudies-arrayexpress