Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1166849 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30831527_1.fastq.gz | Fastqsanger.gz | |||
| SRR30831527_2.fastq.gz | Fastqsanger.gz | |||
| SRR30831528_1.fastq.gz | Fastqsanger.gz | |||
| SRR30831528_2.fastq.gz | Fastqsanger.gz | |||
| SRR30831529_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
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Project description:Synapse loss and glial activation are hallmarks of Alzheimer's disease (AD). In Tau P301S transgenic mice, the complement pathway contributes to neuronal damage through microglial elimination of synapses. Here, we used unbiased proteomic profiling of postsynaptic density (PSD) fractions from Tau P301S mice in C1q-WT versus C1q knockout backgrounds to identify C1q-dependent changes at synapses. Integrative multi-omics analysis revealed that astrocyte- and microglia- specific proteins are increased in Tau P301S synapse fractions with age and in a C1q-dependent manner. The same set of glial proteins (including C1q, C4, Gpnmb, and S100a4) is elevated in human AD synaptic fractions, and C4 levels are raised in cerebrospinal fluid (CSF) from AD patients. Besides microglia, we show that astrocytes contribute substantially to excitatory and inhibitory synapse engulfment in Tau P301S hippocampus. Based on staining of synapse markers within lysosomes, astrocytes showed preference for excitatory synapses whereas microglia preferred to engulf inhibitory synapse markers. Genetic deletion of C1q reduced astrocytic eating of excitatory and inhibitory synapses in Tau P301S mice, and rescued synapse density. Together, our data indicate that astrocytes contact and phagocytose synapses in a C1q- dependent manner and thereby contribute to synapse loss and neurodegeneration in AD.
2021-11-03 | MSV000088313 | MassIVE
Project description:Microglia repair injury and maintain homeostasis in the brain, but whether aberrant microglial activation can contribute to neurodegeneration remains unclear. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive up-regulation of lysosomal and innate immunity genes, increased complement production, and synaptic pruning activity in microglia. During aging, Grn-/- mice show profound accumulation of microglia and preferential elimination of inhibitory synapses in the ventral thalamus, which contribute to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, blocking complement activation by deleting C1qa gene significantly reduces synaptic pruning by Grn-/- microglia, and mitigates neurodegeneration, behavioral phenotypes and premature mortality in Grn-/- mice. These results uncover a previously unrecognized role of progranulin in suppressing microglia activation during aging, and support the idea that blocking complement activation is a promising therapeutic target for neurodegeneration caused by progranulin deficiency. Gene expression study in multiple brain regions from a mouse model of progranulin deficiency Please note that 9 outlier samples were excluded from data analysis. Therefore, there are 326 raw data columns (i.e. 163 samples) in the non_normalized data matrix while 154 samples are represented here.
2016-03-31 | E-GEOD-75083 | biostudies-arrayexpress
Project description:Microglia repair injury and maintain homeostasis in the brain, but whether aberrant microglial activation can contribute to neurodegeneration remains unclear. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive up-regulation of lysosomal and innate immunity genes, increased complement production, and synaptic pruning activity in microglia. During aging, Grn-/- mice show profound accumulation of microglia and preferential elimination of inhibitory synapses in the ventral thalamus, which contribute to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, blocking complement activation by deleting C1qa gene significantly reduces synaptic pruning by Grn-/- microglia, and mitigates neurodegeneration, behavioral phenotypes and premature mortality in Grn-/- mice. These results uncover a previously unrecognized role of progranulin in suppressing microglia activation during aging, and support the idea that blocking complement activation is a promising therapeutic target for neurodegeneration caused by progranulin deficiency.
2016-03-31 | GSE75083 | GEO
Project description:Meningeal lymphatics serve as the primary outlet for cerebrospinal fluid, and their dysfunction is associated with various neurodegenerative conditions. Previous studies have demonstrated that dysfunctional meningeal lymphatics evoke behavioral deficits, but the neural mechanisms underlying those behavioral changes remained elusive. Here, we show that prolonged impairment of meningeal lymphatics alters the balance of cortical excitatory and inhibitory synaptic inputs by reducing inhibitory synapses, accompanied by deficits in novelty recognition tasks. These synaptic and behavioral alterations are mediated by microglia, which exhibit transcriptomic, morphological, and functional alterations as a result of lymphatic dysfunction. Notably, microglial expression of Il6 increases, thereby mediating the reduction in inhibitory synapses via neuronal signaling. Interestingly, improving the function of meningeal lymphatics in aged mice restores the numbers of functional inhibitory synapses and cortical network activity. Our findings suggest that dysfunctional meningeal lymphatics adversely impact cortical circuitry through a microglia−IL-6-dependent mechanism, providing a potential target for the treatment of aging-associated cognitive decline.
2025-03-21 | GSE270428 | GEO
Project description:Meningeal lymphatics serve as the primary outlet for cerebrospinal fluid, and their dysfunction is associated with various neurodegenerative conditions. Previous studies have demonstrated that dysfunctional meningeal lymphatics evoke behavioral deficits, but the neural mechanisms underlying those behavioral changes remained elusive. Here, we show that prolonged impairment of meningeal lymphatics alters the balance of cortical excitatory and inhibitory synaptic inputs by reducing inhibitory synapses, accompanied by deficits in novelty recognition tasks. These synaptic and behavioral alterations are mediated by microglia, which exhibit transcriptomic, morphological, and functional alterations as a result of lymphatic dysfunction. Notably, microglial expression of Il6 increases, thereby mediating the reduction in inhibitory synapses via neuronal signaling. Interestingly, improving the function of meningeal lymphatics in aged mice restores the numbers of functional inhibitory synapses and cortical network activity. Our findings suggest that dysfunctional meningeal lymphatics adversely impact cortical circuitry through a microglia−IL-6-dependent mechanism, providing a potential target for the treatment of aging-associated cognitive decline.
2025-05-29 | GSE285073 | GEO
Project description:Microglia, the resident immune cells of the brain, have emerged as crucial regulators of synaptic refinement and therefore wiring precision. However, whether the remodeling of distinct synapses during development is mediated by specialized microglia is unknown. Here, using in vivo two-photon imaging, we show that GABA-receptive microglia selectively interact with inhibitory synapses during a critical window of mouse postnatal development. GABA initiates a transcriptional synapse remodeling program within these specialized microglia, which in turn sculpt inhibitory connectivity without impacting excitatory synapses. Ablation of GABAB receptors within microglia impairs this process and leads to stereotyped repetitive behavior and hyperactivity. These findings demonstrate that distinct microglia differentially engage with specific synapse types during development.
2021-11-09 | GSE159947 | GEO
Project description:The piriform cortex (PC) plays a critical role in epileptogenesis, where an excitation/inhibition imbalance contributes to epilepsy etiology. However, the epileptic dynamics of the GABA system and the precise role of GABAergic neurons within the PC in epilepsy remain unclear. Here, we combined Ca2+ and GABA sensors to investigate the dynamics of Gad2-expressing neurons and GABA levels, and selectively manipulated GABAergic neurons in the PC through chemogenetic inhibition and caspase3-mediated apoptosis targeting Gad2 interneurons. The chronic deficiency of PC Gad2 neurons triggered spontaneous recurrent seizures. These findings uncover the dynamic interplay within PC inhibitory components and elaborate counteractive mechanisms in seizure regulation.
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Project description:we used DNA microarray analysis to identify genes that are induced by neuronal activity in excitatory neurons at the time when inhibitory synapses are forming and maturing on them. Keywords: Primary neuron culture, depolarization, activity-dependent
2008-09-24 | GSE11256 | GEO
Project description:Network hyperexcitability is manifested as frequent ictal discharges, often caused by unbalanced neurotransmission. We assessed synaptic changes in the hyperexcitable visual cortex of tetanus neurotoxin-injected mice (TeNT). A proteomics analysis of synaptic content revealed Carboxypeptidase E (CPE) up-regulation following TeNT injection. To quantify CPE effect on vesicle clustering, we used an ultrastructural measure of synaptic activity to investigate functional differences at excitatory and inhibitory synapses. We found homeostatic changes in hyperexcitable networks expressed as an early onset lengthening of active zones at inhibitory synapses followed by spatial reorganization at excitatory synapses. Moreover, inhibition of CPE decreases ictal discharges in vivo. This study reveals a complex landscape of homeostatic changes affecting the synaptic release machinery , differentially at inhibitory and excitatory terminals. We propose a novel homeostatic presynaptic mechanism which may impact release timing rather than synaptic strength.
2021-09-09 | PXD022270 | Pride
Project description:GABAergic interneurons are lost in conditions including epilepsy and CNS injury, but there are few culture models available to study their function. Towards the goal of obtaining renewable sources of GABAergic neurons, we used the molecular profile of a functionally-incomplete GABAergic precursor clone to screen 17 new clones isolated from GFP+ rat E14.5 cortex and ganglionic eminence (GE) that were generated by viral introduction of v-myc. The clones grow as neurospheres in medium with FGF2, and after withdrawal of FGF2 they exhibit varying patterns of differentiation. Transcriptional profiling and qPCR indicated that one clone (GE6) expresses high levels of mRNAs encoding Dlx1, 2, 5 and 6, glutamate decarboxylases, and presynaptic proteins including neuropeptide Y and somatostatin. Protein expression confirmed that GE6 is a progenitor with restricted differentiation giving rise mostly to neurons with GABAergic markers. In co-cultures with hippocampal neurons, GE6 neurons became electrically excitable and received both inhibitory and excitatory synapses. After withdrawal of FGF2 in cultures of GE6 alone, neurons matured to express BetaIII-tubulin, and staining for synaptophysin and vesicular GABA transporter (VGAT) were robust after 1-2 weeks of differentiation. GE6 neurons also became electrically excitable and displayed synaptic activity, but synaptic currents were carried by chloride and were blocked by bicuculline. The results suggest that the GE6 clone, which is ventrally derived from the GE, resembles GABAergic interneuron progenitors that migrate into the developing forebrain. This is the first report of a relatively stable fetal clone that can be differentiated into GABAergic interneurons with functional synapses. The purpose was to compare differentiation patterns of several different immortalized rat neural progenitor clones to identify early stages in differentiation. The cell clones studies were: GE6 (GABAergic neuronal precursor), GE2 (non-neuronal precursor, CTX8 (multipotential precursor), L2.2 (interneuronal precursor), and L2.3 (multipotential precursor). Five rat neural precursor cell clones were compared at three different time points following FGF2 withdrawal, which triggers differentiation. Three sister culture replicates were performed for each cell clone and time point, yielding 45 samples. One microarray failed so we have 44 microarray results in the dataset.
2011-11-09 | E-GEOD-31635 | biostudies-arrayexpress