Prions induce an early Arc response in the hippocampus of prion-infected mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE207251 | GEO | 2023/01/01
REPOSITORIES: GEO
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Project description:Longitudinal PET imaging of Alzheimer models reveals synaptic rescue by an mGluR5 modulator with selective normalization of neuronal transcriptomes. Alzheimer’s disease symptoms are initiated by synapse loss in the setting of microglial reactivity, but the basis for immune mediator attack on synapses is not clear. The mGluR5 silent allosteric modulator (SAM), BMS-984923, prevents Alzheimer’s triggered aberrant synaptic signaling while preserving physiological Glu activation. Here, we show that oral BMS-984923 effectively occupies brain mGluR5 sites visualized by [18F]FPEB PET at doses 250-fold below adverse effect doses in rodent and non-human primate. For aged transgenic and double knock-in mouse Alzheimer’s models, SV2A PET imaging with [18F]SynVesT-1 reveals cortical and hippocampal synapse density decreases, which are fully recovered by SAM treatment. The disease-modifying benefit persists after drug washout. Tau accumulation in double knock-in mice is also reduced by SAM treatment. Single nuclei transcriptomics demonstrate that SAM treatment normalizes expression patterns to a much greater extent in neurons than glia. Production of the microglial mediator, C1q, is not altered by the mGluR5 compound, but Alzheimer gene-dependent C1q localization to synapses and synaptic engulfment are prevented. Thus, selective modulation of mGluR5 reverses neuronal gene expression changes to protect synapses from damage by microglial mediators.
2022-06-01 | GSE171095 | GEO
Project description:Prion diseases typically have long pre-clinical incubation periods during which time the infectious prion particle and infectivity steadily propagate in the brain. Abnormal neuritic sprouting and synaptic deficits are apparent during pre-clinical disease, however, gross neuronal loss is not detected until the onset of the clinical phase. The molecular events that accompany early neuronal damage and ultimately conclude with neuronal death remain obscure. In this study, we used laser capture microdissection to isolate hippocampal CA1 neurons and then determined their pre-clinical transcriptional response during infection. We found that gene expression within these neurons is dynamic and characterized by distinct phases of activity. A major cluster of genes is altered during pre-clinical disease after which expression either returns to basal levels, or alternatively undergoes a direct reversal during clinical disease. Strikingly, we show that this cluster contains a signature highly reminiscent of synaptic N-methyl-D-aspartic acid (NMDA) receptor signaling and the activation of neuroprotective pathways. Additionally, genes involved in neuronal projection and dendrite development were also altered throughout the disease, culminating in a general decline of gene expression for synaptic proteins. Similarly, deregulated miRNAs such as miR-132-3p, miR-124a-3p, miR-16-5p, miR-26a-5p, miR-29a-3p and miR-140-5p follow concomitant patterns of expression. This is the first in depth genomic study describing the pre-clinical response of hippocampal neurons to early prion replication. Our findings suggest that prion replication results in the persistent stimulation of a programmed response, at least in part mediated by synaptic NMDA receptor activity that initially promotes cell survival and neurite remodelling. However, this response is terminated prior to the onset of clinical symptoms in the infected hippocampus, seemingly pointing to a critical juncture in the disease. Manipulation of these early neuroprotective pathways may redress the balance between degeneration and survival, providing a potential inroad for treatment. The CA1 hippocampal region was dissected out using LCM and RNA was extracted from these samples. In total, 6 different time points were screened for both RNA and miRNA expression levels in prion infected and control animals. Gene expression profiles from 6 time points (n M-bM-^IM-% 2) were determined using whole mouse 4x44K arrays. We successfully validated a subset of candidate genes that were deregulated during early prion disease. We performed a similar assessment of temporal miRNAs expression levels throughout the infection using the TLDA platform which was further validated by individual real-time PCR assays. In parallel, immunoctyochemistry was used to characterize the cellular presence of astrocytes, microglial and neurons in the CA1 region throughout the disease which correlated well with both mRNA and miRNA expression profiles. Staining for the PrPRes and neuronal toxicity levels was also performed to determine the spatial and temporal PrPRes deposition and assess the level of neuronal death that occurs in the hippocampus, respectively. Using bioinformatic methods, potential pathways that were implicated by our data to be deregulated during early prion disease were presented while potential miRNA regulation of some of these candidate genes implicated in these pathways was also included.
2012-11-09 | E-GEOD-34530 | biostudies-arrayexpress
Project description:The immediate early gene product activity-regulated cytoskeleton-associate protein (Arc or Arg3.1) is a major regulator long-term synaptic plasticity with critical roles in postnatal cortical development and memory formation. However, the molecular basis of Arc function is not defined. Arc is a hub protein with interaction partners in the postsynaptic neuronal compartment and nucleus. In vitro biochemical and biophysical analysis of purified recombinant Arc show formation of low-order oligomers and larger particles including retrovirus-like capsids. Here, we provide evidence for naturally occurring Arc oligomers in mammalian brain. Using in situ protein crosslinking to trap weak Arc-Arc interactions, we identified in various preparations a prominent Arc immunoreactive band on SDS-PAGE of molecular mass corresponding to a dimer. While heavier Arc species or putative trimers and tetramers were detected, they were of lower abundance. In the dentate gyrus (DG) of adult anesthetized rats, induction of long-term potentiation (LTP) by high-frequency stimulation (HFS) of medial perforant synapses or by brief intrahippocampal infusion of BDNF led to a massive increase in Arc dimer expression. Arc immunoprecipitation of crosslinked DG tissue showed enhanced expression of dimer during four hours of LTP maintenance. Mass spectrometric proteomic analysis of immunoprecipitated, gel-excised bands corroborated detection of Arc dimer. Furthermore, Arc dimer was constitutively expressed in naïve cortical, hippocampal and DG tissue, with lowest levels in the DG. Taken together the results implicate Arc dimers as the predominant low-oligomeric form in mammalian brain, exhibiting regional differences in its constitutive expression and pronounced enhanced expression during DG LTP.
2023-07-20 | PXD039612 | Pride
Project description:Prion diseases typically have long pre-clinical incubation periods during which time the infectious prion particle and infectivity steadily propagate in the brain. Abnormal neuritic sprouting and synaptic deficits are apparent during pre-clinical disease, however, gross neuronal loss is not detected until the onset of the clinical phase. The molecular events that accompany early neuronal damage and ultimately conclude with neuronal death remain obscure. In this study, we used laser capture microdissection to isolate hippocampal CA1 neurons and then determined their pre-clinical transcriptional response during infection. We found that gene expression within these neurons is dynamic and characterized by distinct phases of activity. A major cluster of genes is altered during pre-clinical disease after which expression either returns to basal levels, or alternatively undergoes a direct reversal during clinical disease. Strikingly, we show that this cluster contains a signature highly reminiscent of synaptic N-methyl-D-aspartic acid (NMDA) receptor signaling and the activation of neuroprotective pathways. Additionally, genes involved in neuronal projection and dendrite development were also altered throughout the disease, culminating in a general decline of gene expression for synaptic proteins. Similarly, deregulated miRNAs such as miR-132-3p, miR-124a-3p, miR-16-5p, miR-26a-5p, miR-29a-3p and miR-140-5p follow concomitant patterns of expression. This is the first in depth genomic study describing the pre-clinical response of hippocampal neurons to early prion replication. Our findings suggest that prion replication results in the persistent stimulation of a programmed response, at least in part mediated by synaptic NMDA receptor activity that initially promotes cell survival and neurite remodelling. However, this response is terminated prior to the onset of clinical symptoms in the infected hippocampus, seemingly pointing to a critical juncture in the disease. Manipulation of these early neuroprotective pathways may redress the balance between degeneration and survival, providing a potential inroad for treatment.
2012-11-09 | GSE34530 | GEO
Project description:The metabotropic glutamate receptor 5 (mGluR5) is a G-protein coupled receptor with an important role in synaptic function at multiple levels. In physiological conditions, mGluR5 is an essential modulator of synaptic plasticity, learning and memory; whereas in pathological conditions, it is an acknowledged therapeutic target that has been implicated in multiple brain disorders. However, the underlying mechanisms by which mGluR5 acts in these diverse synaptic functions and processes is only partly understood. In this study, we dissected the molecular synaptic modulation mediated by mGluR5 using genetic and pharmacological mouse models to chronically and acutely reduce mGluR5 activity. Using SWATH proteomic analysis, we found that next to dysregulation of synaptic proteins, the major regulation in protein expression in both models concerned specific processes in mitochondria, such as oxidative phosphorylation. Second, we observed morphological alterations in shape and area of specifically postsynaptic mitochondria in mGluR5 KO synapses using electron microscopy. Third, computational and biochemical assays suggested an increase of mitochondrial function in neurons, with increased level of NADP/H and oxidative damage in mGluR5 KO. Altogether, our observations provide diverse lines of evidence of the modulation of synaptic mitochondrial function by mGluR5. This connection suggests a role for mGluR5 as a mediator between synaptic activity and mitochondrial function, a finding which might be a relevant for the improvement of the clinical potential of mGluR5.
2021-08-27 | PXD023809 | Pride
Project description:The rodent hippocampus is a spatially organized neuronal network that supports the formation of spatial and episodic memories. We conducted bulk RNA sequencing and spatial transcriptomics experiments to measure gene expression changes in the dorsal hippocampus following the recall of active place avoidance (APA) memory. Through bulk RNA sequencing, we examined the gene expression changes following memory recall across the functionally distinct subregions of the dorsal hippocampus. We found that recall induced differentially expressed genes (DEGs) in the CA1 and CA3 hippocampal subregions were enriched with genes involved in synaptic transmission and synaptic plasticity, while DEGs in the dentate gyrus (DG) were enriched with genes involved in energy balance and ribosomal function. Through spatial transcriptomics, we examined gene expression changes following memory recall across an array of spots encompassing putative memory-associated neuronal ensembles marked by the expression of the IEGs Arc, Egr1, and c-Jun. Within samples from both trained and untrained mice, the subpopulations of spatial transcriptomic spots marked by these IEGs were transcriptomically and spatially distinct from one another. DEGs detected between Arc+ and Arc- spots exclusively in the trained mouse were enriched in several memory-related gene ontology terms, including “regulation of synaptic plasticity” and “memory.” Our results suggest that APA memory recall is supported by regionalized transcriptomic profiles separating the CA1 and CA3 from the DG, transcriptionally and spatially distinct IEG expressing spatial transcriptomic spots, and biological processes related to synaptic plasticity as a defining the difference between Arc+ and Arc- spatial transcriptomic spots.
2024-10-11 | GSE279273 | GEO
Project description:The rodent hippocampus is a spatially organized neuronal network that supports the formation of spatial and episodic memories. We conducted bulk RNA sequencing and spatial transcriptomics experiments to measure gene expression changes in the dorsal hippocampus following the recall of active place avoidance (APA) memory. Through bulk RNA sequencing, we examined the gene expression changes following memory recall across the functionally distinct subregions of the dorsal hippocampus. We found that recall induced differentially expressed genes (DEGs) in the CA1 and CA3 hippocampal subregions were enriched with genes involved in synaptic transmission and synaptic plasticity, while DEGs in the dentate gyrus (DG) were enriched with genes involved in energy balance and ribosomal function. Through spatial transcriptomics, we examined gene expression changes following memory recall across an array of spots encompassing putative memory-associated neuronal ensembles marked by the expression of the IEGs Arc, Egr1, and c-Jun. Within samples from both trained and untrained mice, the subpopulations of spatial transcriptomic spots marked by these IEGs were transcriptomically and spatially distinct from one another. DEGs detected between Arc+ and Arc- spots exclusively in the trained mouse were enriched in several memory-related gene ontology terms, including “regulation of synaptic plasticity” and “memory.” Our results suggest that APA memory recall is supported by regionalized transcriptomic profiles separating the CA1 and CA3 from the DG, transcriptionally and spatially distinct IEG expressing spatial transcriptomic spots, and biological processes related to synaptic plasticity as a defining the difference between Arc+ and Arc- spatial transcriptomic spots.
2024-10-11 | GSE279272 | GEO
Project description:Prions induce an early Arc response in the hippocampus of prion-infected mice
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Project description:Sepsis-associated encephalopathy (SAE) is a major and frequent complication in patients with sepsis resulting in delirium and premature death. Sepsis survivors commonly suffer from long-term cognitive impairment causing immense burden on patients, caregivers, and economic health systems. Underlying pathophysiology of SAE related cognitive deficits is largely unresolved, Thus treatment options are missing. We report that experimental polymicrobial sepsis in mice induces synaptic pathology in the central nervous system underlying defective long-term potentiation and cognitive dysfunction. Analysis of differentially expressed genes revealed severely affected downregulation of genes related to neuronal and synaptic signaling in the brain, e.g. of the activity-regulated cytoskeleton-associated protein (Arc ), of the transcription-regulatory EGR family, and of the dual-specificity phosphatase 6 (Dusp6). On the protein level, ARC expression and mitogen-activated protein (MAP) kinase signaling in the brain was disturbed during SAE. For targeted rescue of dysregulated synaptic signaling and plasticity, we overexpressed ARC in the hippocampus by bilateral in-vivo stereotactic microinjection of an adeno-associated virus containing a neuron-specific plasmid of the Arc transgene. Hereby, defective synaptic plasticity and signaling in the hippocampus were restored and memory function improved. Accordingly, synaptic plasticity, neuronal spine pathology, and memory dysfunction also improved when post-septic mice were subjected to enriched environment demonstrating the potential for activity-induced recovery of long-term cognitive dysfunction. Together, we identified synaptic pathology of neurocognitive dysfunction after severe systemic infection and provide a proof-of-concept approach to interfere with SAE pathomechanisms leading to cognitive improvement.
2021-02-27 | GSE167610 | GEO
Project description:Cellular prion protein (PrPC) is a high-affinity cell-surface receptor for Amyloid-β oligomers(Aßo). In certain overexpression models of Alzheimer’s Disease (AD), pharmacology and genetics demonstrate its essential role for synaptic plasticity impairment, memory deficits and synapse loss. However, PrPC ’s role in AD-related phenotypes with endogenous expression levels, its role in tau accumulation and its effect on imaging biomarkers are unknown. The necessity of PrPC for transcriptomic alterations driven by Aß across cell types is unexplored.
2023-03-01 | GSE221712 | GEO