Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA356606 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5084310.fastq.gz | Fastqsanger.gz | |||
| SRR5084320.fastq.gz | Fastqsanger.gz | |||
| SRR5084311.fastq.gz | Fastqsanger.gz | |||
| SRR5084321.fastq.gz | Fastqsanger.gz | |||
| SRR5084312.fastq.gz | Fastqsanger.gz |
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Project description:Homeostatic scaling allows neurons to maintain stable activity patterns by globally altering their synaptic strength in response to changing activity levels. Suppression of activity by blocking action potentials increases synaptic strength through an upregulation of surface AMPA receptors. Although this synaptic up-scaling was shown to require transcription, the molecular nature of the intrinsic transcription program underlying this process and its functional significance have been unclear. Using RNA-seq, we identified 73 genes that were specifically upregulated in response to activity suppression. In particular, Neuronal pentraxin-1 (Nptx1) increased within 6 h of activity blockade, and knockdown of this gene blocked the increase in synaptic strength. Notably, Nptx1 induction is mediated by calcium influx through the T-type Voltage-Gated Calcium Channel, as well as two transcription factors, SRF and ELK1. Taken together, these results uncover a transcriptional program that specifically operates when neuronal activity is suppressed, to globally coordinate the increase in synaptic strength.
2017-02-07 | GSE90988 | GEO
Project description:Neural circuits utilize a host of homeostatic plasticity mechanisms, including synaptic scaling, to maintain stability in circuits undergoing experience-dependent remodeling necessary for information processing. During synaptic scaling, compensatory adaptations in synaptic strength are induced after chronic manipulations in neuronal firing, but our understanding of this process is largely limited to its initial induction. How these homeostatic synaptic adaptations evolve when activity renormalizes and their impact on subsequent homeostatic compensation are both poorly understood. To examine these issues, we investigated whether a previous history of homeostatic scaling in networks of cultured hippocampal neurons altered their subsequent homeostatic responses to chronic activity manipulations. Unexpectedly, we found that a history of synaptic scaling strongly suppressed future scaling to the same, and even opposite, activity challenges. This history-dependent suppression was specific for future homeostatic compensation, as networks with a prior scaling history showed no deficits in the chemical induction of long-term potentiation (cLTP), a Hebbian form of synaptic plasticity. Hippocampal neurons with a prior scaling history exhibited normal engagement of activity-dependent signaling during subsequent activity challenges (as assessed by examination of the ERK/MAPK pathway) but demonstrated widespread alterations in activity-dependent transcriptional
2024-09-01 | GSE180993 | GEO
Project description:Homeostatic plasticity, a form of synaptic plasticity, maintains the fine balance between overall excitation and inhibition in developing and mature neuronal networks. Although the synaptic mechanisms of homeostatic plasticity are well characterized, the associated transcriptional program remains poorly understood. We show that the Kleefstra syndrome-associated protein, EHMT1, plays a critical and cell-autonomous role in synaptic scaling by responding to attenuated neuronal firing or sensory drive. Chronic activity deprivation increased the amount of neuronal dimethylated H3 at lysine 9 (H3K9me2), the catalytic product of EHMT1 and an epigenetic marker for gene repression. Genetic knockdown and pharmacological blockade of EHMT1 or EHMT2 prevented the increase of H3K9me2 and synaptic scaling up. Furthermore, BDNF repression was preceded by EHMT1/2-mediated H3K9me2 deposition at the Bdnf promoter during synaptic scaling up, both in vivo or in vivo. These findings suggest that changes in chromatin state through H3K9me2 governs a repressive program to achieve synaptic scaling. 12 samples (4 conditions in biological triplicate), 3 wt, 3 wt tetradotoxin treated, 3 k.d., 3 k.d. tetradotoxin treated
2016-06-30 | E-GEOD-68960 | biostudies-arrayexpress
Project description:Homeostatic plasticity, a form of synaptic plasticity, maintains the fine balance between overall excitation and inhibition in developing and mature neuronal networks. Although the synaptic mechanisms of homeostatic plasticity are well characterized, the associated transcriptional program remains poorly understood. We show that the Kleefstra syndrome-associated protein, EHMT1, plays a critical and cell-autonomous role in synaptic scaling by responding to attenuated neuronal firing or sensory drive. Chronic activity deprivation increased the amount of neuronal dimethylated H3 at lysine 9 (H3K9me2), the catalytic product of EHMT1 and an epigenetic marker for gene repression. Genetic knockdown and pharmacological blockade of EHMT1 or EHMT2 prevented the increase of H3K9me2 and synaptic scaling up. Furthermore, BDNF repression was preceded by EHMT1/2-mediated H3K9me2 deposition at the Bdnf promoter during synaptic scaling up, both in vivo or in vivo. These findings suggest that changes in chromatin state through H3K9me2 governs a repressive program to achieve synaptic scaling.
2016-06-30 | GSE68960 | GEO
Project description:Wu C, Tatavarty V, Jean-Beltran PM, Guerrero A, Keshishian H, Krug K, MacMullan M, de Arce KP, Carr SA, Cottrell J, Turrigiano GG. 2021
Homeostatic synaptic plasticity requires widespread remodeling of synaptic signaling and scaffolding networks, but the role of posttranslational modifications in this process has not been systematically studied. Here we analyzed changes in the phosphoproteome during synaptic scaling up and down and found wide-spread and temporally complex changes. These included 424 bidirectionally modulated phosphosites that were strongly enrichment for synapse-associated proteins, including the ASD-associated synaptic scaffold protein Shank3. Shank3 was dephosphorylated at two highly conserved sites (rat S1586 and S1615) during scaling up, and hyperphosphorylated during scaling down. These changes modified the synaptic localization of Shank3 during scaling, and phosphomimetic or deficient mutants of Shank3 prevented scaling up or down, respectively. Finally, we found that dephosphorylation of these sites via PP2A activity was essential for the maintenance of synaptic scaling up. Thus Shank3 undergoes an activity-dependent switch between hypo- and hyperphosphorylation at S1586/ S1615, that is necessary to enable scaling up or down, respectively. More broadly, our data suggest that widespread and bidirectional changes in the synaptic phosphoproteome are essential for the functional reconfiguration of synaptic scaffolds during homeostatic plasticity.
2021-07-30 | MSV000087926 | MassIVE
Project description:Synaptic scaling is a form of homeostatic plasticity which allows neurons to reduce their action potential firing rate in response to chronic alterations in neural activity. Synaptic scaling requires profound changes in gene expression, but the relative contribution of local and cell-wide mechanisms to synaptic scaling is controversial. Here we performed a comprehensive multi-omics characterization of the somatic and process compartments of primary rat hippocampal neurons during synaptic scaling. Thereby, we uncovered highly compartment-specific and correlated changes in the neuronal transcriptome and proteome. Specifically, we identified highly compartment-specific downregulation of crucial regulators of neuronal excitability and excitatory synapse structure. Motif analysis further suggests an important role for trans-acting post-transcriptional regulators, including RNA-binding proteins and microRNAs, in the local regulation of the corresponding mRNAs. Altogether, our study indicates that compartmentalized gene expression changes are widespread in synaptic scaling and might co-exist with neuron-wide mechanism to allow synaptic computation and homeostasis.
2021-07-06 | GSE155540 | GEO
Project description:Synaptic scaling is a form of homeostatic plasticity which allows neurons to adjust their action potential firing rate in response to chronic alterations in neural activity. Synaptic scaling requires profound changes in gene expression, but the relative contribution of local and cell-wide mechanisms is controversial. Here we performed a comprehensive multi-omics characterization of the somatic and process compartments of primary rat hippocampal neurons during synaptic scaling. Thereby, we uncovered highly compartment-specific and correlated changes in the neuronal transcriptome and proteome. Specifically, we identified highly compartment-specific downregulation of crucial regulators of neuronal excitability and excitatory synapse structure. Motif analysis further suggests an important role for trans-acting post-transcriptional regulators, including RNA-binding proteins and microRNAs, in the local regulation of the corresponding mRNAs. Altogether, our study indicates that compartmentalized gene expression changes are widespread in synaptic scaling and might co-exist with neuron-wide mechanisms to allow synaptic computation and homeostasis
2021-07-09 | PXD020745 | Pride
Project description:Homeostatic scaling adjusts synaptic strength in response to persistent changes in neuronal network activity. This compensatory mechanism requires proteome remodeling accomplished via regulation of protein synthesis as well as degradation, but the global patterns of proteome remodeling and the underlying dynamics of individual proteins remain elusive. Here we used dynamic SILAC labeling in cultured hippocampal cells to identify proteins involved in homeostatic up- or down-scaling and to quantify their changes in synthesis and degradation as well as resulting changes in protein abundance or turnover. Our data demonstrate that a large fraction of the neuronal proteome is remodeled during homeostatic scaling. Most proteins were down-regulated by decreased synthesis or up-regulated by decreased degradation. Comparably fewer proteins showed increased synthesis or degradation rates. More than half of the quantified synaptic proteins were regulated, including pre- as well as postsynaptic proteins with diverse molecular functions.
2020-03-31 | PXD016004 | Pride
Project description:Histone H3 lysine 4 methylaton (H3K4me), a hallmark of transcriptionally engaged chromatin, is installed by the lysine methyltransferases 2 (KMT2) family of six enzymes in mammals. The six enzymes appear to have arisen from gene duplication of the ancient three enzymes found in the fruit fly. Heterozygous mutations in any of the six enzymes result in monogenic neurodevelopmental disorders, indicating nonredundant yet poorly understood roles of KMT2 family enzymes in neurodevelopment. Recent evidence suggests that histone methyltransferase activity may not be central to KMT2 functions; however, the enzymatic activity is evolutionary conserved, implicating the presence of selective pressure to maintain the catalytic activity. Here, we show that H3K4 methylation is dynamically regulated during prolonged alteration of neuronal activity. The perturbation of H3K4me by the H3.3K4M mutant blocks synaptic scaling, a form of homeostatic plasticity that buffers the impact of prolonged reductions or increases in network activity. Unexpectedly, we found that the six individual enzymes are all necessary for synaptic scaling and that the roles of KMT2 enzymes segregate into evolutionary-defined subfamilies; KMT2A and KMT2B (fly-Trx homologs) for synaptic downscaling, KMT2C and KMT2D (Trr homologs) for upscaling, and KMT2F and KMT2G (dSet homologs) for both directions. Selective blocking of KMT2A enzymatic activity by a small molecule and targeted disruption of the enzymatic domain both blocked the synaptic downscaling and interfered with the activity-dependent transcriptional program. Furthermore, our study revealed specific phases of synaptic downscaling, i.e., induction and maintenance, in which KMT2A and KMT2B play distinct roles. These results suggest that mammalian brains have co-opted intricate H3K4me installation to achieve stability of the expanding neuronal circuits.
2024-08-01 | GSE239471 | GEO
Project description:Homeostatic synaptic scaling is a compensatory mechanism that allows adjustment of the strength of synaptic connections up or down in response to changes in input to maintain global network stability. To characterize the molecular changes on the level of protein modification that contribute to synaptic scaling, we examined changes of the proteome and phosphoproteome in response to activity manipulation. For this purpose, we pharmacologically induced up- or down-scaling in primary cultured cortical neurons for different time spans ranging from minutes (5 min, 15 min) up to one day. Temporal snapshots of the neuronal proteome and phosphoproteome were obtained using high-resolution LC-MS/MS analyses. Our data cover 45,395 phosphorylated peptide species that map to 26,642 unique phosphorylation sites. Activity manipulation elicited significant regulation of 3,382 phosphorylation events on proteins predominantly located at the synaptic compartment or involved in organization of the cytoskeleton. With respect to the temporal regulation, we discovered that phosphomodulation during scaling was not only achieved by time-limited phosphorylation, but for a quarter of initial sites also by persistent regulation. Persistence in phosphorylation was associated with reciprocity in the sign of its regulation, reflecting the two different scaling polarities.
2021-08-12 | PXD021834 | Pride