Synaptic scaling regulates the transcriptome in hippocampal neurons
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE111384 | GEO | 2019/02/13
REPOSITORIES: GEO
Similar Datasets
Project description:Synaptic scaling regulates the transcriptome in hippocampal neurons
| PRJNA450745 | ENA
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: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: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:Neuronal networks are subject to fluctuations in both the magnitude and frequency of inputs, requiring plasticity mechanisms to stabilize network activity. Homeostatic synaptic scaling is a form of synaptic plasticity that adjusts the strength of neuronal connections up or down in response to large changes in input. Although homeostatic plasticity requires changes in gene expression, there is only limited data describing the molecular changes associated with homeostatic scaling, focusing mostly on the expression mechanisms involving glutamate receptors. The fact that neuronal networks can be scaled up (in response to reduced activity) or down (in response to enhanced activity) provides a unique opportunity to examine the molecular and proteomic response to opposite ends of the phenotypic spectrum of synaptic plasticity. Here we first demonstrate that homeostatic scaling required protein synthesis. We then examined the plasticity-induced changes in the newly-synthesized neuronal proteome of neurons to identify the landscape of proteomic changes that contribute to opposing forms of homeostatic plasticity. Cultured rat hippocampal neurons (21 DIV) underwent homeostatic upscaling or downscaling (treatments with TTX and Bicucculine, respectively). We used BONCAT (BioOrthogonal Non-Canonical Amino acid Tagging) to metabolically label, capture and identify newly-synthesized proteins, detecting and analysing 5940 newly-synthesized proteins using liquid chromatography-coupled tandem mass spectrometry and label-free quantitation. Neither up- or down-scaling produced changes in the number of different proteins translated. Rather, our findings indicate that synaptic up- and down-scaling elicit opposing translational regulation of several molecular pathways, producing targeted adjustments in the neuronal proteome. We detected ~ 300 differentially regulated proteins involved in neurite outgrowth, reorganization of nerve terminals, axon guidance and targeting, neurotransmitter transport, filopodia assembly, excitatory synapses and glutamate receptor complexes. These proteins include well-characterized mediators of synaptic plasticity, e.g. the ionotropic glutamate receptor complex that is down-regulated during down-scaling and coordinately upregulated during upscaling. We also identified differentially regulated proteins that in addition to their regulation in homeostatic plasticity, are also associated with multiple diseases and disorders, including intellectual disability, schizophrenia, epilepsy, and Parkinson’s disease.
2016-12-22 | PXD004889 | Pride
Project description:To explore the potential mediators of corticostriatal synaptic scaling in GAT1–/– mice, whole-tissue mRNA sequencing was carried out for the dorsal striatum of GAT1+/+ and GAT1–/– mice.
2022-08-20 | GSE211419 | 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:Compartment-specific regulation of gene expression orchestrates homeostatic synaptic scaling
| PRJNA650210 | ENA
Project description:N-methyl-D-aspartate type glutamate receptors (NMDARs) are key mediators of synaptic activity-regulated gene transcription in neurons, both during development and in the adult brain. Developmental differences in the GluN2 subunit composition of NMDARs determines whether NMDARs activate the transcription factor CREB. However, whether the developmentally-regulated GluN3A subunit also modulates NMDAR-induced transcription was unknown. Here we show that knocking down GluN3A in rat hippocampal neurons promotes the inducible transcription of a subset of NMDAR-sensitive genes. This enhancement is mediated by the accumulation of phosphorylated p38 MAP kinase in the nucleus, which drives the activation of the transcription factor MEF2C and promotes the transcription of a subset of synaptic activity-induced genes including Bdnf and Arc. Our evidence that GluN3A negatively regulates MEF2C-dependent transcription reveals a novel mechanism by which NMDAR subunit composition confers specificity on the program of synaptic activity-regulated gene transcription in developing neurons.
2019-07-08 | GSE133917 | GEO