Activity-Induced Regulation of Synaptic Strength through the Chromatin Reader L3mbtl1
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA413882 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6156950.fastq.gz | Fastqsanger.gz | |||
| SRR6156951.fastq.gz | Fastqsanger.gz | |||
| SRR6156952.fastq.gz | Fastqsanger.gz | |||
| SRR6156953.fastq.gz | Fastqsanger.gz | |||
| SRR6156954.fastq.gz | Fastqsanger.gz |
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Project description:Homeostatic synaptic downscaling reduces neuronal excitability by modulating the number of postsynaptic receptors. Histone modifications and the subsequent chromatin remodeling play critical roles in activity-dependent gene expression. Histone modification codes are recognized by chromatin readers that affect gene expression by altering chromatin structure. We show that L3mbtl1 (lethal 3 malignant brain tumor-like 1), a polycomb chromatin reader, is downregulated by neuronal activity and is essential for synaptic response and downscaling. Genome-scale mapping of L3mbtl1 occupancies identified Ctnnb1 as a key gene downstream of L3mbtl1. Importantly, the occupancy of L3mbtl1 on the Ctnnb1 gene was regulated by neuronal activity. L3mbtl1 knockout neurons exhibited reduced Ctnnb1 expression. Partial knockdown of Ctnnb1 in wild-type neurons reduced excitatory synaptic transmission and abolished homeostatic downscaling, and transfecting Ctnnb1 in L3mbtl1 knockout neurons enhanced synaptic transmission and restored homeostatic downscaling. These results highlight a role for L3mbtl1 in regulating homeostasis of synaptic efficacy.
2018-06-12 | GSE104802 | GEO
Project description:Homeostatic synaptic downscaling reduces neuronal excitability by modulating the number of postsynaptic receptors. Histone modifications and the subsequent chromatin remodeling play critical roles in activity-dependent gene expression. Histone modification codes are recognized by chromatin readers that affect gene expression by altering chromatin structure. We show that L3mbtl1 (lethal 3 malignant brain tumor-like 1), a polycomb chromatin reader, is downregulated by neuronal activity and is essential for synaptic response and downscaling. Genome-scale mapping of L3mbtl1 occupancies identified Ctnnb1 as a key gene downstream of L3mbtl1. Importantly, the occupancy of L3mbtl1 on the Ctnnb1 gene was regulated by neuronal activity. L3mbtl1 knockout neurons exhibited reduced Ctnnb1 expression. Partial knockdown of Ctnnb1 in wild-type neurons reduced excitatory synaptic transmission and abolished homeostatic downscaling, and transfecting Ctnnb1 in L3mbtl1 knockout neurons enhanced synaptic transmission and restored homeostatic downscaling. These results highlight a role for L3mbtl1 in regulating homeostasis of synaptic efficacy.
| S-EPMC6309677 | biostudies-literature
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:Activity-dependent changes in synapses rely on functional changes in resident proteins and on gene expression. We addressed the relationship between synapse activity and the expression of synaptic genes by comparing RNA levels in the neocortex of normal mice versus synaptically silent munc18-1 null mutants, using microarray expression analysis, quantitative PCR and Northern blotting. We hypothesized that genes under control of synaptic activity are differentially expressed between mutants and controls and found that few synaptic signaling genes were differentially expressed. However, all neuropeptide genes with detectable expression on the microarray were differentially expressed, being 3-20 fold higher in control cortex. Genes encoding their receptors and most other synaptic components were not differentially expressed. Differential expression of the neuropeptide genes was confirmed by qPCR analysis. In situ hybridization indicated that the difference in neuropeptide expression was uniform and not due to the loss of specific cells in the mutant. In primary sensory neurons, which do not depend on synaptic activity for their input, the differential expression of neuropeptides was not observed. These data reveal no simple relation between activity of synapses and expression of their resident proteins, but instead identified a unique feature of neuropeptide gene expression, which appears to depend on synaptic activity. 4 biological replicates of munc18-1 null mutants, hybridized with 4 pooled biological replicates. On one array the mutant sample was labeled with cy3 and on the other three with cy5.
2006-07-31 | E-GEOD-3638 | biostudies-arrayexpress
Project description:Activity-dependent changes in synapses rely on functional changes in resident proteins and on gene expression. We addressed the relationship between synapse activity and the expression of synaptic genes by comparing RNA levels in the neocortex of normal mice versus synaptically silent munc18-1 null mutants, using microarray expression analysis, quantitative PCR and Northern blotting. We hypothesized that genes under control of synaptic activity are differentially expressed between mutants and controls and found that few synaptic signaling genes were differentially expressed. However, all neuropeptide genes with detectable expression on the microarray were differentially expressed, being 3-20 fold higher in control cortex. Genes encoding their receptors and most other synaptic components were not differentially expressed. Differential expression of the neuropeptide genes was confirmed by qPCR analysis. In situ hybridization indicated that the difference in neuropeptide expression was uniform and not due to the loss of specific cells in the mutant. In primary sensory neurons, which do not depend on synaptic activity for their input, the differential expression of neuropeptides was not observed. These data reveal no simple relation between activity of synapses and expression of their resident proteins, but instead identified a unique feature of neuropeptide gene expression, which appears to depend on synaptic activity. Keywords: munc18-1 null mutant mice are characterized by the complete loss of both evoked and spontaneous transmitter release 11 biological replicates of munc18-1 null mutants, hybridized with 11 pooled biological replicates. On six arrays the mutant sample was labeled with cy3 and on the other five with cy5.
2006-07-31 | E-GEOD-3639 | biostudies-arrayexpress
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:Activity-dependent changes in synapses rely on functional changes in resident proteins and on gene expression. We addressed the relationship between synapse activity and the expression of synaptic genes by comparing RNA levels in the neocortex of normal mice versus synaptically silent munc18-1 null mutants, using microarray expression analysis, quantitative PCR and Northern blotting. We hypothesized that genes under control of synaptic activity are differentially expressed between mutants and controls and found that few synaptic signaling genes were differentially expressed. However, all neuropeptide genes with detectable expression on the microarray were differentially expressed, being 3-20 fold higher in control cortex. Genes encoding their receptors and most other synaptic components were not differentially expressed. Differential expression of the neuropeptide genes was confirmed by qPCR analysis. In situ hybridization indicated that the difference in neuropeptide expression was uniform and not due to the loss of specific cells in the mutant. In primary sensory neurons, which do not depend on synaptic activity for their input, the differential expression of neuropeptides was not observed. These data reveal no simple relation between activity of synapses and expression of their resident proteins, but instead identified a unique feature of neuropeptide gene expression, which appears to depend on synaptic activity. Keywords: munc18-1 null mutant mice are characterized by the complete loss of both evoked and spontaneous transmitter release
2006-08-01 | GSE3638 | GEO
Project description:Activity-dependent changes in synapses rely on functional changes in resident proteins and on gene expression. We addressed the relationship between synapse activity and the expression of synaptic genes by comparing RNA levels in the neocortex of normal mice versus synaptically silent munc18-1 null mutants, using microarray expression analysis, quantitative PCR and Northern blotting. We hypothesized that genes under control of synaptic activity are differentially expressed between mutants and controls and found that few synaptic signaling genes were differentially expressed. However, all neuropeptide genes with detectable expression on the microarray were differentially expressed, being 3-20 fold higher in control cortex. Genes encoding their receptors and most other synaptic components were not differentially expressed. Differential expression of the neuropeptide genes was confirmed by qPCR analysis. In situ hybridization indicated that the difference in neuropeptide expression was uniform and not due to the loss of specific cells in the mutant. In primary sensory neurons, which do not depend on synaptic activity for their input, the differential expression of neuropeptides was not observed. These data reveal no simple relation between activity of synapses and expression of their resident proteins, but instead identified a unique feature of neuropeptide gene expression, which appears to depend on synaptic activity. Keywords: munc18-1 null mutant mice are characterized by the complete loss of both evoked and spontaneous transmitter release
2006-08-01 | GSE3637 | GEO
Project description:Activity-dependent changes in synapses rely on functional changes in resident proteins and on gene expression. We addressed the relationship between synapse activity and the expression of synaptic genes by comparing RNA levels in the neocortex of normal mice versus synaptically silent munc18-1 null mutants, using microarray expression analysis, quantitative PCR and Northern blotting. We hypothesized that genes under control of synaptic activity are differentially expressed between mutants and controls and found that few synaptic signaling genes were differentially expressed. However, all neuropeptide genes with detectable expression on the microarray were differentially expressed, being 3-20 fold higher in control cortex. Genes encoding their receptors and most other synaptic components were not differentially expressed. Differential expression of the neuropeptide genes was confirmed by qPCR analysis. In situ hybridization indicated that the difference in neuropeptide expression was uniform and not due to the loss of specific cells in the mutant. In primary sensory neurons, which do not depend on synaptic activity for their input, the differential expression of neuropeptides was not observed. These data reveal no simple relation between activity of synapses and expression of their resident proteins, but instead identified a unique feature of neuropeptide gene expression, which appears to depend on synaptic activity. Keywords: munc18-1 null mutant mice are characterized by the complete loss of both evoked and spontaneous transmitter release
2006-08-01 | GSE3639 | GEO
Project description:Synapses contain a limited number of synaptic vesicles (SVs) that are released in response to action potentials (APs). Therefore, sustaining synaptic transmission over a wide range of AP firing rates and timescales depends on SV release and replenishment. Although actin dynamics impact synaptic transmission, how presynaptic regulators of actin signaling cascades control SV release and replenishment remains unresolved. Rac1, a Rho GTPase, regulates actin signaling cascades that control synaptogenesis, neuronal development, and postsynaptic function. However, the presynaptic role of Rac1 in regulating synaptic transmission is unclear. To unravel Rac1's roles in controlling transmitter release, we performed selective presynaptic ablation of Rac1 at the mature mouse calyx of Held synapse. Loss of Rac1 increased synaptic strength, accelerated EPSC recovery after conditioning stimulus trains, and augmented spontaneous SV release with no change in presynaptic morphology or AZ ultrastructure. Analyses with constrained short-term plasticity models revealed faster SV priming kinetics and, depending on model assumptions, elevated SV release probability or higher abundance of tightly docked fusion-competent SVs in Rac1-deficient synapses. We conclude that presynaptic Rac1 is a key regulator of synaptic transmission and plasticity mainly by regulating the dynamics of SV priming and potentially SV release probability.
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