Browse
Submit Data
Databases
API
Help

Dataset Information

28 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Remodeling of the Homer-Shank interactome mediates homeostatic plasticity.

ABSTRACT: Neurons maintain stable levels of excitability using homeostatic synaptic scaling, which adjusts the strength of a neuron's postsynaptic inputs to compensate for extended changes in overall activity. Here, we investigated whether prolonged changes in activity affect network-level protein interactions at the synapse. We assessed a glutamatergic synapse protein interaction network (PIN) composed of 380 binary associations among 21 protein members in mouse neurons. Manipulating the activation of cultured mouse cortical neurons induced widespread bidirectional PIN alterations that reflected rapid rearrangements of glutamate receptor associations involving synaptic scaffold remodeling. Sensory deprivation of the barrel cortex in live mice (by whisker trimming) caused specific PIN rearrangements, including changes in the association between the glutamate receptor mGluR5 and the kinase Fyn. These observations are consistent with emerging models of experience-dependent plasticity involving multiple types of homeostatic responses. However, mice lacking Homer1 or Shank3B did not undergo normal PIN rearrangements, suggesting that the proteins encoded by these autism spectrum disorder-linked genes serve as structural hubs for synaptic homeostasis. Our approach demonstrates how changes in the protein content of synapses during homeostatic plasticity translate into functional PIN alterations that mediate changes in neuron excitability.

SUBMITTER: Heavner WE

PROVIDER: S-EPMC8300860 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Dystroglycan mediates homeostatic synaptic plasticity at GABAergic synapses.

Project description:Dystroglycan (DG), a cell adhesion molecule well known to be essential for skeletal muscle integrity and formation of neuromuscular synapses, is also present at inhibitory synapses in the central nervous system. Mutations that affect DG function not only result in muscular dystrophies, but also in severe cognitive deficits and epilepsy. Here we demonstrate a role of DG during activity-dependent homeostatic regulation of hippocampal inhibitory synapses. Prolonged elevation of neuronal activity up-regulates DG expression and glycosylation, and its localization to inhibitory synapses. Inhibition of protein synthesis prevents the activity-dependent increase in synaptic DG and GABAA receptors (GABAARs), as well as the homeostatic scaling up of GABAergic synaptic transmission. RNAi-mediated knockdown of DG blocks homeostatic scaling up of inhibitory synaptic strength, as does knockdown of like-acetylglucosaminyltransferase (LARGE)--a glycosyltransferase critical for DG function. In contrast, DG is not required for the bicuculline-induced scaling down of excitatory synaptic strength or the tetrodotoxin-induced scaling down of inhibitory synaptic strength. The DG ligand agrin increases GABAergic synaptic strength in a DG-dependent manner that mimics homeostatic scaling up induced by increased activity, indicating that activation of this pathway alone is sufficient to regulate GABAAR trafficking. These data demonstrate that DG is regulated in a physiologically relevant manner in neurons and that DG and its glycosylation are essential for homeostatic plasticity at inhibitory synapses.

| S-EPMC4020085 | biostudies-other

The postsynaptic density proteins Homer and Shank form a polymeric network structure.

Project description:The postsynaptic density (PSD) is crucial for synaptic functions, but the molecular architecture retaining its structure and components remains elusive. Homer and Shank are among the most abundant scaffolding proteins in the PSD, working synergistically for maturation of dendritic spines. Here, we demonstrate that Homer and Shank, together, form a mesh-like matrix structure. Crystallographic analysis of this region revealed a pair of parallel dimeric coiled coils intercalated in a tail-to-tail fashion to form a tetramer, giving rise to the unique configuration of a pair of N-terminal EVH1 domains at each end of the coiled coil. In neurons, the tetramerization is required for structural integrity of the dendritic spines and recruitment of proteins to synapses. We propose that the Homer-Shank complex serves as a structural framework and as an assembly platform for other PSD proteins.

| S-EPMC2680917 | biostudies-literature

Astrocyte-secreted IL-33 mediates homeostatic synaptic plasticity in the adult hippocampus.

Project description:Hippocampal synaptic plasticity is important for learning and memory formation. Homeostatic synaptic plasticity is a specific form of synaptic plasticity that is induced upon prolonged changes in neuronal activity to maintain network homeostasis. While astrocytes are important regulators of synaptic transmission and plasticity, it is largely unclear how they interact with neurons to regulate synaptic plasticity at the circuit level. Here, we show that neuronal activity blockade selectively increases the expression and secretion of IL-33 (interleukin-33) by astrocytes in the hippocampal cornu ammonis 1 (CA1) subregion. This IL-33 stimulates an increase in excitatory synapses and neurotransmission through the activation of neuronal IL-33 receptor complex and synaptic recruitment of the scaffold protein PSD-95. We found that acute administration of tetrodotoxin in hippocampal slices or inhibition of hippocampal CA1 excitatory neurons by optogenetic manipulation increases IL-33 expression in CA1 astrocytes. Furthermore, IL-33 administration in vivo promotes the formation of functional excitatory synapses in hippocampal CA1 neurons, whereas conditional knockout of IL-33 in CA1 astrocytes decreases the number of excitatory synapses therein. Importantly, blockade of IL-33 and its receptor signaling in vivo by intracerebroventricular administration of its decoy receptor inhibits homeostatic synaptic plasticity in CA1 pyramidal neurons and impairs spatial memory formation in mice. These results collectively reveal an important role of astrocytic IL-33 in mediating the negative-feedback signaling mechanism in homeostatic synaptic plasticity, providing insights into how astrocytes maintain hippocampal network homeostasis.

| S-EPMC7817131 | biostudies-literature

MicroRNA regulation of homeostatic synaptic plasticity.

Project description:Homeostatic mechanisms are required to control formation and maintenance of synaptic connections to maintain the general level of neural impulse activity within normal limits. How genes controlling these processes are co-coordinately regulated during homeostatic synaptic plasticity is unknown. MicroRNAs (miRNAs) exert regulatory control over mRNA stability and translation and may contribute to local and activity-dependent posttranscriptional control of synapse-associated mRNAs. However, identifying miRNAs that function through posttranscriptional gene silencing at synapses has remained elusive. Using a bioinformatics screen to identify sequence motifs enriched in the 3'UTR of rapidly destabilized mRNAs, we identified a developmentally and activity-regulated miRNA (miR-485) that controls dendritic spine number and synapse formation in an activity-dependent homeostatic manner. We find that many plasticity-associated genes contain predicted miR-485 binding sites and further identify the presynaptic protein SV2A as a target of miR-485. miR-485 negatively regulated dendritic spine density, postsynaptic density 95 (PSD-95) clustering, and surface expression of GluR2. Furthermore, miR-485 overexpression reduced spontaneous synaptic responses and transmitter release, as measured by miniature excitatory postsynaptic current (EPSC) analysis and FM 1-43 staining. SV2A knockdown mimicked the effects of miR-485, and these effects were reversed by SV2A overexpression. Moreover, 5 d of increased synaptic activity induced homeostatic changes in synaptic specializations that were blocked by a miR-485 inhibitor. Our findings reveal a role for this previously uncharacterized miRNA and the presynaptic protein SV2A in homeostatic plasticity and nervous system development, with possible implications in neurological disorders (e.g., Huntington and Alzheimer's disease), where miR-485 has been found to be dysregulated.

| S-EPMC3136313 | biostudies-other

Homer 1a gates the induction mechanism for endocannabinoid-mediated synaptic plasticity.

Project description:At hippocampal excitatory synapses, endocannabinoids (eCBs) mediate two forms of retrograde synaptic inhibition that are induced by postsynaptic depolarization or activation of metabotropic glutamate receptors (mGluRs). The homer family of molecular scaffolds provides spatial organization to regulate postsynaptic signaling cascades, including those activated by mGluRs. Expression of the homer 1a (H1a) immediate-early gene produces a short homer protein that lacks the domain required for homer oligomerization, enabling it to uncouple homer assemblies. Here, we report that H1a differentially modulates two forms of eCB-mediated synaptic plasticity, depolarization-induced suppression of excitation (DSE) and metabotropic suppression of excitation (MSE). EPSCs were recorded from cultured hippocampal neurons and DSE evoked by a 15 s depolarization to 0 mV and MSE evoked by a type I mGluR agonist. Expression of H1a enhanced DSE and inhibited MSE at the same synapse. Many physiologically important stimuli initiate H1a expression including brain-derived neurotrophic factor (BDNF). Treating hippocampal cultures with BDNF increased transcription of H1a and uncoupled homer 1c-GFP (green fluorescent protein) clusters. BDNF treatment blocked MSE and enhanced DSE. Thus, physiological changes in H1a expression gate the induction pathway for eCB-mediated synaptic plasticity by uncoupling mGluR from eCB production.

| S-EPMC2843151 | biostudies-literature

Arc-dependent synapse-specific homeostatic plasticity.

Project description:Both theoretical and experimental research has indicated that the synaptic strength between neurons in a network needs to be properly fine-tuned and controlled by homeostatic mechanisms to ensure proper network function. One such mechanism that has been extensively characterized is synaptic homeostatic plasticity or global synaptic scaling. This mechanism refers to the bidirectional ability of all synapses impinging on a neuron to actively compensate for changes in the neuron's overall excitability. Here, using a combination of electrophysiological, two-photon glutamate uncaging and imaging methods, we show that mature individual synapses, independent of neighboring synapses, have the ability to autonomously sense their level of activity and actively compensate for it in a homeostatic-like fashion. This synapse-specific homeostatic plasticity, similar to global synaptic plasticity, requires the immediate early gene Arc. Together, our results document an extra level of regulation of synaptic function that bears important computational consequences on information storage in the brain.

| S-EPMC3021034 | biostudies-literature

Astrocyte-secreted IL-33 mediates homeostatic synaptic plasticity in the adult hippocampus

2020-12-14 | GSE161540 | GEO

Mutation of Drosophila homer disrupts control of locomotor activity and behavioral plasticity.

Project description:Homer proteins have been proposed to play a role in synaptogenesis, synapse function, receptor trafficking, and axon pathfinding. Here we report the isolation and characterization of the Drosophila gene homer, the single Homer-related gene in fly. Using anti-Homer antibody we show that Homer is expressed in a broad range of tissues but is highly enriched in the CNS. Similarly to its mammalian counterpart, the Drosophila Homer localizes to the dendrites and the endoplasmic reticulum (ER). This subcellular distribution is dependent on an intact Enabled/Vasp homology 1 domain, suggesting that Homer must bind to one or more of its partners for proper localization. We have created a mutation of homer and show that flies homozygous for this mutation are viable and show coordinated locomotion, suggesting that Homer is not essential for basic neurotransmission. However, we found that homer mutants display defects in behavioral plasticity and the control of locomotor activity. Our results argue that in the CNS, Homer-related proteins operate in the ER and in dendrites to regulate the development and function of neural networks underlying locomotor control and behavioral plasticity.

| S-EPMC6758666 | biostudies-literature

Disassembly of shank and homer synaptic clusters is driven by soluble beta-amyloid(1-40) through divergent NMDAR-dependent signalling pathways.

Project description:Disruption of the postsynaptic density (PSD), a network of scaffold proteins located in dendritic spines, is thought to be responsible for synaptic dysfunction and loss in early-stage Alzheimer's disease (AD). Extending our previous demonstration that derangement of the PSD by soluble amyloid-beta (Abeta) involves proteasomal degradation of PSD-95, a protein important for ionotropic glutamate receptor trafficking, we now show that Abeta also disrupts two other scaffold proteins, Homer1b and Shank1, that couple PSD-95 with ionotropic and metabotropic glutamate receptors. Treatment of fronto-cortical neurons with soluble Abeta results in rapid (within 1 h) and significant thinning of the PSD, decreased synaptic levels of Homer1b and Shank1, and reduced synaptic mGluR1 levels. We show that de novo protein synthesis is required for the declustering effects of Abeta on Homer1b (but not Shank1) and that, in contrast to PSD-95, Abeta-induced Homer1b and Shank1 cluster disassembly does not depend on proteasome activity. The regulation of Homer1b and Shank1 by Abeta diverges in two other respects: i) whereas the activity of both NMDAR and VDCC is required for Abeta-induced declustering of Homer1b, Abeta-induced declustering of Shank1 only requires NMDAR activity; and ii) whereas the effects of Abeta on Homer1b involve engagement of the PI-3K pathway and calcineurin phosphatase (PP2B) activity, those on Shank1 involve activation of the ERK pathway. In summary, soluble Abeta recruits discrete signalling pathways to rapidly reduce the synaptic localization of major components of the PSD and to regulate the availability of mGluR1 in the synapse.

| S-EPMC2695780 | biostudies-literature

protein turnover during homeostatic plasticity

Project description:Using quantitative proteomics we identified group of synaptic genes with decreased protein synthesis during homeostatic plasticity. To obtain further information about their mRNA levels/sequences (3’UTR) we performed polyA RNAseq. Using EISA analysis of Ribominus RNAseq dataset we could further differentiate between transcriptional respective post-transcriptional dependent alterations in mRNA levels. In addition Ribominus RNAseq from cell body and processes (dendrites, axons) RNA samples showed us local changes in mRNA levels during homeostatic plasticity. At the end, small RNAseq helped us to identify miRNAs that are increased during homeostatic plasticity and might regulate downregulated genes.

2017-04-05 | PXD004150 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data