MicroRNA-218-5p Coordinates Scaling of Excitatory and Inhibitory Synapses during Homeostatic Synaptic Plasticity
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ABSTRACT:
PROVIDER: PRJNA1027270 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26373309_1.fastq.gz | Fastqsanger.gz | |||
| SRR26373309_2.fastq.gz | Fastqsanger.gz | |||
| SRR26373310_1.fastq.gz | Fastqsanger.gz | |||
| SRR26373310_2.fastq.gz | Fastqsanger.gz | |||
| SRR26373311_1.fastq.gz | Fastqsanger.gz |
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Project description:Homeostatic synaptic plasticity (HSP) is a fundamental neuronal mechanism that allows networks to compensate for prolonged changes in activity by adjusting synaptic strength. This process is crucial for maintaining stable brain function and has been implicated in memory consolidation during sleep. While scaling of both excitatory and inhibitory synapses plays an important role during homeostatic synaptic plasticity, molecules coordinating both of these processes are unknown. In this study, we investigate the role of miR-218-5p as a regulator of inhibitory and excitatory synapses in the context of picrotoxin (PTX)-induced homeostatic synaptic downscaling (HSD) in rat hippocampal neurons. Using enrichment analysis of miRNA-binding sites in differentially expressed genes changing upon PTX-induced HSD, we bioinformatically predicted and experimentally validated increased miR-218-5p activity upon PTX-treatment in the process compartment. By monitoring synapse structure in vitro with confocal microscopy, we demonstrate that miR-218-5p exerts a dual effect in HSD: it prevents the downscaling of excitatory synapses and dendritic spines, while at the same time blocking inhibitory synapse upscaling. Furthermore, we identify the Neuroligin2 interacting molecule Mdga1 as a crucial target of miR-218-5p in the context of homeostatic upscaling of inhibitory synapses. By performing long-term electroencephalographic (EEG) recordings, we further revealed that local inhibition of miR-218-5p in the somatosensory cortex reduced local slow-wave activity (SWA) during non-rapid-eye-movement (NREM) sleep. In summary, this study uncovers miR-218-5p as a key player in coordinating inhibitory and excitatory synapses during homeostatic plasticity and sleep. Our findings contribute to a deeper understanding of how neural circuits maintain stability in the face of activity-induced perturbations, with potential implications for both physiological and pathological conditions.
2025-03-17 | GSE245158 | GEO
Project description:Homeostatic scaling is a global form of synaptic plasticity used by neurons to adjust overall synaptic weight and maintain neuronal firing rates while protecting information coding. While homeostatic scaling has been demonstrated in vitro, a clear physiological function of this plasticity type has not been defined. Sleep is an essential process that modifies synapses to support cognitive functions such as learning and memory. Evidence suggests that information coding during wake drives synapse strengthening which is offset by weakening of synapses during sleep .Here we use biochemical fractionation, proteomics and in vivo two-photon imaging to characterize wide-spread changes in synapse composition in mice through the wake/sleep cycle. We find that during the sleep phase, synapses are weakened through dephosphorylation and removal of synaptic AMPA-type glutamate receptors (AMPARs) driven by the immediate early gene Homer1a and signaling from group I metabotropic glutamate receptors (mGluR1/5), consistent with known mechanisms of homeostatic scaling-down in vitro. Further, we find that these changes are important in the consolidation of contextual memories. While Homer1a gene expression is driven by neuronal activity during wake, Homer1a protein targeting to synapses serves as an integrator of arousal and sleep need through signaling by the wake-promoting neuromodulator noradrenaline (NA) and sleep-promoting modulator adenosine. During sleep or periods of increased sleep need Homer1a enters synapses where it remodels mGluR1/5 signaling complexes to promote AMPAR removal. Thus, we have characterized widespread changes occurring at synapses through the wake/sleep cycle and demonstrated that known mechanisms of homeostatic scaling-down previously demonstrated only in vitro are active in the brain during sleep to remodel synapses, contributing to memory consolidation.
2017-02-13 | PXD004537 | Pride
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:Schizophrenia is a complex genetic and developmental disorder. We present a model of disease resulting from disruption of a specific stage of homeostatic scaling (HS). HS modifies synapses and circuits in response to changes in neuronal activity and underlies cortical development and memory consolidation. Neuronal pentraxin 2 (NPTX2) plays a critical role in HS and its homeostatic action requires exocytosis at excitatory synapses on parvalbumin interneurons (PV) whereupon a portion is later shed into the CSF. CSF NPTX2 is reduced in two independent cohorts of patients with schizophrenia. To understand the relationship of this biomarker to disease we confirmed that in normal volunteers CSF NPTX2 increases rapidly with sleep deprivation consistent with behavior-linked exocytosis/shedding. In mouse neocortex NPTX2 exocytosis/shedding are activity-dependent and coupled to circadian behavioral. By contrast, in mouse genetic models that interrupt early events in HS NPTX2 exocytosis/shedding are erratic and not linked to behavior. The vital contribution of NPTX2 to homeostasis is revealed in Nptx2-/- mice, which exhibit sensitivity to social isolation stress and multiple schizophrenia-domain phenotypes. NPTX2 is not implicated by human genome studies; rather we propose that diverse mutations linked to schizophrenia disrupt activity-dependent mechanisms required for NPTX2 function. The ability to monitor NPTX2 in human subjects provides an opportunity to translate fundamental neuroscience to human neuropsychiatric disease.
2021-05-15 | GSE150671 | GEO
Project description:NPTX2, Homeostatic Scaling, and Schizophrenia
| PRJNA633132 | ENA
Project description:In homeostatic scaling, the cellular mechanisms that detect the offset from the set-point, the duration of the offset and implement a cellular response are not well-understood. To understand the time-dependent dynamics,we manipulated activity for 2 hrs to induce the process of up or down-scaling and metabolically labelled nascent proteins using BONCAT. We analyzed the newly synthesized proteins that exhibited significant increases or decreases in expression in response to activity manipulations and identified 168 proteins. Then, to obtain a temporal trajectory of the cellular response, we compared the proteins synthesized within 2 and 24 hrs of an activity manipulation. Surprisingly, there was little overlap in the significantly regulated newly synthesized proteins identified in the early- and late-response datasets. There was, however, overlap in the functional categories that are modulated early and late, indicating that within protein function groups, different proteomic choices can be made to effect early and late homeostatic responses.
2018-02-16 | PXD008271 | 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: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:Excitatory synapses occur mainly on dendritic spines, and spine density is usually correlated with the strength of excitatory synaptic transmission. We report that Nr4a1, an activity-inducible gene encoding a nuclear receptor, regulates the density and distribution of dendritic spines in CA1 pyramidal neurons. Nr4a1 overexpression resulted in elimination of the majority of spines; however, postsynaptic densities were preserved on dendritic shafts, and the strength of excitatory synaptic transmission was unaffected, showing that excitatory synapses can be dissociated from spines. mRNA expression profiling studies suggest that Nr4a1-mediated transcriptional regulation of the actin cytoskeleton contributes to this effect. Under conditions of chronically elevated activity, when Nr4a1 was induced, Nr4a1 knockdown increased the density of spines and PSDs specifically at the distal ends of dendrites. Thus, Nr4a1 is a key component of an activity-induced transcriptional program that regulates the density and distribution of spines and synapses. After 10 days in culture, dissociated mouse hippocampal neurons in 6-well plates were infected with lentivirus expressing either Flag-Nr4a1 or GFP and incubated for 6 days to allow for transgene expression. Total RNA was then isolated using RNeasy Plus kit (QIAGEN). Samples passing an mRNA quality check proceeded to quantitative analysis on Agilent-026655 4x44 Mouse Microarrays.
2016-01-13 | E-GEOD-76805 | 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