A model for studying homeostatic plasticity in human stem cell derived neuronal networks
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ABSTRACT:
PROVIDER: PRJNA937294 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23576600_1.fastq.gz | Fastqsanger.gz | |||
| SRR23576600_2.fastq.gz | Fastqsanger.gz | |||
| SRR23576601_1.fastq.gz | Fastqsanger.gz | |||
| SRR23576601_2.fastq.gz | Fastqsanger.gz | |||
| SRR23576602_1.fastq.gz | Fastqsanger.gz |
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Project description:The capacity of neurons to maintain stable activity levels through homeostatic plasticity is essential for proper brain function. Primary cilia, which are non-motile, antenna-like organelles projecting from the surface of most vertebrate cells, serve as key hubs for signal transduction, playing crucial roles in tissue development and cellular homeostasis. In this study, we identify a previously unrecognised role for primary cilia in mediating neuronal homeostatic plasticity using human induced pluripotent stem cell-derived neurons. We show that neuronal cilia exhibit dynamic, bidirectional changes in volume in response to alterations in network activity: elongating during chronic activity suppression and shortening after increased activity. To assess the functional relevance of this ciliary plasticity, we modelled ciliary dysfunction in neurons carrying homozygous loss-of-function mutations in genes associated with neuronal ciliopathies, including NPHP1 and CEP290. Mutations affecting ciliary function either increased ciliary length or led to ciliary loss, and these mutant neurons exhibited severe impairments in homeostatic regulation across multiple domains—morphological, functional, and transcriptional. Specifically, NPHP1 and CEP290 deficient neurons failed to adapt synaptic strength, intrinsic excitability, and ciliary morphology in response to prolonged activity suppression. They also displayed dysregulated baseline network activity, and exhibited blunted gene expression changes. Together, these findings establish the primary cilium as a critical regulator of homeostatic plasticity in human neurons and provide a new framework through which to examine neurodevelopmental and neuropsychiatric disorders linked to ciliary dysfunction.
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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.
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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.
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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
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Project description:The nervous system has a tremendous capacity for experience-dependent plasticity. In response to changes in activity induced by environmental cues, many types of neurons undergo a process known as homeostatic plasticity, which serves to maintain overall network function in the face of mounting experience-dependent changes in synaptic strengths. Homeostatic plasticity involves both changes in synaptic scaling and regulation of intrinsic excitability. Increases in spontaneous firing and excitability of sensory neurons are evident in some forms of chronic pain in both animal models and in human patients. However, it is not known whether homeostatic plasticity is engaged in sensory neurons under normal conditions or whether dysfunction in these homeostatic mechanisms might contribute to the pathophysiology of chronic pain. To address these questions, we tested the impact of sustained depolarization on various measures of excitability in mouse and human sensory neurons. Depolarization induced by 30mM KCl induces a compensatory decrease in the excitability of both mouse and human sensory neurons. Moreover, we also find that voltage-gated sodium currents are robustly inhibited in mouse sensory neurons after chronic depolarization, thus contributing to the overall decrease in neuronal excitability and serving as a potential regulatory mechanism to drive intrinsic neuronal homeostatic control. Our results indicate that mouse and human sensory neurons undergo homeostatic regulation of intrinsic excitability in response to sustained depolarization. Decreased efficacy of these homeostatic mechanisms could potentially contribute to the development of pathological conditions, including chronic pain.
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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.
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