GABAB receptor modulation of membrane excitability in human pluripotent stem cell-derived sensory neurons by baclofen and α-conotoxin Vc1.1
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ABSTRACT:
PROVIDER: PRJNA1190960 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31518300_1.fastq.gz | Fastqsanger.gz | |||
| SRR31518300_2.fastq.gz | Fastqsanger.gz | |||
| SRR31518289_1.fastq.gz | Fastqsanger.gz | |||
| SRR31518289_2.fastq.gz | Fastqsanger.gz | |||
| SRR31518290_1.fastq.gz | Fastqsanger.gz |
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Project description:GABAB receptor (GABABR) activation is known to alleviate pain by reducing neuronal excitability, primarily through inhibition of high voltage-activated (HVA) calcium (CaV2.2) channels and potentiating G protein-coupled inwardly rectifying potassium (GIRK) channels. While the analgesic properties of small molecules and peptides have been primarily tested on isolated murine dorsal root ganglion (DRG) neurons, emerging strategies to develop, study, and characterise human pluripotent stem cell (hPSC)-derived sensory neurons present a promising alternative. In this study, hPSCs were efficiently differentiated into peripheral DRG-induced sensory neurons (iSNs) using a combined chemical and transcription factor-driven approach, via a neural crest cell intermediate. Molecular characterisation and transcriptomic analysis confirmed the expression of key DRG markers such as BRN3A, ISLET1, and PRPH, in addition to GABABR and ion channels including CaV2.2 and GIRK1 in iSNs. Functional characterisation of GABABR was conducted using whole-cell patch clamp electrophysiology, assessing neuronal excitability under current clamp conditions in the absence and presence of GABABR agonists baclofen and α-conotoxin Vc1.1. Both baclofen (100 mM) and Vc1.1 (1 mM) significantly reduced membrane excitability by hyperpolarizing the resting membrane potential, and increasing the rheobase for action potential firing. In voltage-clamp mode, baclofen and Vc1.1 inhibited HVA Ca2+ channel currents, which were attenuated by the selective GABABR antagonist CGP 55845. However, modulation of GIRK channels by GABABRs was not observed in the presence of baclofen or Vc1.1, suggesting that functional GIRK1/2 channels were not coupled to GABABRs in hPSC-derived iSNs. This study reports is the first to report GABABR modulation of membrane excitability in iSNs by baclofen and Vc1.1, highlighting their potential as a future model for studying analgesic compounds.
2024-12-01 | GSE282901 | GEO
Project description:Schwann cell-secreted PGE2 promotes sensory neuron excitability during development [scRNAseq_Dataset1]
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Project description:Schwann cell-secreted PGE2 promotes sensory neuron excitability during development [scRNAseq_Dataset2]
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Project description:Schwann cell-secreted PGE2 promotes sensory neuron excitability during development [RNA-Seq]
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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.
2024-01-31 | GSE236109 | GEO
Project description:Electrical excitability—the ability to fire and propagate action potentials—is a signature feature of neurons. How neurons become excitable during development and whether excitability is an intrinsic property of neurons or requires signaling from glial cells remain unclear. Here, we demonstrate that Schwann cells, the most abundant glia in the peripheral nervous system, promote somatosensory neuron excitability during development. We find that Schwann cells secrete prostaglandin E2, which is necessary and sufficient to induce developing somatosensory neurons to express normal levels of genes required for neuronal function, including voltage gated sodium channels, and to fire action potential trains. In this RNA-Seq study, we discovered that treating cultured DRG neurons with Schwann cell-conditioned media or PGE2 increased the expression of several genes required for neuronal maturation and excitability, including voltage-gated sodium channels.
2024-06-03 | GSE268606 | GEO
Project description:Electrical excitability—the ability to fire and propagate action potentials—is a signature feature of neurons. How neurons become excitable during development and whether excitability is an intrinsic property of neurons or requires signaling from glial cells remain unclear. Here, we demonstrate that Schwann cells, the most abundant glia in the peripheral nervous system, promote somatosensory neuron excitability during development. We find that Schwann cells secrete prostaglandin E2, which is necessary and sufficient to induce developing somatosensory neurons to express normal levels of genes required for neuronal function, including voltage gated sodium channels, and to fire action potential trains. In this scRNAseq study, we found that inactivating PGE2 synthesis in Schwann cells, in vivo, impaired somatosensory neuron maturation, with the most dramatic effects on nociceptor and proprioceptor somatosensory neuron subtypes.
2024-06-03 | GSE268625 | GEO
Project description:Electrical excitability—the ability to fire and propagate action potentials—is a signature feature of neurons. How neurons become excitable during development and whether excitability is an intrinsic property of neurons or requires signaling from glial cells remain unclear. Here, we demonstrate that Schwann cells, the most abundant glia in the peripheral nervous system, promote somatosensory neuron excitability during development. We find that Schwann cells secrete prostaglandin E2, which is necessary and sufficient to induce developing somatosensory neurons to express normal levels of genes required for neuronal function, including voltage gated sodium channels, and to fire action potential trains. In this scRNAseq study, we found that inactivating PGE2 synthesis in Schwann cells in vivo impaired somatosensory neuron maturation, with the most dramatic effects on nociceptor and proprioceptor somatosensory neuron subtypes.
2024-06-03 | GSE268620 | GEO
Project description:We investigated the role of NEAT1 knockdown on neuronal excitability in iPSC-derived neurons.
2017-01-26 | E-MTAB-3447 | biostudies-arrayexpress
Project description:Newborn neurons enter an extended maturation stage, during which they acquire excitability characteristics crucial for development of presynaptic and postsynaptic connectivity. In contrast to earlier specification programs, little is known aboutthe regulatory mechanisms that control neuronal maturation. The Pet-1 ETS (E26 transformation-specific) factor is continuously expressed in serotonin (5-HT) neurons and initially acts in postmitotic precursors to control acquisition of 5-HT transmitter identity. Using a combination of RNA sequencing, electrophysiology, and conditional targeting approaches, we determined gene expression patterns in maturing flow-sorted 5-HT neurons and the temporal requirements for Pet-1 in shaping these patterns for functional maturation of mouse 5-HT neurons. We report a profound disruption of postmitotic expression trajectories in Pet-1 / neurons, which prevented postnatal maturation of 5-HT neuron passive and active intrinsic membrane properties, G-protein signaling, and synaptic responses to glutamatergic, lysophosphatidic, and adrenergic agonists. Unexpectedly, conditional targeting revealed a postnatal stage-specific switch in Pet-1 targets from 5-HT synthesis genes to transmitter receptor genes required for afferent modulation of 5-HT neuron excitability. 5-HT1a autoreceptor expression depended transiently on Pet-1, thus revealing an early postnatal sensitive period for control of 5-HT excitability genes. Chromatin immunoprecipitation followed by sequencing revealed that Pet-1 regulates 5-HT neuron maturation through direct gene activation and repression. Moreover, Pet-1 directly regulates the 5-HT neuron maturation factor Engrailed 1, which suggests Pet-1 orchestrates maturationthrough secondary postmitotic regulatoryfactors. The early postnatal switch in Pet-1targets uncovers a distinct neonatal stage-specific function for Pet-1, during which it promotes maturation of 5-HT neuron excitability. 5-HT neuron mRNA profiles of E11.5, E15.5, and postnatal (P1-P3) wild type (WT) and Pet-1-/- mice were generated by deep sequencing, in triplicate, using Illumina HiSeq 2500. Myc-tagged Pet-1 ChIP-seq was performed on E12.5 to E14.5 hindbrains and sequencing using NextSeq 500.
2016-01-08 | E-GEOD-74315 | biostudies-arrayexpress