Functional specification of CCK+ interneurons by alternative isoforms of Kv4.3 auxiliary subunits
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ABSTRACT:
PROVIDER: PRJNA553202 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9652930_1.fastq.gz | Fastqsanger.gz | |||
| SRR9652930_2.fastq.gz | Fastqsanger.gz | |||
| SRR9652931_1.fastq.gz | Fastqsanger.gz | |||
| SRR9652931_2.fastq.gz | Fastqsanger.gz | |||
| SRR9652932_1.fastq.gz | Fastqsanger.gz |
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Project description:CCK-expressing interneurons (CCK+INs) are crucial for controlling hippocampal activity. We found two firing phenotypes of CCK+INs in rat CA3 area; either possessing a previously undetected membrane potential-dependent firing or regular firing phenotype, due to different low-voltage-activated potassium currents. These different excitability properties destine the two types for distinct functions, because the former is essentially silenced during realistic 8-15 Hz oscillations. The general excitability, morphology and gene-profiles of the two types were surprisingly similar. Even the expression of Kv4.3 channels were comparable, despite evidences showing that Kv4.3-mediated currents underlie the distinct firing properties. Instead, the firing phenotypes were correlated with the presence of distinct isoforms of Kv4 auxiliary subunits (KChIP1 vs. KChIP4e and DPP6S). Our results reveal the underlying mechanisms of two previously unknown types of CCK+INs and demonstrate that alternative splicing of few genes, which may be viewed as a minor event in the cells’ whole transcriptome, can underlie distinct cell-type identity.
2019-12-31 | GSE133951 | GEO
Project description:CCK-expressing interneurons (CCK+INs) are crucial for controlling hippocampal activity. We found two firing phenotypes of CCK+INs in rat hippocampal CA3 area; either possessing a previously undetected membrane potential-dependent firing or regular firing phenotype, due to different low-voltage-activated potassium currents. These different excitability properties destine the two types for distinct functions, because the former is essentially silenced during realistic 8-15 Hz oscillations. By contrast, the general intrinsic excitability, morphology and gene-profiles of the two types were surprisingly similar. Even the expression of Kv4.3 channels were comparable, despite evidences showing that Kv4.3-mediated currents underlie the distinct firing properties. Instead, the firing phenotypes were correlated with the presence of distinct isoforms of Kv4 auxiliary subunits (KChIP1 vs. KChIP4e and DPP6S). Our results reveal the underlying mechanisms of two previously unknown types of CCK+INs and demonstrate that alternative splicing of few genes, which may be viewed as a minor change in the cells' whole transcriptome, can determine cell-type identity.
| S-EPMC7269670 | biostudies-literature
Project description:During cortical development, radial glial cells, known as neural stem cells, initially generate a large number of cortical glutamatergic pyramidal neurons through a process called neurogenesis. This is followed by the generation of a diversity of cortical astrocytes, oligodendrocytes, and olfactory bulb interneurons, known as gliogenesis. However, the molecular mechanisms underlying the switch from cortical neurogenesis to gliogenesis, and the subsequent fate determination of cortical astrocytes, oligodendrocytes, and olfactory bulb interneurons, remain unclear. Here, we report that extracellular signal-regulated kinase (ERK) signaling plays a fundamental role in promoting cortical gliogenesis and the generation of cortical glial progenitors. Additionally, SHH-SMO-GLI activator signaling has an auxiliary function to ERK during these processes. We further demonstrate that NOTCH signaling is absolutely required for the fate determination of astrocytes, while ERK signaling plays a prominent role in oligodendrocyte fate specification, and SHH signaling is crucial for the fate determination of olfactory bulb interneurons from cortical progenitors. We provide evidence suggesting that this mechanism is conserved in both mice and humans. Finally, we propose a unifying principle of mammalian cortical gliogenesis.
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Project description:Unilateral Traumatic Brain Injury (TBI) causes functional disturbances of the neuronal networks spreading even to the undamaged cortical hemisphere. The phenomenon, referred to as transhemispheric diaschisis, is suggested to be mediated by an imbalance of the strength of glutamatergic, excitatory vs. GABAergic, inhibitory neurotransmission. Here we present evidence that a switch in expression of α Subunits of pore-forming L-Type voltage-gated calcium channels (VGCC), by an expression of CaV1.3 and simultaneous ablation of CaV1.2 in GABAergic interneurons could balance early cortical disturbances manifested as contralateral hyperexcitability in the early phase after TBI. The switch of the VGCC alpha Subunits in GABAergic interneurons was detected using the GAD67-GFP (Glutamate Decarboxylase 67 – Green Fluorescent Protein) Knock-in mouse line. Mice received a TBI with a Controlled Cortical Impact (CCI) to the primary motor and somatosensory cortex at postnatal day 19-21 under anesthesia in vivo. Single GFP+ interneurons located in the undamaged, contralateral cortex were isolated by Fluorescence-Activated Cell Sorting (FACS) and further analyzed by Mass Spectrometry (MS). The switch was associated with an increased excitability of Somatostatin (SST) interneurons and extracellular network activity in acute brain slices in Microelectrode Array (MEA) recordings, which could be restored in presence of isradipine (100 nM), which selectively blocks CaV1.3-containing VGCCs. These data suggest that a switch in alpha.subunits of VGCCs expressed on SST-positive interneurons stabilizes early hyperactivity of the contralateral cortical network at 72 h after TBI, thereby promoting an adaptive mechanism to counterbalance post-traumatic hyperexcitabilty that might lead to epileptogenesis.
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Project description:During cortical development, radial glial cells, known as neural stem cells, initially generate a large number of cortical glutamatergic pyramidal neurons through a process called neurogenesis. This is followed by the generation of a diversity of cortical astrocytes, oligodendrocytes, and olfactory bulb interneurons, known as gliogenesis. However, the molecular mechanisms underlying the switch from cortical neurogenesis to gliogenesis, and the subsequent fate determination of cortical astrocytes, oligodendrocytes, and olfactory bulb interneurons, remain unclear. Here, we report that extracellular signal-regulated kinase (ERK) signaling plays a fundamental role in promoting cortical gliogenesis and the generation of cortical glial progenitors. Additionally, SHH-SMO-GLI activator signaling has an auxiliary function to ERK during these processes. We further demonstrate that NOTCH signaling is absolutely required for the fate determination of astrocytes, while ERK signaling plays a prominent role in oligodendrocyte fate specification, and SHH signaling is crucial for the fate determination of olfactory bulb interneurons from cortical progenitors. We provide evidence suggesting that this mechanism is conserved in both mice and humans. Finally, we propose a unifying principle of mammalian cortical gliogenesis.
2024-08-21 | GSE275004 | GEO
Project description:10 biopsies from one patient undergoing a auxiliary liver and combined kidney transplantation, where one liver lobe is replaced by an auxiliary liver lobe. Thereafter the kidney is transplanted. Keywords: Time course study 10 samples, no replicates.
2011-03-02 | E-GEOD-8941 | biostudies-arrayexpress
Project description:10 biopsies from one patient undergoing a auxiliary liver and combined kidney transplantation, where one liver lobe is replaced by an auxiliary liver lobe. Thereafter the kidney is transplanted. Keywords: Time course study
2011-03-02 | GSE8941 | GEO
Project description:The goal of this project was to assess how alternative splicing programs are arrayed across neuronal cells types. We systematically mapped ribosome-associated transcript isoforms in genetically-defined neuron types of the mouse forebrain. The endogenous ribosomal protein Rpl22 was conditionally HA-tagged in glutamatergic neurons (using CamK2-cre for most neocortical pyramidal cells and Scnn1a-cre for spiny stellate and star pyramid layer 4 cells), and GABAergic interneurons [with somatostatin-cre (SST), parvalbumin-cre (PV) and vasointestinal peptide-cre (VIP)]. Within the hippocampus, we further targeted Cornu ammonis 1 (CA1) neurons (CamK2-cre), CA3 neurons (Grik4-cre), and SST-positive interneurons (SST-cre). Four replicates were deep sequenced (~100 million reads) using an Illumina platform. We find that neuronal transcript isoform profiles reliably distinguish even closely-related classes of pyramidal cells and inhibitory interneurons in the mouse hippocampus and neocortex, positing transcript diversification by alternative splicing as a central mechanism for the functional specification of neuronal cell types and circuits.
2019-07-01 | GSE133291 | GEO
Project description:Fast-spiking (FS) interneurons are important elements of neocortical circuitry that constitute the primary source of synaptic inhibition in adult cortex and impart temporal organization on ongoing cortical activity. The highly specialized intrinsic membrane and firing properties that allow cortical FS interneurons to perform these functions are attributable to equally specialized gene expression, which is ultimately coordinated by cell-type-specific transcriptional regulation. Although embryonic transcriptional events govern the initial steps of cell-type specification in most cortical interneurons, including FS cells, the electrophysiological properties that distinguish adult cortical cell types emerge relatively late in postnatal development, and the transcriptional events that drive this maturational process are not known. To address this, we used mouse whole-genome microarrays and whole-cell patch clamp to characterize the transcriptional and electrophysiological maturation of cortical FS interneurons between postnatal day 7 (P7) and P40. We found that the intrinsic and synaptic physiology of FS cells undergoes profound regulation over the first 4 postnatal weeks and that these changes are correlated with primarily monotonic but bidirectional transcriptional regulation of thousands of genes belonging to multiple functional classes. Using our microarray screen as a guide, we discovered that upregulation of two-pore K leak channels between P10 and P25 contributes to one of the major differences between the intrinsic membrane properties of immature and adult FS cells and found a number of other candidate genes that likely confer cell-type specificity on mature FS cells. Experiment Overall Design: We characterized the transcriptional maturation of genetically labeled FS interneurons in mouse S1 cortex using whole-genome microarrays.mRNA was harvested from manually sorted GFPexpressing neurons dissociated from acutely prepared brain slices at a range of developmental time points (P7, P10, P15, P25, and P40) and subsequently reverse transcribed, amplified, labeled, and hybridized to Affymetrix 430 2.0 whole-genome microarrays (three microarrays from three different animals per condition). We used the G42 transgenic mice described by Chattopadhyaya et al. (2004) for all experiments.
2009-09-17 | E-GEOD-17806 | biostudies-arrayexpress
Project description:Transplantation of GABAergic interneurons (INs) can sustain long-standing benefits in animal models of epilepsy and other neurological disorders. In a therapeutic perspective, a renewable source of functional GABAergic INs is needed. Here, we identified five factors (Foxg1, Sox2, Ascl1, Dlx5 and Lhx6) able to convert fibroblasts directly into induced GABAergic INs (iGABA-INs), displaying the molecular signature of telencephalic INs. The selected factors recapitulate in fibroblasts the activation of transcriptional networks required for the specification of GABAergic fate during telencephalon development. iGABA-INs exhibited progressively maturing firing patterns comparable to those of cortical INs, had synaptic currents and released GABA. Importantly, upon grafting in the hippocampus, iGABA-INs survived, matured and their optogenetic stimulation triggered GABAergic transmission and inhibited the activity of connected granule cells. The five factors also converted human cells into functional GABAergic neurons. These properties define iGABA-INs as a promising tool for disease modeling and cell-based therapeutic approaches. Comparison of iGABA-INs transcriptional profile with those of starting fibroblasts and GAD67-GFP+ cortical interneurons.
2015-12-15 | E-GEOD-74065 | biostudies-arrayexpress