ORCID Profile
0000-0001-8279-2790
Current Organisation
Uppsala Universitet
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Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.NBD.2019.104583
Abstract: Dravet syndrome (DS) is an early onset refractory epilepsy typically caused by de novo heterozygous variants in SCN1A encoding the α-subunit of the neuronal sodium channel Na
Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1016/J.JNEUROIM.2017.01.013
Abstract: The amino acid glutamate opens cation permeable ion channels, the iGlu receptors. These ion channels are abundantly expressed in the mammalian brain where glutamate is the main excitatory neurotransmitter. The neurotransmitters and their receptors are being increasingly detected in the cells of immune system. Here we examined the expression of the 18 known subunits of the iGlu receptors families α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, N-methyl-d-aspartate (NMDA) and delta in human peripheral blood mononuclear cells (PBMCs). We compared the expression of the subunits between four groups: men, non-pregnant women, healthy pregnant women and depressed pregnant women. Out of 18 subunits of the iGlu receptors, mRNAs for 11 subunits were detected in PBMCs from men and non-pregnant women AMPA: GluA3, GluA4, kainate: GluK2, GluK4, GluK5, NMDA: GluN1, GluN2C, GluN2D, GluN3A, GluN3B, and delta: GluD1. In the healthy and the depressed pregnant women, in addition, the delta GluD2 subunit was identified. The mRNAs for GluK4, GluK5, GluN2C and GluN2D were expressed at a higher level than other subunits. Gender, pregnancy or depression during pregnancy altered the expression of GluA3, GluK4, GluN2D, GluN3B and GluD1 iGlu subunit mRNAs. The greatest changes recorded were the lower GluA3 and GluK4 mRNA levels in pregnant women and the higher GluN2D mRNA level in healthy but not in depressed pregnant women as compared to non-pregnant in iduals. Using subunit specific antibodies, the GluK4, GluK5, GluN1, GluN2C and GluN2D subunit proteins were identified in the PBMCs. The results show expression of specific iGlu receptor subunit in the PBMCs and support the idea of physiology-driven changes of iGlu receptors subtypes in the immune cells.
Publisher: MDPI AG
Date: 06-12-2019
DOI: 10.3390/IJMS20246172
Abstract: Immunomodulation is increasingly being recognised as a part of mental diseases. Here, we examined whether levels of immunological protein markers changed with depression, age, or the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). An analysis of plasma s les from patients with a major depressive episode and control blood donors (CBD) revealed the expression of 67 inflammatory markers. Thirteen of these markers displayed augmented levels in patients compared to CBD. Twenty-one markers correlated with the age of the patients, whereas 10 markers correlated with the age of CBD. Interestingly, CST5 and CDCP1 showed the strongest correlation with age in the patients and CBD, respectively. IL-18 was the only marker that correlated with the MADRS-S scores of the patients. Neuronal growth factors (NGFs) were significantly enhanced in plasma from the patients, as was the average plasma GABA concentration. GABA modulated the release of seven cytokines in anti-CD3-stimulated peripheral blood mononuclear cells (PBMCs) from the patients. The study reveals significant changes in the plasma composition of small molecules during depression and identifies potential peripheral biomarkers of the disease.
Publisher: American Diabetes Association
Date: 11-08-2014
DOI: 10.2337/DB14-0668
Abstract: Glucagon-like peptide-1 (GLP-1) is a hormone that stimulates insulin secretion. Receptors for GLP-1 are also found in the brain, including the hippoc us, the center for memory and learning. Diabetes is a risk factor for decreased memory functions. We studied effects of GLP-1 and exendin-4, a GLP-1 receptor agonist, on γ-aminobutyric acid (GABA) signaling in hippoc al CA3 pyramidal neurons. GABA is the main inhibitory neurotransmitter and decreases neuronal excitability. GLP-1 (0.01–1 nmol/L) transiently enhanced synaptic and tonic currents, and the effects were blocked by exendin (9-39). Ten pmol/L GLP-1 increased both the spontaneous inhibitory postsynaptic current (sIPSC) litudes and frequency by a factor of 1.8. In 0.1, 1 nmol/L GLP-1 or 10, 50, or 100 nmol/L exendin-4, only the sIPSC frequency increased. The tonic current was enhanced by 0.01–1 nmol/L GLP-1 and by 0.5–100 nmol/L exendin-4. When action potentials were inhibited by tetrodotoxin (TTX), inhibitory postsynaptic currents decreased and currents were no longer potentiated by GLP-1 or exendin-4. In contrast, although the tonic current decreased in TTX, it was still enhanced by GLP-1 or exendin-4. The results demonstrate GLP-1 receptor regulation of hippoc al function and are consistent with GLP-1 receptor agonists enhancing GABAA signaling by pre- and postsynaptic mechanisms.
Publisher: MDPI AG
Date: 17-01-2020
DOI: 10.3390/IJMS21020600
Abstract: In pancreatic islets, the major cell-types are α, β and δ cells. The γ-aminobutyric acid (GABA) signalling system is expressed in human pancreatic islets. In single hormone transcript-expressing cells, we have previously characterized the functional properties of islet GABAA receptors (iGABAARs). Here, we extended these studies to islet cells expressing mRNAs for more than one hormone and sought for correlation between iGABAAR activity level and relative mRNA expression ratio. The single-cell RT-PCR in combination with the patch-cl current recordings was used to examine functional properties of iGABAARs in the multiple hormone mRNA-expressing cells. We detected cells expressing double (α/β, α/δ, β/δ cell-types) and triple (α/β/δ cell-type) hormone transcripts. The most common mixed-identity cell-type was the α/β group where the cells could be grouped into β- and α-like subgroups. The β-like cells had low GCG/INS expression ratio ( .6) and significantly higher frequency of iGABAAR single-channel openings than the α-like cells where the GCG/INS expression ratio was high ( .2). The hormone expression levels and iGABAAR single-channel characteristics varied in the α/β/δ cell-type. Clearly, multiple hormone transcripts can be expressed in islet cells whereas iGABAAR single-channel functional properties appear to be α or β cell specific.
Publisher: Public Library of Science (PLoS)
Date: 13-12-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Springer Science and Business Media LLC
Date: 12-2017
Publisher: Frontiers Media SA
Date: 24-10-2022
DOI: 10.3389/FNMOL.2022.988993
Abstract: Mowat-Wilson syndrome (MWS) is a severe neurodevelopmental disorder caused by heterozygous variants in the gene encoding transcription factor ZEB2 . Affected in iduals present with structural brain abnormalities, speech delay and epilepsy. In mice, conditional loss of Zeb2 causes hippoc al degeneration, altered migration and differentiation of GABAergic interneurons, a heterogeneous population of mainly inhibitory neurons of importance for maintaining normal excitability. To get insights into GABAergic development and function in MWS we investigated ZEB2 haploinsufficient induced pluripotent stem cells (iPSC) of MWS subjects together with iPSC of healthy donors. Analysis of RNA-sequencing data at two time points of GABAergic development revealed an attenuated interneuronal identity in MWS subject derived iPSC with enrichment of differentially expressed genes required for transcriptional regulation, cell fate transition and forebrain patterning. The ZEB2 haploinsufficient neural stem cells (NSCs) showed downregulation of genes required for ventral telencephalon specification, such as FOXG1, accompanied by an impaired migratory capacity. Further differentiation into GABAergic interneuronal cells uncovered upregulation of transcription factors promoting pallial and excitatory neurons whereas cortical markers were downregulated. The differentially expressed genes formed a neural protein-protein network with extensive connections to well-established epilepsy genes. Analysis of electrophysiological properties in ZEB2 haploinsufficient GABAergic cells revealed overt perturbations manifested as impaired firing of repeated action potentials. Our iPSC model of ZEB2 haploinsufficient GABAergic development thus uncovers a dysregulated gene network leading to immature interneurons with mixed identity and altered electrophysiological properties, suggesting mechanisms contributing to the neuropathogenesis and seizures in MWS.
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.EJPHAR.2014.12.001
Abstract: GABAA receptors are pentameric chloride ion channels that are opened by GABA. We have screened a cell line derived from human glioblastoma, U3047MG, for expression of GABAA receptor subunit isoforms and formation of functional ion channels. We identified GABAA receptors subunit α2, α3, α5, β1, β2, β3, δ, γ3, π, and θ mRNAs in the U3047MG cell line. Whole-cell GABA-activated currents were recorded and the half-maximal concentration (EC₅₀) for the GABA-activated current was 36 μM. The currents were activated by THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) and enhanced by the benzodiazepine diazepam (1 μM) and the general anesthetics etomidate and propofol (50 μM). In line with the expressed GABAA receptors containing at least the α3β3θ subunits, the receptors were highly sensitive to etomidate (EC₅₀=55 nM). Immunocytochemistry identified expression of the α3 and β3 subunit proteins. Our results show that the GABAA receptors in the glial cell line are functional and are modulated by classical GABAA receptor drugs. We propose that the U3047MG cell line may be used as a model system to study GABAA receptors function and pharmacology in glial cells.
Publisher: Public Library of Science (PLoS)
Date: 30-04-2015
Publisher: Cold Spring Harbor Laboratory
Date: 02-07-2019
DOI: 10.1101/689984
Abstract: Immunomodulation is increasingly being recognised as a part of mental diseases. Here, we examined if levels of immunological protein markers altered with depression, age or by the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Analysis of plasma s les from patients with major depressive episode and control blood donors (CBD) revealed expression of 67 inflammatory markers. Thirteen of these markers had augmented levels in patients as compared to CBD. and 21 markers correlated with age of the patients, whereas 10 markers correlated with the age of CBD. Interestingly, CST5 and CDCP1 showed the strongest correlation with age in the patients and in the CBD, respectively. IL-18 was the only marker that correlated with the MADRS-S scores of the patients. Neuronal growth factors (NGFs) were significantly enhanced in plasma from the patients and so was the average plasma GABA concentration. GABA modulated release of seven cytokines in CD3 + stimulated peripheral blood mononuclear cells (PBMC) from the patients. The study reveals significant changes in plasma composition of small molecules during depression and identifies potential peripheral biomarkers of the disease.
Publisher: Elsevier BV
Date: 04-2018
Publisher: Wiley
Date: 21-03-2021
DOI: 10.1111/APHA.13623
Abstract: We examined if tonic γ‐aminobutyric acid (GABA)‐activated currents in primary hippoc al neurons were modulated by insulin in wild‐type and tg‐APPSwe mice, an Alzheimer's disease (AD) model. GABA‐activated currents were recorded in dentate gyrus (DG) granule cells and CA3 pyramidal neurons in hippoc al brain slices, from 8 to 10 weeks old (young) wild‐type mice and in dorsal DG granule cells in adult, 5‐6 and 10‐12 (aged) months old wild‐type and tg‐APPSwe mice, in the absence or presence of insulin, by whole‐cell patch‐cl electrophysiology. In young mice, insulin (1 nmol/L) enhanced the total spontaneous inhibitory postsynaptic current (sIPSC T ) density in both dorsal and ventral DG granule cells. The extrasynaptic current density was only increased by insulin in dorsal CA3 pyramidal neurons. In absence of action potentials, insulin enhanced DG granule cells and dorsal CA3 pyramidal neurons miniature IPSC (mIPSC) frequency, consistent with insulin regulation of presynaptic GABA release. sIPSC T densities in DG granule cells were similar in wild‐type and tg‐APPSwe mice at 5‐6 months but significantly decreased in aged tg‐APPSwe mice where insulin normalized currents to wild‐type levels. The extrasynaptic current density was increased in tg‐APPSwe mice relative to wild‐type littermates but, only in aged tg‐APPSwe mice did insulin decrease and normalize the current. Insulin effects on GABA signalling in hippoc al neurons are selective while multifaceted and context‐based. Not only is the response to insulin related to cell‐type, hippoc al axis‐location, age of animals and disease but also to the subtype of neuronal inhibition involved, synaptic or extrasynaptic GABA A receptors‐activated currents.
Publisher: Public Library of Science (PLoS)
Date: 24-06-2013
Publisher: Cold Spring Harbor Laboratory
Date: 20-04-2023
DOI: 10.1101/2023.04.18.537327
Abstract: Metabolic programs of immune cells are closely linked to their effector functions 1 , where physiological molecules provide environmental cues and guidance 2–5 . Exactly how it happens is still being unraveled. Insulin maintains normal blood glucose levels 6 and glucose is the main source of energy and a precursor for many biomolecules in T cells 7, 8 , whereas γ-aminobutyric acid (GABA), best known as a neurotransmitter, is increasingly recognized as a regulatory molecule in the immune system 4, 9 . Here, we demonstrate that GABA-mediated reduction of metabolic activity and release of inflammatory molecules, including IFNγ and IL-10, was abolished in human CD4 + T cells, when the glucose concentration was elevated above normal levels. In a glucose concentration-dependent manner, insulin enhanced the GABA A receptors activated currents and GABA-dependent Ca 2+ influx. GABA decreased, whereas insulin maintained glycolysis but in a SGLT (Na + -glucose transporter)-dependent manner, revealing expression of SGLTs in activated CD4 + T cells. The SGLTs antagonist phlorizin, alone or together with GABA, restored the inhibition of IFNγ and IL-10 release in presence of high glucose. This study exposes concerted effects of GABA, glucose and insulin on CD4 + T cells metabolic activity and release of inflammatory molecules, and identifies a role for SGLTs in CD4 + T cells function.
Publisher: American Chemical Society (ACS)
Date: 12-01-2023
Publisher: Springer Science and Business Media LLC
Date: 26-11-2015
DOI: 10.1007/S00702-015-1446-9
Abstract: TNFα is a very potent and pleiotropic pro-inflammatory cytokine, essential to the immune system for eradicating cancer and microorganisms, and to the nervous system, for brain development and ongoing function. Yet, excess and/or chronic TNFα secretion causes massive tissue damage in autoimmune, inflammatory and neurological diseases and injuries. Therefore, many patients with autoimmune/inflammatory diseases receive anti-TNFα medications. TNFα is secreted primarily by CD4(+) T cells, macrophages, monocytes, neutrophils and NK cells, mainly after immune stimulation. Yet, the cause for the pathologically high and chronic TNFα secretion is unknown. Can blocking of a particular ion channel in T cells induce by itself TNFα secretion? Such phenomenon was never revealed or even hypothesized. In this interdisciplinary study we discovered that: (1) normal human T cells express Kv1.1 voltage-gated potassium channel mRNA, and the Kv1.1 membrane-anchored protein channel (2) Kv1.1 is expressed in most CD4(+)CD3(+) helper T cells (mean CD4(+)CD3(+)Kv1.1(+) T cells of 7 healthy subjects: 53.09 ± 22.17 %), but not in CD8(+)CD3(+) cytotoxic T cells (mean CD8(+)CD3(+)Kv1.1(+) T cells: 4.12 ± 3.04 %) (3) electrophysiological whole-cell recordings in normal human T cells revealed Kv currents (4) Dendrotoxin-K (DTX-K), a highly selective Kv1.1 blocker derived from snake toxin, increases the rate of rise and decay of Kv currents in both resting and activated T cells, without affecting the peak current (5) DTX-K by itself induces robust TNFα production and secretion by normal human T cells, without elevating IFNγ, IL-4 and IL-10 (6) intact Ca(2+) channels are required for DTX-induced TNFα secretion (7) selective anti-Kv1.1 antibodies also induce by themselves TNFα secretion (8) DTX-K activates NFκB in normal human T cells via the unique non-canonical-pathway (9) injection of Kv1.1-blocked human T cells to SCID mice, causes recruitment of resident mouse cells into the liver, alike reported after TNFα injection into the brain. Based on our discoveries we speculate that abnormally blocked Kv1.1 in T cells (and other immune cells?), due to either anti-Kv1.1 autoimmune antibodies, or Kv1.1-blocking toxins alike DTX-K, or Kv1.1-blocking genetic mutations, may be responsible for the chronic/excessive TNFα in autoimmune/inflammatory diseases. Independently, we also hypothesize that selective block of Kv1.1 in CD4(+) T cells of patients with cancer or chronic infectious diseases could be therapeutic, since it may: a. augment beneficial secretion and delivery of TNFα to the disease-affected sites b. induce recruitment and extravasation of curative immune cells and factors c. improve accessibility of drugs to the brain and few peripheral organs thanks to TNFα-induced increased permeability of organ's barriers.
Publisher: Wiley
Date: 13-06-2020
DOI: 10.1002/HIPO.23245
Publisher: Cold Spring Harbor Laboratory
Date: 12-05-2019
DOI: 10.1101/635144
Abstract: In pancreatic islets the major cell-types are α, β and δ cells, secreting the hormones glucagon (GCG), insulin (INS) and somatostatin (SST), respectively. The GABA (γ-aminobutyric acid) signalling system is expressed in human pancreatic islets. We have previously used single-cell RT-PCR in combination with current recordings to correlate expression of single hormone transcript with functional GABA A receptor ( iGABA A R ) properties in islets. Here we extended these studies to islet cells from non-diabetic and type 2 diabetic donors that express mRNAs for more than one hormone. We detected cells expressing double (α/β, α/δ, β/δ cell-types) and triple (α/β/δ cell-type) hormone transcripts. The most common mixed-identity cell-type was the α/β group where the cells could be grouped into β- and α-like subgroups. The β-like cells had low GCG/INS expression ratio ( 0.6) and significantly higher frequency of single-channel iGABA A R openings than the α-like cells where the GCG/INS expression ratio was high ( 1.2). The difference in expression levels and single channel iGABA A R characteristics varied in the α/β/δ cell-type. No correlation was observed between the cell-types identity with time in culture or cell size. Clearly, multiple hormone transcripts can be expressed in islet cells whereas iGABA A R functional properties appear α or β cell specific.
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.NEULET.2018.02.022
Abstract: Insulin, a pancreatic hormone, can access the central nervous system, activate insulin receptors distributed in selective brain regions and affect various cellular functions such as neurotransmission. We have previously shown that physiologically relevant concentration of insulin potentiates the GABA
No related grants have been discovered for Sergiy V. Korol.