Publications by authors named "S Ivar Walaas"

98 Publications

Differential Levels and Phosphorylation of Type 1 Inositol 1,4,5-Trisphosphate Receptor in Four Different Murine Models of Huntington Disease.

J Huntingtons Dis 2019 ;8(3):271-289

The Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway.

Background: The intracellular ion channel type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) releases Ca2+ from the endoplasmic reticulum upon stimulation with IP3. Perturbation of IP3R1 has been implicated in the development of several neurodegenerative disorders, including Huntington disease (HD).

Objective: To elucidate the putative role of IP3R1 phosphorylation in HD, we investigated IP3R1 levels and protein phosphorylation state in the striatum, hippocampus and cerebellum of four murine HD models.

Methods: Quantitative immunoblotting with antibodies to IP3R1 protein and its phosphorylated serines 1589 and 1755 was applied to brain homogenates from R6/1 mice to study early-onset aggressive HD. To determine if IP3R1 changes precede overt pathology, we immunostained tissues from the regions of interest and several control regions for IP3R1 in tgHDCAG51n rats and BACHD and zQ175DNKI mice, all recognized models for late-onset HD.

Results: R6/1 mice had reduced total IP3R1 immunoreactivity, variably reduced serine1755-phosphorylation in all regions investigated, and reduced serine1589-phosphorylation in cerebellum. IP3R1 levels were decreased relative to cell-specific marker proteins. In tgHDCAG51n rats we found reduced IP3R1 levels in the cerebellum, but otherwise unchanged IP3R1 phosphorylation and protein levels. In BACHD and zQ175DNKI mice only age-dependent decline of IP3R1 was observed.

Conclusion: The level and phosphorylation of IP3R1 is reduced to a variable degree in the different HD models relative to control, indicating that earlier findings in more aggressive exon 1-truncated HD models may not be replicated in models with higher construct validity. Further analysis of possible coupling of reduced IP3R1 levels with development of neuropathological responses and cell-specific degeneration is warranted.
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http://dx.doi.org/10.3233/JHD-180301DOI Listing
July 2020

Presynaptic increase in IP receptor type 1 concentration in the early phase of hippocampal synaptic plasticity.

Brain Res 2019 03 5;1706:125-134. Epub 2018 Nov 5.

Division of Anatomy, Department of Molecular Medicine, Institute of Basic Medical Science, University of Oslo, Oslo, Norway. Electronic address:

The inositol 1,4,5-trisphosphate receptor (IPR) subtype IPR1 is highly enriched in the brain, including hippocampal neurons. It plays an important function in regulating intracellular calcium concentrations. Residing on the smooth endoplasmic reticulum (sER), the IPR1 mobilizes calcium into the cytosol upon binding the intracellular signaling molecule IP, whose concentration is increased by stimulating certain metabotropic glutamate receptors. Increased calcium may mediate synaptic changes occurring during long-term plasticity, which includes molecular mechanisms underlying memory encoding. The exact synaptic localization of IPR1 in the central nervous system (CNS) remains unclear. We hypothesized that IPR1, in addition to its known expression in soma and dendritic shafts of hippocampal CA1 pyramidal neurons, also may be present in postsynaptic spines. Moreover, we hypothesized that IPR1 may be present in presynaptic terminals as well, given the importance of calcium in regulating presynaptic neurotransmitter exocytosis. To test these two hypotheses, we used IPR1 immunocytochemistry at the light and electron microscopical levels in the CA1 area of the hippocampus. Furthermore, we hypothesized that induction of long-term potentiation (LTP) would be accompanied by an increase in synaptic IPR1 concentrations, thereby facilitating synaptic mechanisms of long term plasticity. To investigate this, we used quantitative immunogold electron microscopy to determine possible changes in IPR1 concentration in sub-synaptic compartments before and five minutes after high frequency tetanizations. Firstly, our data confirm localization of IPR1 in both presynaptic terminals and postsynaptic spines. Secondly, the concentration of IPR1 after tetanization was significantly increased in the presynaptic compartment, suggesting a presynaptic role of IPR1 in early phases of synaptic plasticity. It is therefore possible that IPR1 is involved in modulating neurotransmitter release by regulating calcium homeostasis presynaptically.
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http://dx.doi.org/10.1016/j.brainres.2018.10.030DOI Listing
March 2019

Omega-3 fatty acids regulate plasticity in distinct hippocampal glutamatergic synapses.

Eur J Neurosci 2019 01 19;49(1):40-50. Epub 2018 Nov 19.

Division of Anatomy, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.

Dietary omega-3 fatty acids accumulate and are actively retained in central nervous system membranes, mainly in synapses, dendrites and photoreceptors. Despite this selective enrichment, their impact on synaptic function and plasticity has not been fully determined at the molecular level. In this study, we explored the impact of omega-3 fatty acid deficiency on synaptic function in the hippocampus. Dietary omega-3 fatty acid deficiency for 5 months after weaning led to a 65% reduction in the concentration of docosahexaenoic acid in whole brain synaptosomal phospholipids with no impact on global dopaminergic or serotonergic turnover. We observed reduced concentrations of glutamate receptor subunits, including GluA1, GluA2 and NR2B, and synaptic vesicle proteins synaptophysin and synaptotagmin 1 in hippocampal synaptosomes of omega-3 fatty acid-deficient mice as compared to the omega-3 fatty acid rich group. In contrast, an increased concentration of neuronal inositol 1,4,5-trisphosphate-receptor (IP -R) was observed in the deficient group. Furthermore, omega-3 fatty acid deficiency reduced the long-term potentiation (LTP) in stratum oriens of the hippocampal CA1 area, but not in stratum radiatum. Thus, omega-3 fatty acids seem to have specific effects in distinct subsets of glutamatergic synapses, suggesting specific molecular interactions in addition to altering plasma membrane properties on a more global scale.
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http://dx.doi.org/10.1111/ejn.14224DOI Listing
January 2019

The fungal neurotoxin penitrem A induces the production of reactive oxygen species in human neutrophils at submicromolar concentrations.

Toxicology 2017 12 13;392:64-70. Epub 2017 Oct 13.

Section of Chemistry and Toxicology, Norwegian Veterinary Institute, P.O. Box 750 Sentrum, N-0106 Oslo, Norway; R&D Section, PET-center, University Hospital of North Norway (UNN), P.O. Box 100 Langnes, N-9038 Tromsø, Norway. Electronic address:

Penitrem A is a fungal neurotoxin that recurrently causes intoxication in animals, and occasionally also in humans. We have previously reported that penitrem A induced the production of reactive oxygen species (ROS) in rat cerebellar granule cells, opening for a new mechanism of action for the neurotoxin. The aim of this study was to examine the potential of penitrem A to induce ROS production in isolated human neutrophil granulocytes, and to study possible mechanisms involved. Penitrem A significantly increased the production of ROS in human neutrophils at concentrations as low as 0.25μM (40% increase over basal levels), as measured with the DCF fluorescence assay. The EC determined for the production of ROS by penitrem A was 3.8μM. The maximal increase in ROS production was approximately 330% over basal levels at a concentration of 12.5μM. ROS formation was significantly inhibited by the antioxidant vitamin E (50μM), the intracellular Ca chelator BAPTA-AM (5μM), the mitogen activated protein kinase kinase (MEK) 1/2 and 5 inhibitor U0126 (1 and 10μM), the p38 mitogen activated protein kinase (MAPK) inhibitor SB203580 (1μM), the c-Jun amino-terminal kinase (JNK) inhibitor SP600125 (10μM), and the calcineurin inhibitors FK-506 and cyclosporine A (1.5 and 0.5μM, respectively). These finding suggest that penitrem A is able to induce an increase in ROS production in neutrophils via the activation of several MAPK-signalling pathways. We suggest that this increase may partly explain the pathophysiology generated by penitrem A neuromycotoxicosis in both humans and animals.
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http://dx.doi.org/10.1016/j.tox.2017.10.008DOI Listing
December 2017

Low-Chlorinated Non-Dioxin-like Polychlorinated Biphenyls Present in Blood and Breast Milk Induce Higher Levels of Reactive Oxygen Species in Neutrophil Granulocytes than High-Chlorinated Congeners.

Basic Clin Pharmacol Toxicol 2016 Dec 12;119(6):588-597. Epub 2016 Jun 12.

Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.

Despite their ban several decades ago, polychlorinated biphenyls (PCBs) still pose a health threat to human beings due to their persistent and accumulative nature and continued presence in the environment. Non-dioxin-like (NDL)-PCBs have earlier been found to have effects on the immune system, including human neutrophil granulocytes. The aim of this study was to investigate the differences between ortho-chlorinated NDL-PCBs with a low or high degree of chlorination in their capability to induce the production of reactive oxygen species (ROS) in human neutrophil granulocytes in vitro. We used some of the congeners occurring at the highest levels in blood, breast milk and food: PCB 52 representing the low-chlorinated congeners and PCB 180 the high-chlorinated congeners. In addition, the extensively studied PCB 153 was included as a reference compound. ROS production was assessed with the luminol-amplified chemiluminescence and DCF fluorescence assays. The involvement of intracellular signalling mechanisms was investigated using different pharmacological substances. At high concentrations (10-20 μM), PCB 52 induced more ROS than PCB 153 and PCB 180. The role of extracellular signal-regulated kinase (ERK) 1/2 and/or ERK 5 signalling in PCB-induced ROS production was implicated through the reduction in ROS in the presence of the specific inhibitor U0126, whereas reduced ROS production after the use of SB203580 and SP600125 indicated the involvement of the p38 mitogen-activated protein kinase (MAPK) and c-Jun amino-terminal kinase (JNK) pathways, respectively. In addition, the calcineurin inhibitor FK-506, the intracellular calcium chelator BAPTA-AM and the antioxidant vitamin E reduced the levels of ROS. The intracellular signalling mechanisms involved in ROS production in human neutrophil granulocytes appeared to be similar for PCB 52, PCB 153 and PCB 180. Based on the results from the present and previous studies, we conclude that for abundant ortho-chlorinated PCBs found in the blood, low-chlorinated congeners induce higher production of ROS in neutrophil granulocytes than high-chlorinated congeners. This could be relevant during acute exposure scenarios when high concentrations of PCBs are present.
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http://dx.doi.org/10.1111/bcpt.12620DOI Listing
December 2016