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      Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells


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          A plethora of neurological disorders shares a final common deadly pathway known as excitotoxicity. Among these disorders, ischemic injury is a prominent cause of death and disability worldwide. Brain ischemia stems from cardiac arrest or stroke, both responsible for insufficient blood supply to the brain parenchyma. Glucose and oxygen deficiency disrupts oxidative phosphorylation, which results in energy depletion and ionic imbalance, followed by cell membrane depolarization, calcium (Ca 2+) overload, and extracellular accumulation of excitatory amino acid glutamate. If tight physiological regulation fails to clear the surplus of this neurotransmitter, subsequent prolonged activation of glutamate receptors forms a vicious circle between elevated concentrations of intracellular Ca 2+ ions and aberrant glutamate release, aggravating the effect of this ischemic pathway. The activation of downstream Ca 2+-dependent enzymes has a catastrophic impact on nervous tissue leading to cell death, accompanied by the formation of free radicals, edema, and inflammation. After decades of “neuron-centric” approaches, recent research has also finally shed some light on the role of glial cells in neurological diseases. It is becoming more and more evident that neurons and glia depend on each other. Neuronal cells, astrocytes, microglia, NG2 glia, and oligodendrocytes all have their roles in what is known as glutamate excitotoxicity. However, who is the main contributor to the ischemic pathway, and who is the unsuspecting victim? In this review article, we summarize the so-far-revealed roles of cells in the central nervous system, with particular attention to glial cells in ischemia-induced glutamate excitotoxicity, its origins, and consequences.

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          Cell Biology of Astrocyte-Synapse Interactions

          Astrocytes, the most abundant glial cells in the mammalian brain, are critical regulators of brain development and physiology through dynamic and often bidirectional interactions with neuronal synapses. Despite the clear importance of astrocytes for the establishment and maintenance of proper synaptic connectivity, our understanding of their role in brain function is still in its infancy. We propose that this is at least in part due to large gaps in our knowledge of the cell biology of astrocytes and the mechanisms they use to interact with synapses. In this review, we summarize some of the seminal findings that yield important insight into the cellular and molecular basis of astrocyte-neuron communication, focusing on the role of astrocytes in the development and remodeling of synapses. Furthermore, we will pose some pressing questions that need to be addressed to advance our mechanistic understanding of the role of astrocytes in regulating synaptic development.
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            Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke.

            Cerebral edema contributes significantly to morbidity and death associated with many common neurological disorders. However, current treatment options are limited to hyperosmolar agents and surgical decompression, therapies introduced more than 70 years ago. Here we show that mice deficient in aquaporin-4 (AQP4), a glial membrane water channel, have much better survival than wild-type mice in a model of brain edema caused by acute water intoxication. Brain tissue water content and swelling of pericapillary astrocytic foot processes in AQP4-deficient mice were significantly reduced. In another model of brain edema, focal ischemic stroke produced by middle cerebral artery occlusion, AQP4-deficient mice had improved neurological outcome. Cerebral edema, as measured by percentage of hemispheric enlargement at 24 h, was decreased by 35% in AQP4-deficient mice. These results implicate a key role for AQP4 in modulating brain water transport, and suggest that AQP4 inhibition may provide a new therapeutic option for reducing brain edema in a wide variety of cerebral disorders.
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              Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha.

              The proinflammatory cytokine tumor necrosis factor-alpha (TNFalpha) causes a rapid exocytosis of AMPA receptors in hippocampal pyramidal cells and is constitutively required for the maintenance of normal surface expression of AMPA receptors. Here we demonstrate that TNFalpha acts on neuronal TNFR1 receptors to preferentially exocytose glutamate receptor 2-lacking AMPA receptors through a phosphatidylinositol 3 kinase-dependent process. This increases excitatory synaptic strength while changing the molecular stoichiometry of synaptic AMPA receptors. Conversely, TNFalpha causes an endocytosis of GABA(A) receptors, resulting in fewer surface GABA(A) receptors and a decrease in inhibitory synaptic strength. These results suggest that TNFalpha can regulate neuronal circuit homeostasis in a manner that may exacerbate excitotoxic damage resulting from neuronal insults.

                Author and article information

                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                19 March 2020
                : 14
                : 51
                [1] 1Department of Cellular Neurophysiology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic (ASCR) , Prague, Czechia
                [2] 2Second Faculty of Medicine, Charles University , Prague, Czechia
                Author notes

                Edited by: Balázs Pál, University of Debrecen, Hungary

                Reviewed by: Yuriy Pankratov, University of Warwick, United Kingdom; Mario Valentino, University of Malta, Malta

                *Correspondence: Miroslava Anderova miroslava.anderova@ 123456iem.cas.cz
                Copyright © 2020 Belov Kirdajova, Kriska, Tureckova and Anderova.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                : 29 November 2019
                : 21 February 2020
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 372, Pages: 27, Words: 24772
                Funded by: Grantová Agentura České Republiky 10.13039/501100001824
                Award ID: 19-02046S, 19-03016S
                Cellular Neuroscience

                ischemic pathway,glutamate excitotoxicity,glutamate uptake/release,cell death,astrocytes,oligodendrocytes,ng2 glia,glutamate receptors and transporters


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