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Special Issue "Astrocytes: Emerging Roles in the Pathogenesis and Treatment of CNS disorders"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2018).

Special Issue Editors

Prof. Dr. Yukihiro Ohno
E-Mail Website
Guest Editor
Department of Pharmacology Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
Interests: astrocytes; neuron–glia interaction; synaptic release; monoamine neurons; Parkinson’s disease; epilepsy; schizophrenia; mood disorders
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Schuichi Koizumi
E-Mail Website
Guest Editor
Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan
Interests: astrocytes; microglia; neuron–glia interaction; P2 receptors; ischemia; synaptogenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Astrocytes are the major glial cells and play crucial roles in maintaining the structural and functional integrity of the brain, participating in the formation of the blood–brain barrier, the maintenance of water and ion homeostasis, the metabolism of neurotransmitters, and the secretion of various neuroactive molecules (e.g., gliotransmitters, neurotrophic factors, and cytokines). Moreover, a new vision emerges from the recent progress in astrocyte research that astrocytes serve as a promising target in the treatment of various central nervous system (CNS) disorders, such as schizophrenia, major depression, pain, epilepsy, ischemic stroke, Parkinson’s disease, Alzheimer’s disease, and other neurodegenerative disorders (e.g., amyotrophic lateral sclerosis and multiple sclerosis). The primary purpose of this Special Issue is to collect scientific contributions providing novel insights into the roles of astrocytes in modulating CNS disorders.

Prof. Yukihiro Ohno
Prof. Schuichi Koizumi
Guest Editors

Manuscript Submission Information

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Keywords

  • Astrocytes
  • Neuron–Glia interactions
  • Gliotransmitters
  • Neurotrophic factors
  • Neurodegenerative disorders
  • Psychiatric disorders
  • Epilepsy
  • Pain

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Published Papers (20 papers)

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Research

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Article
High and Low Molecular Weight Hyaluronic Acid Differentially Influences Oxylipins Synthesis in Course of Neuroinflammation
Int. J. Mol. Sci. 2019, 20(16), 3894; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20163894 - 09 Aug 2019
Cited by 16 | Viewed by 2112
Abstract
Hyaluronic acid (HA), a major glycosaminoglycan of the extracellular matrix, has cell signaling functions that are dependent on its molecular weight. Anti-inflammatory effects for high-molecular-weight (HMW) HA and pro-inflammatory effects for low-molecular-weight (LMW) HA effects were found for various myeloid cells, including microglia. [...] Read more.
Hyaluronic acid (HA), a major glycosaminoglycan of the extracellular matrix, has cell signaling functions that are dependent on its molecular weight. Anti-inflammatory effects for high-molecular-weight (HMW) HA and pro-inflammatory effects for low-molecular-weight (LMW) HA effects were found for various myeloid cells, including microglia. Astrocytes are cells of ectodermal origin that play a pivotal role in brain inflammation, but the link between HA with different molecular weights and an inflammatory response in these cells is not clear. We tested the effects of LMW and HMW HA in rat primary astrocytes, stimulated with Poly:IC (PIC, TLR3 agonist) and lipopolysaccharide (LPS, TLR4 agonist). Oxylipin profiles were measured by the UPLC-MS/MS analysis and metabolites HDoHEs (from docosahexaenoic acid), -HETEs, prostaglandins (from arachidonic acid), DiHOMEs and HODEs (from linoleic acid) were detected. Both, HMW and LMW HA downregulated the cyclooxygenase-mediated polyunsaturated fatty acids metabolism, LMW also reduced lipoxygenase-mediated fatty acid metabolism. Taken together, the data show that both LMW and HMW (i) influence themselves on cytokines (TNFα, IL-6, IL-10), enzymes iNOS, COX-2, and oxylipin levels in extracellular medium of cultured astrocytes, (ii) induced cellular adaptations in long-term applications, (iii) modulate TLR4- and TLR3-signaling pathways. The effects of HMW and LMW HA are predominantly revealed in TLR4– and TLR3- mediated responses, respectively. Full article
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Article
Hypoxia Induces Astrocyte-Derived Lipocalin-2 in Ischemic Stroke
Int. J. Mol. Sci. 2019, 20(6), 1271; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20061271 - 13 Mar 2019
Cited by 14 | Viewed by 2407
Abstract
Ischemic stroke causes rapid hypoxic damage to the core neural tissue which is followed by graded chronological tissue degeneration in the peri-infarct zone. The latter process is mainly triggered by neuroinflammation, activation of inflammasomes, proinflammatory cytokines, and pyroptosis. Besides microglia, astrocytes play an [...] Read more.
Ischemic stroke causes rapid hypoxic damage to the core neural tissue which is followed by graded chronological tissue degeneration in the peri-infarct zone. The latter process is mainly triggered by neuroinflammation, activation of inflammasomes, proinflammatory cytokines, and pyroptosis. Besides microglia, astrocytes play an important role in the fine-tuning of the inflammatory network in the brain. Lipocalin-2 (LCN2) is involved in the control of innate immune responses, regulation of excess iron, and reactive oxygen production. In this study, we analyzed LCN2 expression in hypoxic rat brain tissue after ischemic stroke and in astrocyte cell cultures receiving standardized hypoxic treatment. Whereas no LCN2-positive cells were seen in sham animals, the number of LCN2-positive cells (mainly astrocytes) was significantly increased after stroke. In vitro studies with hypoxic cultured astroglia revealed that LCN2 expression is significantly increased after only 2 h, then further increased, followed by a stepwise decline. The expression pattern of several proinflammatory cytokines mainly followed that profile in wild type (WT) but not in cultured LCN2-deficient astrocytes. Our data revealed that astrocytes are an important source of LCN2 in the peri-infarct region under hypoxic conditions. However, we must also stress that brain-intrinsic LCN2 after the initial hypoxia period might come from other sources such as invaded immune cells and peripheral organs via blood circulation. In any case, secreted LCN2 might have an influence on peripheral organ functions and the innate immune system during brain hypoxia. Full article
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Article
Down-Regulation of Astrocytic Kir4.1 Channels during the Audiogenic Epileptogenesis in Leucine-Rich Glioma-Inactivated 1 (Lgi1) Mutant Rats
Int. J. Mol. Sci. 2019, 20(5), 1013; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20051013 - 26 Feb 2019
Cited by 8 | Viewed by 1897
Abstract
The dysfunction of astrocytic inwardly rectifying potassium (Kir) 4.1 channels, which mediate the spatial potassium-buffering function of astrocytes, is known to be involved in the development of epilepsy. Here, we analyzed the Kir4.1 expressional changes in Leucine-Rich Glioma-Inactivated 1 (Lgi1) mutant [...] Read more.
The dysfunction of astrocytic inwardly rectifying potassium (Kir) 4.1 channels, which mediate the spatial potassium-buffering function of astrocytes, is known to be involved in the development of epilepsy. Here, we analyzed the Kir4.1 expressional changes in Leucine-Rich Glioma-Inactivated 1 (Lgi1) mutant rats, which is a model of autosomal dominant lateral temporal lobe epilepsy in humans, to clarify the role of astrocytic Kir4.1 channels in Lgi1-related epileptogenesis. Priming acoustic stimulation (at postnatal day 16) conferred seizure susceptibility on Lgi1 mutant rats, which evoked audiogenic seizures with test stimulation at eight weeks. In the seizure-susceptible Lgi1 mutant rats (before test stimulation), astrocytic Kir4.1 expression was down-regulated region-specifically in the cerebral cortex, hippocampus, and amygdala. In addition, prophylactic treatments of Lgi1 mutant rats with valproic acid (VPA, 30 mg/kg and 200 mg/kg) for two weeks prevented both the development of seizure susceptibility and the down-regulation of Kir4.1 expression in astrocytes. The present study demonstrated for the first time that the astrocytic Kir4.1 expression was reduced in the Lgi1-related seizure model, suggesting that the down-regulation of Kir4.1 channels in astrocytes is involved in audiogenic epileptogenesis caused by Lgi1 mutation. In addition, VPA seemed to have a prophylactic effect on Lgi1-related seizures. Full article
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Article
Region-Specific Neuroprotective Features of Astrocytes against Oxidative Stress Induced by 6-Hydroxydopamine
Int. J. Mol. Sci. 2019, 20(3), 598; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20030598 - 30 Jan 2019
Cited by 7 | Viewed by 1755
Abstract
In previous studies, we found regional differences in the induction of antioxidative molecules in astrocytes against oxidative stress, postulating that region-specific features of astrocytes lead region-specific vulnerability of neurons. We examined region-specific astrocytic features against dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) as an oxidative stress [...] Read more.
In previous studies, we found regional differences in the induction of antioxidative molecules in astrocytes against oxidative stress, postulating that region-specific features of astrocytes lead region-specific vulnerability of neurons. We examined region-specific astrocytic features against dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) as an oxidative stress using co-culture of mesencephalic neurons and mesencephalic or striatal astrocytes in the present study. The 6-OHDA-induced reduction of mesencephalic dopamine neurons was inhibited by co-culturing with astrocytes. The co-culture of midbrain neurons with striatal astrocytes was more resistant to 6-OHDA than that with mesencephalic astrocytes. Furthermore, glia conditioned medium from 6-OHDA-treated striatal astrocytes showed a greater protective effect on the 6-OHDA-induced neurotoxicity and oxidative stress than that from mesencephalic astrocytes. The cDNA microarray analysis showed that the number of altered genes in both mesencephalic and striatal astrocytes was fewer than that changed in either astrocyte. The 6-OHDA treatment, apparently up-regulated expressions of Nrf2 and some anti-oxidative or Nrf2-regulating phase II, III detoxifying molecules related to glutathione synthesis and export in the striatal astrocytes but not mesencephalic astrocytes. There is a profound regional difference of gene expression in astrocytes induced by 6-OHDA. These results suggest that protective features of astrocytes against oxidative stress are more prominent in striatal astrocytes, possibly by secreting humoral factors in striatal astrocytes. Full article
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Article
Cystine/Glutamate Antiporter and Aripiprazole Compensate NMDA Antagonist-Induced Dysfunction of Thalamocortical L-Glutamatergic Transmission
Int. J. Mol. Sci. 2018, 19(11), 3645; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19113645 - 19 Nov 2018
Cited by 26 | Viewed by 1753
Abstract
To explore pathophysiology of schizophrenia, this study analyzed the regulation mechanisms that are associated with cystine/glutamate antiporter (Sxc), group-II (II-mGluR), and group-III (III-mGluR) metabotropic glutamate-receptors in thalamo-cortical glutamatergic transmission of MK801-induced model using dual-probe microdialysis. L-glutamate release in medial pre-frontal cortex (mPFC) was [...] Read more.
To explore pathophysiology of schizophrenia, this study analyzed the regulation mechanisms that are associated with cystine/glutamate antiporter (Sxc), group-II (II-mGluR), and group-III (III-mGluR) metabotropic glutamate-receptors in thalamo-cortical glutamatergic transmission of MK801-induced model using dual-probe microdialysis. L-glutamate release in medial pre-frontal cortex (mPFC) was increased by systemic- and local mediodorsal thalamic nucleus (MDTN) administrations of MK801, but was unaffected by local administration into mPFC. Perfusion into mPFC of activators of Sxc, II-mGluR, and III-mGluR, and into the MDTN of activators of Sxc, II-mGluR, and GABAA receptor inhibited MK801-evoked L-glutamate release in mPFC. Perfusion of aripiprazole (APZ) into MDTN and mPFC also inhibited systemic MK801-evoked L-glutamate release in mPFC. Inhibition of II-mGluR in mPFC and MDTN blocked inhibitory effects of Sxc-activator and APZ on MK801-evoked L-glutamate release; however, their inhibitory effects were blocked by the inhibition of III-mGluR in mPFC but not in MDTN. These results indicate that reduced activation of the glutamate/NMDA receptor (NMDAR) in MDTN enhanced L-glutamate release in mPFC possibly through GABAergic disinhibition in MDTN. Furthermore, MDTN-mPFC glutamatergic transmission receives inhibitory regulation of Sxc/II-mGluR/III-mGluR functional complex in mPFC and Sxc/II-mGluR complex in MDTN. Established antipsychotic, APZ inhibits MK801-evoked L-glutamate release through the activation of Sxc/mGluRs functional complexes in both MDTN and mPFC. Full article
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Article
Sex-Mediated Differences in LPS Induced Alterations of TNFα, IL-10 Expression, and Prostaglandin Synthesis in Primary Astrocytes
Int. J. Mol. Sci. 2018, 19(9), 2793; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19092793 - 17 Sep 2018
Cited by 21 | Viewed by 2116
Abstract
Although many neurological and psychiatric disorders reveal clear sex-dependent variations, the molecular mechanism of this process is not clear enough. Astrocytes are involved in the response of neural tissue to injury and inflammation, produce steroid hormones, and sense steroid presence. To explore the [...] Read more.
Although many neurological and psychiatric disorders reveal clear sex-dependent variations, the molecular mechanism of this process is not clear enough. Astrocytes are involved in the response of neural tissue to injury and inflammation, produce steroid hormones, and sense steroid presence. To explore the hypothesis that astrocytes may participate in sex-mediated differences of inflammatory responses, we have examined whether male and female primary rat astrocytes show different responses to lipopolysaccharide (LPS) as a toll-like receptor 4 (TLR4) agonist. Levels of mRNA and proteins of tumor necrosis factor alpha (TNFα), interleukin-10 (IL-10), and cyclooxygenase (COX)-2 were assessed using qPCR, immunoblotting, and ELISA. UPLC-MS/MS was used to detect prostaglandins (PGs). LPS stimulation resulted in different levels of cytokine production; more TNFα and less IL-10 were produced in female cells compared with male astrocytes. Although the levels of the COX-2 expression were not altered, LPS significantly induced the synthesis of PGs with notable sex-related differences. PGE2 and PGD2 were less and 6-keto-PGF was more upregulated in female astrocytes, and TXB2 had similar levels in cells obtained from males and females. Trilostane, an inhibitor of 3β-Hydroxysteroid dehydrogenase (3β-HSD), inhibited the LPS-induced TNFα production and the release of PGE2, PGD2, and 6-keto-PGF in female astrocytes. Thus, male and female astrocytes differentially respond to inflammatory challenges on the level of production of cytokines and steroid hormones. Sex-mediated differences in pro- and anti-inflammatory responses should be taken into consideration for the effective treatment of disorders with neuroinflammation. Full article
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Review

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Review
Modeling Neurological Disorders with Human Pluripotent Stem Cell-Derived Astrocytes
Int. J. Mol. Sci. 2019, 20(16), 3862; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20163862 - 08 Aug 2019
Cited by 9 | Viewed by 1872
Abstract
Astrocytes play vital roles in neurological disorders. The use of human induced pluripotent stem cell (iPSC)-derived astrocytes provides a chance to explore the contributions of astrocytes in human diseases. Here we review human iPSC-based models for neurological disorders associated with human astrocytes and [...] Read more.
Astrocytes play vital roles in neurological disorders. The use of human induced pluripotent stem cell (iPSC)-derived astrocytes provides a chance to explore the contributions of astrocytes in human diseases. Here we review human iPSC-based models for neurological disorders associated with human astrocytes and discuss the points of each model. Full article
Review
Perspectives for Ezrin and Radixin in Astrocytes: Kinases, Functions and Pathology
Int. J. Mol. Sci. 2019, 20(15), 3776; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20153776 - 02 Aug 2019
Cited by 8 | Viewed by 1857
Abstract
Astrocytes are increasingly perceived as active partners in physiological brain function and behaviour. The structural correlations of the glia–synaptic interaction are the peripheral astrocyte processes (PAPs), where ezrin and radixin, the two astrocytic members of the ezrin-radixin-moesin (ERM) family of proteins are preferentially [...] Read more.
Astrocytes are increasingly perceived as active partners in physiological brain function and behaviour. The structural correlations of the glia–synaptic interaction are the peripheral astrocyte processes (PAPs), where ezrin and radixin, the two astrocytic members of the ezrin-radixin-moesin (ERM) family of proteins are preferentially localised. While the molecular mechanisms of ERM (in)activation appear universal, at least in mammalian cells, and have been studied in great detail, the actual ezrin and radixin kinases, phosphatases and binding partners appear cell type specific and may be multiplexed within a cell. In astrocytes, ezrin is involved in process motility, which can be stimulated by the neurotransmitter glutamate, through activation of the glial metabotropic glutamate receptors (mGluRs) 3 or 5. However, it has remained open how this mGluR stimulus is transduced to ezrin activation. Knowing upstream signals of ezrin activation, ezrin kinase(s), and membrane-bound binding partners of ezrin in astrocytes might open new approaches to the glial role in brain function. Ezrin has also been implicated in invasive behaviour of astrocytomas, and glial activation. Here, we review data pertaining to potential molecular interaction partners of ezrin in astrocytes, with a focus on PKC and GRK2, and in gliomas and other diseases, to stimulate further research on their potential roles in glia-synaptic physiology and pathology. Full article
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Review
Diverse Actions of Astrocytes in GABAergic Signaling
Int. J. Mol. Sci. 2019, 20(12), 2964; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20122964 - 18 Jun 2019
Cited by 12 | Viewed by 2198
Abstract
An imbalance of excitatory and inhibitory neurotransmission leading to over excitation plays a crucial role in generating seizures, while enhancing GABAergic mechanisms are critical in terminating seizures. In recent years, it has been reported in many studies that astrocytes are deeply involved in [...] Read more.
An imbalance of excitatory and inhibitory neurotransmission leading to over excitation plays a crucial role in generating seizures, while enhancing GABAergic mechanisms are critical in terminating seizures. In recent years, it has been reported in many studies that astrocytes are deeply involved in synaptic transmission. Astrocytes form a critical component of the “tripartite” synapses by wrapping around the pre- and post-synaptic elements. From this location, astrocytes are known to greatly influence the dynamics of ions and transmitters in the synaptic cleft. Despite recent extensive research on excitatory tripartite synapses, inhibitory tripartite synapses have received less attention, even though they influence inhibitory synaptic transmission by affecting chloride and GABA concentration dynamics. In this review, we will discuss the diverse actions of astrocytic chloride and GABA homeostasis at GABAergic tripartite synapses. We will then consider the pathophysiological impacts of disturbed GABA homeostasis at the tripartite synapse. Full article
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Review
Targeting Apolipoprotein E for Alzheimer’s Disease: An Industry Perspective
Int. J. Mol. Sci. 2019, 20(9), 2161; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20092161 - 01 May 2019
Cited by 14 | Viewed by 3321
Abstract
Apolipoprotein E (apoE), a key lipid transport protein in the brain, is predominantly produced by astrocytes. Astrocytes are the most numerous cell type in the brain and are the main support network for neurons. They play a critical role in the synthesis and [...] Read more.
Apolipoprotein E (apoE), a key lipid transport protein in the brain, is predominantly produced by astrocytes. Astrocytes are the most numerous cell type in the brain and are the main support network for neurons. They play a critical role in the synthesis and delivery of cholesterol in the brain. Humans have three common apoE isoforms, apoE2, apoE3 and apoE4, that show a strong genotype effect on the risk and age of onset for sporadic and late onset forms of Alzheimer’s disease (AD). Carriers of an ε4 allele have an increased risk of developing AD, while those with an ε2 allele are protected. Investigations into the contribution of apoE to the development of AD has yielded conflicting results and there is still much speculation about the role of this protein in disease. Here, we review the opposing hypotheses currently described in the literature and the approaches that have been considered for targeting apoE as a novel therapeutic strategy for AD. Additionally, we provide our perspective on the rationale for targeting apoE and the challenges that arise with respect to “drug-ability” of this target. Full article
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Review
Osmotic Demyelination: From an Oligodendrocyte to an Astrocyte Perspective
Int. J. Mol. Sci. 2019, 20(5), 1124; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20051124 - 05 Mar 2019
Cited by 15 | Viewed by 2161
Abstract
Osmotic demyelination syndrome (ODS) is a disorder of the central myelin that is often associated with a precipitous rise of serum sodium. Remarkably, while the myelin and oligodendrocytes of specific brain areas degenerate during the disease, neighboring neurons and axons appear unspoiled, and [...] Read more.
Osmotic demyelination syndrome (ODS) is a disorder of the central myelin that is often associated with a precipitous rise of serum sodium. Remarkably, while the myelin and oligodendrocytes of specific brain areas degenerate during the disease, neighboring neurons and axons appear unspoiled, and neuroinflammation appears only once demyelination is well established. In addition to blood‒brain barrier breakdown and microglia activation, astrocyte death is among one of the earliest events during ODS pathology. This review will focus on various aspects of biochemical, molecular and cellular aspects of oligodendrocyte and astrocyte changes in ODS-susceptible brain regions, with an emphasis on the crosstalk between those two glial cells. Emerging evidence pointing to the initiating role of astrocytes in region-specific degeneration are discussed. Full article
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Review
Aberrant Calcium Signals in Reactive Astrocytes: A Key Process in Neurological Disorders
Int. J. Mol. Sci. 2019, 20(4), 996; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20040996 - 25 Feb 2019
Cited by 35 | Viewed by 2937
Abstract
Astrocytes are abundant cells in the brain that regulate multiple aspects of neural tissue homeostasis by providing structural and metabolic support to neurons, maintaining synaptic environments and regulating blood flow. Recent evidence indicates that astrocytes also actively participate in brain functions and play [...] Read more.
Astrocytes are abundant cells in the brain that regulate multiple aspects of neural tissue homeostasis by providing structural and metabolic support to neurons, maintaining synaptic environments and regulating blood flow. Recent evidence indicates that astrocytes also actively participate in brain functions and play a key role in brain disease by responding to neuronal activities and brain insults. Astrocytes become reactive in response to injury and inflammation, which is typically described as hypertrophy with increased expression of glial fibrillary acidic protein (GFAP). Reactive astrocytes are frequently found in many neurological disorders and are a hallmark of brain disease. Furthermore, reactive astrocytes may drive the initiation and progression of disease processes. Recent improvements in the methods to visualize the activity of reactive astrocytes in situ and in vivo have helped elucidate their functions. Ca2+ signals in reactive astrocytes are closely related to multiple aspects of disease and can be a good indicator of disease severity/state. In this review, we summarize recent findings concerning reactive astrocyte Ca2+ signals. We discuss the molecular mechanisms underlying aberrant Ca2+ signals in reactive astrocytes and the functional significance of aberrant Ca2+ signals in neurological disorders. Full article
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Review
Metabolic Plasticity of Astrocytes and Aging of the Brain
Int. J. Mol. Sci. 2019, 20(4), 941; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20040941 - 21 Feb 2019
Cited by 24 | Viewed by 2952
Abstract
As part of the blood-brain-barrier, astrocytes are ideally positioned between cerebral vasculature and neuronal synapses to mediate nutrient uptake from the systemic circulation. In addition, astrocytes have a robust enzymatic capacity of glycolysis, glycogenesis and lipid metabolism, managing nutrient support in the brain [...] Read more.
As part of the blood-brain-barrier, astrocytes are ideally positioned between cerebral vasculature and neuronal synapses to mediate nutrient uptake from the systemic circulation. In addition, astrocytes have a robust enzymatic capacity of glycolysis, glycogenesis and lipid metabolism, managing nutrient support in the brain parenchyma for neuronal consumption. Here, we review the plasticity of astrocyte energy metabolism under physiologic and pathologic conditions, highlighting age-dependent brain dysfunctions. In astrocytes, glycolysis and glycogenesis are regulated by noradrenaline and insulin, respectively, while mitochondrial ATP production and fatty acid oxidation are influenced by the thyroid hormone. These regulations are essential for maintaining normal brain activities, and impairments of these processes may lead to neurodegeneration and cognitive decline. Metabolic plasticity is also associated with (re)activation of astrocytes, a process associated with pathologic events. It is likely that the recently described neurodegenerative and neuroprotective subpopulations of reactive astrocytes metabolize distinct energy substrates, and that this preference is supposed to explain some of their impacts on pathologic processes. Importantly, physiologic and pathologic properties of astrocytic metabolic plasticity bear translational potential in defining new potential diagnostic biomarkers and novel therapeutic targets to mitigate neurodegeneration and age-related brain dysfunctions. Full article
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Review
The Astrocytic cAMP Pathway in Health and Disease
Int. J. Mol. Sci. 2019, 20(3), 779; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20030779 - 12 Feb 2019
Cited by 12 | Viewed by 3501
Abstract
Astrocytes are major glial cells that play critical roles in brain homeostasis. Abnormalities in astrocytic functions can lead to brain disorders. Astrocytes also respond to injury and disease through gliosis and immune activation, which can be both protective and detrimental. Thus, it is [...] Read more.
Astrocytes are major glial cells that play critical roles in brain homeostasis. Abnormalities in astrocytic functions can lead to brain disorders. Astrocytes also respond to injury and disease through gliosis and immune activation, which can be both protective and detrimental. Thus, it is essential to elucidate the function of astrocytes in order to understand the physiology of the brain to develop therapeutic strategies against brain diseases. Cyclic adenosine monophosphate (cAMP) is a major second messenger that triggers various downstream cellular machinery in a wide variety of cells. The functions of astrocytes have also been suggested as being regulated by cAMP. Here, we summarize the possible roles of cAMP signaling in regulating the functions of astrocytes. Specifically, we introduce the ways in which cAMP pathways are involved in astrocyte functions, including (1) energy supply, (2) maintenance of the extracellular environment, (3) immune response, and (4) a potential role as a provider of trophic factors, and we discuss how these cAMP-regulated processes can affect brain functions in health and disease. Full article
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Review
Astrocytes in Flavivirus Infections
Int. J. Mol. Sci. 2019, 20(3), 691; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20030691 - 06 Feb 2019
Cited by 26 | Viewed by 2730
Abstract
Virus infections of the central nervous system (CNS) can manifest in various forms of inflammation, including that of the brain (encephalitis) and spinal cord (myelitis), all of which may have long-lasting deleterious consequences. Although the knowledge of how different viruses affect neural cells [...] Read more.
Virus infections of the central nervous system (CNS) can manifest in various forms of inflammation, including that of the brain (encephalitis) and spinal cord (myelitis), all of which may have long-lasting deleterious consequences. Although the knowledge of how different viruses affect neural cells is increasing, understanding of the mechanisms by which cells respond to neurotropic viruses remains fragmented. Several virus types have the ability to infect neural tissue, and astrocytes, an abundant and heterogeneous neuroglial cell type and a key element providing CNS homeostasis, are one of the first CNS cell types to get infected. Astrocytes are morphologically closely aligned with neuronal synapses, blood vessels, and ventricle cavities, and thereby have the capacity to functionally interact with neurons and endothelial cells. In this review, we focus on the responses of astrocytes to infection by neurotropic flaviviruses, including tick-borne encephalitis virus (TBEV), Zika virus (ZIKV), West Nile virus (WNV), and Japanese encephalitis virus (JEV), which have all been confirmed to infect astrocytes and cause multiple CNS defects. Understanding these mechanisms may help design new strategies to better contain and mitigate virus- and astrocyte-dependent neuroinflammation. Full article
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Review
Dual Roles of Astrocyte-Derived Factors in Regulation of Blood-Brain Barrier Function after Brain Damage
Int. J. Mol. Sci. 2019, 20(3), 571; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20030571 - 29 Jan 2019
Cited by 68 | Viewed by 4988
Abstract
The blood-brain barrier (BBB) is a major functional barrier in the central nervous system (CNS), and inhibits the extravasation of intravascular contents and transports various essential nutrients between the blood and the brain. After brain damage by traumatic brain injury, cerebral ischemia and [...] Read more.
The blood-brain barrier (BBB) is a major functional barrier in the central nervous system (CNS), and inhibits the extravasation of intravascular contents and transports various essential nutrients between the blood and the brain. After brain damage by traumatic brain injury, cerebral ischemia and several other CNS disorders, the functions of the BBB are disrupted, resulting in severe secondary damage including brain edema and inflammatory injury. Therefore, BBB protection and recovery are considered novel therapeutic strategies for reducing brain damage. Emerging evidence suggests key roles of astrocyte-derived factors in BBB disruption and recovery after brain damage. The astrocyte-derived vascular permeability factors include vascular endothelial growth factors, matrix metalloproteinases, nitric oxide, glutamate and endothelin-1, which enhance BBB permeability leading to BBB disruption. By contrast, the astrocyte-derived protective factors include angiopoietin-1, sonic hedgehog, glial-derived neurotrophic factor, retinoic acid and insulin-like growth factor-1 and apolipoprotein E which attenuate BBB permeability resulting in recovery of BBB function. In this review, the roles of these astrocyte-derived factors in BBB function are summarized, and their significance as therapeutic targets for BBB protection and recovery after brain damage are discussed. Full article
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Review
Bursting at the Seams: Molecular Mechanisms Mediating Astrocyte Swelling
Int. J. Mol. Sci. 2019, 20(2), 330; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20020330 - 15 Jan 2019
Cited by 16 | Viewed by 2437
Abstract
Brain swelling is one of the most robust predictors of outcome following brain injury, including ischemic, traumatic, hemorrhagic, metabolic or other injury. Depending on the specific type of insult, brain swelling can arise from the combined space-occupying effects of extravasated blood, extracellular edema [...] Read more.
Brain swelling is one of the most robust predictors of outcome following brain injury, including ischemic, traumatic, hemorrhagic, metabolic or other injury. Depending on the specific type of insult, brain swelling can arise from the combined space-occupying effects of extravasated blood, extracellular edema fluid, cellular swelling, vascular engorgement and hydrocephalus. Of these, arguably the least well appreciated is cellular swelling. Here, we explore current knowledge regarding swelling of astrocytes, the most abundant cell type in the brain, and the one most likely to contribute to pathological brain swelling. We review the major molecular mechanisms identified to date that contribute to or mitigate astrocyte swelling via ion transport, and we touch upon the implications of astrocyte swelling in health and disease. Full article
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Review
NMDA Receptors in Astrocytes: In Search for Roles in Neurotransmission and Astrocytic Homeostasis
Int. J. Mol. Sci. 2019, 20(2), 309; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20020309 - 14 Jan 2019
Cited by 37 | Viewed by 2578
Abstract
Studies of the last two decades have demonstrated the presence in astrocytic cell membranes of N-methyl-d-aspartate (NMDA) receptors (NMDARs), albeit their apparently low abundance makes demonstration of their presence and function more difficult than of other glutamate (Glu) receptor classes [...] Read more.
Studies of the last two decades have demonstrated the presence in astrocytic cell membranes of N-methyl-d-aspartate (NMDA) receptors (NMDARs), albeit their apparently low abundance makes demonstration of their presence and function more difficult than of other glutamate (Glu) receptor classes residing in astrocytes. Activation of astrocytic NMDARs directly in brain slices and in acutely isolated or cultured astrocytes evokes intracellular calcium increase, by mutually unexclusive ionotropic and metabotropic mechanisms. However, other than one report on the contribution of astrocyte-located NMDARs to astrocyte-dependent modulation of presynaptic strength in the hippocampus, there is no sound evidence for the significant role of astrocytic NMDARs in astrocytic-neuronal interaction in neurotransmission, as yet. Durable exposure of astrocytic and neuronal co-cultures to NMDA has been reported to upregulate astrocytic synthesis of glutathione, and in this way to increase the antioxidative capacity of neurons. On the other hand, overexposure to NMDA decreases, by an as yet unknown mechanism, the ability of cultured astrocytes to express glutamine synthetase (GS), aquaporin-4 (AQP4), and the inward rectifying potassium channel Kir4.1, the three astroglia-specific proteins critical for homeostatic function of astrocytes. The beneficial or detrimental effects of astrocytic NMDAR stimulation revealed in the in vitro studies remain to be proven in the in vivo setting. Full article
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Review
Astrocyte Signaling in the Neurovascular Unit After Central Nervous System Injury
Int. J. Mol. Sci. 2019, 20(2), 282; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20020282 - 11 Jan 2019
Cited by 38 | Viewed by 2473
Abstract
Astrocytes comprise the major non-neuronal cell population in the mammalian neurovascular unit. Traditionally, astrocytes are known to play broad roles in central nervous system (CNS) homeostasis, including the management of extracellular ion balance and pH, regulation of neurotransmission, and control of cerebral blood [...] Read more.
Astrocytes comprise the major non-neuronal cell population in the mammalian neurovascular unit. Traditionally, astrocytes are known to play broad roles in central nervous system (CNS) homeostasis, including the management of extracellular ion balance and pH, regulation of neurotransmission, and control of cerebral blood flow and metabolism. After CNS injury, cell–cell signaling between neuronal, glial, and vascular cells contribute to repair and recovery in the neurovascular unit. In this mini-review, we propose the idea that astrocytes play a central role in organizing these signals. During CNS recovery, reactive astrocytes communicate with almost all CNS cells and peripheral progenitors, resulting in the promotion of neurogenesis and angiogenesis, regulation of inflammatory response, and modulation of stem/progenitor response. Reciprocally, changes in neurons and vascular components of the remodeling brain should also influence astrocyte signaling. Therefore, understanding the complex and interdependent signaling pathways of reactive astrocytes after CNS injury may reveal fundamental mechanisms and targets for re-integrating the neurovascular unit and augmenting brain recovery. Full article
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Review
The Gliocentric Brain
Int. J. Mol. Sci. 2018, 19(10), 3033; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19103033 - 05 Oct 2018
Cited by 11 | Viewed by 2071
Abstract
The Neuron Doctrine, the cornerstone of research on normal and abnormal brain functions for over a century, has failed to discern the basis of complex cognitive functions. The location and mechanisms of memory storage and recall, consciousness, and learning, remain enigmatic. The purpose [...] Read more.
The Neuron Doctrine, the cornerstone of research on normal and abnormal brain functions for over a century, has failed to discern the basis of complex cognitive functions. The location and mechanisms of memory storage and recall, consciousness, and learning, remain enigmatic. The purpose of this article is to critically review the Neuron Doctrine in light of empirical data over the past three decades. Similarly, the central role of the synapse and associated neural networks, as well as ancillary hypotheses, such as gamma synchrony and cortical minicolumns, are critically examined. It is concluded that each is fundamentally flawed and that, over the past three decades, the study of non-neuronal cells, particularly astrocytes, has shown that virtually all functions ascribed to neurons are largely the result of direct or indirect actions of glia continuously interacting with neurons and neural networks. Recognition of non-neural cells in higher brain functions is extremely important. The strict adherence of purely neurocentric ideas, deeply ingrained in the great majority of neuroscientists, remains a detriment to understanding normal and abnormal brain functions. By broadening brain information processing beyond neurons, progress in understanding higher level brain functions, as well as neurodegenerative and neurodevelopmental disorders, will progress beyond the impasse that has been evident for decades. Full article
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