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Astrocytes in Space and Time

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (20 June 2020) | Viewed by 72271

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Prof. Dr. Robert Zorec

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Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana & Celica BIOMEDICAL, Lab Cell Engineering, Technology Park, Ljubljana, Slovenia
Interests: astroglia; membrane fusion; exocytosis; endocytosis; neuroendocrine cells; neurons; electrophysiology; metabolism; calcium homeostasis; cytoskeleton; vesicle trafficking; neuroinfections; autophagy, neurodegeneration; hybridoma cells; pathophysiology
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Dr. Maja Potokar

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Laboratory of Neuroendocrinology–Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000 Ljubljana, Slovenia
Interests: astroglia; neurons; cytoskeleton; vesicle trafficking; neuroinfections; autophagy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Astrocytes are diverse glial cells in the central nervous system (CNS) supporting numerous physiological functions to maintain homeostasis in the CNS, and when homeostasis is impaired, they contribute to pathologic processes. Although many roles of astrocytes have been discovered in the last decades, various new roles are being reported, reflecting their anatomical positioning that changes during development. Astrocytes have a prominent role in integrating diverse responses to alterations in the intracellular and extracellular milieus, and respond in the time domain that is more typical for endocrine cells than for neurons. Given these important spatial and temporal aspects of their function, processes that underlie a variety of pathologic perturbations are increasingly being untangled. This Special Issue of Cells aims to bring up-to-date insight into the involvement of astrocytes in physiologic and pathologic conditions. The original research and review papers will cover topics that address homeostasis, including metabolism, signaling with vesicles entering exo- and endocytosis, and network functions where astrocytes play a key role, including inflammatory responses, responses to neurotrauma, neuroinfections, and the role of astroglia in neurodevelopmental and psychiatric conditions.

Prof. Dr. Robert Zorec
Dr. Maja Potokar
Guest Editors

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Keywords

astrocytes
intermediate filaments
cytoskeleton
aquaporins
vesicles
glial metabolism
neurodegeneration
neuroinflammation
neurodevelopment
gliocrine secretion
metabolism
gliosignaling molecules
cytotoxic edema

Published Papers (11 papers)

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Research

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12 pages, 2176 KiB

Open AccessFeature PaperArticle

Slc38a1 Conveys Astroglia-Derived Glutamine into GABAergic Interneurons for Neurotransmitter GABA Synthesis

by Tayyaba Qureshi, Mona Bjørkmo, Kaja Nordengen, Vidar Gundersen, Tor Paaske Utheim, Leiv Otto Watne, Jon Storm-Mathisen, Bjørnar Hassel and Farrukh Abbas Chaudhry

Cells 2020, 9(7), 1686; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9071686 - 13 Jul 2020

Cited by 16 | Viewed by 3738

Abstract

GABA signaling is involved in a wide range of neuronal functions, such as synchronization of action potential firing, synaptic plasticity and neuronal development. Sustained GABA signaling requires efficient mechanisms for the replenishment of the neurotransmitter pool of GABA. The prevailing theory is that exocytotically released GABA may be transported into perisynaptic astroglia and converted to glutamine, which is then shuttled back to the neurons for resynthesis of GABA—i.e., the glutamate/GABA-glutamine (GGG) cycle. However, an unequivocal demonstration of astroglia-to-nerve terminal transport of glutamine and the contribution of astroglia-derived glutamine to neurotransmitter GABA synthesis is lacking. By genetic inactivation of the amino acid transporter Solute carrier 38 member a1 (Slc38a1)—which is enriched on parvalbumin⁺ GABAergic neurons—and by intraperitoneal injection of radiolabeled acetate (which is metabolized to glutamine in astroglial cells), we show that Slc38a1 mediates import of astroglia-derived glutamine into GABAergic neurons for synthesis of GABA. In brain slices, we demonstrate the role of Slc38a1 for the uptake of glutamine specifically into GABAergic nerve terminals for the synthesis of GABA depending on demand and glutamine supply. Thus, while leaving room for other pathways, our study demonstrates a key role of Slc38a1 for newly formed GABA, in harmony with the existence of a GGG cycle. Full article

(This article belongs to the Special Issue Astrocytes in Space and Time)

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18 pages, 2232 KiB

Open AccessFeature PaperArticle

Chemically Functionalized Water-Soluble Single-Walled Carbon Nanotubes Obstruct Vesicular/Plasmalemmal Recycling in Astrocytes Down-Stream of Calcium Ions

by Manoj K. Gottipati, Elena Bekyarova, Robert C. Haddon and Vladimir Parpura

Cells 2020, 9(7), 1597; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9071597 - 1 Jul 2020

Cited by 2 | Viewed by 2137

Abstract

We used single-walled carbon nanotubes chemically functionalized with polyethylene glycol (SWCNT-PEG) to assess the effects of this nanomaterial on astrocytic endocytosis and exocytosis. We observed that the SWCNT-PEG do not affect the adenosine triphosphate (ATP)-evoked Ca²⁺ elevations in astrocytes but significantly reduce the Ca²⁺-dependent glutamate release. There was a significant decrease in the endocytic load of the recycling dye during constitutive and ATP-evoked recycling. Furthermore, SWCNT-PEG hampered ATP-evoked exocytotic release of the loaded recycling dye. Thus, by functionally obstructing evoked vesicular recycling, SWCNT-PEG reduced glutamate release from astrocytes via regulated exocytosis. These effects implicate SWCNT-PEG as a modulator of Ca²⁺-dependent exocytosis in astrocytes downstream of Ca²⁺, likely at the level of vesicle fusion with/pinching off the plasma membrane. Full article

(This article belongs to the Special Issue Astrocytes in Space and Time)

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26 pages, 2539 KiB

Open AccessArticle

CaSR Antagonist (Calcilytic) NPS 2143 Hinders the Release of Neuroinflammatory IL-6, Soluble ICAM-1, RANTES, and MCP-2 from Aβ-Exposed Human Cortical Astrocytes

by Anna Chiarini, Ubaldo Armato, Peng Hu and Ilaria Dal Prà

Cells 2020, 9(6), 1386; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9061386 - 2 Jun 2020

Cited by 10 | Viewed by 3288

Abstract

Available evidence shows that human cortical neurons’ and astrocytes’ calcium-sensing receptors (CaSRs) bind Amyloid-beta (Aβ) oligomers triggering the overproduction/oversecretion of several Alzheimer’s disease (AD) neurotoxins—effects calcilytics suppress. We asked whether Aβ•CaSR signaling might also play a direct pro-neuroinflammatory role in AD. Cortical nontumorigenic adult human astrocytes (NAHAs) in vitro were untreated (controls) or treated with Aβ_25–35 ± NPS 2143 (a calcilytic) and any proinflammatory agent in their protein lysates and growth media assayed via antibody arrays, enzyme-linked immunosorbent assays (ELISAs), and immunoblots. Results show Aβ•CaSR signaling upregulated the synthesis and release/shedding of proinflammatory interleukin (IL)-6, intercellular adhesion molecule-1 (ICAM-1) (holoprotein and soluble [s] fragment), Regulated upon Activation, normal T cell Expressed and presumably Secreted (RANTES), and monocyte chemotactic protein (MCP)-2. Adding NPS 2143 (i) totally suppressed IL-6′s oversecretion while remarkably reducing the other agents’ over-release; and (ii) more effectively than Aβ alone increased over controls the four agents’ distinctive intracellular accumulation. Conversely, NPS 2143 did not alter Aβ-induced surges in IL-1β, IL-3, IL-8, and IL-16 secretion, consequently revealing their Aβ•CaSR signaling-independence. Finally, Aβ_25–35 ± NPS 2143 treatments left unchanged MCP-1′s and TIMP-2′s basal expression. Thus, NAHAs Aβ•CaSR signaling drove four proinflammatory agents’ over-release that NPS 2143 curtailed. Therefore, calcilytics would also abate NAHAs’ Aβ•CaSR signaling direct impact on AD’s neuroinflammation. Full article

(This article belongs to the Special Issue Astrocytes in Space and Time)

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17 pages, 2802 KiB

Open AccessArticle

Indirect Role of AQP4b and AQP4d Isoforms in Dynamics of Astrocyte Volume and Orthogonal Arrays of Particles

by Marjeta Lisjak, Maja Potokar, Robert Zorec and Jernej Jorgačevski

Cells 2020, 9(3), 735; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9030735 - 17 Mar 2020

Cited by 15 | Viewed by 3259

Abstract

Water channel aquaporin 4 (AQP4) plays a key role in the regulation of water homeostasis in the central nervous system (CNS). It is predominantly expressed in astrocytes lining blood–brain and blood–liquor boundaries. AQP4a (M1), AQP4c (M23), and AQP4e, present in the plasma membrane, participate in the cell volume regulation of astrocytes. The function of their splicing variants, AQP4b and AQP4d, predicted to be present in the cytoplasm, is unknown. We examined the cellular distribution of AQP4b and AQP4d in primary rat astrocytes and their role in cell volume regulation. The AQP4b and AQP4d isoforms exhibited extensive cytoplasmic localization in early and late endosomes/lysosomes and in the Golgi apparatus. Neither isoform localized to orthogonal arrays of particles (OAPs) in the plasma membrane. The overexpression of AQP4b and AQP4d isoforms in isoosmotic conditions reduced the density of OAPs; in hypoosmotic conditions, they remained absent from OAPs. In hypoosmotic conditions, the AQP4d isoform was significantly redistributed to early endosomes, which correlated with the increased trafficking of AQP4-laden vesicles. The overexpression of AQP4d facilitated the kinetics of cell swelling, without affecting the regulatory volume decrease. Therefore, although they reside in the cytoplasm, AQP4b and AQP4d isoforms may play an indirect role in astrocyte volume changes. Full article

(This article belongs to the Special Issue Astrocytes in Space and Time)

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21 pages, 8838 KiB

Open AccessArticle

Spontaneous Ultraslow Na⁺ Fluctuations in the Neonatal Mouse Brain

by Lisa Felix, Daniel Ziemens, Gerald Seifert and Christine R. Rose

Cells 2020, 9(1), 102; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9010102 - 31 Dec 2019

Cited by 6 | Viewed by 3012 | Correction

Abstract

In the neonate forebrain, network formation is driven by the spontaneous synchronized activity of pyramidal cells and interneurons, consisting of bursts of electrical activity and intracellular Ca²⁺ oscillations. By employing ratiometric Na⁺ imaging in tissue slices obtained from animals at postnatal day 2–4 (P2–4), we found that 22% of pyramidal neurons and 43% of astrocytes in neonatal mouse hippocampus also exhibit transient fluctuations in intracellular Na⁺. These occurred at very low frequencies (~2/h), were exceptionally long (~8 min), and strongly declined after the first postnatal week. Similar Na⁺ fluctuations were also observed in the neonate neocortex. In the hippocampus, Na⁺ elevations in both cell types were diminished when blocking action potential generation with tetrodotoxin. Neuronal Na⁺ fluctuations were significantly reduced by bicuculline, suggesting the involvement of GABA_A-receptors in their generation. Astrocytic signals, by contrast, were neither blocked by inhibition of receptors and/or transporters for different transmitters including GABA and glutamate, nor of various Na⁺-dependent transporters or Na⁺-permeable channels. In summary, our results demonstrate for the first time that neonatal astrocytes and neurons display spontaneous ultraslow Na⁺ fluctuations. While neuronal Na⁺ signals apparently largely rely on suprathreshold GABAergic excitation, astrocytic Na⁺ signals, albeit being dependent on neuronal action potentials, appear to have a separate trigger and mechanism, the source of which remains unclear at present. Full article

(This article belongs to the Special Issue Astrocytes in Space and Time)

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16 pages, 2944 KiB

Open AccessArticle

Vimentin Phosphorylation Is Required for Normal Cell Division of Immature Astrocytes

by Yolanda de Pablo, Pavel Marasek, Andrea Pozo-Rodrigálvarez, Ulrika Wilhelmsson, Masaki Inagaki, Marcela Pekna and Milos Pekny

Cells 2019, 8(9), 1016; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8091016 - 1 Sep 2019

Cited by 16 | Viewed by 5811

Abstract

Vimentin (VIM) is an intermediate filament (nanofilament) protein expressed in multiple cell types, including astrocytes. Mice with VIM mutations of serine sites phosphorylated during mitosis (VIM^SA/SA) show cytokinetic failure in fibroblasts and lens epithelial cells, chromosomal instability, facilitated cell senescence, and increased neuronal differentiation of neural progenitor cells. Here we report that in vitro immature VIM^SA/SA astrocytes exhibit cytokinetic failure and contain vimentin accumulations that co-localize with mitochondria. This phenotype is transient and disappears with VIM^SA/SA astrocyte maturation and expression of glial fibrillary acidic protein (GFAP); it is also alleviated by the inhibition of cell proliferation. To test the hypothesis that GFAP compensates for the effect of VIM^SA/SA in astrocytes, we crossed the VIM^SA/SA and GFAP^−/− mice. Surprisingly, the fraction of VIM^SA/SAimmature astrocytes with abundant vimentin accumulations was reduced when on GFAP^−/− background. This indicates that the disappearance of vimentin accumulations and cytokinetic failure in mature astrocyte cultures are independent of GFAP expression. Both VIM^SA/SA and VIM^SA/SAGFAP^−/− astrocytes showed normal mitochondrial membrane potential and vulnerability to H₂O₂, oxygen/glucose deprivation, and chemical ischemia. Thus, mutation of mitotic phosphorylation sites in vimentin triggers formation of vimentin accumulations and cytokinetic failure in immature astrocytes without altering their vulnerability to oxidative stress. Full article

(This article belongs to the Special Issue Astrocytes in Space and Time)

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12 pages, 2480 KiB

Open AccessArticle

Opioid-Mediated Astrocyte–Neuron Signaling in the Nucleus Accumbens

by Michelle Corkrum, Patrick E. Rothwell, Mark J. Thomas, Paulo Kofuji and Alfonso Araque

Cells 2019, 8(6), 586; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8060586 - 14 Jun 2019

Cited by 42 | Viewed by 6464

Abstract

Major hallmarks of astrocyte physiology are the elevation of intracellular calcium in response to neurotransmitters and the release of neuroactive substances (gliotransmitters) that modulate neuronal activity. While μ-opioid receptor expression has been identified in astrocytes of the nucleus accumbens, the functional consequences on astrocyte–neuron communication remains largely unknown. The present study has investigated the astrocyte responsiveness to μ-opioid signaling and the regulation of gliotransmission in the nucleus accumbens. Through the combination of calcium imaging and whole-cell patch clamp electrophysiology in brain slices, we have found that μ-opioid receptor activation in astrocytes elevates astrocyte cytoplasmic calcium and stimulates the release of the gliotransmitter glutamate, which evokes slow inward currents through the activation of neuronal N-methyl-D-aspartate (NMDA) receptors. These results indicate the existence of molecular mechanisms underlying opioid-mediated astrocyte–neuron signaling in the nucleus accumbens. Full article

(This article belongs to the Special Issue Astrocytes in Space and Time)

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Review

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20 pages, 1960 KiB

Open AccessReview

Astrocytic Factors Controlling Synaptogenesis: A Team Play

by Giuliana Fossati, Michela Matteoli and Elisabetta Menna

Cells 2020, 9(10), 2173; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9102173 - 26 Sep 2020

Cited by 18 | Viewed by 7523

Abstract

Astrocytes are essential players in brain circuit development and homeostasis, controlling many aspects of synapse formation, function, plasticity and elimination both during development and adulthood. Accordingly, alterations in astrocyte morphogenesis and physiology may severely affect proper brain development, causing neurological or neuropsychiatric conditions. Recent findings revealed a huge astrocyte heterogeneity among different brain areas, which is likely at the foundation of the different synaptogenic potential of these cells in selected brain regions. This review highlights recent findings on novel mechanisms that regulate astrocyte-mediated synaptogenesis during development, and the control of synapse number in the critical period or upon synaptic plasticity. Full article

(This article belongs to the Special Issue Astrocytes in Space and Time)

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24 pages, 1073 KiB

Open AccessReview

The Diversity of Intermediate Filaments in Astrocytes

by Maja Potokar, Mitsuhiro Morita, Gerhard Wiche and Jernej Jorgačevski

Cells 2020, 9(7), 1604; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9071604 - 2 Jul 2020

Cited by 34 | Viewed by 6064

Abstract

Despite the remarkable complexity of the individual neuron and of neuronal circuits, it has been clear for quite a while that, in order to understand the functioning of the brain, the contribution of other cell types in the brain have to be accounted for. Among glial cells, astrocytes have multiple roles in orchestrating neuronal functions. Their communication with neurons by exchanging signaling molecules and removing molecules from extracellular space takes place at several levels and is governed by different cellular processes, supported by multiple cellular structures, including the cytoskeleton. Intermediate filaments in astrocytes are emerging as important integrators of cellular processes. Astrocytes express five types of intermediate filaments: glial fibrillary acidic protein (GFAP); vimentin; nestin; synemin; lamins. Variability, interactions with different cellular structures and the particular roles of individual intermediate filaments in astrocytes have been studied extensively in the case of GFAP and vimentin, but far less attention has been given to nestin, synemin and lamins. Similarly, the interplay between different types of cytoskeleton and the interaction between the cytoskeleton and membranous structures, which is mediated by cytolinker proteins, are understudied in astrocytes. The present review summarizes the basic properties of astrocytic intermediate filaments and of other cytoskeletal macromolecules, such as cytolinker proteins, and describes the current knowledge of their roles in normal physiological and pathological conditions. Full article

(This article belongs to the Special Issue Astrocytes in Space and Time)

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11 pages, 698 KiB

Open AccessEditor’s ChoiceReview

Regulation of Synaptic Development by Astrocyte Signaling Factors and Their Emerging Roles in Substance Abuse

by Christopher D. Walker, W. Christopher Risher and Mary-Louise Risher

Cells 2020, 9(2), 297; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9020297 - 26 Jan 2020

Cited by 24 | Viewed by 6907

Abstract

Astrocytes have critical functions throughout the central nervous system (CNS) and have emerged as regulators of synaptic development and function. With their highly complex morphologies, they are able to interact with thousands of synapses via peripheral astrocytic processes (PAPs), ensheathing neuronal axons and dendrites to form the tripartite synapse. In this way, astrocytes engage in crosstalk with neurons to mediate a variety of CNS processes including the regulation of extracellular matrix protein signaling, formation and maintenance of the blood-brain barrier (BBB), axon growth and guidance, homeostasis of the synaptic microenvironment, synaptogenesis, and the promotion of synaptic diversity. In this review, we discuss several key astrocyte signaling factors (thrombospondins, netrins, apolipoproteins, neuregulins, bone morphogenetic proteins, and neuroligins) in the maintenance and regulation of synapse formation. We also explore how these astrocyte signaling factors are impacted by and contribute to substance abuse, particularly alcohol and cocaine use. Full article

(This article belongs to the Special Issue Astrocytes in Space and Time)

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27 pages, 1014 KiB

Open AccessReview

Astrocytes Maintain Glutamate Homeostasis in the CNS by Controlling the Balance between Glutamate Uptake and Release

by Shaimaa Mahmoud, Marjan Gharagozloo, Camille Simard and Denis Gris

Cells 2019, 8(2), 184; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8020184 - 20 Feb 2019

Cited by 361 | Viewed by 22968

Abstract

Glutamate is one of the most prevalent neurotransmitters released by excitatory neurons in the central nervous system (CNS); however, residual glutamate in the extracellular space is, potentially, neurotoxic. It is now well-established that one of the fundamental functions of astrocytes is to uptake most of the synaptically-released glutamate, which optimizes neuronal functions and prevents glutamate excitotoxicity. In the CNS, glutamate clearance is mediated by glutamate uptake transporters expressed, principally, by astrocytes. Interestingly, recent studies demonstrate that extracellular glutamate stimulates Ca²⁺ release from the astrocytes’ intracellular stores, which triggers glutamate release from astrocytes to the adjacent neurons, mostly by an exocytotic mechanism. This released glutamate is believed to coordinate neuronal firing and mediate their excitatory or inhibitory activity. Therefore, astrocytes contribute to glutamate homeostasis in the CNS, by maintaining the balance between their opposing functions of glutamate uptake and release. This dual function of astrocytes represents a potential therapeutic target for CNS diseases associated with glutamate excitotoxicity. In this regard, we summarize the molecular mechanisms of glutamate uptake and release, their regulation, and the significance of both processes in the CNS. Also, we review the main features of glutamate metabolism and glutamate excitotoxicity and its implication in CNS diseases. Full article

(This article belongs to the Special Issue Astrocytes in Space and Time)

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