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Cells
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Astroglial (Patho)Physiology
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Astroglial (Patho)Physiology

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 (18 April 2023) | Viewed by 14032

Special Issue Editors

Prof. Dr. Robert Zorec

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Guest Editor
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
Special Issues, Collections and Topics in MDPI journals
Dr. Jernej Jorgačevski

E-Mail Website
Guest Editor
Celica Biomedical, Ljubljana, Slovenia
Interests: astroglia; membrane fusion; exocytosis; endocytosis; neuroendocrine cells; neurons; electrophysiology; metabolism; calcium homeostasis; cytoskeleton; vesicle trafficking; neuroinfections; autophagy; neurodegeneration; hybridoma cells; pathophysiology

Special Issue Information

Dear Colleagues,

Astrocytes are an abundant type of neuroglial cells, deriving from neuroectoderm, playing a key role in multiple homeostatic functions in the central nervous system (CNS), including those in neurogenesis, synaptogenesis, blood–brain barrier permeability, and extracellular space homeostasis. Anatomically, astrocytes are engaged in the physical association with capillaries, through which glucose, but also blood-borne pathogens, can enter the CNS. Moreover, capillaries mediate the passage of water and sodium in the process of cerebral edema. Astrocytes are crucial for the maturation and maintenance of synaptic connectivity, as astroglial perisynaptic processes enwrap synapses, an important energy consumer. Thus, astrocytes are one of the key cell types maintaining proper functioning of the healthy CNS and significantly contribute to the pathologic processes that are initiated by neurotrauma, neuroinfections, as well as in neurodevelopmental and psychiatric diseases. Under such conditions, astrocytes acquire a reactive phenotype, characterized by functional and morphological remodeling due to a pathologic insult. This Special Issue on “Astroglial (Patho)Physiology” focuses on novel insights into astrocyte signaling, metabolism and inflammatory responses to neurotrauma, neuroinfections, and the role of astroglia in neurodegenerative, neurodevelopmental, and psychiatric conditions.

Prof. Dr. Robert Zorec
Dr. Jernej Jorgačevski
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (6 papers)

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Research

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20 pages, 3665 KiB  
Article
S1P Lyase Deficiency in the Brain Promotes Astrogliosis and NLRP3 Inflammasome Activation via Purinergic Signaling
by Shah Alam, Sumaiya Yasmeen Afsar, Maya Anik Wolter, Luisa Michelle Volk, Daniel Nicolae Mitroi, Dagmar Meyer zu Heringdorf and Gerhild van Echten-Deckert
Cells 2023, 12(14), 1844; https://doi.org/10.3390/cells12141844 - 13 Jul 2023
Cited by 3 | Viewed by 1489
Abstract
Astrocytes are critical players in brain health and disease. Brain pathologies and lesions are usually accompanied by astroglial alterations known as reactive astrogliosis. Sphingosine 1-phosphate lyase (SGPL1) catalysis, the final step in sphingolipid catabolism, irreversibly cleaves its substrate sphingosine 1-phosphate (S1P). We have [...] Read more.
Astrocytes are critical players in brain health and disease. Brain pathologies and lesions are usually accompanied by astroglial alterations known as reactive astrogliosis. Sphingosine 1-phosphate lyase (SGPL1) catalysis, the final step in sphingolipid catabolism, irreversibly cleaves its substrate sphingosine 1-phosphate (S1P). We have shown that neural ablation of SGPL1 causes accumulation of S1P and hence neuronal damage, cognitive deficits, as well as microglial activation. Moreover, the S1P/S1P-receptor signaling axis enhances ATP production in SGPL1-deficient astrocytes. Using immunohistochemical methods as well as RNA Seq and CUT&Tag we show how S1P signaling causes activation of the astrocytic purinoreceptor P2Y1 (P2Y1R). With specific pharmacological agonists and antagonists, we uncover the P2Y1R as the key player in S1P-induced astrogliosis, and DDX3X mediated the activation of the NLRP3 inflammasome, including caspase-1 and henceforward generation of interleukin-1ß (IL-1ß) and of other proinflammatory cytokines. Our results provide a novel route connecting S1P metabolism and signaling with astrogliosis and the activation of the NLRP3 inflammasome, a central player in neuroinflammation, known to be crucial for the pathogenesis of numerous brain illnesses. Thus, our study opens the door for new therapeutic strategies surrounding S1P metabolism and signaling in the brain. Full article
(This article belongs to the Special Issue Astroglial (Patho)Physiology)
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21 pages, 4104 KiB  
Article
Astroglial Cell-to-Cell Interaction with Autoreactive Immune Cells in Experimental Autoimmune Encephalomyelitis Involves P2X7 Receptor, β3-Integrin, and Connexin-43
by Katarina D. Milicevic, Danijela B. Bataveljic, Jelena J. Bogdanovic Pristov, Pavle R. Andjus and Ljiljana M. Nikolic
Cells 2023, 12(13), 1786; https://doi.org/10.3390/cells12131786 - 5 Jul 2023
Cited by 1 | Viewed by 1506
Abstract
In multiple sclerosis (MS), glial cells astrocytes interact with the autoreactive immune cells that attack the central nervous system (CNS), which causes and sustains neuroinflammation. However, little is known about the direct interaction between these cells when they are in close proximity in [...] Read more.
In multiple sclerosis (MS), glial cells astrocytes interact with the autoreactive immune cells that attack the central nervous system (CNS), which causes and sustains neuroinflammation. However, little is known about the direct interaction between these cells when they are in close proximity in the inflamed CNS. By using an experimental autoimmune encephalomyelitis (EAE) model of MS, we previously found that in the proximity of autoreactive CNS-infiltrated immune cells (CNS-IICs), astrocytes respond with a rapid calcium increase that is mediated by the autocrine P2X7 receptor (P2X7R) activation. We now reveal that the mechanisms regulating this direct interaction of astrocytes and CNS-IICs involve the coupling between P2X7R, connexin-43, and β3-integrin. We found that P2X7R and astroglial connexin-43 interact and concentrate in the immediate proximity of the CNS-IICs in EAE. P2X7R also interacts with β3-integrin, and the block of astroglial αvβ3-integrin reduces the P2X7R-dependent calcium response of astrocytes upon encountering CNS-IICs. This interaction was dependent on astroglial mitochondrial activity, which regulated the ATP-driven P2X7R activation and facilitated the termination of the astrocytic calcium response evoked by CNS-IICs. By further defining the interactions between the CNS and the immune system, our findings provide a novel perspective toward expanding integrin-targeting therapeutic approaches for MS treatment by controlling the cell–cell interactions between astrocytes and CNS-IICs. Full article
(This article belongs to the Special Issue Astroglial (Patho)Physiology)
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23 pages, 4295 KiB  
Article
Ketamine Reduces the Surface Density of the Astroglial Kir4.1 Channel and Inhibits Voltage-Activated Currents in a Manner Similar to the Action of Ba2+ on K+ Currents
by Mićo Božić, Samo Pirnat, Katja Fink, Maja Potokar, Marko Kreft, Robert Zorec and Matjaž Stenovec
Cells 2023, 12(10), 1360; https://doi.org/10.3390/cells12101360 - 10 May 2023
Cited by 1 | Viewed by 2031
Abstract
A single sub-anesthetic dose of ketamine evokes rapid and long-lasting beneficial effects in patients with a major depressive disorder. However, the mechanisms underlying this effect are unknown. It has been proposed that astrocyte dysregulation of extracellular K+ concentration ([K+]o [...] Read more.
A single sub-anesthetic dose of ketamine evokes rapid and long-lasting beneficial effects in patients with a major depressive disorder. However, the mechanisms underlying this effect are unknown. It has been proposed that astrocyte dysregulation of extracellular K+ concentration ([K+]o) alters neuronal excitability, thus contributing to depression. We examined how ketamine affects inwardly rectifying K+ channel Kir4.1, the principal regulator of K+ buffering and neuronal excitability in the brain. Cultured rat cortical astrocytes were transfected with plasmid-encoding fluorescently tagged Kir4.1 (Kir4.1-EGFP) to monitor the mobility of Kir4.1-EGFP vesicles at rest and after ketamine treatment (2.5 or 25 µM). Short-term (30 min) ketamine treatment reduced the mobility of Kir4.1-EGFP vesicles compared with the vehicle-treated controls (p < 0.05). Astrocyte treatment (24 h) with dbcAMP (dibutyryl cyclic adenosine 5′-monophosphate, 1 mM) or [K+]o (15 mM), which increases intracellular cAMP, mimicked the ketamine-evoked reduction of mobility. Live cell immunolabelling and patch-clamp measurements in cultured mouse astrocytes revealed that short-term ketamine treatment reduced the surface density of Kir4.1 and inhibited voltage-activated currents similar to Ba2+ (300 µM), a Kir4.1 blocker. Thus, ketamine attenuates Kir4.1 vesicle mobility, likely via a cAMP-dependent mechanism, reduces Kir4.1 surface density, and inhibits voltage-activated currents similar to Ba2+, known to block Kir4.1 channels. Full article
(This article belongs to the Special Issue Astroglial (Patho)Physiology)
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17 pages, 6224 KiB  
Article
Induced Remodelling of Astrocytes In Vitro and In Vivo by Manipulation of Astrocytic RhoA Activity
by Cátia Domingos, Franziska E. Müller, Stefan Passlick, Dagmar Wachten, Evgeni Ponimaskin, Martin K. Schwarz, Susanne Schoch, André Zeug and Christian Henneberger
Cells 2023, 12(2), 331; https://doi.org/10.3390/cells12020331 - 15 Jan 2023
Cited by 1 | Viewed by 2517
Abstract
Structural changes of astrocytes and their perisynaptic processes occur in response to various physiological and pathophysiological stimuli. They are thought to profoundly affect synaptic signalling and neuron-astrocyte communication. Understanding the causal relationship between astrocyte morphology changes and their functional consequences requires experimental tools [...] Read more.
Structural changes of astrocytes and their perisynaptic processes occur in response to various physiological and pathophysiological stimuli. They are thought to profoundly affect synaptic signalling and neuron-astrocyte communication. Understanding the causal relationship between astrocyte morphology changes and their functional consequences requires experimental tools to selectively manipulate astrocyte morphology. Previous studies indicate that RhoA-related signalling can play a major role in controlling astrocyte morphology, but the direct effect of increased RhoA activity has not been documented in vitro and in vivo. Therefore, we established a viral approach to manipulate astrocytic RhoA activity. We tested if and how overexpression of wild-type RhoA, of a constitutively active RhoA mutant (RhoA-CA), and of a dominant-negative RhoA variant changes the morphology of cultured astrocytes. We found that astrocytic expression of RhoA-CA induced robust cytoskeletal changes and a withdrawal of processes in cultured astrocytes. In contrast, overexpression of other RhoA variants led to more variable changes of astrocyte morphology. These induced morphology changes were reproduced in astrocytes of the hippocampus in vivo. Importantly, astrocytic overexpression of RhoA-CA did not alter the branching pattern of larger GFAP-positive processes of astrocytes. This indicates that a prolonged increase of astrocytic RhoA activity leads to a distinct morphological phenotype in vitro and in vivo, which is characterized by an isolated reduction of fine peripheral astrocyte processes in vivo. At the same time, we identified a promising experimental approach for investigating the functional consequences of astrocyte morphology changes. Full article
(This article belongs to the Special Issue Astroglial (Patho)Physiology)
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19 pages, 5070 KiB  
Article
β-COP Regulates TWIK1/TREK1 Heterodimeric Channel-Mediated Passive Conductance in Astrocytes
by Seong-Seop Kim, Yeonju Bae, Osung Kwon, Seung-Hae Kwon, Jong Bok Seo, Eun Mi Hwang and Jae-Yong Park
Cells 2022, 11(20), 3322; https://doi.org/10.3390/cells11203322 - 21 Oct 2022
Cited by 1 | Viewed by 1819
Abstract
Mature astrocytes are characterized by a K+ conductance (passive conductance) that changes with a constant slope with voltage, which is involved in K+ homeostasis in the brain. Recently, we reported that the tandem of pore domains in a weak inward rectifying [...] Read more.
Mature astrocytes are characterized by a K+ conductance (passive conductance) that changes with a constant slope with voltage, which is involved in K+ homeostasis in the brain. Recently, we reported that the tandem of pore domains in a weak inward rectifying K+ channel (TWIK1 or KCNK1) and TWIK-related K+ channel 1 (TREK1 or KCNK2) form heterodimeric channels that mediate passive conductance in astrocytes. However, little is known about the binding proteins that regulate the function of the TWIK1/TREK1 heterodimeric channels. Here, we found that β-coat protein (COP) regulated the surface expression and activity of the TWIK1/TREK1 heterodimeric channels in astrocytes. β-COP binds directly to TREK1 but not TWIK1 in a heterologous expression system. However, β-COP also interacts with the TWIK1/TREK1 heterodimeric channel in a TREK1 dependent manner and enhances the surface expression of the heterodimeric channel in astrocytes. Consequently, it regulates TWIK1/TREK1 heterodimeric channel-mediated passive conductance in astrocytes in the mouse brain. Taken together, these results suggest that β-COP is a potential regulator of astrocytic passive conductance in the brain. Full article
(This article belongs to the Special Issue Astroglial (Patho)Physiology)
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Review

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24 pages, 893 KiB  
Review
The Water Transport System in Astrocytes–Aquaporins
by Zuoyi Zhou, Jiangshan Zhan, Qingyun Cai, Fanqing Xu, Ruichao Chai, Kalista Lam, Zuo Luan, Guoying Zhou, Sue Tsang, Markus Kipp, Wenling Han, Rong Zhang and Albert Cheung Hoi Yu
Cells 2022, 11(16), 2564; https://doi.org/10.3390/cells11162564 - 18 Aug 2022
Cited by 17 | Viewed by 4204
Abstract
Astrocytes have distinctive morphological and functional characteristics, and are found throughout the central nervous system. Astrocytes are now known to be far more than just housekeeping cells in the brain. Their functions include contributing to the formation of the blood–brain barrier, physically and [...] Read more.
Astrocytes have distinctive morphological and functional characteristics, and are found throughout the central nervous system. Astrocytes are now known to be far more than just housekeeping cells in the brain. Their functions include contributing to the formation of the blood–brain barrier, physically and metabolically supporting and communicating with neurons, regulating the formation and functions of synapses, and maintaining water homeostasis and the microenvironment in the brain. Aquaporins (AQPs) are transmembrane proteins responsible for fast water movement across cell membranes. Various subtypes of AQPs (AQP1, AQP3, AQP4, AQP5, AQP8 and AQP9) have been reported to be expressed in astrocytes, and the expressions and subcellular localizations of AQPs in astrocytes are highly correlated with both their physiological and pathophysiological functions. This review describes and summarizes the recent advances in our understanding of astrocytes and AQPs in regard to controlling water homeostasis in the brain. Findings regarding the features of different AQP subtypes, such as their expression, subcellular localization, physiological functions, and the pathophysiological roles of astrocytes are presented, with brain edema and glioma serving as two representative AQP-associated pathological conditions. The aim is to provide a better insight into the elaborate “water distribution” system in cells, exemplified by astrocytes, under normal and pathological conditions. Full article
(This article belongs to the Special Issue Astroglial (Patho)Physiology)
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