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Cells
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Astroglial Connexin Physiology
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Astroglial Connexin Physiology

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 30084

Special Issue Editor

Dr. Martine Cohen-Salmon

E-Mail Website
Guest Editor
Physiology and physiopathology of the gliovascular unit, Centre Interdisciplinaire de Recherche en Biologie (CIRB), CNRS UMR 7241 / INSERM U1050, Collège de France, 11 place Marcelin Berthelot, 75005 Paris, France
Interests: astrocytes; glia; connexins; gliovascular unit; blood-brain barrier; local translation; neuropathologies

Special Issue Information

Dear Colleagues,

Astrocytes are key active elements of the brain that contribute to information processing. Astrocytes closely interact with neurons and provide them with metabolic and structural support. They regulate neurogenesis, brain wiring, synaptic activity, and plasticity. Astrocytes also interact with brain vessels and control blood-brain barrier integrity, immunity, and blood flow. Dysfunction of astrocytes can induce major alterations in neuronal and vascular functions, contributing to the pathogenesis of several brain disorders. A typical feature of astrocytes compared to other brain cell populations is their high level of Connexin (Cx) expression with two major Cxs: Cx43 and Cx30. Cxs assemble in gap junction channels permeable to ions and small signaling molecules allowing direct cell-to-cell communication and providing the basis for intercellular pathways between large populations of astrocytes. Cxs also work as hemichannels and play a paracrine role by allowing exchanges between the cytoplasm and the extracellular medium. Finally, besides these channel functions, Cxs play adhesive and signaling functions. Astroglial Cxs are implicated in a wide variety of processes. They contribute to neurotransmission, endowing neurons with an optimal state to process information. They also control BBB integrity and immune surveillance. Determining how astroglial Cxs confers specific features and functions to astrocytes and their role in brain physiology is a key issue that we propose to develop in this Special Issue of Cells.

Dr. Martine Cohen-Salmon
Guest Editor

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Keywords

  • astrocyte
  • connexins
  • gap junctions
  • physiology
  • physiopathology

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Published Papers (7 papers)

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Research

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20 pages, 3904 KiB  
Article
Megalencephalic Leukoencephalopathy with Subcortical Cysts Disease-Linked MLC1 Protein Favors Gap-Junction Intercellular Communication by Regulating Connexin 43 Trafficking in Astrocytes
by Angela Lanciotti, Maria Stefania Brignone, Marcello Belfiore, Sandra Columba-Cabezas, Cinzia Mallozzi, Olimpia Vincentini, Paola Molinari, Tamara Corinna Petrucci, Sergio Visentin and Elena Ambrosini
Cells 2020, 9(6), 1425; https://doi.org/10.3390/cells9061425 - 8 Jun 2020
Cited by 17 | Viewed by 3777
Abstract
Astrocytes, the most numerous cells of the central nervous system, exert critical functions for brain homeostasis. To this purpose, astrocytes generate a highly interconnected intercellular network allowing rapid exchange of ions and metabolites through gap junctions, adjoined channels composed of hexamers of connexin [...] Read more.
Astrocytes, the most numerous cells of the central nervous system, exert critical functions for brain homeostasis. To this purpose, astrocytes generate a highly interconnected intercellular network allowing rapid exchange of ions and metabolites through gap junctions, adjoined channels composed of hexamers of connexin (Cx) proteins, mainly Cx43. Functional alterations of Cxs and gap junctions have been observed in several neuroinflammatory/neurodegenerative diseases. In the rare leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts (MLC), astrocytes show defective control of ion/fluid exchanges causing brain edema, fluid cysts, and astrocyte/myelin vacuolation. MLC is caused by mutations in MLC1, an astrocyte-specific protein of elusive function, and in GlialCAM, a MLC1 chaperon. Both proteins are highly expressed at perivascular astrocyte end-feet and astrocyte-astrocyte contacts where they interact with zonula occludens-1 (ZO-1) and Cx43 junctional proteins. To investigate the possible role of Cx43 in MLC pathogenesis, we studied Cx43 properties in astrocytoma cells overexpressing wild type (WT) MLC1 or MLC1 carrying pathological mutations. Using biochemical and electrophysiological techniques, we found that WT, but not mutated, MLC1 expression favors intercellular communication by inhibiting extracellular-signal-regulated kinase 1/2 (ERK1/2)-mediated Cx43 phosphorylation and increasing Cx43 gap-junction stability. These data indicate MLC1 regulation of Cx43 in astrocytes and Cx43 involvement in MLC pathogenesis, suggesting potential target pathways for therapeutic interventions. Full article
(This article belongs to the Special Issue Astroglial Connexin Physiology)
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18 pages, 3296 KiB  
Article
Activation of Astroglial Connexin Is Involved in Concentration-Dependent Double-Edged Sword Clinical Action of Clozapine
by Kouji Fukuyama, Ruri Okubo, Masahiko Murata, Takashi Shiroyama and Motohiro Okada
Cells 2020, 9(2), 414; https://doi.org/10.3390/cells9020414 - 11 Feb 2020
Cited by 31 | Viewed by 3172
Abstract
Clozapine (CLZ) is a gold-standard antipsychotic against treatment-refractory schizophrenia, but is one of the most toxic antipsychotic agents. Pharmacological mechanisms of the double-edged sword clinical action of CLZ remain to be clarified. To explore the mechanisms of CLZ, the present study determined the [...] Read more.
Clozapine (CLZ) is a gold-standard antipsychotic against treatment-refractory schizophrenia, but is one of the most toxic antipsychotic agents. Pharmacological mechanisms of the double-edged sword clinical action of CLZ remain to be clarified. To explore the mechanisms of CLZ, the present study determined the astroglial transmission associated with connexin43 (Cx43), which is the most principal expression in astrocytes and myocardial cells, and expression of Cx43 in primary cultured astrocytes. Both acute and subchronic administrations of CLZ concentration-dependently increased Cx43-associated astroglial release of l-glutamate and d-serine, whereas therapeutic-relevant concentration of CLZ acutely did not affect but subchronically increased astroglial release. In contrast, after the subchronic administration of therapeutic-relevant concentration of valproate (VPA), acute administration of therapeutic-relevant concentration of CLZ drastically increased Cx43-associated astroglial releases. VPA increased Cx43 expression in cytosol fraction without affecting plasma membrane fraction, whereas CLZ increased Cx43 expression in both fractions. Acute administration of therapeutic-relevant concentration of CLZ drastically increased Cx43 expression in the plasma membrane fraction of astrocytes subchronically treated with VPA. The present findings suggest that CLZ-induced the activation of Cx43-associated channel activity and transported Cx43 to plasma membrane, probably contribute to the double-edged sword clinical action of CLZ, such as improvement of cognitive dysfunction and CLZ-induced myocarditis. Full article
(This article belongs to the Special Issue Astroglial Connexin Physiology)
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11 pages, 1443 KiB  
Article
Astroglial Connexin 43 Deficiency Protects against LPS-Induced Neuroinflammation: A TSPO Brain µPET Study with [18F]FEPPA
by Nicolas Vignal, Anne-Cécile Boulay, Carine San, Martine Cohen-Salmon, Nathalie Rizzo-Padoin, Laure Sarda-Mantel, Xavier Declèves, Salvatore Cisternino and Benoît Hosten
Cells 2020, 9(2), 389; https://doi.org/10.3390/cells9020389 - 7 Feb 2020
Cited by 9 | Viewed by 3231
Abstract
Astroglial connexin 43 (Cx43) has been recognized as a crucial immunoregulating factor in the brain. Its inactivation leads to a continuous immune recruitment, cytokine expression modification and a specific humoral autoimmune response against the astrocytic extracellular matrix but without brain lesions or cell [...] Read more.
Astroglial connexin 43 (Cx43) has been recognized as a crucial immunoregulating factor in the brain. Its inactivation leads to a continuous immune recruitment, cytokine expression modification and a specific humoral autoimmune response against the astrocytic extracellular matrix but without brain lesions or cell lysis. To assess the impact of Cx43 deletion on the brain’s inflammatory response, TSPO expression was studied by positron emission tomography (PET) imaging with a specific radioligand, [18F]FEPPA, in basal conditions or upon Lipopolysaccharides (LPS)-induced inflammatory challenge. Astroglial Cx43-deleted mice underwent [18F]FEPPA PET/CT dynamic imaging with or without LPS injection (5 mg/kg) 24 h before imaging. Quantification and pharmacokinetic data modelling with a 2TCM-1K compartment model were performed. After collecting the mice brains, TSPO expression was quantified and localized by Western blot and FISH analysis. We found that astroglial Cx43 deficiency does not significantly alter TSPO expression in the basal state as observed with [18F]FEPPA PET imaging, FISH and Western blot analysis. However, deletion of astrocyte Cx43 abolishes the LPS-induced TSPO increase. Autoimmune encephalopathy observed in astroglial Cx43-deleted mice does not involve TSPO overexpression. Consistent with previous studies showing a unique inflammatory status in the absence of astrocyte Cx43, we show that a deficient expression of astrocytic Cx43 protects the animals from LPS-induced neuroinflammation as addressed by TSPO expression. Full article
(This article belongs to the Special Issue Astroglial Connexin Physiology)
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13 pages, 1758 KiB  
Article
Uncoupling of the Astrocyte Syncytium Differentially Affects AQP4 Isoforms
by Shirin Katoozi, Nadia Skauli, Soulmaz Zahl, Tushar Deshpande, Pascal Ezan, Claudia Palazzo, Christian Steinhäuser, Antonio Frigeri, Martine Cohen-Salmon, Ole Petter Ottersen and Mahmood Amiry-Moghaddam
Cells 2020, 9(2), 382; https://doi.org/10.3390/cells9020382 - 7 Feb 2020
Cited by 16 | Viewed by 4819
Abstract
The water channel protein aquaporin-4 (AQP4) and the gap junction forming proteins connexin-43 (Cx43) and connexin-30 (Cx30) are astrocytic proteins critically involved in brain water and ion homeostasis. While AQP4 is mainly involved in water flux across the astrocytic endfeet membranes, astrocytic gap [...] Read more.
The water channel protein aquaporin-4 (AQP4) and the gap junction forming proteins connexin-43 (Cx43) and connexin-30 (Cx30) are astrocytic proteins critically involved in brain water and ion homeostasis. While AQP4 is mainly involved in water flux across the astrocytic endfeet membranes, astrocytic gap junctions provide syncytial coupling allowing intercellular exchange of water, ions, and other molecules. We have previously shown that mice with targeted deletion of Aqp4 display enhanced gap junctional coupling between astrocytes. Here, we investigate whether uncoupling of the astrocytic syncytium by deletion of the astrocytic connexins Cx43 and Cx30 affects AQP4 membrane localization and expression. By using quantitative immunogold cytochemistry, we show that deletion of astrocytic connexins leads to a substantial reduction of perivascular AQP4, concomitant with a down-regulation of total AQP4 protein and mRNA. Isoform expression analysis shows that while the level of the predominant AQP4 M23 isoform is reduced in Cx43/Cx30 double deficient hippocampal astrocytes, the levels of M1, and the alternative translation AQP4ex isoform protein levels are increased. These findings reveal a complex interdependence between AQP4 and connexins, which are both significantly involved in homeostatic functions and astrogliopathologies. Full article
(This article belongs to the Special Issue Astroglial Connexin Physiology)
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22 pages, 6323 KiB  
Article
Involvement of the Gap Junction Protein, Connexin43, in the Formation and Function of Invadopodia in the Human U251 Glioblastoma Cell Line
by Amandine Chepied, Zeinaba Daoud-Omar, Annie-Claire Meunier-Balandre, Dale W. Laird, Marc Mesnil and Norah Defamie
Cells 2020, 9(1), 117; https://doi.org/10.3390/cells9010117 - 3 Jan 2020
Cited by 14 | Viewed by 3431
Abstract
The resistance of glioblastomas to treatments is mainly the consequence of their invasive capacities. Therefore, in order to better treat these tumors, it is important to understand the molecular mechanisms which are responsible for this behavior. Previous work suggested that gap junction proteins, [...] Read more.
The resistance of glioblastomas to treatments is mainly the consequence of their invasive capacities. Therefore, in order to better treat these tumors, it is important to understand the molecular mechanisms which are responsible for this behavior. Previous work suggested that gap junction proteins, the connexins, facilitate the aggressive nature of glioma cells. Here, we show that one of them—connexin43 (Cx43)—is implicated in the formation and function of invadopodia responsible for invasion capacity of U251 human glioblastoma cells. Immunofluorescent approaches—combined with confocal analyses—revealed that Cx43 was detected in all the formation stages of invadopodia exhibiting proteolytic activity. Clearly, Cx43 appeared to be localized in invadopodia at low cell density and less associated with the establishment of gap junctions. Accordingly, lower extracellular matrix degradation correlated with less mature invadopodia and MMP2 activity when Cx43 expression was decreased by shRNA strategies. Moreover, the kinetics of invadopodia formation could be dependent on Cx43 dynamic interactions with partners including Src and cortactin. Interestingly, it also appeared that invadopodia formation and MMP2 activity are dependent on Cx43 hemichannel activity. In conclusion, these results reveal that Cx43 might be involved in the formation and function of the invadopodia of U251 glioblastoma cells. Full article
(This article belongs to the Special Issue Astroglial Connexin Physiology)
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Review

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31 pages, 3287 KiB  
Review
Role of Connexins 30, 36, and 43 in Brain Tumors, Neurodegenerative Diseases, and Neuroprotection
by Oscar F. Sánchez, Andrea V. Rodríguez, José M. Velasco-España, Laura C. Murillo, Jhon-Jairo Sutachan and Sonia-Luz Albarracin
Cells 2020, 9(4), 846; https://doi.org/10.3390/cells9040846 - 31 Mar 2020
Cited by 27 | Viewed by 6008
Abstract
Gap junction (GJ) channels and their connexins (Cxs) are complex proteins that have essential functions in cell communication processes in the central nervous system (CNS). Neurons, astrocytes, oligodendrocytes, and microglial cells express an extraordinary repertory of Cxs that are important for cell to [...] Read more.
Gap junction (GJ) channels and their connexins (Cxs) are complex proteins that have essential functions in cell communication processes in the central nervous system (CNS). Neurons, astrocytes, oligodendrocytes, and microglial cells express an extraordinary repertory of Cxs that are important for cell to cell communication and diffusion of metabolites, ions, neurotransmitters, and gliotransmitters. GJs and Cxs not only contribute to the normal function of the CNS but also the pathological progress of several diseases, such as cancer and neurodegenerative diseases. Besides, they have important roles in mediating neuroprotection by internal or external molecules. However, regulation of Cx expression by epigenetic mechanisms has not been fully elucidated. In this review, we provide an overview of the known mechanisms that regulate the expression of the most abundant Cxs in the central nervous system, Cx30, Cx36, and Cx43, and their role in brain cancer, CNS disorders, and neuroprotection. Initially, we focus on describing the Cx gene structure and how this is regulated by epigenetic mechanisms. Then, the posttranslational modifications that mediate the activity and stability of Cxs are reviewed. Finally, the role of GJs and Cxs in glioblastoma, Alzheimer’s, Parkinson’s, and Huntington’s diseases, and neuroprotection are analyzed with the aim of shedding light in the possibility of using Cx regulators as potential therapeutic molecules. Full article
(This article belongs to the Special Issue Astroglial Connexin Physiology)
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22 pages, 2338 KiB  
Review
Astroglial Isopotentiality and Calcium-Associated Biomagnetic Field Effects on Cortical Neuronal Coupling
by Marcos Martinez-Banaclocha
Cells 2020, 9(2), 439; https://doi.org/10.3390/cells9020439 - 13 Feb 2020
Cited by 16 | Viewed by 4848
Abstract
Synaptic neurotransmission is necessary but does not sufficiently explain superior cognitive faculties. Growing evidence has shown that neuron–astroglial chemical crosstalk plays a critical role in the processing of information, computation, and memory. In addition to chemical and electrical communication among neurons and between [...] Read more.
Synaptic neurotransmission is necessary but does not sufficiently explain superior cognitive faculties. Growing evidence has shown that neuron–astroglial chemical crosstalk plays a critical role in the processing of information, computation, and memory. In addition to chemical and electrical communication among neurons and between neurons and astrocytes, other nonsynaptic mechanisms called ephaptic interactions can contribute to the neuronal synchronization from different brain regions involved in the processing of information. New research on brain astrocytes has clearly shown that the membrane potential of these cells remains very stable among neighboring and distant astrocytes due to the marked bioelectric coupling between them through gap junctions. This finding raises the possibility that the neocortical astroglial network exerts a guiding template modulating the excitability and synchronization of trillions of neurons by astroglial Ca2+-associated bioelectromagnetic interactions. We propose that bioelectric and biomagnetic fields of the astroglial network equalize extracellular local field potentials (LFPs) and associated local magnetic field potentials (LMFPs) in the cortical layers of the brain areas involved in the processing of information, contributing to the adequate and coherent integration of external and internal signals. This article reviews the current knowledge of ephaptic interactions in the cerebral cortex and proposes that the isopotentiality of cortical astrocytes is a prerequisite for the maintenance of the bioelectromagnetic crosstalk between neurons and astrocytes in the neocortex. Full article
(This article belongs to the Special Issue Astroglial Connexin Physiology)
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