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Astrocytes: Emerging Roles in the Pathogenesis and Treatment of CNS Disorders 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 64046

Special Issue Editors

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
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. Dr. Yukihiro Ohno
Prof. Dr. Schuichi Koizumi
Guest Editors

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Keywords

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

Published Papers (18 papers)

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Research

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22 pages, 19631 KiB  
Article
Heterodimer of A2A and Oxytocin Receptors Regulating Glutamate Release in Adult Striatal Astrocytes
by Sarah Amato, Monica Averna, Diego Guidolin, Marco Pedrazzi, Simone Pelassa, Michela Capraro, Mario Passalacqua, Matteo Bozzo, Elena Gatta, Deanna Anderlini, Guido Maura, Luigi F. Agnati, Chiara Cervetto and Manuela Marcoli
Int. J. Mol. Sci. 2022, 23(4), 2326; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042326 - 19 Feb 2022
Cited by 12 | Viewed by 2232
Abstract
Background: Roles of astrocytes in the modulatory effects of oxytocin (OT) in central nervous system are increasingly considered. Nevertheless, OT effects on gliotransmitter release have been neglected. Methods: In purified astrocyte processes from adult rat striatum, we assessed OT receptor (OTR) and adenosine [...] Read more.
Background: Roles of astrocytes in the modulatory effects of oxytocin (OT) in central nervous system are increasingly considered. Nevertheless, OT effects on gliotransmitter release have been neglected. Methods: In purified astrocyte processes from adult rat striatum, we assessed OT receptor (OTR) and adenosine A2A receptor expression by confocal analysis. The effects of receptors activation on glutamate release from the processes were evaluated; A2A-OTR heteromerization was assessed by co-immunoprecipitation and PLA. Structure of the possible heterodimer of A2A and OT receptors was estimated by a bioinformatic approach. Results: Both A2A and OT receptors were expressed on the same astrocyte processes. Evidence for A2A-OTR receptor-receptor interaction was obtained by measuring the release of glutamate: OT inhibited the evoked glutamate release, while activation of A2A receptors, per se ineffective, abolished the OT effect. Biochemical and biophysical evidence for A2A-OTR heterodimers on striatal astrocytes was also obtained. The residues in the transmembrane domains 4 and 5 of both receptors are predicted to be mainly involved in the heteromerization. Conclusions: When considering effects of OT in striatum, modulation of glutamate release from the astrocyte processes and of glutamatergic synapse functioning, and the interaction with A2A receptors on the astrocyte processes should be taken into consideration. Full article
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14 pages, 16688 KiB  
Article
The Role of Nrf2 Transcription Factor and Sp1-Nrf2 Protein Complex in Glutamine Transporter SN1 Regulation in Mouse Cortical Astrocytes Exposed to Ammonia
by Katarzyna Dąbrowska, Katarzyna Skowrońska, Mariusz Popek, Jan Albrecht and Magdalena Zielińska
Int. J. Mol. Sci. 2021, 22(20), 11233; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011233 - 18 Oct 2021
Cited by 3 | Viewed by 1889
Abstract
Ammonia toxicity in the brain primarily affects astrocytes via a mechanism in which oxidative stress (OS), is coupled to the imbalance between glutamatergic and GABAergic transmission. Ammonia also downregulates the astrocytic N system transporter SN1 that controls glutamine supply from astrocytes to neurons [...] Read more.
Ammonia toxicity in the brain primarily affects astrocytes via a mechanism in which oxidative stress (OS), is coupled to the imbalance between glutamatergic and GABAergic transmission. Ammonia also downregulates the astrocytic N system transporter SN1 that controls glutamine supply from astrocytes to neurons for the replenishment of both neurotransmitters. Here, we tested the hypothesis that activation of Nrf2 is the process that links ammonia-induced OS formation in astrocytes to downregulation and inactivation of SN1 and that it may involve the formation of a complex between Nrf2 and Sp1. Treatment of cultured cortical mouse astrocytes with ammonia (5 mM NH4Cl for 24 h) evoked Nrf2 nuclear translocation, increased its activity in a p38 MAPK pathway-dependent manner, and enhanced Nrf2 binding to Slc38a3 promoter. Nrf2 silencing increased SN1 mRNA and protein level without influencing astrocytic [3H]glutamine transport. Ammonia decreased SN1 expression in Nrf2 siRNA treated astrocytes and reduced [3H]glutamine uptake. In addition, while Nrf2 formed a complex with Sp1 in ammonia-treated astrocytes less efficiently than in control cells, treatment of astrocytes with hybrid-mode inactivated Sp1-Nrf2 complex (Nrf2 silencing + pharmacological inhibition of Sp1) did not affect SN1 protein level in ammonia-treated astrocytes. In summary, the results document that SN1 transporter dysregulation by ammonia in astrocytes involves activation of Nrf2 but does not require the formation of the Sp1-Nrf2 complex. Full article
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21 pages, 1992 KiB  
Article
Distinct Effects of Escitalopram and Vortioxetine on Astroglial L-Glutamate Release Associated with Connexin43
by Takashi Shiroyama, Kouji Fukuyama and Motohiro Okada
Int. J. Mol. Sci. 2021, 22(18), 10013; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221810013 - 16 Sep 2021
Cited by 12 | Viewed by 2513
Abstract
It has been established that enhancement of serotonergic transmission contributes to improvement of major depression; however, several post-mortem studies and experimental depression rodent models suggest that functional abnormalities of astrocytes play important roles in the pathomechanisms/pathophysiology of mood disorders. Direct effects of serotonin [...] Read more.
It has been established that enhancement of serotonergic transmission contributes to improvement of major depression; however, several post-mortem studies and experimental depression rodent models suggest that functional abnormalities of astrocytes play important roles in the pathomechanisms/pathophysiology of mood disorders. Direct effects of serotonin (5-HT) transporter inhibiting antidepressants on astroglial transmission systems has never been assessed in this context. Therefore, to explore the effects of antidepressants on transmission associated with astrocytes, the present study determined the effects of the selective 5-HT transporter inhibitor, escitalopram, and the 5-HT partial agonist reuptake inhibitor, vortioxetine, on astroglial L-glutamate release through activated hemichannels, and the expression of connexin43 (Cx43), type 1A (5-HT1AR) and type 7 (5-HT7R) 5-HT receptor subtypes, and extracellular signal-regulated kinase (ERK) in astrocytes using primary cultured rat cortical astrocytes in a 5-HT-free environment. Both escitalopram and 5-HT1AR antagonist (WAY100635) did not affect basal astroglial L-glutamate release or L-glutamate release through activated hemichannels. Subchronic (for seven days) administrations of vortioxetine and the 5-HT7R inverse agonist (SB269970) suppressed both basal L-glutamate release and L-glutamate release through activated hemichannels, whereas 5-HT1AR agonist (BP554) inhibited L-glutamate release through activated hemichannels, but did not affect basal L-glutamate release. In particular, WAY100635 did not affect the inhibitory effects of vortioxetine on L-glutamate release. Subchronic administration of vortioxetine, BP554 and SB269970 downregulated 5-HT1AR, 5-HT7R and phosphorylated ERK in the plasma membrane fraction, but escitalopram and WAY100635 did not affect them. Subchronic administration of SB269970 decreased Cx43 expression in the plasma membrane but did not affect the cytosol; however, subchronic administration of BP554 increased Cx43 expression in the cytosol but did not affect the plasma membrane. Subchronic vortioxetine administration increased Cx43 expression in the cytosol and decreased it in the plasma membrane. WAY100635 prevented an increased Cx43 expression in the cytosol induced by vortioxetine without affecting the reduced Cx43 expression in the plasma membrane. These results suggest that 5-HT1AR downregulation probably increases Cx43 synthesis, but 5-HT7R downregulation suppresses Cx43 trafficking to the plasma membrane. These results also suggest that the subchronic administration of therapeutic-relevant concentrations of vortioxetine inhibits both astroglial L-glutamate and Cx43 expression in the plasma membrane via 5-HT7R downregulation but enhances Cx43 synthesis in the cytosol via 5-HT1AR downregulation. This combination of the downregulation of 5-HT1AR, 5-HT7R and Cx43 in the astroglial plasma membrane induced by subchronic vortioxetine administration suggest that astrocytes is possibly involved in the pathophysiology of depression. Full article
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14 pages, 3692 KiB  
Article
Aquaporin-4 Mediates Permanent Brain Alterations in a Mouse Model of Hypoxia-Aged Hydrocephalus
by José Luis Trillo-Contreras, Juan José Toledo-Aral, Javier Villadiego and Miriam Echevarría
Int. J. Mol. Sci. 2021, 22(18), 9745; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189745 - 09 Sep 2021
Cited by 4 | Viewed by 1753
Abstract
Aquaporin-4 (AQP4) is the principal water channel in the brain being expressed in astrocytes and ependymal cells. AQP4 plays an important role in cerebrospinal fluid (CSF) homeostasis, and alterations in its expression have been associated with hydrocephalus. AQP4 contributes to the development of [...] Read more.
Aquaporin-4 (AQP4) is the principal water channel in the brain being expressed in astrocytes and ependymal cells. AQP4 plays an important role in cerebrospinal fluid (CSF) homeostasis, and alterations in its expression have been associated with hydrocephalus. AQP4 contributes to the development of hydrocephalus by hypoxia in aged mice, reproducing such principal characteristics of the disease. Here, we explore whether these alterations associated with the hydrocephalic state are permanent or can be reverted by reexposure to normoxia. Alterations such as ventriculomegaly, elevated intracranial pressure, and cognitive deficits were reversed, whereas deficits in CSF outflow and ventricular distensibility were not recovered, remaining impaired even one month after reestablishment of normoxia. Interestingly, in AQP4−/− mice, the impairment in CSF drainage and ventricular distensibility was completely reverted by re-normoxia, indicating that AQP4 has a structural role in the chronification of those alterations. Finally, we show that aged mice subjected to two hypoxic episodes experience permanent ventriculomegaly. These data reveal that repetitive hypoxic events in aged cerebral tissue promote the permanent alterations involved in hydrocephalic pathophysiology, which are dependent on AQP4 expression. Full article
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19 pages, 3106 KiB  
Article
Effects on Metabolism in Astrocytes Caused by cGAMP, Which Imitates the Initial Stage of Brain Metastasis
by Toya Okawa, Kurumi Hara, Momoko Goto, Moe Kikuchi, Masataka Kogane, Hiroto Hatakeyama, Hiroki Tanaka, Daiki Shirane, Hidetaka Akita, Akihiro Hisaka and Hiromi Sato
Int. J. Mol. Sci. 2021, 22(16), 9028; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22169028 - 21 Aug 2021
Viewed by 2273
Abstract
The second messenger 2′3′-cyclic-GMP-AMP (cGAMP) is thought to be transmitted from brain carcinomas to astrocytes via gap junctions, which functions to promote metastasis in the brain parenchyma. In the current study, we established a method to introduce cGAMP into astrocytes, which simulates the [...] Read more.
The second messenger 2′3′-cyclic-GMP-AMP (cGAMP) is thought to be transmitted from brain carcinomas to astrocytes via gap junctions, which functions to promote metastasis in the brain parenchyma. In the current study, we established a method to introduce cGAMP into astrocytes, which simulates the state of astrocytes that have been invaded by cGAMP around tumors. Astrocytes incorporating cGAMP were analyzed by metabolomics, which demonstrated that cGAMP increased glutamate production and astrocyte secretion. The same trend was observed for γ-aminobutyric acid (GABA). Conversely, glutamine production and secretion were decreased by cGAMP treatment. Due to the fundamental role of astrocytes in regulation of the glutamine–glutamate cycle, such metabolic changes may represent a potential mechanism and therapeutic target for alteration of the central nervous system (CNS) environment and the malignant transformation of brain carcinomas. Full article
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15 pages, 3687 KiB  
Article
JI017 Attenuates Oxaliplatin-Induced Cold Allodynia via Spinal TRPV1 and Astrocytes Inhibition in Mice
by Ji Hwan Lee, Hyunseung Ji, Seong-Gyu Ko and Woojin Kim
Int. J. Mol. Sci. 2021, 22(16), 8811; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168811 - 16 Aug 2021
Cited by 13 | Viewed by 2616
Abstract
Oxaliplatin, a well-known chemotherapeutic agent, can induce severe neuropathic pain, which can seriously decrease the quality of life of patients. JI017 is an herb mixture composed of Aconitum carmichaelii, Angelica gigas, and Zingiber officinale. Its anti-tumor effect has been reported; [...] Read more.
Oxaliplatin, a well-known chemotherapeutic agent, can induce severe neuropathic pain, which can seriously decrease the quality of life of patients. JI017 is an herb mixture composed of Aconitum carmichaelii, Angelica gigas, and Zingiber officinale. Its anti-tumor effect has been reported; however, the efficacy of JI017 against oxaliplatin-induced allodynia has never been explored. Single oxaliplatin injection [6 mg/kg, intraperitoneal, (i.p.)] induced both cold and mechanical allodynia, and oral administration of JI017 (500 mg/kg) alleviated cold but not mechanical allodynia in mice. Real-time polymerase chain reaction (PCR) analysis demonstrated that the upregulation of mRNA of spinal transient receptor potential vanilloid 1 (TRPV1) and astrocytes following oxaliplatin injection was downregulated after JI017 treatment. Moreover, TRPV1 expression and the activation of astrocytes were intensely increased in the superficial area of the spinal dorsal horn after oxaliplatin treatment, whereas JI017 suppressed both. The administration of TRPV1 antagonist [capsazepine, intrathecal (i.t.), 10 μg] attenuated the activation of astrocytes in the dorsal horn, demonstrating that the functions of spinal TRPV1 and astrocytes are closely related in oxaliplatin-induced neuropathic pain. Altogether, these results suggest that JI017 may be a potent candidate for the management of oxaliplatin-induced neuropathy as it decreases pain, spinal TRPV1, and astrocyte activation. Full article
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11 pages, 7187 KiB  
Article
Protective Effect of Memantine on Bergmann Glia and Purkinje Cells Morphology in Optogenetic Model of Neurodegeneration in Mice
by Anton N. Shuvaev, Olga S. Belozor, Oleg I. Mozhei, Elena D. Khilazheva, Andrey N. Shuvaev, Yana V. Fritsler and S. Kasparov
Int. J. Mol. Sci. 2021, 22(15), 7822; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157822 - 22 Jul 2021
Cited by 3 | Viewed by 2331
Abstract
Spinocerebellar ataxias are a family of fatal inherited diseases affecting the brain. Although specific mutated proteins are different, they may have a common pathogenetic mechanism, such as insufficient glutamate clearance. This function fails in reactive glia, leading to excitotoxicity and overactivation of NMDA [...] Read more.
Spinocerebellar ataxias are a family of fatal inherited diseases affecting the brain. Although specific mutated proteins are different, they may have a common pathogenetic mechanism, such as insufficient glutamate clearance. This function fails in reactive glia, leading to excitotoxicity and overactivation of NMDA receptors. Therefore, NMDA receptor blockers could be considered for the management of excitotoxicity. One such drug, memantine, currently used for the treatment of Alzheimer’s disease, could potentially be used for the treatment of other forms of neurodegeneration, for example, spinocerebellar ataxias (SCA). We previously demonstrated close parallels between optogenetically induced cerebellar degeneration and SCA1. Here we induced reactive transformation of cerebellar Bergmann glia (BG) using this novel optogenetic approach and tested whether memantine could counteract changes in BG and Purkinje cell (PC) morphology and expression of the main glial glutamate transporter—excitatory amino acid transporter 1 (EAAT1). Reactive BG induced by chronic optogenetic stimulation presented increased GFAP immunoreactivity, increased thickness and decreased length of its processes. Oral memantine (~90 mg/kg/day for 4 days) prevented thickening of the processes (1.57 to 1.81 vs. 1.62 μm) and strongly antagonized light-induced reduction in their average length (186.0 to 150.8 vs. 171.9 μm). Memantine also prevented the loss of the key glial glutamate transporter EAAT1 on BG. Finally, memantine reduced the loss of PC (4.2 ± 0.2 to 3.2 ± 0.2 vs. 4.1 ± 0.3 cells per 100 μm of the PC layer). These results identify memantine as potential neuroprotective therapeutics for cerebellar ataxias. Full article
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19 pages, 6856 KiB  
Article
Mapping Astrocyte Transcriptional Signatures in Response to Neuroactive Compounds
by Debosmita Sardar, Brittney Lozzi, Junsung Woo, Teng-Wei Huang, Caroline Cvetkovic, Chad J. Creighton, Robert Krencik and Benjamin Deneen
Int. J. Mol. Sci. 2021, 22(8), 3975; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083975 - 12 Apr 2021
Cited by 8 | Viewed by 3739
Abstract
Astrocytes play central roles in normal brain function and are critical components of synaptic networks that oversee behavioral outputs. Despite their close affiliation with neurons, how neuronal-derived signals influence astrocyte function at the gene expression level remains poorly characterized, largely due to difficulties [...] Read more.
Astrocytes play central roles in normal brain function and are critical components of synaptic networks that oversee behavioral outputs. Despite their close affiliation with neurons, how neuronal-derived signals influence astrocyte function at the gene expression level remains poorly characterized, largely due to difficulties associated with dissecting neuron- versus astrocyte-specific effects. Here, we use an in vitro system of stem cell-derived astrocytes to identify gene expression profiles in astrocytes that are influenced by neurons and regulate astrocyte development. Furthermore, we show that neurotransmitters and neuromodulators induce distinct transcriptomic and chromatin accessibility changes in astrocytes that are unique to each of these neuroactive compounds. These findings are highlighted by the observation that noradrenaline has a more profound effect on transcriptional profiles of astrocytes compared to glutamate, gamma-aminobutyric acid (GABA), acetylcholine, and serotonin. This is demonstrated through enhanced noradrenaline-induced transcriptomic and chromatin accessibility changes in vitro and through enhanced calcium signaling in vivo. Taken together, our study reveals distinct transcriptomic and chromatin architecture signatures in astrocytes in response to neuronal-derived neuroactive compounds. Since astrocyte function is affected in all neurological disorders, this study provides a new entry point for exploring genetic mechanisms of astrocyte–neuron communication that may be dysregulated in disease. Full article
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Review

Jump to: Research

10 pages, 14465 KiB  
Review
Abnormal Ca2+ Signals in Reactive Astrocytes as a Common Cause of Brain Diseases
by Schuichi Koizumi, Eiji Shigetomi, Fumikazu Sano, Kozo Saito, Sun Kwang Kim and Junichi Nabekura
Int. J. Mol. Sci. 2022, 23(1), 149; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010149 - 23 Dec 2021
Cited by 5 | Viewed by 2809
Abstract
In pathological brain conditions, glial cells become reactive and show a variety of responses. We examined Ca2+ signals in pathological brains and found that reactive astrocytes share abnormal Ca2+ signals, even in different types of diseases. In a neuropathic pain model, [...] Read more.
In pathological brain conditions, glial cells become reactive and show a variety of responses. We examined Ca2+ signals in pathological brains and found that reactive astrocytes share abnormal Ca2+ signals, even in different types of diseases. In a neuropathic pain model, astrocytes in the primary sensory cortex became reactive and showed frequent Ca2+ signals, resulting in the production of synaptogenic molecules, which led to misconnections of tactile and pain networks in the sensory cortex, thus causing neuropathic pain. In an epileptogenic model, hippocampal astrocytes also became reactive and showed frequent Ca2+ signals. In an Alexander disease (AxD) model, hGFAP-R239H knock-in mice showed accumulation of Rosenthal fibers, a typical pathological marker of AxD, and excessively large Ca2+ signals. Because the abnormal astrocytic Ca2+ signals observed in the above three disease models are dependent on type II inositol 1,4,5-trisphosphate receptors (IP3RII), we reanalyzed these pathological events using IP3RII-deficient mice and found that all abnormal Ca2+ signals and pathologies were markedly reduced. These findings indicate that abnormal Ca2+ signaling is not only a consequence but may also be greatly involved in the cause of these diseases. Abnormal Ca2+ signals in reactive astrocytes may represent an underlying pathology common to multiple diseases. Full article
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20 pages, 3415 KiB  
Review
Astroglia in Autism Spectrum Disorder
by Kinga Gzielo and Agnieszka Nikiforuk
Int. J. Mol. Sci. 2021, 22(21), 11544; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111544 - 26 Oct 2021
Cited by 13 | Viewed by 4517
Abstract
Autism spectrum disorder (ASD) is an umbrella term encompassing several neurodevelopmental disorders such as Asperger syndrome or autism. It is characterised by the occurrence of distinct deficits in social behaviour and communication and repetitive patterns of behaviour. The symptoms may be of different [...] Read more.
Autism spectrum disorder (ASD) is an umbrella term encompassing several neurodevelopmental disorders such as Asperger syndrome or autism. It is characterised by the occurrence of distinct deficits in social behaviour and communication and repetitive patterns of behaviour. The symptoms may be of different intensity and may vary in types. Risk factors for ASD include disturbed brain homeostasis, genetic predispositions, or inflammation during the prenatal period caused by viruses or bacteria. The number of diagnosed cases is growing, but the main cause and mechanism leading to ASD is still uncertain. Recent findings from animal models and human cases highlight the contribution of glia to the ASD pathophysiology. It is known that glia cells are not only “gluing” neurons together but are key players participating in different processes crucial for proper brain functioning, including neurogenesis, synaptogenesis, inflammation, myelination, proper glutamate processing and many others. Despite the prerequisites for the involvement of glia in the processes related to the onset of autism, there are far too little data regarding the engagement of these cells in the development of ASD. Full article
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12 pages, 1063 KiB  
Review
Extracellular Vesicles Taken up by Astrocytes
by Ari Ogaki, Yuji Ikegaya and Ryuta Koyama
Int. J. Mol. Sci. 2021, 22(19), 10553; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910553 - 29 Sep 2021
Cited by 8 | Viewed by 2837
Abstract
Extracellular vesicles (EVs) are composed of lipid bilayer membranes and contain various molecules, such as mRNA and microRNA (miRNA), that regulate the functions of the recipient cell. Recent studies have reported the importance of EV-mediated intercellular communication in the brain. The brain contains [...] Read more.
Extracellular vesicles (EVs) are composed of lipid bilayer membranes and contain various molecules, such as mRNA and microRNA (miRNA), that regulate the functions of the recipient cell. Recent studies have reported the importance of EV-mediated intercellular communication in the brain. The brain contains several types of cells, including neurons and glial cells. Among them, astrocytes are the most abundant glial cells in the mammalian brain and play a wide range of roles, from structural maintenance of the brain to regulation of neurotransmission. Furthermore, since astrocytes can take up EVs, it is possible that EVs originating from inside and outside the brain affect astrocyte function, which in turn affects brain function. However, it has not been fully clarified whether the specific targeting mechanism of EVs to astrocytes as recipient cells exists. In recent years, EVs have attracted attention as a cell-targeted therapeutic approach in various organs, and elucidation of the targeting mechanism of EVs to astrocytes may pave the way for new therapies for brain diseases. In this review, we focus on EVs in the brain that affect astrocyte function and discuss the targeting mechanism of EVs to astrocytes. Full article
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22 pages, 1896 KiB  
Review
Potential of Multiscale Astrocyte Imaging for Revealing Mechanisms Underlying Neurodevelopmental Disorders
by Takuma Kumamoto and Tomokazu Tsurugizawa
Int. J. Mol. Sci. 2021, 22(19), 10312; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910312 - 24 Sep 2021
Cited by 7 | Viewed by 3119
Abstract
Astrocytes provide trophic and metabolic support to neurons and modulate circuit formation during development. In addition, astrocytes help maintain neuronal homeostasis through neurovascular coupling, blood–brain barrier maintenance, clearance of metabolites and nonfunctional proteins via the glymphatic system, extracellular potassium buffering, and regulation of [...] Read more.
Astrocytes provide trophic and metabolic support to neurons and modulate circuit formation during development. In addition, astrocytes help maintain neuronal homeostasis through neurovascular coupling, blood–brain barrier maintenance, clearance of metabolites and nonfunctional proteins via the glymphatic system, extracellular potassium buffering, and regulation of synaptic activity. Thus, astrocyte dysfunction may contribute to a myriad of neurological disorders. Indeed, astrocyte dysfunction during development has been implicated in Rett disease, Alexander’s disease, epilepsy, and autism, among other disorders. Numerous disease model mice have been established to investigate these diseases, but important preclinical findings on etiology and pathophysiology have not translated into clinical interventions. A multidisciplinary approach is required to elucidate the mechanism of these diseases because astrocyte dysfunction can result in altered neuronal connectivity, morphology, and activity. Recent progress in neuroimaging techniques has enabled noninvasive investigations of brain structure and function at multiple spatiotemporal scales, and these technologies are expected to facilitate the translation of preclinical findings to clinical studies and ultimately to clinical trials. Here, we review recent progress on astrocyte contributions to neurodevelopmental and neuropsychiatric disorders revealed using novel imaging techniques, from microscopy scale to mesoscopic scale. Full article
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17 pages, 2380 KiB  
Review
Emerging Roles of Astrocyte Kir4.1 Channels in the Pathogenesis and Treatment of Brain Diseases
by Yukihiro Ohno, Naofumi Kunisawa and Saki Shimizu
Int. J. Mol. Sci. 2021, 22(19), 10236; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910236 - 23 Sep 2021
Cited by 18 | Viewed by 3897
Abstract
Inwardly rectifying Kir4.1 channels in astrocytes mediate spatial potassium (K+) buffering, a clearance mechanism for excessive extracellular K+, in tripartite synapses. In addition to K+ homeostasis, astrocytic Kir4.1 channels also play an essential role in regulating extracellular glutamate [...] Read more.
Inwardly rectifying Kir4.1 channels in astrocytes mediate spatial potassium (K+) buffering, a clearance mechanism for excessive extracellular K+, in tripartite synapses. In addition to K+ homeostasis, astrocytic Kir4.1 channels also play an essential role in regulating extracellular glutamate levels via coupling with glutamate transporters. Moreover, Kir4.1 channels act as novel modulators of the expression of brain-derived neurotrophic factor (BDNF) in astrocytes. Specifically, inhibition of astrocytic Kir4.1 channels elevates extracellular K+ and glutamate levels at synapses and facilitates BDNF expression in astrocytes. These changes elevate neural excitability, which may facilitate synaptic plasticity and connectivity. In this article, we summarize the functions and pharmacological features of Kir4.1 channels in astrocytes and highlight the importance of these channels in the treatment of brain diseases. Although further validation in animal models and human patients is required, astrocytic Kir4.1 channel could potentially serve as a novel therapeutic target for the treatment of depressive disorders and epilepsy. Full article
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17 pages, 2013 KiB  
Review
Dysregulation of Astrocyte–Neuronal Communication in Alzheimer’s Disease
by Carmen Nanclares, Andres Mateo Baraibar, Alfonso Araque and Paulo Kofuji
Int. J. Mol. Sci. 2021, 22(15), 7887; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157887 - 23 Jul 2021
Cited by 30 | Viewed by 7694
Abstract
Recent studies implicate astrocytes in Alzheimer’s disease (AD); however, their role in pathogenesis is poorly understood. Astrocytes have well-established functions in supportive functions such as extracellular ionic homeostasis, structural support, and neurovascular coupling. However, emerging research on astrocytic function in the healthy brain [...] Read more.
Recent studies implicate astrocytes in Alzheimer’s disease (AD); however, their role in pathogenesis is poorly understood. Astrocytes have well-established functions in supportive functions such as extracellular ionic homeostasis, structural support, and neurovascular coupling. However, emerging research on astrocytic function in the healthy brain also indicates their role in regulating synaptic plasticity and neuronal excitability via the release of neuroactive substances named gliotransmitters. Here, we review how this “active” role of astrocytes at synapses could contribute to synaptic and neuronal network dysfunction and cognitive impairment in AD. Full article
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17 pages, 5135 KiB  
Review
Neuroprotective Function of High Glycolytic Activity in Astrocytes: Common Roles in Stroke and Neurodegenerative Diseases
by Shinichi Takahashi
Int. J. Mol. Sci. 2021, 22(12), 6568; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126568 - 18 Jun 2021
Cited by 37 | Viewed by 4874
Abstract
Astrocytes (also, astroglia) consume huge amounts of glucose and produce lactate regardless of sufficient oxygen availability, indicating a high capacity for aerobic glycolysis. Glycolysis in astrocytes is activated in accordance with neuronal excitation and leads to increases in the release of lactate from [...] Read more.
Astrocytes (also, astroglia) consume huge amounts of glucose and produce lactate regardless of sufficient oxygen availability, indicating a high capacity for aerobic glycolysis. Glycolysis in astrocytes is activated in accordance with neuronal excitation and leads to increases in the release of lactate from astrocytes. Although the fate of this lactate remains somewhat controversial, it is believed to fuel neurons as an energy substrate. Besides providing lactate, astrocytic glycolysis plays an important role in neuroprotection. Among the minor pathways of glucose metabolism, glucose flux to the pentose-phosphate pathway (PPP), a major shunt pathway of glycolysis, is attracting research interest. In fact, PPP activity in astrocytes is five to seven times higher than that in neurons. The astrocytic PPP plays a key role in protecting neurons against oxidative stress by providing neurons with a reduced form of glutathione, which is necessary to eliminate reactive oxygen species. Therefore, enhancing astrocytic glycolysis might promote neuronal protection during acute ischemic stroke. Contrariwise, the dysfunction of astrocytic glycolysis and the PPP have been implicated in the pathogenesis of various neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis, since mitochondrial dysfunction and oxidative stress trigger and accelerate disease progression. Full article
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17 pages, 1185 KiB  
Review
Pathophysiological Responses and Roles of Astrocytes in Traumatic Brain Injury
by Shotaro Michinaga and Yutaka Koyama
Int. J. Mol. Sci. 2021, 22(12), 6418; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126418 - 15 Jun 2021
Cited by 55 | Viewed by 5209
Abstract
Traumatic brain injury (TBI) is immediate damage caused by a blow to the head resulting from traffic accidents, falls, and sporting activity, which causes death or serious disabilities in survivors. TBI induces multiple secondary injuries, including neuroinflammation, disruption of the blood–brain barrier (BBB), [...] Read more.
Traumatic brain injury (TBI) is immediate damage caused by a blow to the head resulting from traffic accidents, falls, and sporting activity, which causes death or serious disabilities in survivors. TBI induces multiple secondary injuries, including neuroinflammation, disruption of the blood–brain barrier (BBB), and brain edema. Despite these emergent conditions, current therapies for TBI are limited or insufficient in some cases. Although several candidate drugs exerted beneficial effects in TBI animal models, most of them failed to show significant effects in clinical trials. Multiple studies have suggested that astrocytes play a key role in the pathogenesis of TBI. Increased reactive astrocytes and astrocyte-derived factors are commonly observed in both TBI patients and experimental animal models. Astrocytes have beneficial and detrimental effects on TBI, including promotion and restriction of neurogenesis and synaptogenesis, acceleration and suppression of neuroinflammation, and disruption and repair of the BBB via multiple bioactive factors. Additionally, astrocytic aquaporin-4 is involved in the formation of cytotoxic edema. Thus, astrocytes are attractive targets for novel therapeutic drugs for TBI, although astrocyte-targeting drugs have not yet been developed. This article reviews recent observations of the roles of astrocytes and expected astrocyte-targeting drugs in TBI. Full article
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25 pages, 2963 KiB  
Review
Dysregulation of Astrocyte Ion Homeostasis and Its Relevance for Stroke-Induced Brain Damage
by Michel J. A. M. van Putten, Christoph Fahlke, Karl W. Kafitz, Jeannette Hofmeijer and Christine R. Rose
Int. J. Mol. Sci. 2021, 22(11), 5679; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115679 - 26 May 2021
Cited by 22 | Viewed by 3890
Abstract
Ischemic stroke is a leading cause of mortality and chronic disability. Either recovery or progression towards irreversible failure of neurons and astrocytes occurs within minutes to days, depending on remaining perfusion levels. Initial damage arises from energy depletion resulting in a failure to [...] Read more.
Ischemic stroke is a leading cause of mortality and chronic disability. Either recovery or progression towards irreversible failure of neurons and astrocytes occurs within minutes to days, depending on remaining perfusion levels. Initial damage arises from energy depletion resulting in a failure to maintain homeostasis and ion gradients between extra- and intracellular spaces. Astrocytes play a key role in these processes and are thus central players in the dynamics towards recovery or progression of stroke-induced brain damage. Here, we present a synopsis of the pivotal functions of astrocytes at the tripartite synapse, which form the basis of physiological brain functioning. We summarize the evidence of astrocytic failure and its consequences under ischemic conditions. Special emphasis is put on the homeostasis and stroke-induced dysregulation of the major monovalent ions, namely Na+, K+, H+, and Cl-, and their involvement in maintenance of cellular volume and generation of cerebral edema. Full article
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19 pages, 1197 KiB  
Review
Not Just a Bystander: The Emerging Role of Astrocytes and Research Tools in Studying Cognitive Dysfunctions in Schizophrenia
by Chia-Yuan Chang, Da-Zhong Luo, Ju-Chun Pei, Ming-Che Kuo, Yi-Chen Hsieh and Wen-Sung Lai
Int. J. Mol. Sci. 2021, 22(10), 5343; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105343 - 19 May 2021
Cited by 14 | Viewed by 4177
Abstract
Cognitive dysfunction is one of the core symptoms in schizophrenia, and it is predictive of functional outcomes and therefore useful for treatment targets. Rather than improving cognitive deficits, currently available antipsychotics mainly focus on positive symptoms, targeting dopaminergic/serotoninergic neurons and receptors in the [...] Read more.
Cognitive dysfunction is one of the core symptoms in schizophrenia, and it is predictive of functional outcomes and therefore useful for treatment targets. Rather than improving cognitive deficits, currently available antipsychotics mainly focus on positive symptoms, targeting dopaminergic/serotoninergic neurons and receptors in the brain. Apart from investigating the neural mechanisms underlying schizophrenia, emerging evidence indicates the importance of glial cells in brain structure development and their involvement in cognitive functions. Although the etiopathology of astrocytes in schizophrenia remains unclear, accumulated evidence reveals that alterations in gene expression and astrocyte products have been reported in schizophrenic patients. To further investigate the role of astrocytes in schizophrenia, we highlighted recent progress in the investigation of the effect of astrocytes on abnormalities in glutamate transmission and impairments in the blood–brain barrier. Recent advances in animal models and behavioral methods were introduced to examine schizophrenia-related cognitive deficits and negative symptoms. We also highlighted several experimental tools that further elucidate the role of astrocytes. Instead of focusing on schizophrenia as a neuron-specific disorder, an additional astrocytic perspective provides novel and promising insight into its causal mechanisms and treatment. The involvement of astrocytes in the pathogenesis of schizophrenia and other brain disorders is worth further investigation. Full article
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