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Cells
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Glutamatergic Transmission: Role of Astrocytes in Health and Disease
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Glutamatergic Transmission: Role of Astrocytes in Health and Disease

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 (30 June 2022) | Viewed by 23928

Special Issue Editors

Dr. Bashayer Al Mubarak

E-Mail Website
Guest Editor
Center for Genomic Medicine (CGM), King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia
Interests: molecular pathology; neurodegeneration; neurodevelopment; neuroscience; cancer genetics
Special Issues, Collections and Topics in MDPI journals
Dr. Jing Qiu

E-Mail Website
Guest Editor
Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK
Interests: neurons; pluripotent stem cells; microglia; mitochondria calcium

Special Issue Information

Dear Colleagues,

Historically glial cells were viewed as simply part of the support system for neurons providing nourishment, protection and structural framework. However, accumulating studies over the past 25 years or more have demonstrated that glia play a myriad of active roles beyond their housekeeping duties. For instance, regulation of nervous system development, synaptic activity and plasticity, as well as response to damage and traumatic injury. While all these functions are essential for maintaining a healthy CNS, emerging evidence is pointing towards a far more dynamic role for glia, specifically astrocytes, at the synapse whereby it assumes the role of a third participant actively engaging in dialogues with pre and post synaptic neurons in the so called “tripartite synapse”. Glutamate is the principle excitatory neurotransmitter in the CNS and like their neuronal partners, glia express a variety of ionotropic and metabotropic glutamate receptors and transporters. The presence of these components not only allow glia to maintain extracellular glutamate at subtoxic levels but also to communicate effectively with neurons and other glial cells and ultimately ensure that functional integrity at the synaptic and circuit level is preserved. Consequently, glial glutamatergic system impairment is a common event in the pathophysiology of a number of chronic and acute neurodegenerative diseases as well as psychiatric illnesses.

In this special issue we aim to focus on the latest advances in the study of the role of glial cells (primarily astrocytes) in regulating glutamate transmission. By covering key components/processes of the glutamatergic system (receptors, plasma membrane and vesicular transporters, downstream signalling and metabolism) we hope to improve our understanding and fill important knowledge gaps such as differences and commonalities
between neurons and glia in the context of;
1) Glutamate receptors composition, properties and response
2) Glutamate triggered intracellular signalling

We are pleased to invite you to submit research articles, reviews and communications covering any aspect of glial regulation of glutamatergic transmission. Looking forward to your contribution.

Dr. Bashayer Al Mubarak
Dr. Jing Qiu
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.

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Published Papers (5 papers)

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Research

Jump to: Review

20 pages, 5164 KiB  
Article
Astrocytes Differentiated from LRRK2-I1371V Parkinson’s-Disease-Induced Pluripotent Stem Cells Exhibit Similar Yield but Cell-Intrinsic Dysfunction in Glutamate Uptake and Metabolism, ATP Generation, and Nrf2-Mediated Glutathione Machinery
by Roon Banerjee, Aishwarya Raj, Chandrakanta Potdar, Pramod Kumar Pal, Ravi Yadav, Nitish Kamble, Vikram Holla and Indrani Datta
Cells 2023, 12(12), 1592; https://doi.org/10.3390/cells12121592 - 8 Jun 2023
Cited by 7 | Viewed by 3769
Abstract
Owing to the presence of multiple enzymatic domains, LRRK2 has been associated with a diverse set of cellular functions and signaling pathways. It also has several pathological mutant-variants, and their incidences show ethnicity biases and drug-response differences with expression in dopaminergic-neurons and astrocytes. [...] Read more.
Owing to the presence of multiple enzymatic domains, LRRK2 has been associated with a diverse set of cellular functions and signaling pathways. It also has several pathological mutant-variants, and their incidences show ethnicity biases and drug-response differences with expression in dopaminergic-neurons and astrocytes. Here, we aimed to assess the cell-intrinsic effect of the LRRK2-I1371V mutant variant, prevalent in East Asian populations, on astrocyte yield and biology, involving Nrf2-mediated glutathione machinery, glutamate uptake and metabolism, and ATP generation in astrocytes derived from LRRK2-I1371V PD patient iPSCs and independently confirmed in LRRK2-I1371V-overexpressed U87 cells. Astrocyte yield (GFAP-immunopositive) was comparable between LRRK2-I1371V and healthy control (HC) populations; however, the astrocytic capability to mitigate oxidative stress in terms of glutathione content was significantly reduced in the mutant astrocytes, along with a reduction in the gene expression of the enzymes involved in glutathione machinery and nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Simultaneously, a significant decrease in glutamate uptake was observed in LRRK2-I1371V astrocytes, with lower gene expression of glutamate transporters SLC1A2 and SLC1A3. The reduction in the protein expression of SLC1A2 was also directly confirmed. Enzymes catalyzing the generation of γ glutamyl cysteine (precursor of glutathione) from glutamate and the metabolism of glutamate to enter the Krebs cycle (α-ketoglutaric acid) were impaired, with significantly lower ATP generation in LRRK2-I1371V astrocytes. De novo glutamine synthesis via the conversion of glutamate to glutamine was also affected, indicating glutamate metabolism disorder. Our data demonstrate for the first time that the mutation in the LRRK2-I1371V allele causes significant astrocytic dysfunction with respect to Nrf2-mediated antioxidant machinery, AT -generation, and glutamate metabolism, even with comparable astrocyte yields. Full article
(This article belongs to the Special Issue Glutamatergic Transmission: Role of Astrocytes in Health and Disease)
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21 pages, 10946 KiB  
Article
Glutamate Prevents Altered Mitochondrial Function Following Recurrent Low Glucose in Hypothalamic but Not Cortical Primary Rat Astrocytes
by Paul G. Weightman Potter, Kate L. J. Ellacott, Andrew D. Randall and Craig Beall
Cells 2022, 11(21), 3422; https://doi.org/10.3390/cells11213422 - 29 Oct 2022
Cited by 1 | Viewed by 2843
Abstract
Astrocytes contribute to glutamatergic signalling, which is required for hypoglycaemia counterregulation and is impaired by recurrent insulin-induced hypoglycaemia. This study examined the glutamate response of astrocytes when challenged with acute and recurrent low glucose (RLG) exposure. The metabolic responses of cortical (CRTAS) and [...] Read more.
Astrocytes contribute to glutamatergic signalling, which is required for hypoglycaemia counterregulation and is impaired by recurrent insulin-induced hypoglycaemia. This study examined the glutamate response of astrocytes when challenged with acute and recurrent low glucose (RLG) exposure. The metabolic responses of cortical (CRTAS) and hypothalamic (HTAS) primary rat astrocytes were measured in acute and recurrent low glucose using extracellular flux analyses. RLG caused mitochondrial adaptations in both HTAS and CRTAS, many of which were attenuated by glutamate exposure during low glucose (LG) treatments. We observed an increase in capacity of HTAS to metabolise glutamine after RLG exposure. Demonstrating astrocytic heterogeneity in the response to LG, CRTAS increased cellular acidification, a marker of glycolysis in LG, whereas this decreased in HTAS. The directional change in intracellular Ca2+ levels of each cell type, correlated with the change in extracellular acidification rate (ECAR) during LG. Further examination of glutamate-induced Ca2+ responses in low glucose treated CRTAS and HTAS identified sub-populations of glucose-excited- and glucose-inhibited-like cells with differing responses to glutamate. Lastly, release of the gliotransmitter ATP by HTAS was elevated by RLG, both with and without concurrent glutamate exposure. Therefore, hypothalamic astrocytes adapt to RLG by increasing glutamate uptake and oxidation in a manner that prevents RLG-induced mitochondrial adaptations. Full article
(This article belongs to the Special Issue Glutamatergic Transmission: Role of Astrocytes in Health and Disease)
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18 pages, 2625 KiB  
Article
AMPK Modulates the Metabolic Adaptation of C6 Glioma Cells in Glucose-Deprived Conditions without Affecting Glutamate Transport
by Inês Belo do Nascimento, Marie Verfaillie, Gamze Ates, Pauline Beckers, Virginie Joris, Nathalie Desmet, Ann Massie and Emmanuel Hermans
Cells 2022, 11(11), 1800; https://doi.org/10.3390/cells11111800 - 31 May 2022
Cited by 4 | Viewed by 2546
Abstract
Energy homeostasis in the central nervous system largely depends on astrocytes, which provide metabolic support and protection to neurons. Astrocytes also ensure the clearance of extracellular glutamate through high-affinity transporters, which indirectly consume ATP. Considering the role of the AMP-activated protein kinase (AMPK) [...] Read more.
Energy homeostasis in the central nervous system largely depends on astrocytes, which provide metabolic support and protection to neurons. Astrocytes also ensure the clearance of extracellular glutamate through high-affinity transporters, which indirectly consume ATP. Considering the role of the AMP-activated protein kinase (AMPK) in the control of cell metabolism, we have examined its implication in the adaptation of astrocyte functions in response to a metabolic stress triggered by glucose deprivation. We genetically modified the astrocyte-like C6 cell line to silence AMPK activity by overexpressing a dominant negative mutant of its catalytic subunit. Upon glucose deprivation, we found that C6 cells maintain stable ATP levels and glutamate uptake capacity, highlighting their resilience during metabolic stress. In the same conditions, cells with silenced AMPK activity showed a reduction in motility, metabolic activity, and ATP levels, indicating that their adaptation to stress is compromised. The rate of ATP production remained, however, unchanged by AMPK silencing, suggesting that AMPK mostly influences energy consumption during stress conditions in these cells. Neither AMPK modulation nor prolonged glucose deprivation impaired glutamate uptake. Together, these results indicate that AMPK contributes to the adaptation of astrocyte metabolism triggered by metabolic stress, but not to the regulation of glutamate transport. Full article
(This article belongs to the Special Issue Glutamatergic Transmission: Role of Astrocytes in Health and Disease)
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Review

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10 pages, 1189 KiB  
Review
Glutamate Signaling and Filopodiagenesis of Astrocytoma Cells in Brain Cancers: Survey and Questions
by Mitra Tabatabaee and Frederic Menard
Cells 2022, 11(17), 2657; https://doi.org/10.3390/cells11172657 - 26 Aug 2022
Cited by 3 | Viewed by 3226
Abstract
Astrocytes are non-excitable cells in the CNS that can cause life-threatening astrocytoma tumors when they transform to cancerous cells. Perturbed homeostasis of the neurotransmitter glutamate is associated with astrocytoma tumor onset and progression, but the factors that govern this phenomenon are less known. [...] Read more.
Astrocytes are non-excitable cells in the CNS that can cause life-threatening astrocytoma tumors when they transform to cancerous cells. Perturbed homeostasis of the neurotransmitter glutamate is associated with astrocytoma tumor onset and progression, but the factors that govern this phenomenon are less known. Herein, we review possible mechanisms by which glutamate may act in facilitating the growth of projections in astrocytic cells. This review discusses the similarities and differences between the morphology of astrocytes and astrocytoma cells, and the role that dysregulation in glutamate and calcium signaling plays in the aberrant morphology of astrocytoma cells. Converging reports suggest that ionotropic glutamate receptors and voltage-gated calcium channels expressed in astrocytes may be responsible for the abnormal filopodiagenesis or process extension leading to astrocytoma cells’ infiltration throughout the brain. Full article
(This article belongs to the Special Issue Glutamatergic Transmission: Role of Astrocytes in Health and Disease)
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26 pages, 14241 KiB  
Review
Astrocytic Glutamatergic Transmission and Its Implications in Neurodegenerative Disorders
by Sairaj Satarker, Sree Lalitha Bojja, Prasada Chowdari Gurram, Jayesh Mudgal, Devinder Arora and Madhavan Nampoothiri
Cells 2022, 11(7), 1139; https://doi.org/10.3390/cells11071139 - 28 Mar 2022
Cited by 49 | Viewed by 10703
Abstract
Several neurodegenerative disorders involve impaired neurotransmission, and glutamatergic neurotransmission sets a prototypical example. Glutamate is a predominant excitatory neurotransmitter where the astrocytes play a pivotal role in maintaining the extracellular levels through release and uptake mechanisms. Astrocytes modulate calcium-mediated excitability and release several [...] Read more.
Several neurodegenerative disorders involve impaired neurotransmission, and glutamatergic neurotransmission sets a prototypical example. Glutamate is a predominant excitatory neurotransmitter where the astrocytes play a pivotal role in maintaining the extracellular levels through release and uptake mechanisms. Astrocytes modulate calcium-mediated excitability and release several neurotransmitters and neuromodulators, including glutamate, and significantly modulate neurotransmission. Accumulating evidence supports the concept of excitotoxicity caused by astrocytic glutamatergic release in pathological conditions. Thus, the current review highlights different vesicular and non-vesicular mechanisms of astrocytic glutamate release and their implication in neurodegenerative diseases. As in presynaptic neurons, the vesicular release of astrocytic glutamate is also primarily meditated by calcium-mediated exocytosis. V-ATPase is crucial in the acidification and maintenance of the gradient that facilitates the vesicular storage of glutamate. Along with these, several other components, such as cystine/glutamate antiporter, hemichannels, BEST-1, TREK-1, purinergic receptors and so forth, also contribute to glutamate release under physiological and pathological conditions. Events of hampered glutamate uptake could promote inflamed astrocytes to trigger repetitive release of glutamate. This could be favorable towards the development and worsening of neurodegenerative diseases. Therefore, across neurodegenerative diseases, we review the relations between defective glutamatergic signaling and astrocytic vesicular and non-vesicular events in glutamate homeostasis. The optimum regulation of astrocytic glutamatergic transmission could pave the way for the management of these diseases and add to their therapeutic value. Full article
(This article belongs to the Special Issue Glutamatergic Transmission: Role of Astrocytes in Health and Disease)
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