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The Multifaceted Roles of Glia: From Cellular Functions to Neurological Implications

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A special issue of Neuroglia (ISSN 2571-6980).

Deadline for manuscript submissions: closed (31 July 2025) | Viewed by 18551

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Dr. Penha Barradas

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Departament of Pharmacology and Psychobiology, Roberto Alcantara Gomes Biology Institute (IBRAG), Rio de Janeiro State University (UERJ), Rio de Janeiro 20551-030, Brazil
Interests: developmental neurobiology; glial cell differentiation; hypoxia–ischemia in neurodevelopment
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Dear Colleagues,

We are excited to announce a Special Issue titled "The Multifaceted Roles of Glia: From Cellular Functions to Neurological Implications". This Special Issue aims to explore the diverse and critical functions of glial cells in the central nervous system, highlighting their roles not only in supporting neuronal health but also in modulating synaptic activity, neuroinflammation, and neurodegeneration. As researchers in the field, we invite you to contribute your findings that delve into the complex interactions between glia and neurons, the implications of glial dysfunction in various neurological disorders, and innovative therapeutic approaches targeting glial cells. Your work can help illuminate the intricate network of cellular communications that underpin brain function and disease. Join us in advancing our understanding of glial biology and its significance in neuroscience. We look forward to your submissions that will enrich this essential dialogue in our field.

Dr. Penha Barradas
Guest Editor

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 250 words) can be sent to the Editorial Office for assessment.

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. Neuroglia is an international peer-reviewed open access quarterly 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 1000 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.

Keywords

microglia
astroglia
oligodendroglia
neuroinflammation
glial roles in neurodevelopment
glial dysfunction

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Related Special Issue

The Multifaceted Roles of Glia: From Cellular Functions to Neurological Implications, 2nd Edition in Neuroglia (1 article)

Published Papers (8 papers)

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Research

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21 pages, 5560 KB

Open AccessArticle

Astrocyte FABP7 Modulates Seizure Activity-Dependent Protein Expression in Mouse Brain

by Adam P. Berg, Shahroz H. Tariq, Carlos C. Flores, Micah Lefton, Yuji Owada, Christopher J. Davis, Thomas N. Ferraro, Jon M. Jacobs, Marina A. Gritsenko, Yool Lee, Wheaton L. Schroeder and Jason R. Gerstner

Neuroglia 2025, 6(3), 33; https://doi.org/10.3390/neuroglia6030033 - 3 Sep 2025

Viewed by 1267

Abstract

Background/Objectives: Patients with epilepsy commonly experience patterns of seizures that change with sleep/wake behavior or diurnal rhythms. The cellular and molecular mechanisms that underlie these patterns in seizure activity are not well understood but may involve non-neuronal cells, such as astrocytes. Our previous studies show the critical importance of one specific astrocyte factor, the brain-type fatty acid binding protein Fabp7, in the regulation of time-of-day-dependent electroshock seizure threshold and neural activity-dependent gene expression in mice. Here, we examined whether Fabp7 influences differential seizure activity-dependent protein expression, by comparing Fabp7 knockout (KO) to wild-type (WT) mice under control conditions and after reaching the maximal electroshock seizure threshold (MEST). Methods: We analyzed the proteome in cortical–hippocampal extracts from MEST and SHAM groups of WT and KO mice using mass spectrometry (MS), followed by Gene Ontology (GO) and pathway analyses. GO and pathway analyses of all groups revealed a diverse set of up- and downregulated differentially expressed proteins (DEPs). Results: We identified 65 significant DEPs in the comparison of KO SHAM versus WT SHAM; 33 proteins were upregulated and 32 were downregulated. We found downregulation in mitochondrial-associated proteins in WT MEST compared to WT SHAM controls, including Slc1a4, Slc25a27, Cox7a2, Cox8a, Micos10, and Atp5mk. Several upregulated DEPs in the KO SHAM versus WT SHAM comparison were associated with the 20S proteasomal subunit, suggesting proteasomal activity is elevated in the absence of Fabp7 expression. We also observed 92 DEPs significantly altered in the KO MEST versus WT MEST, with 49 proteins upregulated and 43 downregulated. Conclusions: Together, these data suggest that the astrocyte Fabp7 regulation of time-of-day-mediated neural excitability is modulated by multiple cellular mechanisms, which include proteasomal pathways, independent of its role in activity-dependent gene expression. Full article

(This article belongs to the Special Issue The Multifaceted Roles of Glia: From Cellular Functions to Neurological Implications)

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Review

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29 pages, 4385 KB

Open AccessReview

The Dual Role of Astrocytes in CNS Homeostasis and Dysfunction

by Aarti Tiwari, Satyabrata Rout, Prasanjit Deep, Chandan Sahu and Pradeep Kumar Samal

Neuroglia 2025, 6(4), 38; https://doi.org/10.3390/neuroglia6040038 - 29 Sep 2025

Cited by 1 | Viewed by 1885

Abstract

Astrocytes are the most common type of glial cell in the central nervous system (CNS). They have many different functions that go beyond just supporting other cells. Astrocytes were once thought of as passive parts of the CNS. However, now they are known to be active regulators of homeostasis and active participants in both neurodevelopmental and neurodegenerative processes. This article looks at the both sides of astrocytic function: how they safeguard synaptic integrity, ion and neurotransmitter balance, and blood-brain barrier (BBB) stability, as well as how astrocytes can become activated and participate in the immune response by releasing cytokines, upregulating interferons, and modulating the blood–brain barrier and inflammation disease condition. Astrocytes affect and influence neuronal function through the tripartite synapse, gliotransmission, and the glymphatic system. When someone is suffering from neurological disorders, reactive astrocytes become activated after being triggered by factors such as pro-inflammatory cytokines, chemokines, and inflammatory mediators, these reactive astrocytes, which have higher levels of glial fibrillary acidic protein (GFAP), can cause neuroinflammation, scar formation, and the loss of neurons. This review describes how astrocytes are involved in important CNS illnesses such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and ischemia. It also emphasizes how these cells can change from neuroprotective to neurotoxic states depending on the situation. Researchers look at important biochemical pathways, such as those involving toll-like receptors, GLP-1 receptors, and TREM2, to see if they can change how astrocytes respond. Astrocyte-derived substances, including BDNF, GDNF, and IL-10, are also essential for protecting and repairing neurons. Astrocytes interact with other CNS cells, especially microglia and endothelial cells, thereby altering the neuroimmune environment. Learning about the molecular processes that control astrocytic plasticity opens up new ways to treat glial dysfunction. This review focuses on the importance of astrocytes in the normal and abnormal functioning of the CNS, which has a significant impact on the development of neurotherapeutics that focus on glia. Full article

(This article belongs to the Special Issue The Multifaceted Roles of Glia: From Cellular Functions to Neurological Implications)

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12 pages, 550 KB

Open AccessReview

Current Knowledge in Planarian Glia and Its Future Implications in Modeling Neurodegenerative Diseases

by David Gonzalez, Víctor Alarcón and Constanza Vásquez-Doorman

Neuroglia 2025, 6(4), 37; https://doi.org/10.3390/neuroglia6040037 - 24 Sep 2025

Viewed by 1308

Abstract

Neurodegenerative diseases are characterized by progressive loss of neurons and remain largely incurable. Numerous mammalian models have been developed to study the mechanisms underlying their physiopathology; however, their high cost, complexity and time requirements highlight the need for alternative systems. Glial cells are increasingly recognized as key contributors to neurodegenerative disease progression through non-cell autonomous mechanisms. Planarians possess a nervous system with diverse neuronal subtypes and glial cells, offering an attractive combination of evolutionary conservation and remarkable regenerative capacity. Unlike mammalian glia, planarian glia originate from phagocytic progenitors and exhibit distinctive molecular markers, including if-1, cali and cathepsin. Emerging evidence suggests that planarian glia may contribute to neurotransmitter homeostasis, neuron–glia interactions and phagocytic activity. Additionally, planarians display robust and quantifiable behavioral responses, making them well suited for modeling neurodegenerative disease. In this review, we summarize the current findings regarding neuronal subtypes and glial cells in planaria, emphasizing their relevance as a model system. Further research into planarian glia will be crucial for understanding their roles in pathological contexts and for exploring their potential applications in neurodegenerative diseases research. Planarian simplicity, regenerative capacity, and compatibility with high-throughput approaches position planarians as a powerful model for investigating the cellular and molecular mechanisms underlying neurodegenerative diseases and for identifying potential therapeutic targets. Full article

(This article belongs to the Special Issue The Multifaceted Roles of Glia: From Cellular Functions to Neurological Implications)

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27 pages, 708 KB

Open AccessReview

Environmental Enrichment as a Possible Adjunct Therapy in Autism Spectrum Disorder: Insights from Animal and Human Studies on the Implications of Glial Cells

by Enrique Hernández-Arteaga, Josué Antonio Camacho-Candia, Roxana Pluma-Romo, María Isabel Solís-Meza, Myriam Nayeli Villafuerte-Vega and Francisco Aguilar-Guevara

Neuroglia 2025, 6(2), 18; https://doi.org/10.3390/neuroglia6020018 - 25 Apr 2025

Viewed by 3600

Abstract

Background/Objectives: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition influenced by genetic, environmental, and epigenetic factors, leading to cognitive, emotional, and social impairments. Due to the heterogeneity of ASD, conventional therapies often have limited effectiveness, highlighting the need for complementary interventions. Enriched environments (EEs), characterized by enhanced sensory, cognitive, and motor stimulation, have shown promise in alleviating ASD symptoms. This review examines the role of glial cells in mediating the effects of EE. Methods: A literature review was conducted, analyzing studies on EE interventions in animal models and humans, with a focus on glial involvement in neuroplasticity and synaptic remodeling. Results: Evidence from animal models suggests that EE induces significant glial modifications, including increased synaptogenesis and enhanced neuronal connectivity. Studies in rodent models of ASD have demonstrated that EE reduces stereotypical behaviors, improves social interactions, and enhances cognitive function, effects that are closely associated with astrocyte and microglia activity. Similarly, human studies indicate that EE interventions lead to reduced autism symptom severity and improved cognitive outcomes, further supporting the hypothesis that glial cells play a central role in mediating the beneficial effects of EE. Conclusions: This review highlights the potential of EE as a modulator of the brain’s microenvironment, emphasizing the critical role of glial processes in ASD intervention. These findings suggest that future therapeutic strategies for ASD should integrate approaches that specifically target a glial function to optimize intervention outcomes. However, further research is needed to optimize EE protocols and address ASD heterogeneity. Full article

(This article belongs to the Special Issue The Multifaceted Roles of Glia: From Cellular Functions to Neurological Implications)

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16 pages, 2325 KB

Open AccessReview

Central and Peripheral Immunity Responses in Parkinson’s Disease: An Overview and Update

by Ghaidaa Ebrahim, Hunter Hutchinson, Melanie Gonzalez and Abeer Dagra

Neuroglia 2025, 6(2), 17; https://doi.org/10.3390/neuroglia6020017 - 4 Apr 2025

Cited by 1 | Viewed by 2679

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, with increasing evidence supporting the role of immune dysregulation in its pathophysiology. Neuroinflammation, mediated by microglial activation, pro-inflammatory cytokine production, and blood–brain barrier dysfunction, plays a crucial role in dopaminergic neuronal degeneration. Furthermore, peripheral immune changes, including T cell infiltration, gut microbiota dysbiosis, and systemic inflammation, contribute to disease progression. The bidirectional interaction between the central and peripheral immune systems suggests that immune-based interventions may hold therapeutic potential. While dopaminergic treatments remain the standard of care, immunomodulatory therapies, monoclonal antibodies targeting α-synuclein, and deep brain stimulation (DBS) have demonstrated immunological effects, though clinical efficacy remains uncertain. Advances in immune phenotyping offer new avenues for personalized treatment approaches, optimizing therapeutic responses by stratifying patients based on inflammatory biomarkers. This review highlights the complexities of immune involvement in PD and discusses emerging strategies targeting immune pathways to develop disease-modifying treatments. Full article

(This article belongs to the Special Issue The Multifaceted Roles of Glia: From Cellular Functions to Neurological Implications)

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14 pages, 24413 KB

Open AccessReview

Rosenfeld’s Staining: A Valuable Tool for In Vitro Assessment of Astrocyte and Microglia Morphology

by Alana Alves Farias, Ana Carla dos Santos Costa, Jéssica Teles Souza, Érica Novaes Soares, Cinthia Cristina de Oliveira Santos Costa, Ravena Pereira do Nascimento, Silvia Lima Costa, Victor Diogenes Amaral da Silva and Maria de Fátima Dias Costa

Neuroglia 2025, 6(2), 16; https://doi.org/10.3390/neuroglia6020016 - 3 Apr 2025

Viewed by 2287

Abstract

In homeostasis, the glial cells support pivotal functions, such as neuronal differentiation, neuroprotection, nutrition, drug metabolism, and immune response in the central nervous system (CNS). Among these cells, astrocytes and microglia have been highlighted due to their role in the pathogenesis of several diseases or due to their role in the defense against several insults (ex., chemicals, and pathogens). In Vitro cytological analysis of astrocytes and microglia has contributed to the understanding of the role of morphological changes in glial cells associated with a neuroprotective or neurotoxic phenotype. Currently, the main tools used for the investigation of glial cell morphology in culture are phase contrast microscopy or immunolabeling/fluorescence microscopy. However, generally, phase contrast microscopy does not generate images with high resolution and therefore does not contribute to visualizing a single cell morphology in confluent cell cultures. On the other hand, immunolabeling requires high-cost consumable antibodies, epifluorescence microscope or confocal microscope, and presents critical steps during the procedure. Therefore, identifying a fast, reproducible, low-cost alternative method that allows the evaluation of glial morphology is essential, especially for neuroscientists from low-income countries. This article aims to revise the use of Rosenfeld’s staining, as an alternative low-cost and easy-to-reproduce method to analyze astrocytic and microglial morphology in culture. Additionally, it shows Rosenfeld’s staining as a valuable tool to analyze changes in neural cell morphology in toxicological studies. Full article

(This article belongs to the Special Issue The Multifaceted Roles of Glia: From Cellular Functions to Neurological Implications)

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18 pages, 689 KB

Open AccessReview

Beyond the Neuron: The Integrated Role of Glia in Psychiatric Disorders

by André Demambre Bacchi

Neuroglia 2025, 6(2), 15; https://doi.org/10.3390/neuroglia6020015 - 25 Mar 2025

Cited by 2 | Viewed by 3759

Abstract

In recent decades, substantial evidence has highlighted the integral roles of neuroglia, particularly astrocytes, microglia, oligodendrocytes, and ependymal cells, in the regulation of synaptic transmission, metabolic support, and immune mechanisms within the central nervous system. In addition to their structural role, these cells actively modulate neurotransmitter homeostasis and influence neuronal plasticity, thereby affecting cognition, mood, and behavior. This review discusses how neuroglial alterations contribute to the pathophysiology of five common psychiatric disorders: major depression, bipolar disorder, anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), and schizophrenia. We synthesized preclinical and clinical findings illustrating that glial dysfunction, including impaired myelination and aberrant neuroinflammatory responses, often parallels disease onset and severity. Moreover, we outline how disruptions in astrocytic glutamate uptake, microglia-mediated synaptic pruning, and blood–brain barrier integrity may underlie the neurobiological heterogeneity observed in these disorders. The therapeutic implications range from anti-inflammatory agents to investigational compounds that aim to stabilize glial function or promote remyelination. However, challenges due to interindividual variability, insufficient biomarkers, and the multifactorial nature of psychiatric illnesses remain. Advances in neuroimaging, liquid biopsy, and more precise molecular techniques may facilitate targeted interventions by stratifying patient subgroups with distinct glial phenotypes. Continued research is essential to translate these insights into clinically efficacious and safe treatments. Full article

(This article belongs to the Special Issue The Multifaceted Roles of Glia: From Cellular Functions to Neurological Implications)

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Other

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14 pages, 2421 KB

Open AccessSystematic Review

Antineoplastic Effect of Metformin Against Glioblastoma Multiforme In Vitro and In Vivo: A Systematic Review and Meta-Analysis

by Bhavya Vashi, Daniel Gonzales-Portillo and Jorge Cervantes

Neuroglia 2025, 6(4), 40; https://doi.org/10.3390/neuroglia6040040 - 14 Oct 2025

Viewed by 632

Abstract

Background/Objectives: Glioblastoma multiforme (GBM) is a highly aggressive brain tumor associated with poor survival outcomes. Given the significant financial burden of cancer treatments, repurposing existing drugs can reduce costs and enhance therapeutic efficacy. Metformin, an antidiabetic medication, has been investigated for its antineoplastic effects against GBM. Here, we reviewed the in vitro and in vivo effects of metformin through GBM cell viability and overall animal survival, respectively. Methods: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data extraction and statistical analyses were performed using Microsoft Excel, and R. Effect sizes were calculated as standard mean differences (SMDs) for in vitro studies assessing cell viability and hazard ratios (HRs) for in vivo mice survival analyses. Results: A total of two-hundred-thirty in vitro studies and five-hundred-sixty-six in vivo studies were screened. Of these, seven in vitro and eight in vivo studies were compatible for the meta-analysis. The random-effects model showed a reduction in cell viability (SMD [95% CI]: 3.70 [2.28, 5.12]). A pooled in vivo survival analysis suggests an increase in overall survival in mice receiving metformin (p-value = 0.055). A random-effects model for overall survival supports this pooled analysis (HR [95% CI]: 0.76 [0.39, 1.46]). Additionally, metformin also showed a reduction in cell viability (SMD [CI]; 2.27 [0.79, 3.75]) and an increase in overall animal survival (HR [CI], 0.23 [0.12, 0.45]) when it was added as an adjuvant to traditional GBM therapies. Conclusions: Our findings from in vitro and in vivo studies support the potential of metformin as an antineoplastic agent against GBM. We plan to extend our analyses into clinical studies to determine if these benefits extend to human patients. Metformin has the potential to revolutionize GBM therapy if a relationship exists due to its inexpensive nature. Full article

(This article belongs to the Special Issue The Multifaceted Roles of Glia: From Cellular Functions to Neurological Implications)

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