Neuroglia

Neurodevelopmental disorders represent a significant health concern, leading to a wide range of clinical, cognitive, and social impairments. Although the exact causes of these disorders remain unclear, genetic, epigenetic, and environmental factors all contribute to their emergence. Recently, the role of neuroglia in the pathophysiology of these conditions has received increasing attention. Various glial mechanisms (e.g., neuroinflammation, neurotransmitter regulation, gliosis) have been implicated in both shared and distinct features of these disorders. The identification of novel etiological factors may facilitate the development of new therapeutic modalities targeting glial dysfunction. This review provides a comprehensive overview of neuroglia and summarizes the current understanding of neurodevelopmental disorders and co-occurring disruptive behavioral disorders from a glial perspective. Furthermore, gaps in the literature are highlighted, and potential strategies for addressing these gaps and integrating findings into clinical practice are discussed. Full article

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

Pain is a multifactorial phenomenon involving neuronal, immune, and glial components. Annexin A1 (AnxA1), a glucocorticoid-regulated protein with pro-resolving properties, has emerged as a critical modulator of pain. Present in both peripheral and central compartments, AnxA1 acts through the formyl peptide receptor FPR2/ALX to regulate immune responses, modulate nociceptive signaling, and promote tissue homeostasis. Its mimetic peptide, Ac_2–26, has demonstrated robust antinociceptive effects in various pain models, including those induced by inflammation, tissue injury, viral infection, and opioid exposure. AnxA1 modulates cytokine expression, inhibits pro-nociceptive pathways such as TRPV1 and CXCL12/CXCR4, and reprograms macrophages. In the central nervous system, it attenuates neuroinflammation and central sensitization. Notably, AnxA1 can exhibit context-dependent effects, contributing to either the resolution or exacerbation of inflammation. This review examines the molecular mechanisms by which AnxA1 bridges the immune and nervous system pathways, highlighting its therapeutic potential in pain management. Full article

Microglia and macrophages are critical immune cells within the central nervous system (CNS), with distinct roles in development, homeostasis, and disease. Once viewed as passive bystanders, these cells are now recognized for their dynamic phenotypic plasticity, which enables them to respond to a wide range of physiological and pathological stimuli. During homeostasis, microglia and CNS-resident macrophages actively participate in synaptic pruning, neuronal support, myelin regulation, and immune surveillance, contributing to CNS integrity. However, under pathological conditions, these cells can adopt neurotoxic phenotypes, exacerbating neuroinflammation, oxidative stress, and neuronal damage in diseases such as Alzheimer’s, Parkinson’s, multiple sclerosis, and glioblastoma. This review synthesizes emerging insights into the molecular, epigenetic, and metabolic mechanisms that govern the behavior of microglia and macrophages, highlighting their developmental origins, niche-specific programming, and interactions with other CNS cells. We also explore novel therapeutic strategies aimed at modulating these immune cells to restore CNS homeostasis, including nanotechnology-based approaches for selective targeting, reprogramming, and imaging. Understanding the complex roles of microglia and macrophages in both health and disease is crucial for the development of precise therapies targeting neuroimmune interfaces. Continued advances in single-cell technologies and nanomedicine are paving the way for future therapeutic interventions in neurological disorders. Full article

The oral microbiota, long recognized for their role in local pathologies, are increasingly implicated in systemic disorders, particularly cardiovascular disease (CVD). This review focuses on emerging evidence linking oral dysbiosis to neuroglial activation and autonomic dysfunction as key mediators of cardiovascular pathology. Pathogen-associated molecular patterns, as well as gingipains and leukotoxin A from Porphyromonas gingivalis, Fusobacterium nucleatum, Treponema denticola, Aggregatibacter actinomycetemcomitans, etc., disrupt the blood–brain barrier, activate glial cells in autonomic centers, and amplify pro-inflammatory signaling. This glia driven sympathetic overactivity fosters hypertension, endothelial injury, and atherosclerosis. Crucially, sex hormones modulate these neuroimmune interactions, with estrogen and testosterone shaping microbial composition, glial reactivity, and cardiovascular outcomes in distinct ways. Female-specific factors such as early menarche, pregnancy, adverse pregnancy outcomes, and menopause exert profound influences on oral microbial ecology, systemic inflammation, and long-term CVD risk. By mapping this oral–brain–heart axis, this review highlights the dual role of oral microbial virulence factors and glial dynamics as mechanistic bridges linking periodontal disease to neurogenic cardiovascular regulation. Integrating salivary microbiome profiling with glial biomarkers [e.g., GFAP (Glial Fibrillary Acidic Protein) and sTREM2 (soluble Triggering Receptor Expressed on Myeloid cells 2)] offers promising avenues for sex-specific precision medicine. This framework not only reframes oral dysbiosis as a modifiable cardiovascular risk factor, but also charts a translational path toward gender tailored diagnostics and therapeutics to reduce the global CVD burden. Full article

Hydrocephalus is a neurological disorder caused by cerebrospinal fluid (CSF) accumulation due to impaired production, circulation, or reabsorption from trauma, neurocysticercosis, neoplasms, subarachnoid hemorrhage, or genetic mutations. This review examines glial remodeling in the ventricular–subventricular zone (V-SVZ) and corpus callosum (CC) in response to hydrocephalus, as ventricular enlargement leads to structural alterations that impact cellular composition in the V-SVZ and CC of patients with hydrocephalus. Animal models of hydrocephalus indicate V-SVZ niche remodeling, ependymal thinning, reduced neuroblast proliferation, increased microglia and astrocytes, increased cell death, and enlarged extracellular matrix structures (fractones). Alterations in the corpus callosum encompass a reduction in width, abnormalities in myelin, astrogliosis, microglial reactivity, a decreased expression of myelin-related proteins (MOG and CNPase), and a reduced number of oligodendrocytes. Additionally, this narrative review highlights important cellular and molecular findings before and after CSF diversion surgery. This primary treatment restores the ventricular size but does not completely reverse glial changes, indicating that ongoing neuroinflammatory processes may interfere with neural recovery. Full article

Brain cancer is a heterogeneous collection of malignant neoplasms, such as glioblastoma multiforme (GBM), astrocytomas and medulloblastomas, with high morbidity and mortality. Its treatment is complicated by the tumor’s site, infiltrative growth mode and selective permeability of the blood–brain barrier (BBB). During tumor formation, the BBB dynamically remodels into the blood–brain tumor barrier (BBTB), disrupting homeostasis and preventing drug delivery. Furthermore, the TME (Tumor Micro Environment) supports drug resistance, immune evasion and treatment failure. This review points out the ways in which nanomedicine overcomes these obstacles with custom-designed delivery systems, sophisticated diagnostics and personalized therapies. Traditional treatments fail through a lack of BBB penetration, non-specific cytotoxicity and swift tumor adaptation. Nanomedicine provides greater drug solubility, protection against enzymatic degradation, target drug delivery and control over the release. Nanotheranostics’ confluence of therapeutic and diagnostic modalities allows for dynamic adjustment and real-time monitoring. Nanotechnology has paved the way for the initiation of a new era in precision neuro-oncology. Transcending the limitations of conventional therapy protocols, nanomedicine promises to deliver better outcomes by way of enhanced targeting, BBB penetration and real-time monitoring. Multidisciplinary collaboration, regulatory advancements and patient-centered therapy protocols customized to the individual patient’s tumor biology will be necessary to facilitate translation success in the future. Full article

Background: Astrocytes are not only structural cells but also play a pivotal role in neurogenesis and neuroprotection by secreting a variety of neurotrophic factors that support neuronal survival, growth, and repair. This study investigates the time-dependent responses of primary rat cortical astrocytes to oxygen–glucose deprivation (OGD) and evaluates the neuroprotective potential of astrocyte-conditioned medium (ACM). Methods: Primary rat cortical astrocytes and neurons were obtained from postnatal Sprague Dawley rat pups (P1–3) and embryos (E17–18), respectively. Astrocytes exposed to 6, 24, and 48 h of OGD (0.3% O₂) were assessed for viability, metabolic function, hypoxia-inducible factor 1 and its downstream genes expression. Results: While 6 h OGD upregulated protective genes such as Vegf, Glut1, and Pfkfb3 without cell loss, prolonged OGD, e.g., 24 or 48 h, led to significant astrocyte death and stress responses, including elevated LDH release, reduced mitochondrial activity, and increased expression of pro-apoptotic marker Bnip3. ACM from 6 h OGD-treated astrocytes significantly enhanced neuronal survival following 6 h OGD and 24 h reperfusion, preserving dendritic architecture, improving mitochondrial function, and reducing cell death. This protective effect was not observed with ACM from 24 h OGD astrocytes. Furthermore, 6 h OGD-ACM induced autophagy in neurons, as indicated by elevated LC3b-II and decreased p62 levels, suggesting autophagy as a key mechanism in ACM-mediated neuroprotection. Conclusions: These findings demonstrate that astrocytes exhibit adaptive, time-sensitive responses to ischemic stress and secrete soluble factors that can confer neuroprotection. This study highlights the therapeutic potential of targeting astrocyte-mediated signalling pathways to enhance neuronal survival following ischemic stroke. Full article

Epilepsy is one of the most prevalent chronic medical conditions that really can affect individuals at any age. A broader study of the pathogenesis of the epileptic condition will probably serve as the cornerstone for the development of new antiepileptic remedies that aim to treat epilepsy symptomatically as well as prevent the epileptogenesis process or regulate its progression. Cellular changes in the brain include oxidative stress, neuroinflammation, inflammatory cell invasion, angiogenesis, and extracellular matrix associated changes. The extensive molecular profiling of epileptogenic tissue has revealed details on the molecular pathways that might start and sustain cellular changes. In healthy brains, epilepsy develops because of vascular disruptions, such as blood–brain barrier permeability and pathologic angiogenesis. Key inflammatory mediators are elevated during epileptic seizures, increasing the risk of recurrent seizures and resulting in secondary brain injury. Prostaglandins and cytokines are well-known inflammatory mediators in the brain and, after seizures, their production is increased. These inflammatory mediators may serve as therapeutic targets in the clinical research of novel antiepileptic medications. The functions of inflammatory mediators in epileptogenesis are covered in this review. Oxidative stress also plays a significant role in the pathogenesis of various neurological disorders, specifically epilepsy. Antioxidant therapy seems to be crucial for treating epileptic patients, as it prevents neuronal death by scavenging excess free radicals formed during the epileptic condition. The significance of antioxidants in mitochondrial dysfunction prevention and the relationship between oxidative stress and inflammation in epileptic patients are the major sections covered in this review. Full article

Background: Elevated levels of methylmalonic acid (MMA) are observed in the bodily fluids and tissues of patients with methylmalonic aciduria, a metabolic disorder characterized by manifestations such as vomiting, lethargy, muscle weakness, seizures, and coma. Objectives and Methods: To better understand the neuropathological mechanisms underlying this condition, we investigated the effects of intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administration of MMA on antioxidant defenses, citric acid cycle functioning, and glial reactivity in the cerebral cortex and striatum of Wistar rats. Amino acid levels were also quantified. Results: i.p. and i.c.v. administration of MMA decreased reduced glutathione levels and altered the activities of different antioxidant enzymes in the cortex and striatum. The activity of the citric acid cycle enzyme succinate dehydrogenase was diminished in both brain regions by i.p. and i.c.v. administration. Citrate synthase, isocitrate dehydrogenase, and malate dehydrogenase activities were further inhibited in the striatum. Furthermore, the i.p. administration increased glial fibrillary acidic protein (GFAP) and glucose transporter 1 (GLUT1) levels, whereas i.c.v. administration elevated GFAP and ionized calcium-binding adaptor molecule 1 (IBA1) levels in the striatum, suggesting glial activation. In contrast, no significant changes in glial markers were detected in the cortex. Moreover, synaptophysin levels remained unaltered in both regions. Finally, i.p. administration increased glutamate, glycine, and serine levels and reduced tyrosine concentrations in the striatum. Conclusions: Our findings indicate that oxidative stress, bioenergetic dysfunction, and glial reactivity induced by MMA may contribute to the neurological deficits observed in methylmalonic aciduria. Full article

Glial cells exhibit multifaceted functions and represent essential contributors to various physiological processes in the brain, rather than just being silent supportive cells to neurons. Different glial populations of the central nervous system within involved brain regions play various functions, express different proteins, and result in fluctuating effects when altered. Glial cell pathologies were detected in most mental disorders including suicidal behavior. Suicidal behavior represents a health problem of high importance worldwide, where protective measures are required to be taken at many levels. Studies on patients with mental disorders that represent risk factors for suicidal behavior revealed multiple changes in the glia at diverse levels, including variations regarding the expressed glial markers. This review summarizes the role of glia in some psychiatric disorders and highlights the crosslink between changes at the level of glial cells and development of suicidal behavior in patients with an underlying psychiatric condition; in addition, the interplay and interconnection between suicidal behavior and other mental diseases will shed light on the routes of personalized therapy involving the development of glia-related drugs. Full article

HIV, primarily targeting CD4 cells, infiltrates the CNS through various mechanisms, including chemokine-mediated signaling and blood–brain barrier disruption, leading to neuroinflammation and neuronal dysfunction. Viral proteins such as gp120, Tat, and Vpr directly induce neurotoxicity, oxidative stress, and mitochondrial dysfunction, exacerbating cognitive deficits and motor impairments observed in HIV-associated neurocognitive disorders (HANDs). Host genetic factors, including CCR5 mutations and HLA alleles, influence susceptibility to HIV-related neurologic complications, shaping disease progression and treatment responses. Advanced molecular and bioinformatics techniques, from genome sequencing to structural modeling and network analysis, provide insights into viral pathogenesis and identify potential therapeutic targets. These findings underscore the future potential of precision medicine approaches tailored to individual genetic profiles to mitigate neurologic complications and improve outcomes in HIV-infected populations. This comprehensive review explores the intricate interplay between HIV infection and neurogenetics, focusing on how the virus impacts the central nervous system (CNS) and contributes to neurocognitive disorders. This report delves into how the virus influences genetic expression, neuroinflammation, and neurodegeneration, offering insights into molecular mechanisms behind HAND. Full article

This review synthesizes the emerging understanding of the roles of glial cells and non-coding RNAs (ncRNAs) in the pathogenesis and progression of Alzheimer’s disease and related dementias (ADRDs). ADRDs encompass a spectrum of neurodegenerative disorders characterized by cognitive decline, memory impairment, and functional deterioration. The interplay between the most common types of glial cells—astrocytes, microglia, and oligodendrocytes—and ncRNAs is emerging as a critical factor in the development of ADRDs. Glial cells are essential for maintaining homeostasis within the central nervous system (CNS); however, their dysregulation can lead to neuroinflammation and neuronal dysfunction, exacerbating neurodegeneration. Reactive astrocytes and activated microglia can create neurotoxic environments that further impair neuronal health. Concurrently, ncRNAs, particularly long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have emerged as significant regulators of glial gene expression, influencing inflammatory responses and glial cell function. Understanding the complex interactions between glial cells and ncRNAs is crucial for developing targeted therapeutic strategies. By elucidating the mechanisms underlying their interactions, this review aims to highlight the critical importance of glial cells and ncRNAs in the context of neurodegenerative diseases, paving the way for innovative approaches to prevent and treat ADRDs. Ultimately, enhancing our understanding of these processes may lead to novel therapies and improved outcomes for individuals affected by these debilitating conditions. Full article

Background/Objectives: Nitric oxide (NO) and electromagnetic fields (EMFs) have been reported to influence central nervous system (CNS) function and organization. This study explores the effects of NO modulation and EMF exposure on neurodevelopment and glial fibrillary acidic protein (GFAP) expression and cell morphology, extending the prior work on perinatal EMF exposure in Wistar rats. Methods: Rats were perinatally exposed to water, 1 g/L L-arginine (LA), or 0.5 g/L N-methylarginine (NMA), along with a 7 Hz square-wave EMF at intensities of 0 nT, ≤50 nT, or 500 nT, starting three days before birth and continuing for 14 days postnatally. GFAP expression and cell morphology were analyzed via immunohistochemistry in regions including the hypothalamus, amygdala, hippocampus, and cortex. Results: Significant changes in GFAP morphology and expression are observed. A main EMF effect emerged in the right ventromedial hypothalamus, where the branch length of GFAP-expressing cells increased in EMF-exposed groups compared to the controls [t(32) = −2.52, p = 0.017]. In the hippocampus, LA exposure decreased GFAP expression in the right dentate gyrus compared to water controls [t(23) = 2.37, p = 0.027]. A sex-specific EMF effect was detected in the left CA2 hippocampus, where males exposed to EMF showed significant differences from unexposed males [t(15) = −2.90, p = 0.011]. Conclusions: These findings reveal complex interactions between EMF exposure, sex, and NO modulation, with region-specific effects on GFAP expression in the developing rat brain. Full article

Müller glia exhibit a remarkable regenerative capacity in zebrafish through spontaneous reprogramming post-injury but remain limited in mammals. This review highlights the key mechanisms underlying Müller glia reprogramming, including gene regulatory networks, cytokine signaling, signal transduction pathways, epigenetic modifications, and transcriptional regulation. Cross-species analyses have uncovered conserved gene networks that suppress neurogenesis in mammals, while injury-induced transcriptional profiles reveal divergent regenerative strategies. Combinatorial approaches may enhance the reprogramming of mammalian Müller glia into functional neurons. Nevertheless, significant challenges remain, such as variability in the efficacy of direct reprogramming methods and the limited regeneration of cone photoreceptors, even in regenerative species. We conclude that targeting epigenetic barriers and species-specific regulatory pathways offers promising avenues for clinical translation in retinal disorders such as glaucoma and retinitis pigmentosa. Moving forward, research efforts should prioritize the functional integration of regenerated neurons and the development of standardized methodologies to accelerate therapeutic advancements. Full article

Background/Objectives: The annexin A1 (AnxA1) protein has proven important in ocular disease homeostasis and holds great therapeutic promise. However, its role in the context of the healthy retina remains unknown. Therefore, this study used electroretinography (ERG) to investigate the role of endogenous AnxA1 in the retinal function of wild-type (WT) and AnxA1 knockout mice (AnxA1^−/−). Methods: An extensive repertoire of full-field ERG was applied to AnxA1^−/− and WT mice to examine retinal physiology. Morphometric analyses of the retina were conducted. Results: Our results revealed significant differences in the implicit time of a-wave and b-wave between the WT and AnxA1^−/− groups under scotopic conditions. The negative and positive amplitude components of mesopic ON responses were higher in the AnxA1^-/- group than in the WT group. In contrast, the implicit time of mesopic ON responses were significantly higher in the WT group than in the AnxA1^-/- WT group. However, in photopic OFF responses, only the implicit time was significantly longer in the WT group than in the AnxA1^−/− group. In the histomorphometric analysis, the retina of AnxA1^−/− mice shows increased thickness. Conclusions: The absence of AnxA1 alters retinal morphology and physiology. Full article

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

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

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