Neuroglia

Background: Neuroinflammation is increasingly recognized as a central mechanism in the pathogenesis of epilepsy, particularly drug-resistant epilepsy (DRE), where conventional anti-seizure medications fail to achieve adequate control. Microglia, the resident immune cells of the central nervous system, play a critical role in mediating inflammatory responses that contribute to seizure initiation, propagation, and pharmacoresistance. Persistent microglial activation promotes the release of pro-inflammatory mediators, exacerbating neuronal hyperexcitability and epileptogenesis. Objectives: This scoping review aimed to systematically map the existing evidence on microglial activation in DRE and to identify emerging therapeutic strategies targeting microglia-mediated neuroinflammation. Methods: The review was conducted in accordance with Joanna Briggs Institute (JBI) methodology and reported following PRISMA-ScR guidelines. A comprehensive search of PubMed, PubMed Central, Scopus, Google Scholar, Embase, and Web of Science was performed without date restrictions. Eligible studies included preclinical, clinical, and review articles investigating microglial activation, neuroinflammatory pathways, or microglia-targeted therapies in epilepsy. Data were charted and synthesized using a narrative approach. Results: A total of 521 records were identified, of which 53 studies met the inclusion criteria after screening and full-text review. The included studies, published between 1998 and 2021, demonstrated a growing research interest in microglia-related mechanisms in epilepsy. Evidence consistently highlighted the role of microglial activation in promoting neuroinflammation and seizure persistence. Emerging therapeutic strategies included anti-inflammatory pharmacotherapies, microglial modulators, cannabinoid-based interventions, gene therapy, and stem cell-based approaches. Conclusions: Targeting microglial activation represents a promising and evolving therapeutic strategy for DRE. While preclinical and early clinical evidence is encouraging, challenges related to specificity, timing, and translational applicability remain. Future research should focus on precision-based interventions to optimize clinical outcomes and enable disease modification beyond seizure control. Full article

Background: Endotoxin tolerance describes the phenomenon whereby prior lipopolysaccharide (LPS) exposure attenuates inflammatory responses to subsequent LPS challenge. Studies have reported the involvement of different mediators of the toll-like receptor (TLR)-4 signaling pathway in endotoxin tolerance. Methods: We first examined dose- and time-dependent production of cytokines following LPS treatment and then examined cytokine production in BV2 cells pretreated with 5 ng/mL LPS for 24 h, followed by secondary challenge with 1 µg/mL LPS for four hours. To examine which inflammatory cytokine could induce tolerance, we pretreated BV2 cells with 1 µg/mL IL-1β, IL-6, or TNF-α for 24 h, followed by secondary challenge with 1 μg/mL LPS for four hours, and then examined cytokine production by ELISA. Results: Our data showed that LPS induced dose- and time-dependent production of IL-1β, IL-6, and TNF-α. Pretreatment with 5 ng/mL LPS significantly reduced the production of IL-1β and TNF-α in response to secondary challenge, while IL-6 production was slightly enhanced. We also found that pretreatment with IL-1β did not attenuate production of TNF-α but slightly enhanced IL-6 following secondary challenge with 1 µg/mL LPS. In contrast, pretreatment with IL-6 or TNF-α significantly attenuated subsequent LPS-induced IL-1β production without affecting the production of the other. Conclusions: Endotoxin tolerance in BV2 microglial cells selectively suppresses IL-1β and TNF-α while preserving IL-6 production. Both IL-6 and TNF-α independently induce tolerance specifically to IL-1β, suggesting negative feedback regulations. These findings reveal that endotoxin tolerance involves selective rather than global suppression of inflammatory mediators and cross-regulation between LPS and cytokine-induced signaling pathways. Full article

Background: Neuromyelitis optica spectrum disease (NMOSD) is a severe and highly disabling autoimmune astrocytopathy in which humoral immunity, mediated by the presence of autoantibodies, and cellular immunity, through Th17 cells and related cytokines, are key contributors to the pathogenesis. This neuroglial disease affects the central nervous system and is predominantly described in the young productive population. For many years, NMOSD treatment lacked disease-specific therapies and relied on conventional immunosuppressive agents. Progress in elucidating underlying mechanisms of the disease has led to the development and approval of highly specific and effective pathology-modifying drugs. Objective: The objective of this paper is to analyze current and emerging monoclonal antibody-based therapies for NMOSD. Methods: A systematic review of the literature was conducted focusing on approved and investigational monoclonal antibodies targeting major immunopathogenic pathways in NMOSD. Both long-term maintenance therapies and treatments for acute relapses were considered. Results: Targeted monoclonal antibody therapies have significantly transformed the therapeutic management of NMOSD. Drugs directed at B-cell depletion, IL-6 receptor inhibition, and complement blockade have demonstrated substantial efficacy in reducing relapse rates and improving clinical outcomes. Emerging therapies and biomolecular engineering represent promising strategies aimed at further modulating disease activity. These treatments offer improved specificity compared with traditional immunosuppressive regimens and contribute to better long-term disease control. Conclusions: The growing understanding of NMOSD immunopathogenesis has led to the development of highly specific monoclonal antibody-based therapies that have substantially redefined long-term maintenance strategies. Emerging biological targets may expand future therapeutic options. Continued research is essential to optimize individualized treatment approaches and improve outcomes for patients with NMOSD. Full article

The discovery of the glymphatic system (GS) transformed understanding of central nervous system homeostasis by revealing a brain-wide network that facilitates cerebrospinal and interstitial fluid exchange along perivascular pathways. This system clears metabolic waste and maintains the precise ionic environment required for neuronal function through the coordinated action of astrocytic aquaporin-4 channels and intact perivascular architecture. Glioblastoma multiforme (GBM), the most aggressive primary brain tumor in adults, alters physiological barriers through pathological angiogenesis, compression of perivascular spaces, depolarization of aquaporin-4 at astrocytic endfeet, and obstruction of venous and lymphatic drainage. This narrative review synthesizes current experimental and clinical literature identified through targeted searches of PubMed and Scopus to examine interactions between glioblastoma, glymphatic system dysfunction, and tumor microenvironmental changes. To minimize selection bias, studies were categorized according to evidence source and experimental design. Evidence from rodent models and advanced imaging demonstrates as tumor growth impairs glymphatic function, the resulting dysfunction promotes tumor progression by enabling accumulation of pro-tumorigenic growth factors, inflammatory mediators, and acidic metabolites, while elevated interstitial fluid pressure limits drug delivery. Impaired antigen drainage further diminishes immune surveillance, contributing to the immunosuppressive microenvironment that limits immunotherapy efficacy. A critical evaluation of these mechanisms highlights how the glymphatic system influences disease progression and suggests novel avenues for diagnostic imaging and therapeutic intervention. Although significant challenges remain in modeling human fluid dynamics, understanding these hidden networks offers a promising frontier for strategies aimed at restoring cerebral clearance and improving clinical outcomes. Full article

The coronavirus disease 2019 (COVID-19) pandemic has been associated with a wide range of neurological complications, among which persistent cognitive impairment and memory deficits are increasingly recognized as key symptoms of the post-acute sequelae of SARS-CoV-2 infection (PASC or long COVID). Although clinical and epidemiological studies have documented these symptoms across diverse patient populations, the underlying neurobiological mechanisms remain incompletely understood. Growing evidence from human studies, neuropathological analyses, and experimental models indicates that neuroimmune and inflammatory processes plays a central role in COVID-19-associated cognitive dysfunction. As the brain’s resident immune cells, microglia are vital for synaptic health, neuroplasticity, and memory, yet these processes may be compromised after SARS-CoV-2 infection. Systemic inflammation, blood–brain barrier (BBB) disruption, endothelial injury, and cytokine signaling can induce sustained microglial activation and priming, leading to inflammasome activation, complement-mediated synaptic remodeling, oxidative stress, and impaired hippocampal neurogenesis. These processes collectively disrupt neural circuits involved in learning and memory and may underlie the persistent “brain fog” reported by COVID-19 survivors. This review synthesizes clinical, biomarker, neuroimaging, and mechanistic evidence linking SARS-CoV-2 infection to microglia-mediated neuroinflammation and memory impairment. In contrast to prior reviews that broadly describe neuroinflammation in COVID-19, we integrate multidimensional evidence into a microglia-centric immunovascular framework that highlights converging pathogenic pathways underlying cognitive symptoms. We further discuss emerging biomarkers of glial activation and evaluate current and prospective therapeutic strategies targeting microglial and neuroimmune pathways. Understanding the role of microglial dysregulation in post-COVID cognitive impairment may facilitate the development of targeted interventions to mitigate long-term neurological consequences of COVID-19. Full article

Background: Schwannomas of the third cranial nerve are exceedingly rare benign tumors, and standardized management guidelines are lacking. Their close relationship with critical neurovascular structures makes diagnosis and treatment challenging, with a significant risk of postoperative neurological deficits. Methods: A systematic review of the literature was conducted according to the PRISMA guidelines, including case reports and clinical studies on oculomotor nerve schwannomas (ONSs). Demographic data, clinical presentation, tumor location, diagnostic methods, treatment strategies, and functional outcomes were analyzed. In addition, an illustrative case treated with a multimodal approach is presented. Results: Ninety-six cases met the inclusion criteria. The mean age at diagnosis was 34 years, with a slight female predominance. The most common presenting symptoms were diplopia and ptosis. Contrast-enhanced magnetic resonance imaging was the diagnostic modality of choice. Surgical resection was the primary treatment in most cases but was associated with worsening oculomotor nerve function in 43.1% of surgically treated patients. Stereotactic radiotherapy demonstrated favorable tumor control with lower neurological morbidity. In the presented case, subtotal resection followed by stereotactic radiotherapy resulted in sustained tumor stability at the one-year follow-up. Conclusions: Management of oculomotor nerve schwannomas should be individualized. For small or mildly symptomatic lesions, stereotactic radiotherapy appears to be an effective and less invasive option, while surgery should be reserved for large tumors causing a mass effect or progressive neurological deterioration. Full article

Background: The principal glial cells of the retina, Müller glia, play a central role in retinal regeneration in teleost fish and have recently attracted attention as potential sources of neuronal regeneration in mammals. Objectives: In this study, we examined whether SV40-immortalized rat Müller glia could be directed toward neuronal differentiation using a non-genetic approach with defined culture conditions. Methods: Comprehensive transcriptomic profiling by RNA sequencing indicated that changes in culture medium alone could induce transcriptional reprogramming toward a neuronal lineage. Results: Specifically, expression of Müller glia-related genes decreased, while a subset of photoreceptor-related transcription factors and specific genes showed altered expression, suggesting early-stage induction toward a photoreceptor-like fate. This finding suggests that even immortalized cells may exhibit activation of neuronal genes through non-genetic culture interventions. Gene set enrichment analysis further revealed upregulation of pathways related to the synaptic vesicle cycle, metabolic activation, oxidative stress defense, and lysosomal function, consistent with initiation of neuronal differentiation. Conversely, pathways associated with cell cycle regulation and stemness signaling were downregulated, reflecting a transition from a proliferative to a differentiation-prone state. Collectively, these results provide preliminary molecular markers for early neuronal induction and potential targets for chemical screening. Conclusions: Importantly, this strategy enables neuronal-like differentiation of Müller glia without genetic manipulation, offering a safe and cost-effective platform. Overall, our findings may support the development of in vitro models for retinal neuroregeneration and facilitate research toward regenerative therapies for retinal disorders. Full article

Satellite glial cells (SGCs) in sensory ganglia are increasingly recognized as active regulators of neuronal excitability and inflammatory signaling involved in pain conditions. In craniofacial and orofacial pain, trigeminal SGCs exhibit stimulus-dependent responses that develop over time and contribute to disease-related plasticity. Additionally, advances in experimental modeling, computational analysis, and data integration have fueled interest in “digital twins” as tools for hypothesis generation and decision support in biomedicine. However, most current biomedical applications are loosely defined and rarely explicitly address glial biology. Here, we propose a digital twin-inspired framework focused on trigeminal satellite glial cells to combine stimulus-response experiments with computational state modeling. Instead of claiming a fully developed digital twin, we describe a hybrid experimental–computational approach where glial activation states are inferred from measurable outputs, iteratively refined, and used to explore what-if scenarios related to pain mechanisms and treatments. These scenarios are intended to guide experimental design and hypothesis prioritization rather than to generate clinical predictions. We detail how this framework could enhance understanding of underlying mechanisms, prioritize potential interventions, and align with New Approach Methodologies (NAMs) and the 3Rs by reducing exploratory animal use. We also discuss key limitations, including biological simplification, uncertainty, and translational challenges. By viewing glial systems as dynamic, updateable entities rather than static readouts, this approach offers a practical and ethically grounded pathway toward more integrated research on craniofacial pain. Full article

Background/Objectives: Injuries to spinal ventral roots induce complex retrograde reactions that compromise motoneuron survival, synaptic organization, and glial responses, ultimately limiting the potential for regeneration. The endocannabinoid system (ECS) has emerged as a crucial modulator of neuroprotective processes, primarily through the activation of CB1 and CB2. However, the individual and combined contributions of these receptors to post-injury spinal responses remain poorly understood. Here, we examined the effects of selective blockade of CB1 and CB2 receptors in a murine model of ventral root crush (VRC). Methods: Female C57BL/6JUnib mice received daily intraperitoneal injections of the CB1 antagonist AM-251 and/or the CB2 antagonist AM-630 (1 mg/kg) for 14 days post-lesion. At 28 days after injury, spinal cords were analyzed for motoneuron survival (Nissl staining), glial responses (immunohistochemistry for GFAP and Iba-1), and synaptic coverage (immunohistochemistry for synaptophysin). Results: Selective blockade of CB2 receptors led to a marked reduction in motoneuron survival, enhanced microglial activation-associated morphology (morphological classification and Sholl analysis), and decreased synaptic coverage. CB1 blockade produced milder, context-dependent effects. Dual blockade exacerbated all outcomes, indicating complementary CB1/CB2 functions in the spinal microenvironment. Conclusions: Under the conditions tested, CB2 signaling is necessary for motoneuron preservation, limiting microglial activation-associated morphology, and maintaining synaptic coverage after VRC. The knowledge of specific actions of CB1 and CB2 provides mechanistic insight into the neuroprotective potential of endocannabinoid signaling and reinforces its therapeutic relevance for motoneuron preservation and functional recovery after axotomy. Full article

Background/Objective: Parkinson’s disease (PD) has long been viewed from a neurocentric perspective; however, increasing evidence indicates that glial dysfunction also contributes to dopaminergic neurodegeneration. Although neurotoxic glial phenotypes have been described in amyotrophic lateral sclerosis and Alzheimer’s disease in vivo models, it remains unclear whether similar states arise in the pathological milieu of PD. This study aimed to determine whether glial cells with intrinsic neurotoxic properties emerge in the substantia nigra pars compacta (SNpc) in a PD context. Methods: The classical 6-hydroxydopamine rat model was used to obtain glial cultures from the ipsilateral, toxin-damaged SNpc. These cultures were characterized by quantifying cell number and morphology, as well as by assessing the expression of glial markers. Their neurotoxic potential was evaluated in vitro through co-cultures with PC12 cells, and in vivo by transplanting the isolated cells into the SNpc of naïve rats. Assessments included PC12 cell survival, and integrity of the nigrostriatal pathway and motor performance in the cylinder test. Results: Ipsilateral SNpc cultures yielded 25-fold more cells than contralateral controls. Cultured cells co-expressed astrocytic and microglial markers, thus defining a population of damage-derived reactive glia (DDRG). When co-cultured, DDRG reduced PC12 cell survival, whereas control glial cells showed no neurotoxic effects. In vivo, DDRG transplantation induced a dose-dependent loss of dopaminergic neurons and motor impairments, while vehicle and control glia produced no detectable effects. Conclusions: Our findings suggest that glial cells emerging from a neuroinflammatory/neurodegenerative environment in the SNpc may contribute to dopaminergic neuron loss. Within the context of the experimental PD model used, DDRG appears to represent a glial population with potential pathogenic relevance and may constitute a candidate target for further investigation as a therapeutic strategy in Parkinson’s disease. Full article

COVID-19 has raised significant concern regarding its neurological impact, particularly during the early pandemic waves when severe systemic inflammation and neuroimmune dysregulation were more common. Although SARS-CoV-2 has been extensively studied, the precise mechanisms underlying its neurological effects remain incompletely understood, and much of the available evidence is derived from early variants with higher pathogenicity. Current research indicates that neuroinflammatory processes—driven primarily by systemic cytokine elevation, microglial activation, and blood–brain barrier dysfunction—contribute to a wide range of neurological symptoms. Severe complications such as encephalopathy, stroke, and cognitive impairment were predominantly reported in critically ill patients infected with the Wuhan, Alpha, or Delta variants, while such manifestations are considerably less frequent in the Omicron era. Most proposed mechanisms, including ACE2-mediated viral entry into the central nervous system, are supported mainly by experimental or preclinical studies rather than definitive human evidence. Biomarkers such as IL-6 and TNF-α, along with neuroimaging modalities including MRI and PET, offer useful but indirect indicators of neuroinflammation. Therapeutic approaches continue to focus on controlling systemic inflammation through immunomodulatory agents, complemented by targeted non-pharmacological strategies—such as physical rehabilitation, cognitive support, and psychological interventions—for the minority of patients with persistent neurological deficits. Overall, current evidence supports a variant-dependent neuroinflammatory profile and underscores the need for longitudinal, mechanism-focused studies to better characterize long-term neurological outcomes and refine therapeutic strategies. Full article

The microglia, first identified by Pío del Río-Hortega, are resident macrophages in the CNS that aid in immune monitoring, synaptic remodeling, and tissue repair. Microglial biology’s dual functions in maintaining homeostasis and contributing to neurodegeneration are examined in this review, with a focus on neurodegenerative disease treatment targets. Methods: We reviewed microglial research using single-cell transcriptomics, molecular genetics, and neuroimmunology to analyze heterogeneity and activation states beyond the M1/M2 paradigm. Results: Microglia maintains homeostasis through phagocytosis, trophic factor production, and synaptic pruning. They acquire activated morphologies in pathological conditions, releasing proinflammatory cytokines and reactive oxygen species via NF-κB, MAPK, and NLRP3 signaling. Single-cell investigations show TREM2 and APOE-expressing disease-associated microglia (DAM) in neurodegenerative lesions. Microglial senescence, mitochondrial failure, and chronic inflammation result from Nrf2/Keap1 redox pathway malfunction in ageing. Microglial interactions with astrocytes via IL-1α, TNF-α, and C1q result in neurotoxic or neuroprotective A2 astrocytes, demonstrating linked glial responses. Microglial inflammatory or reparative responses are influenced by epigenetic and metabolic reprogramming, such as regulation of PGC-1α, SIRT1, and glycolytic flux. Microglia are essential to neuroprotection and neurodegeneration. TREM2 agonists, NLRP3 inhibitors, and epigenetic modulators can treat chronic neuroinflammation and restore CNS homeostasis in neurodegenerative illnesses by targeting microglial signaling pathways. Full article

Background/Objectives: A healthy lifestyle based on a balanced diet promotes overall well-being and supports brain health, while the consumption of high-energy foods can negatively affect cognitive function, particularly during early developmental stages, such as adolescence. Astrocytes are essential for brain homeostasis, including modulation of neurogenesis in the hippocampus, a region involved in cognitive functions. The impact of short-term high-fat diet (HFD) exposure on astrocytes during adolescence remains unclear. In this study, we examined if brief periods of HFD influence astrocyte morphology, density, and territory volume and, in parallel, the maturation of doublecortin-positive (DCX⁺) cells in the dorsal hippocampus of adolescent male mice. Methods: We performed 3D reconstructions, analyzed morphometric features as well as other parameters of astrocytes and DCX⁺ cells following 1 week of HFD (1 w-HFD), 2 weeks of HFD (2 w-HFD), and 1 week of HFD followed by 1 week of return to a low-fat diet (1 w-HFD – 1w-LFD). Results: We observed that 1 w-HFD significantly increased astrocyte morphological complexity and density compared with the control group (1 w-LFD). After 2 w-HFD, astrocyte complexity declined, whereas density was unchanged. Notably, in the 1 w-HFD – 1 w-LFD group, astrocyte complexity was comparable to that of the 2 w-HFD group; density increased compared to both control groups (2 w-LFD and 2 w-HFD). Moreover, both 1 w- and 2 w-HFD impaired granular cell layer (GCL) DCX⁺ cells density and maturation, and a return to LFD after 1 w-HFD restored maturation but not density. Conclusions: Altogether, these data suggest that short-term HFD exposure has complex effects on GCL astrocytes and impairs DCX⁺ cell maturation in the dorsal hippocampus of adolescent mice. Full article

Introduction: This study investigates how early aging affects the rat brain, focusing on aquaporin-4 and IL-17 levels in the whole brain, as well as glial cell alterations in the hippocampus. The hippocampus, essential for learning and memory, undergoes age-related changes contributing to cognitive decline and neuroinflammation. Glial cells—particularly microglia and astrocytes—are central to these processes. Most research focuses on advanced aging; in this study, we examine early aging effects. Methods: Male Wistar rats (13 weeks and 13 months old) were used. Whole-brain IL-17 and aquaporin-4 levels were assessed by ELISA. Immunohistology targeting GFAP, Iba1, and CD31 was performed on hippocampal sections to assess glial and vascular changes in CA1, CA2/3, and the dentate gyrus (DG). Results: Middle-aged rats brains showed significantly higher IL-17 and aquaporin-4 levels, confirming low-grade inflammation and metabolic alteration. In the hippocampus, microglia, astrocytes, and cerebral microvessels increased in CA2/3, with no significant changes in CA1 or DG. Conclusions: Early aging induces whole-brain neuroinflammation and metabolic changes and region-specific hippocampal alterations, with CA2/3 being particularly susceptible. These findings advance understanding of early brain aging and highlight CA2/3 as a potential target for intervention. Full article

Oligodendrocytes (OLs) constitute the main glial population in the central nervous system and are indispensable for the stability and performance of neural networks. Although best known for generating and maintaining myelin to speed impulse conduction, their influence extends further. By modulating myelin in response to activity, supplying metabolic substrates, and engaging in neuroimmune communication, OLs help preserve the structural integrity and plasticity of neuronal circuits. Growing evidence now positions defective OLs as central players in Alzheimer’s disease (AD). Experimental work suggests that OL injury can act as an early trigger, fostering amyloid-β (Aβ) deposition and Tau hyperphosphorylation. Conversely, toxic Aβ aggregates and pathological Tau proteins damage OLs, causing myelin breakdown and progressive neurodegeneration that fuels a self-perpetuating cycle. Here, we synthesize current knowledge of OL physiology and its multifaceted contributions to AD pathogenesis, with particular attention to the bidirectional interplay between OL dysfunction and the disease’s core features—Aβ and tau. On this basis, we outline prospective therapeutic avenues to protect or restore oligodendrocyte function in AD. Full article

Maternal immune activation (MIA) during pregnancy has been associated with increased risk of fetal loss and neurodevelopmental disorders in offspring. This review summarizes recent findings on the effects of MIA on fetal survival and microglial phenotype. Studies using polyinosinic–polycytidylic acid [poly(I:C)-induced MIA mouse models have revealed the crucial role of interleukin-17A (IL-17A) in mediating these effects. Overexpression of RORγt, a key transcription factor for IL-17A production, enhances poly(I: C)-induced fetal loss, possibly due to increased placental vulnerability. Intraventricular administration of IL-17A in fetal brains activates microglia and alters their localization, particularly in periventricular regions and the medial cortex. These activated microglia may contribute to abnormal synaptic pruning and excessive phagocytosis of neural progenitor cells, potentially leading to long-term neurodevelopmental abnormalities. The insights gained from MIA research have important clinical implications, including the potential for early identification of high-risk pregnancies and the development of novel preventive and therapeutic strategies. Future research should focus on elucidating the roles of other cytokines, determining critical periods of MIA susceptibility, and translating findings to human populations, while carefully considering ethical implications and the need for appropriate risk communication. Full article

Background: Glioblastoma (GBM) remains refractory to chemoradiotherapy. Glial populations—microglia/monocyte-derived macrophages, reactive astrocytes, and the oligodendrocyte lineage—shape both treatment resistance and radiation-related brain injury. Scope: We synthesize how myeloid ontogeny and plasticity, astrocytic hubs (IL-6/STAT3, TGF-β, connexin-43/gap junctions), and oligodendrocyte precursor cells (OPCs)–linked programs intersect with DNA-damage responses, hypoxia-driven metabolism, and extracellular vesicle signaling to support tumor fitness while predisposing normal brain to radiotoxicity. Translational implications: Convergent, targetable pathways (IL-6/JAK–STAT3, TGF-β, chemokine trafficking, DDR/senescence) enable co-design of radiosensitization and neuroprotection. Pragmatic levers include myeloid reprogramming (CSF-1R, CCR2), astrocyte-axis modulation (STAT3, TGF-β, Cx43), and brain-penetrant DDR inhibition (e.g., ATM inhibitors), paired with delivery strategies that raise intratumoral exposure while sparing healthy tissue (focused-ultrasound blood–brain barrier opening, myeloid-targeted dendrimers; Tumor Treating Fields as an approved adjunct therapy). Biomarker frameworks (TSPO-PET, macrophage-oriented MRI radiomics, extracellular vesicle liquid biopsy) can support selection and pharmacodynamic readouts alongside neurocognitive endpoints. Outlook: Timing-aware combinations around radiotherapy and hippocampal/white-matter sparing offer a near-term roadmap for “glia-informed” precision radiotherapy. Full article

Background: During development, reelin sets the pace of neocortical neurogenesis, enabling newborn neurons to migrate. However, whether—and, if so, how—reelin signaling affects the adult neurogenic niches remains uncertain. Methods: In the present study, we use both loss- and gain-of-function genetic approaches, along with in vivo and ex vivo assays, to investigate this question. Results: We show that reelin signaling, resulting in Dab1 phosphorylation, occurs in the ependymal-subependymal zone (EZ/SEZ) of the lateral ventricles, where, along with its associated rostral migratory stream (RMS), the highest density of functional ApoER2 accumulates. Mice deficient in Reelin, ApoER2, or Dab1 exhibit enlarged ventricles and a dysplastic RMS. Moreover, while the conditional ablation of Dab1 in neural progenitor cells (NPCs) enlarges the ventricles and impairs neuroblast clearance from the SEZ, the transgenic misexpression of Reelin in NPCs of Reelin-deficient mice normalizes the ventricular lumen and the density of ependymal cilia, thereby ameliorating neuroblast migration. Consistently, intraventricular infusion of reelin reroutes neuroblasts. Conclusions: These results demonstrate that reelin signaling persists, sustaining the germinal niche of the lateral ventricles and influencing neuroblast migration in the adult brain. Full article

Major Depressive Disorder (MDD) remains a leading cause of disability worldwide, perpetuated by an incomplete understanding of its pathophysiology and the limited efficacy of conventional antidepressants. Historically, research has focused on neuron-centric models, particularly the monoamine hypothesis. However, the field is now recognizing the critical role of glial cells such as astrocytes, microglia, and oligodendrocytes, establishing them as key contributors to the molecular basis of depression. Rather than serving solely supportive roles, these cells actively modulate neuroinflammation, synaptic plasticity, neurotransmitter homeostasis, and metabolic regulation, processes disrupted in MDD. We discuss how stress-induced epigenetic modifications such as histone acetylation, methylation, and DNA methylation are linked to alterations in astrocytic glutamate transport, microglial inflammatory states, and oligodendrocyte-mediated myelination. Special emphasis is placed on the concept of glial transcriptional plasticity, whereby environmental adversity induces durable and cell type specific gene expression changes that underlie neuroinflammation, excitatory–inhibitory imbalance, and white matter deficits observed in MDD. By integrating findings from postmortem human tissue, single-cell omics, and stress-based animal models, this review highlights converging molecular mechanisms linking stress to glial dysfunction. We further outline how targeting glial transcriptional regulators may provide new therapeutic avenues beyond conventional monoaminergic approaches. Full article