Glia最新文献

{"title":"Impaired Volume Regulation and Electrophysiology of Astrocytes In Situ in a Mouse Model for Megalencephalic Leukoencephalopathy With Subcortical Cysts.","authors":"Sven Kerst, Nina Meesters, Tim S Heistek, Marjo S van der Knaap, Huibert D Mansvelder, Rogier Min","doi":"10.1002/glia.70047","DOIUrl":"https://doi.org/10.1002/glia.70047","url":null,"abstract":"<p><p>Electrical signaling, driven by ion fluxes between intra- and extracellular compartments, is central to brain functioning. Astrocytes provide crucial support by maintaining the homeostasis of water and ions in the brain. This is disrupted in the leukodystrophy Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC). Studies on cultured primary astrocytes and other isolated cell lines point to a central defect in astrocyte volume regulation in MLC. However, cell culture severely alters the properties and polarity of astrocytes. Therefore, whether astrocytes in the intact MLC brain exhibit aberrant physiology related to water and ion homeostasis remains unknown. To investigate astrocyte physiology in intact astrocytes, we performed experiments in acute brain slices from a validated MLC mouse model, the Glialcam-null mouse. We combined viral sensor delivery with two-photon microscopy to study astrocyte volume regulation and associated chloride dynamics. Cortical Glialcam-null astrocytes showed normal intracellular chloride dynamics but reduced volume recovery upon potassium-induced cell swelling. Whole-cell patch-clamp recordings revealed a modestly depolarized resting membrane potential and slower glutamate uptake in Glialcam-null astrocytes. Gap junction coupling of the astrocyte syncytium was modestly reduced, but it remained sufficient to preserve functional electrical isopotentiality. In conclusion, our findings confirm that the previously observed disturbance of astrocyte volume regulation observed in cultured cells is also observed in intact astrocytes in situ, and we uncover additional changes in astrocyte electrophysiological properties. These findings support the concept that dysfunctional astrocyte volume regulation is central to the MLC disease mechanism.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover Image, Volume 73, Issue 7","authors":"Joseph Matthew Holden,&nbsp;Andrew M. Boal,&nbsp;Lauren Katie Wareham,&nbsp;David John Calkins","doi":"10.1002/glia.24556","DOIUrl":"https://doi.org/10.1002/glia.24556","url":null,"abstract":"<p>Cover Illustration: Stochastically labeled astrocytes (cyan) and Müller glia (magenta) contacting blood vessels (orange) and neural cell bodies and axons bundles (green) in a mouse retina. (See Holden, JM, et al, https://doi.org/10.1002/glia.70022)\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 7","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24556","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myelin Lipid Composition in the Central Nervous System Is Regionally Distinct and Requires Mechanistic Target of Rapamycin Signaling.","authors":"Marie L Mather, Angelina V Evangelou, Jennifer N Bourne, Wendy B Macklin, Teresa L Wood","doi":"10.1002/glia.70042","DOIUrl":"https://doi.org/10.1002/glia.70042","url":null,"abstract":"<p><p>Cholesterol is highly enriched in the myelin sheath and is often dysregulated in neurodegenerative diseases affecting myelin integrity. Despite the prominence of promyelinating drugs targeting sterol synthesis and our increasing knowledge of oligodendrocyte heterogeneity, few studies have defined regional differences in lipid metabolism across the CNS. Previous analyses revealed that spinal cord oligodendroglia have a higher capacity for endogenous cholesterol biosynthesis compared to brain oligodendroglia. Our current findings reveal that, in contrast to spinal cord oligodendroglia, brain oligodendroglia have a higher capacity to uptake and respond to extracellular lipoproteins. Moreover, brain myelin has lower lipid concentrations compared to spinal cord myelin. Comparisons between spinal cord and subregions of the brain revealed that myelin lipid content is correlated to average axon diameter such that regions with smaller diameter axons, such as corpus callosum and cortical gray matter, have myelin with lower cholesterol and phospholipid content compared to regions containing higher diameter axons, including spinal cord and brain stem. When differentiated on synthetic nanofibers in vitro, spinal cord oligodendrocytes maintained a higher cholesterol content compared to brain oligodendrocytes irrespective of fiber diameter but displayed fiber diameter-dependent changes in fatty acid content. Establishment and maintenance of regional differences in myelin composition are supported by the mechanistic target of rapamycin (mTOR) signaling, as deletion of mTOR in oligodendroglia abolishes regional differences in myelin lipid content, with the greatest decreases in spinal cord and brain stem. These data highlight multiple differences in brain and spinal cord lipid metabolism, which result in regionally distinct myelin composition.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial Transcriptomic Analysis Reveals HDAC Inhibition Modulates Microglial Dynamics to Protect Against Ischemic Stroke in Mice.","authors":"Kevin Jayaraj, Ritesh Kumar, Sukanya Shyamasundar, Thiruma V Arumugam, Jai S Polepalli, S Thameem Dheen","doi":"10.1002/glia.70035","DOIUrl":"https://doi.org/10.1002/glia.70035","url":null,"abstract":"<p><p>Ischemic stroke significantly contributes to global morbidity and disability through a cascade of neurological responses. Microglia, the immune modulators within the brain, exhibit dual roles in exacerbating and ameliorating ischemic injury through neuroinflammatory and neuroprotective roles, respectively. Despite emerging insights into microglia's role in neuronal support, the potential of epigenetic intervention to modulate microglial activity remains largely unexplored. We have previously shown that sodium butyrate, a histone deacetylase inhibitor (HDACi) epigenetically regulates the inflammatory response of microglia after ischemic stroke, and this study was aimed at characterizing the transcriptomic profiles of microglia and their spatial distribution in the stroke brain following HDACi administration. We hypothesized that the administration of HDACi epigenetically modulates microglial activation and a region-specific microglial phenotype in the stroke brain, shifting their phenotype from neurotoxic to neuroprotective and facilitating neuronal repair in the ischemic penumbra. Utilizing a rodent model of stroke, spatial transcriptomics and 3D morphometric reconstruction techniques were employed to investigate microglial responses in critical penumbral regions following HDACi administration. We found HDACi significantly altered the microglial transcriptomic landscape involving biological pathways of neuroinflammation, neuroprotection, and phagocytosis, as well as morphological phenotype, promoting a shift toward reparative, neurotrophic profiles within the ischemic penumbra. These changes were associated with enhanced neuronal survival and reduced neuroinflammation in specific regions in the ischemic brain. By elucidating the mechanisms through which HDACi influences microglial function, our findings propose therapeutic avenues for neuroprotection and rehabilitation in ischemic stroke, and possibly other neurodegenerative conditions that involve microglia-mediated neuroinflammation.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Morphological Characterization of Glial Cells Surrounding Cajal's Initial Glomerulus of the Dorsal Root Ganglion Neurons Revealed Myelinating Schwann Cell Production.","authors":"Taro Koike, Souichi Oe, Yukie Hirahara, Shinichi Hayashi, Ryohei Seki-Omura, Yosuke Nakano, Yuki Sato, Hikaru Iwashita, Mitsuyo Maeda, Yosky Kataoka, Susumu Tanaka, Tetsuji Mori, Hisao Yamada, Masaaki Kitada","doi":"10.1002/glia.70046","DOIUrl":"https://doi.org/10.1002/glia.70046","url":null,"abstract":"<p><p>Satellite glial cells (SGCs) cover the following two areas of a large-diameter dorsal root ganglion (DRG) neuron: neuronal soma and initial region of the neuronal projection, namely Cajal's initial glomerulus (IG). The morphological and functional features of SGCs covering the neuronal soma have been studied extensively. However, those of SGCs surrounding the IG [periaxonal SGCs (aSGCs)] are poorly understood. In the present study, we aimed to investigate the histological characteristics of aSGCs in adult rats. The IG's length was approximately 120 μm, where approximately 10 aSGCs surrounded the IG. The SGC markers, including Kca2.3, Kir4.1, and FABP7, were obviously expressed in aSGCs located in the proximal and middle parts of the IG. Contrarily, the signal intensity of these cell markers decreased in aSGCs surrounding the distal part of the IG, and these cells expressed the promyelinating Schwann cell marker Oct-6. Electron microscopy revealed aSGCs winding their thin processes around the IG. Additionally, the 5-bromo-2'-deoxyuridine incorporation study demonstrated that these glial cells matured into myelinating Schwann cells. Oct-6-positive aSGCs were also found in the IG in the human DRG. Our results collectively imply that the IG is involved in the differentiation and maturation of Schwann cells, where aSGCs gradually change their ultrastructural characteristics and immunoreactivity to differentiate and mature into myelinating Schwann cells through the promyelinating stage, and that this differentiation and maturation system may be conserved among mammals.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathways to Progressive Disability in Multiple Sclerosis: The Role of Glial Cells in Chronic CNS Inflammation.","authors":"Volker Siffrin","doi":"10.1002/glia.70044","DOIUrl":"https://doi.org/10.1002/glia.70044","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is the most common non-infectious inflammatory CNS disease, characterized by progressive neurodegeneration and focal demyelinated lesions. Traditionally considered an autoimmune disease, MS is driven by the immune system's attack on CNS myelin, resulting in cumulative disability. However, conventional anti-inflammatory treatments often fail to prevent progressive deterioration, particularly in the absence of overt inflammation, highlighting the need for a deeper understanding of its pathogenesis. Recent research has revealed a more complex disease mechanism involving both peripheral immune responses and intrinsic CNS factors, with glial cells playing a central role. Persistent inflammation in MS is associated with mixed active/inactive lesions dominated by microglia and astrocyte dysregulation. These glial populations exhibit maladaptive activation, contributing to failed remyelination and ongoing neurodegeneration. Transcriptomic and epigenomic alterations as well as aging further exacerbate glial dysfunction, creating a self-perpetuating cycle of inflammation and damage. Emerging evidence suggests that the interplay between peripheral immune cells and glial populations and the potential dual-use nature of molecular tools shared by the immune system and CNS disrupts homeostatic signaling, leading to a loss of tissue integrity. This review synthesizes findings on glial cell biology in MS, with a focus on microglia and astrocytes, while addressing their roles in demyelination, synapse loss, and neurodegeneration. The limitations of animal models, particularly EAE, in replicating the complexity of MS are also addressed. Finally, critical questions are outlined to guide future research into glial pathology and to identify novel therapeutic approaches targeting progressive MS.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping Glial Autophagy Dynamics in an Amyotrophic Lateral Sclerosis Mouse Model Reveals Microglia and Astrocyte Autophagy Dysfunction.","authors":"Nirma D Perera, Subhavi De Silva, Doris Tomas, Brittany Cuic, Bradley J Turner","doi":"10.1002/glia.70045","DOIUrl":"https://doi.org/10.1002/glia.70045","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is defined by motor neuron death. However, recent research has identified non-cell-autonomous mechanisms, with significant involvement of glia in disease progression. We link previous observations of intracellular protein aggregates in glia to the autophagy pathway, the primary mediator of intracellular degradation of large protein aggregates. While dysfunctional autophagy is reported in ALS motor neurons, pre-clinical and clinical outcomes of autophagy modulators have been inconsistent, indicating the need for a nuanced understanding of autophagy dynamics across CNS cell types and ALS-affected regions. We hypothesized that glial autophagy is defective in ALS, with glial-type-specific dysfunction. To investigate in vivo autophagy dynamics, we intercrossed SOD1^G93A mice with transgenic RFP-EGFP-LC3 autophagy reporter mice, enabling the quantification of autophagy degradation, termed flux. Investigation of autophagy dynamics in SOD1 oligodendrocytes, microglia, and astrocytes at key disease stages uncovered useful insights. While oligodendrocytes seemed to mount effective compensatory autophagic responses to combat mutant SOD1, significantly increased autophagy flux was observed in symptomatic spinal microglia and astrocytes in comparison to controls. Symptomatic SOD1 astrocytes displayed greater autophagy dysfunction compared to microglia, with subcellular analysis revealing cell compartment-specific, transient autophagy defects that returned to control levels by end stage. Interestingly, spinal glia showed more pronounced and earlier autophagy dysfunction compared to motor cortex glia, where autophagy dysfunction emerged later in disease end stage, aligning with greater spinal cord pathology reported in this model. Our results suggest that cell-type- and time-specific targeting might be essential when developing autophagy therapeutics for ALS, with prioritization of astrocytic autophagy modulation.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"What Does Iron Mean to an Oligodendrocyte?","authors":"Quinn W Wade, James R Connor","doi":"10.1002/glia.70043","DOIUrl":"https://doi.org/10.1002/glia.70043","url":null,"abstract":"<p><p>Iron is essential for life and plays a key role in multiple fundamental cellular functions. The brain has the highest rate of energy consumption, and within the brain, oligodendrocytes have the highest level of oxidative metabolism per volume. Oligodendrocytes also stain the strongest for iron. The high requirement for iron is related to an oligodendrocyte's primary function to produce the myelin sheath, which requires iron as a cofactor. In addition to the high-energy demands that accompany the production of such dense and extensive membranous sheaths, iron is also required for lipid synthesis. Although the involvement of iron in oligodendrocyte functioning is clear, how iron is specifically acquired and utilized by oligodendrocytes is not completely understood. The purpose of this review is to provide a complete and thorough overview of the role of iron in oligodendrocytes. Here, we discuss in detail what is currently known about key iron transport proteins that participate in the balance of iron in oligodendrocytes. Understanding how oligodendrocytes utilize iron is beneficial in understanding dysmyelinating diseases, and the knowledge could be utilized to develop treatment options.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glial Versus Neuronal Na⁺/K⁺-ATPase in Activity-Evoked K⁺ Clearance and Their Sensitivity to Elevated Extracellular K<sup />.","authors":"Brian Skriver Nielsen, Brian Roland Larsen, Afnan Bilal Ghazal, Adriana Katz, K C Brennan, Steven J D Karlish, Nanna MacAulay","doi":"10.1002/glia.70034","DOIUrl":"https://doi.org/10.1002/glia.70034","url":null,"abstract":"<p><p>Neuronal activity in the central nervous system is associated with a [K⁺]_o transient that is swiftly cleared from the extracellular space, predominantly by the Na⁺/K⁺-ATPase. The temporal contribution of the glial (α2β2) and the neuronal (α3β1) isoform complexes remains unresolved due to the lack of an isoform-specific inhibitor. The role of the two main brain isoform complexes in spreading depression (SD) also remains unresolved, but an SD-mediated increase in [K⁺]_o may suppress Na⁺/K⁺-ATPase activity and thereby promote SD propagation. As demonstrated here, inhibitor assays of purified recombinant human and heterologously expressed rat Na⁺/K⁺-ATPase isoforms demonstrated significant selectivity for inhibition of α2β2 compared to α3β1 isoform complexes by a cyclobutyl perhydro-1,4-oxazepine derivative of digoxin (DcB). This phenomenon was utilized to demonstrate the temporal role of α2β2 and α3β1 in [K⁺]_o clearance in electrically stimulated rat hippocampal slices, as monitored with ion-sensitive microelectrodes. The observations demonstrate a role of α2β2 in regulating the [K⁺]_o during electrical stimulus of hippocampal slices, whereas α3β1 serves to restore [K⁺]_o to baseline post-stimulus. SD can be triggered by elevated [K⁺]_o but elevated [K⁺]_o did not reduce the activity of the Na⁺/K⁺-ATPase or the glutamate transporters in hippocampal brain slices or upon heterologous expression of individual isoforms in Xenopus oocytes. Our results demonstrate the temporal contribution of the glial and neuronal Na⁺/K⁺-ATPase isoform complexes to clearance of [K⁺]_o but do not support the concept that direct effects of elevated [K⁺]_o on Na⁺/K⁺-ATPase activity or glutamate transport underlie SD propagation.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oligodendrogenesis in Evolution, Development and Adulthood.","authors":"Hao Hu, Tianhao Gao, Jingwei Zhao, Huiliang Li","doi":"10.1002/glia.70033","DOIUrl":"https://doi.org/10.1002/glia.70033","url":null,"abstract":"<p><p>Oligodendrogenesis and myelin formation are important processes in the central nervous system (CNS) of jawed vertebrates, underpinning the highly efficient neural computation within the compact CNS architecture. Myelin, the dense lipid sheath wrapped around axons, enables rapid signal transmission and modulation of neural circuits. Oligodendrocytes are generated from oligodendrocyte precursor cells (OPCs), which are widely distributed in the adult CNS and continue to produce new oligodendrocytes throughout life. Adult oligodendrogenesis is integral to adaptive myelination, which fine-tunes neural circuits in response to neuronal activity, contributing to neuroplasticity, learning, and memory. Emerging evidence also highlights the role of oligodendrogenesis in specialized brain regions, linking oligodendrocytes to metabolic and homeostatic functions. In the aging and diseased brain, dysregulated oligodendrogenesis exacerbates myelin loss and may contribute to pathogenesis. In addition, maladaptive myelination driven by aberrant neuronal activity could sustain a dysfunction in conditions such as epilepsy. This review summarizes the current understanding of oligodendrogenesis, with insights into its evolution, regulation, and impact on aging and disease.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}