Glia最新文献

{"title":"The Concept of Neuroglia - the State of the Art Circa 1900.","authors":"Helmut Kettenmann, Bilge Ugursu, Bruce R Ransom, Christian Steinhäuser","doi":"10.1002/glia.24678","DOIUrl":"https://doi.org/10.1002/glia.24678","url":null,"abstract":"<p><p>Glial cells were first defined by Rudolf Virchow in 1856. About 40 years later, glial research had developed into a field distinct from the mainstream study of neurons as the central elements governing brain function. By that time, substantial knowledge about the properties of glial cells had accumulated, exemplified by five important publications by four distinguished investigators: Gustav Retzius, Michael von Lenhossek, Carl Weigert, and Hans Held. These treatises broadly summarized what was known about glial cells, comparing findings from leeches to humans. Practically speaking, these articles represent the foundation of our current knowledge. All five contributions were published in German, which at the time was one of the dominant languages for scientific exchange. This article summarizes and comments on their findings and thus provides insight into what was known about glial cells at that time. More importantly, in the Supporting Information, we provide English translations and original scans of these five publications, making them accessible to an international readership.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187805","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":"Contributions of Genetic Variation in Astrocytes to Cell and Molecular Mechanisms of Risk and Resilience to Late-Onset Alzheimer's Disease.","authors":"Hyo Lee, Richard V Pearse, Alexandra M Lish, Cheryl Pan, Zachary M Augur, Gizem Terzioglu, Pallavi Gaur, Meichen Liao, Masashi Fujita, Earvin S Tio, Duc M Duong, Daniel Felsky, Nicholas T Seyfried, Vilas Menon, David A Bennett, Philip L De Jager, Tracy L Young-Pearse","doi":"10.1002/glia.24677","DOIUrl":"10.1002/glia.24677","url":null,"abstract":"<p><p>Reactive astrocytes are associated with Alzheimer's disease (AD), and several AD genetic risk variants are associated with genes highly expressed in astrocytes. However, the contribution of genetic risk within astrocytes to cellular processes relevant to the pathogenesis of AD remains ill-defined. Here, we present a resource for studying AD genetic risk in astrocytes using a large collection of induced pluripotent stem cell (iPSC) lines from deeply phenotyped individuals with a range of neuropathological and cognitive outcomes. IPSC lines from 44 individuals were differentiated into astrocytes followed by unbiased molecular profiling using RNA sequencing and tandem mass tag-mass spectrometry. We demonstrate the utility of this resource in examining gene- and pathway-level associations with clinical and neuropathological traits, as well as in analyzing genetic risk and resilience factors through parallel analyses of iPSC-astrocytes and brain tissue from the same individuals. Our analyses reveal that genes and pathways altered in iPSC-derived astrocytes from individuals with AD are concordantly dysregulated in AD brain tissue. This includes increased levels of prefoldin proteins, extracellular matrix factors, COPI-mediated trafficking components and reduced levels of proteins involved in cellular respiration and fatty acid oxidation. Additionally, iPSC-derived astrocytes from individuals resilient to high AD neuropathology show elevated basal levels of interferon response proteins and increased secretion of interferon gamma. Correspondingly, higher polygenic risk scores for AD are associated with lower levels of interferon response proteins in astrocytes. This study establishes an experimental system that integrates genetic information with a matched iPSC lines and brain tissue data from a large cohort of individuals to identify genetic contributions to molecular pathways affecting AD risk and resilience.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121866","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 3","authors":"","doi":"10.1002/glia.24548","DOIUrl":"https://doi.org/10.1002/glia.24548","url":null,"abstract":"<p>\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 3","pages":"C1"},"PeriodicalIF":5.4,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24548","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121340","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":"Glia Modulates Immune Responses in the Retina Through Distinct MHC Pathways","authors":"Simona Intonti,&nbsp;Despina Kokona,&nbsp;Martin S. Zinkernagel,&nbsp;Volker Enzmann,&nbsp;Jens V. Stein,&nbsp;Federica M. Conedera","doi":"10.1002/glia.24656","DOIUrl":"10.1002/glia.24656","url":null,"abstract":"<p>Glia antigen-presenting cells (APCs) are pivotal regulators of immune surveillance within the retina, maintaining tissue homeostasis and promptly responding to insults. However, the intricate mechanisms underlying their local coordination and activation remain unclear. Our study integrates an animal model of retinal injury, retrospective analysis of human retinas, and in vitro experiments to gain insights into the crucial role of antigen presentation in neuroimmunology during retinal degeneration (RD), uncovering the involvement of various glial cells, notably Müller glia and microglia. Glial cells act as sentinels, detecting antigens released during degeneration and interacting with T-cells via MHC molecules, which are essential for immune responses. Microglia function as APCs via the MHC Class II pathway, upregulating key molecules such as Csf1r and cytokines. In contrast, Müller cells act through the MHC Class I pathway, exhibiting upregulated antigen processing genes and promoting a CD8⁺ T-cell response. Distinct cytokine signaling pathways, including TNF-α and IFN Type I, contribute to the immune balance. Human retinal specimens corroborate these findings, demonstrating glial activation and MHC expression correlating with degenerative changes. In vitro assays also confirmed differential T-cell migration responses to activated microglia and Müller cells, highlighting their role in shaping the immune milieu within the retina. In summary, our study emphasizes the involvement of retinal glial cells in modulating the immune response after insults to the retinal parenchyma. Unraveling the intricacies of glia-mediated antigen presentation in RD is essential for developing precise therapeutic interventions for retinal pathologies.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 4","pages":"822-839"},"PeriodicalIF":5.4,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24656","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051156","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":"The Impact of Astroglia Kir4.1 Channel Dysfunction on Neuronal Activity and Autism-Related Behavioral Abnormalities.","authors":"Shima Davoudi, Mona Rahdar, Mehdi Borjkhani, Hamid Alavi-Majd, Narges Hosseinmardi, Gila Behzadi, Mahyar Janahmadi","doi":"10.1002/glia.24676","DOIUrl":"https://doi.org/10.1002/glia.24676","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) is marked by neurobehavioral developmental deficits, potentially linked to disrupted neuron-glia interactions. The astroglia Kir4.1 channel plays a vital role in regulating potassium levels during neuronal activation, and mutations in this channel have been associated with ASD. This study investigates astroglia Kir4.1 as a regulator of neuronal excitability and behavioral abnormalities in rats with autistic-like traits induced by prenatal exposure to valproic acid (VPA). Whole-cell patch-clamp recordings were obtained from pyramidal neurons in the hippocampal CA1 region, showing that inhibition of Kir4.1 channels led to electrophysiological changes indicative of neuronal hyperexcitability, similar to that seen in VPA-exposed neurons. Specifically, there was increased input resistance and voltage threshold, alongside decreased time constant and rheobase. Behavioral assessments after 7 days of intrahippocampal PA6 (5 μg/mL/day) administration revealed significant social withdrawal, heightened anxiety, reduced exploration, and impaired recognition memory, underscoring the behavioral deficits linked to autism. While Kir4.1 inhibition affected excitability, it did not alter the output of CA1 pyramidal neurons in autistic-like rats. These findings emphasize the critical role of astroglia Kir4.1 channels in modulating neuronal excitability and associated behavioral impairments within the VPA-induced autism model, suggesting a promising target for future therapeutic interventions.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997042","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":"CD11c-Expressing Microglia Are Transient, Driven by Interactions With Apoptotic Cells.","authors":"Nathaniel Ghena, Sarah R Anderson, Jacqueline M Roberts, Emmalyn Irvin, Joon Schwakopf, Alejandra Bosco, Monica L Vetter","doi":"10.1002/glia.24674","DOIUrl":"10.1002/glia.24674","url":null,"abstract":"<p><p>Microglia, the parenchymal macrophage of the central nervous system, serve crucial remodeling functions throughout development. Microglia are transcriptionally heterogenous, suggesting that distinct microglial states confer discrete roles. Currently, little is known about how dynamic these states are, the cues that promote them, or how they impact microglial function. In the developing retina, we previously found a significant proportion of microglia express CD11c (Integrin αX, Itgax, subunit of complement receptor 4) which has also been reported in other developmental and disease contexts. Here, we sought to understand the regulation and function of CD11c+ microglia. We found that CD11c+ microglia track with prominent waves of neuronal apoptosis in postnatal retina. Using genetic fate mapping, we provide evidence that microglia transition out of the CD11c state to return to homeostasis. We show that CD11c+ microglia have elevated lysosomal content and contribute to the clearance of apoptotic neurons, and found that acquisition of CD11c expression is partially dependent upon the TAM receptor AXL. Using selective ablation, we found CD11c+ microglia are not uniquely critical for phagocytic clearance of apoptotic cells. Together, our data suggest that CD11c+ microglia are a transient state induced by developmental apoptosis rather than a specialized subset mediating phagocytic elimination.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997041","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":"Acute Extrinsic Activation of the RANKL Pathway Decreases Wound Healing and Functional Recovery After Spinal Cord Injury in Mice.","authors":"A L Vivinetto, A Bernstein, M Soliman, J W Cave, E Hollis","doi":"10.1002/glia.24667","DOIUrl":"https://doi.org/10.1002/glia.24667","url":null,"abstract":"<p><p>Manipulating wound healing-associated signaling after SCI presents a promising avenue for increasing the recovery of function after injury. This study explores the potential of targeting molecular regulators of wound healing, initially identified in nonneural tissues, to enhance outcomes after SCI. Astrocytes, pivotal in central nervous system wound healing, play a crucial role in tissue remodeling and recovery. However, the optimal manipulation of astrogliosis for beneficial outcomes remains elusive. Previous research demonstrated a transcriptional response in astrocytes resembling epithelial-to-mesenchymal transitions (EMTs) after CNS injury. Here, we investigate the extrinsic manipulation of wound healing through the Receptor Activator of Nuclear-factor Kappa-Β (RANK) pathway, known for its involvement in nonneural tissue remodeling and linked to EMT pathway. Using a severe thoracic spinal cord contusion mouse model, we demonstrate that acute activation of the RANK pathway with RANK ligand (RANKL) adversely affects tissue remodeling, resulting in larger lesion volumes and delayed recovery of posture and locomotion. These findings suggest that early perturbations in the tight molecular regulation of tissue remodeling negatively impact the wound-healing process after SCI. The study provides a proof-of-concept demonstration that exogenous nonneural remodeling ligands can modify astrocyte responses and functional recovery after SCI, raising questions about the optimal time frame for beneficial remodeling interventions during injury progression. These insights open new avenues for therapeutic strategies aimed at improving functional outcomes following SCI.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997021","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":"Astrocytes Mediate Psychostimulant-Induced Alterations of Spike-Timing Dependent Synaptic Plasticity.","authors":"Samuel Alberquilla, Carmen Nanclares, Sara Expósito, Grace Gall, Paulo Kofuji, Alfonso Araque, Eduardo D Martín, Rosario Moratalla","doi":"10.1002/glia.24672","DOIUrl":"https://doi.org/10.1002/glia.24672","url":null,"abstract":"<p><p>At cellular and circuit levels, drug addiction is considered a dysregulation of synaptic plasticity. In addition, dysfunction of the glutamate transporter 1 (GLT-1) in the nucleus accumbens (NAc) has also been proposed as a mechanism underlying drug addiction. However, the cellular and synaptic impact of GLT-1 alterations in the NAc remain unclear. Here we show in the NAc that 10 days withdraw after 5 days treatment with cocaine or amphetamine decreases GLT-1 expression in astrocytes, which results in the prolongation of the excitatory postsynaptic potential (EPSP) decay kinetics in D1 receptor-containing medium spiny neurons (D1R-MSNs). Using the spike timing dependent plasticity (STDP) paradigm, we found that enlargement of EPSP duration results in switching the LTP elicited in control animals to LTD in psychostimulant-treated mice. In contrast to D1-MSNs, D2-MSNs did not display changes in EPSP kinetics and synaptic plasticity. Notably, the psychostimulant-induced synaptic transmission and synaptic plasticity effects were absent in IP3R2^-/- mice, which lack astrocyte calcium signal, but were mimicked by the selective astrocytes stimulation with DREADDs. Finally, ceftriaxone, which upregulates GLT-1, restored normal GLT-1 function, EPSP kinetics, and synaptic plasticity in psychostimulant-treated mice. Therefore, we propose that cocaine and amphetamine increase dopaminergic levels in the NAc, which stimulates astrocytes and downregulates the GLT-1. The decreased GLT-1 function prolonged the EPSP kinetics, leading to the modulation of the STDP, transforming the LTP observed in control animals into LTD in psychostimulant-treated mice. Present work reveals a novel mechanism underlying the synaptic plasticity changes induced by these drugs of abuse.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968961","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":"Temperature Regulates Astroglia Morphogenesis Through Thermosensory Circuitry in Caenorhabditis elegans.","authors":"Junyu Zheng, Mengqing Wang, Shaocheng Wang, Zhiyong Shao","doi":"10.1002/glia.24668","DOIUrl":"https://doi.org/10.1002/glia.24668","url":null,"abstract":"<p><p>Astrocytes are the most abundant type of macroglia in the brain and play crucial roles in regulating neural development and functions. The diverse functions of astrocytes are largely determined by their morphology, which is regulated by genetic and environmental factors. However, whether and how the astrocyte morphology is affected by temperature remains largely unknown. Here we discovered that elevated cultivation temperature (26°C) stimulates Caenorhabditis elegans ventral CEPsh glia endfoot extension during early developmental stages. This extension depends on the activation of glutamate AWC neurons, which inhibit the postsynaptic cholinergic AIY interneurons through glutamate-gated chloride channels, GLC-3 and GLC-4. In responding to the thermosensory signal, the guanyl-nucleotide exchange factor EPHX-1 and Rho GTPase CDC-42/Cdc42 in the glia facilitate the endfoot extension via F-actin assembly. This study elucidates the significant role of thermosensory circuitry in glia morphogenesis and the underlying molecular mechanism.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941671","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":"Characterizing Microglial Signaling Dynamics During Inflammation Using Single-Cell Mass Cytometry.","authors":"Sushanth Kumar, August D Kahle, Austin B Keeler, Eli R Zunder, Christopher D Deppmann","doi":"10.1002/glia.24670","DOIUrl":"10.1002/glia.24670","url":null,"abstract":"<p><p>Microglia play a critical role in maintaining central nervous system (CNS) homeostasis and display remarkable plasticity in their response to inflammatory stimuli. However, the specific signaling profiles that microglia adopt during such challenges remain incompletely understood. Traditional transcriptomic approaches provide valuable insights, but fail to capture dynamic post-translational changes. In this study, we utilized time-resolved single-cell mass cytometry (CyTOF) to measure distinct signaling pathways activated in microglia upon exposure to bacterial and viral mimetics-lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid (Poly(I:C)), respectively. Furthermore, we evaluated the immunomodulatory role of astrocytes on microglial signaling in mixed cultures. Microglia or mixed cultures derived from neonatal mice were treated with LPS or Poly(I:C) for 48 h. Cultures were stained with a panel of 33 metal-conjugated antibodies targeting signaling and identity markers. High-dimensional clustering analysis was used to identify emergent signaling modules. We found that LPS treatment led to more robust early activation of pp38, pERK, pRSK, and pCREB compared to Poly(I:C). Despite these differences, both LPS and Poly(I:C) upregulated the classical reactivity markers CD40 and CD86 at later time points. Strikingly, the presence of astrocytes significantly blunted microglial responses to both stimuli, particularly dampening CD40 upregulation. Our studies demonstrate that single-cell mass cytometry effectively captures the dynamic signaling landscape of microglia under pro-inflammatory conditions. This approach may pave the way for targeted therapeutic investigations of various neuroinflammatory disorders. Moreover, our findings underscore the necessity of considering cellular context, such as astrocyte presence, in interpreting microglial behavior during inflammation.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941665","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}