Glia最新文献

{"title":"Single-Nucleus Multiomic Analysis Reveals Immune–Metabolic Reprogramming Consistent With Maladaptive Trained Immunity in HIV-Associated Neurocognitive Disorders","authors":"Siera Martinez,&nbsp;Anelia Horvath,&nbsp;Luke Johnson,&nbsp;Tatiana Pushkarsky,&nbsp;Larisa Dubrovsky,&nbsp;Daria Starosyla,&nbsp;Ashley Bastin,&nbsp;Dmitri Sviridov,&nbsp;Michael Bukrinsky","doi":"10.1002/glia.70191","DOIUrl":"https://doi.org/10.1002/glia.70191","url":null,"abstract":"<p>HIV-associated neurocognitive disorders (HAND) remain prevalent in people with HIV (PWH) despite effective antiretroviral therapy, suggesting that persistent immune activation contributes to ongoing neurological dysfunction. Maladaptive trained immunity (TRIM), long-term innate immune reprogramming characterized by sustained inflammatory responses, metabolic rewiring, and epigenetic remodeling, has been proposed as a sustaining mechanism. We performed single-nucleus RNA-seq and ATAC-seq on post-mortem brain from PWH with HIV-associated dementia (HAD) or asymptomatic neurocognitive impairment (ANI) and compared these data with published HIV-uninfected (PWoH) datasets. In PWH versus PWoH, glia, led by microglia, showed enrichment of innate immune signaling and upregulation of inflammatory mediators including <i>NLRP3</i>, <i>TLR2</i>, and <i>TLR4</i>. In parallel, glia showed coordinated cholesterol remodeling, with efflux transporter and apolipoprotein upregulation alongside <i>LDLR</i> downregulation, and partial microglial glycolytic reprogramming (<i>PFKFB3</i>, <i>HK2</i>, <i>PGK1</i> upregulation). Chromatin accessibility profiling showed concordant gains at inflammatory, cholesterol regulatory (notably <i>RXRA</i> and <i>APOE</i>), and glycolytic loci. The HAD versus ANI comparison revealed selective reorganization rather than uniform amplification, with increased lipid scavenger receptor accessibility in oligodendrocytes and reduced accessibility at cholesterol efflux and glycolytic loci. Neurons exhibited predominantly bystander epigenetic changes. Three features distinguish this pattern from chronic inflammation alone and align it with trained immunity hallmarks: concordant transcriptional and chromatin-level priming at inflammatory loci, parallel rewiring of glycolytic and cholesterol metabolism, and persistence despite long-term viral suppression. These multiomic data are consistent with maladaptive trained immunity sustaining neuroinflammation in HAND, though functional validation is required.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 8","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70191","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148324507","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":"Alzheimer's Protection by PLCγ2 Compacts Plaques, Redistributes Microglia, and Protects Synapses in AppNL-G-F Mice","authors":"Ryan J. Bevan,&nbsp;Emily Maguire,&nbsp;Eilish Mackinnon,&nbsp;Elisa Salis,&nbsp;Thomas Phillips,&nbsp;Elena Simonazzi,&nbsp;Marieta Vassileva,&nbsp;Nicholas D. Allen,&nbsp;Julie Williams,&nbsp;Philip R. Taylor","doi":"10.1002/glia.70192","DOIUrl":"https://doi.org/10.1002/glia.70192","url":null,"abstract":"<p>The Alzheimer's disease protective P522R <i>PLCG2</i> coding variant (rs72824905) is downstream of TREM2, but how it confers disease protection is poorly understood. Using a <i>Plcg2</i>-R522 knock-in mouse and <i>Plcg2</i>-P522 control on both wildtype and Alzheimer's disease-like <i>App</i>^{<i>NL-G-F</i>} amyloidosis mouse backgrounds, aged mice were assayed for amyloid load, microglial activity, and synaptic integrity. In the absence of Alzheimer's disease-like pathology, the R522 variant increased microglial coverage and was associated with reduced ramification complexity, fewer terminal points, and elevated lysosomal CD68 expression. On the <i>App</i>^{<i>NL-G-F</i>} background, total amyloid burden was unaffected, but expression of the R522 variant led to increased plaque compaction compared to the P522 common variant. The protective R522 variant was also associated with: enhanced microglial engagement with less compact amyloid plaques; reduced microglial localisation around highly compacted plaques; protection from amyloid-induced synapse loss; and decreased engulfment of synaptic material by microglia. Our data indicate a significant direct PLCγ2 role in controlling microglial-plaque interactions and synaptic protection downstream of amyloid deposition, prioritizing it as a therapeutic target, potentially as an adjunct to other approaches, such as those targeting amyloid.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 8","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70192","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148324570","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":"Early Developmental Neuronal Activity Impacts Oligodendrocyte Differentiation Through AMPA Receptors","authors":"Tessa E. Allen,&nbsp;Graham Peet,&nbsp;Luis E. Gomez Wulschner,&nbsp;Won Chan Oh,&nbsp;Wendy B. Macklin","doi":"10.1002/glia.70157","DOIUrl":"10.1002/glia.70157","url":null,"abstract":"<p>Oligodendrocytes produce myelin, a lipid-rich membrane that wraps neuronal axons in the central nervous system to provide metabolic and trophic support and allow for saltatory conduction. Developation requires precisely timed and localized neuron-oligodendrocyte communication. In the mature brain, neuronal activity promotes oligodendrocyte precursor cell (OPC) proliferation and differentiation, but how OPCs respond to neuronal activity in early brain development, before the onset of myelination, is less well characterized. Here, we investigate how glutamatergic neuronal activity regulates early developmental oligodendrocyte maturation in the olfactory system, somatosensory cortex, and corpus callosum in mice. We find that decreased neuronal activity increases oligodendrocyte differentiation in early development, both in a sensory deprivation model and when using in vivo chemogenetics. Conversely, enhanced neuronal activity in early development reduces oligodendrocyte differentiation. Additionally, single-cell RNA sequencing revealed transcriptional changes in oligodendrocytes when neuronal activity was reduced, including upregulation of glutamate receptor gene expression and pathways relating to synapse development. Finally, using ex vivo cortical slice culture, we identify AMPAR signaling as a critical regulator of the later steps of oligodendrocyte maturation, but not the initiation of differentiation.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 8","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70157","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148300450","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":"Longitudinal Tracking of Astrocyte Reactivity During the Development of Chronic Orofacial Neuropathic Pain Using [18F]-SMBT-1 Positron-Emission Tomography","authors":"Lewis S. Crawford,&nbsp;James W. M. Kang,&nbsp;OIivia I. Davanzo,&nbsp;Hyunsol Lim,&nbsp;Sabrina Salberg,&nbsp;Marissa Srgo,&nbsp;Crystal Li,&nbsp;Gaelle M. Emvalomenos,&nbsp;Bianca Jupp,&nbsp;Matthew Long,&nbsp;Wayne Noonan,&nbsp;Mohammad B. Haskali,&nbsp;Richelle Mychasiuk,&nbsp;Kevin A. Keay,&nbsp;Luke A. Henderson","doi":"10.1002/glia.70182","DOIUrl":"10.1002/glia.70182","url":null,"abstract":"<p>Chronic neuropathic pain represents a significant global health burden and is hypothesized to be maintained by an altered astrocyte-neuron interplay. Evidence of astrocyte contributions to neuropathic pain are derived from both post-mortem immunohistochemical analyses and in vivo pharmacological studies. These data cannot provide insights into dynamic changes in astrocytes within an individual as pain develops. Here, we present the first use of [¹⁸F]-SMBT-1, a radioisotope that binds monoamine oxidase-B (MAO-B) in reactive astrocytes, in a longitudinal (35 days) study of the development of orofacial neuropathic pain. We used the chronic constriction injury of the infraorbital nerve (ION-CCI) to produce orofacial neuropathic pain in adult male Sprague–Dawley rats, which we compared to both sham-injury and anesthesia controls. Between 14 and 28 days following ION-CCI, increases in SMBT-1 binding occurred in: the trigeminal nerve, ganglion and the spinal trigeminal nucleus; as well as the nucleus accumbens and dorsal striatum. Increased MAO-B expression in these regions was confirmed using immunohistochemical analysis. MAO-B expression was also confirmed in the ION, the trigeminal ganglion, and trigeminal root entry zone. These data provide evidence of regional and temporally specific increases in astrocyte reactivity, which may be critical for establishing chronic orofacial neuropathic pain. Longitudinal mapping of changes in astrocyte reactivity during the development of chronic orofacial neuropathic pain will provide an opportunity to test the potential of astrocyte specific compounds delivered at specific time points following nerve injury, to determine the key brain regions that could be targeted to prevent and/or reverse the development of chronic neuropathic pain.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 8","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70182","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148275358","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":"Astrocytic mGluR5 Regulation of Synaptic Transmission is Activity-Dependent in Adult Rats","authors":"Sarah Mountadem,&nbsp;Muna L. Hilal,&nbsp;Dylan Pommier,&nbsp;Dorian Arnouil,&nbsp;Valentin Clément Langlais,&nbsp;Vincent Simon,&nbsp;Aurélie Amadio,&nbsp;Marie Miegebielle,&nbsp;Sébastien Marais,&nbsp;Charlène Joséphine,&nbsp;Astrid Cannich,&nbsp;Marjorie Varilh,&nbsp;Julien Bourel,&nbsp;Daniela Cota,&nbsp;Giovanni Marsicano,&nbsp;Alexis-Pierre Bemelmans,&nbsp;Philippe Ciofi,&nbsp;Stéphane Henri Richard Oliet,&nbsp;Aude Panatier","doi":"10.1002/glia.70162","DOIUrl":"10.1002/glia.70162","url":null,"abstract":"<p>Data accumulated over the last two decades have demonstrated that astrocytes play key roles in the regulation of synaptic transmission and plasticity. This is due, among other mechanisms, to their capability to detect and regulate synaptic transmission by expressing receptors and releasing gliotransmitters, respectively. Importantly, in juvenile rats, astrocytes are able to detect glutamate release at the level of individual synapses through mGluR5 and consequently up-regulate excitatory synaptic transmission efficacy through the release of purines. Whether this upregulation is still present in the adult brain is an open question. Using immunohistochemistry and RNAscope on fixed tissue, as well as electrophysiological recordings on acute hippocampal brain slices of adult male rats, we demonstrated that this regulatory pathway also prevails in adult rats. Most surprisingly, such facilitation of glutamate release that is readily observed when a small number of synapses are activated was completely abolished under conditions where a large number of inputs were stimulated. These findings thus suggest that astrocytes integrate the incoming afferent information and adapt their responses depending on the network activity.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 8","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70162","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148262490","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":"Herpes Simplex Virus Type 1 Infects Schwann Cells via Exosomal CD81, Exploits the MVB–Exosomal Pathway, and Induces Demyelination","authors":"Xixi Kang,&nbsp;Freyja Vanden Broucke,&nbsp;Anita Yousefi,&nbsp;Ya Gao,&nbsp;Waqar Zaib,&nbsp;Wim Van Den Broeck,&nbsp;Waqar Saleem,&nbsp;Olivier Schollaert,&nbsp;Moloud Jalilishahmansouri,&nbsp;Tommy Teirlynck,&nbsp;Sofía González Hernández,&nbsp;Febe Lippens,&nbsp;Camille Kaviani,&nbsp;Joren Portaels,&nbsp;Kathlyn Laval","doi":"10.1002/glia.70178","DOIUrl":"10.1002/glia.70178","url":null,"abstract":"<div>\u0000 \u0000 <p>Herpes simplex virus type 1 (HSV1) is a highly prevalent neurotropic pathogen that causes a wide range of diseases, including cold sores, blinding keratitis, and life-threatening encephalitis. HSV1 first replicates in the epithelial cells of the oronasal mucosa and enters the peripheral nervous system (PNS) to establish latency in sensory neurons. HSV1 persistence in the host has been associated with neurological diseases, including multiple sclerosis. Several in vivo studies reported that HSV1 infection can cause PNS and CNS demyelination; however, the viral pathogenesis remains unclear. Schwann cells (SCs) are the main myelinating cells of the PNS, but it is unknown whether they can be infected by HSV1. Here, we demonstrated that HSV1 productively infects SCs, but the infection efficiency is viral strain-dependent. We showed that HSV1 downregulates the expression of the myelin-related PMP22 gene at late stages of infection. In vivo studies confirmed that HSV1 infection induces PNS demyelination with a clear loss of myelin basic protein (MBP) expression observed in infected tissues together with the presence of demyelinating lesions. Besides, we demonstrated that HSV1 hijacks the multivesicular bodies (MVB)-exosomal pathway in SCs in vitro for efficient infection and spread. TEM confirmed the presence of MVB containing virions and the release of extracellular vesicles with virions near the plasma membrane. By function-blocking antibody and siRNA treatments, we demonstrated that HSV1 uses tetraspanin CD81 as the main entry receptor in SCs. Overall, this study provides new insights into the role of SCs in the pathogenesis of herpesviruses and viral-induced demyelination processes.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 8","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148256628","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":"Geranylgeranylacetone-Induced HSP70 Modulates AQP4 Trafficking via SNX27-Retromer to Alleviate Retinal Ischemia/Reperfusion Injury","authors":"Weijian Qian,&nbsp;Lirong Zhang,&nbsp;Xuefeng Cheng,&nbsp;Kaige Xue,&nbsp;Ran Tian,&nbsp;Ping Fan,&nbsp;Jin Xu,&nbsp;Shujuan Zhu,&nbsp;Guoping Qiu,&nbsp;Jianhua Ran,&nbsp;Shengwei Gan","doi":"10.1002/glia.70184","DOIUrl":"10.1002/glia.70184","url":null,"abstract":"<div>\u0000 \u0000 <p>Retinal ischemia/reperfusion (I/R) injury is a major cause of vision loss, characterized by retinal edema and progressive retinal ganglion cell (RGC) death. Aquaporin-4 (AQP4), a water channel abundantly expressed in glial cells, plays a pivotal role in edema formation by regulating water homeostasis. Geranylgeranylacetone (GGA), a clinically approved anti-ulcer drug, functions as a potent and non-toxic inducer of heat shock protein 70 (HSP70) and has recently been implicated in the regulation of aquaporin trafficking. In parallel, the sorting nexin 27 (SNX27)-retromer complex is a key mediator of endosomal sorting and recycling of membrane proteins back to the plasma membrane, thereby maintaining their functional activity. In this study, we demonstrate that retinal I/R injury triggers altered subcellular localization of AQP4, with enhanced internalization compared with sham retinas. Concomitantly, SNX27-retromer expression was significantly upregulated at both mRNA and protein levels, and biochemical as well as imaging assays confirmed its interaction with AQP4. In a pre-ischemia dosing paradigm (prophylactic), GGA markedly attenuated retinal edema and RGC loss, and promoted the interaction between HSP70 and the SNX27-retromer complex. Importantly, GGA treatment reduced SNX27-retromer expression, thereby limiting AQP4 recycling to the plasma membrane and favoring its lysosome-associated trafficking. These effects were largely reversed by quercetin, a pharmacological inhibitor of HSP70, highlighting an HSP70-dependent mechanism. Together, our findings identify a previously unrecognized role of HSP70 in regulating SNX27-retromer–mediated AQP4 trafficking. By disrupting AQP4 recycling, GGA alleviates early retinal edema following I/R injury, providing mechanistic rationale for future therapeutic development.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 8","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148248186","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":"Yin Yang 1 Specifically Supports the Development of Olig2 Positive Cerebellar Astrocytes","authors":"Masoumeh Zarei-Kheirabadi,&nbsp;Katarzyna M. Tyc,&nbsp;Lauren Dain,&nbsp;Maryam Ashrafi Kheirabadi,&nbsp;Jennifer Hanco,&nbsp;Karli Mockenhaupt,&nbsp;Soha Munir,&nbsp;Adam McQuiston,&nbsp;Sandeep K. Singh,&nbsp;Tomasz Kordula","doi":"10.1002/glia.70185","DOIUrl":"10.1002/glia.70185","url":null,"abstract":"<p>Astrocytes regulate the assembly and functions of neural circuits, contribute to synaptic homeostasis, provide metabolic support to neurons, and control ion balance and blood–brain barrier integrity. These cells are morphologically and molecularly very heterogeneous and perform unique functions to accommodate the needs of subsets of neurons. In this study, we identified and characterized a subpopulation of cerebellar astrocytes expressing the transcription factor Olig2 (O2AST). We defined their molecular identity and transcriptional divergence from other well-established subpopulations of cerebellar astrocytes and cells of the oligodendrocyte lineage that also express Olig2. Specific deletion of Olig2 from astrocytes in vivo affects the locomotion of mice. We found that cerebellar O2AST are relatively abundant in the cerebellar nuclei but not in the cerebellar lobes. Cerebellar O2AST highly express a set of unique genes, including <i>Slc6a11, Gpc5, Igsf1, Alpl,</i> and <i>Egfl6</i>. Furthermore, we examined the regulatory influence of the transcription factor Yin Yang 1 (YY1), known to control maturation of cerebellar astrocytes, on O2AST differentiation and morphology. Specific deletion of <i>Yy1</i> from astrocytes increases the number of O2AST in the cerebellar nuclei, affects O2AST differentiation, and cross-communication with the cells of oligodendrocyte lineage, diminishing differentiation of oligodendrocyte precursor cells (OPCs) to mature oligodendrocytes. In sum, our findings reveal a distinct, transcriptionally unique subpopulation of astrocytes expressing Olig2 in the cerebellum, uncovering novel regulatory mechanisms orchestrated by Yy1 during postnatal development.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 8","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70185","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148222197","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":"Anoctamin-1 Is a Calcium-Dependent Chloride Channel (CaCC) in Müller Cells Involved in Cell Volume Regulation","authors":"Alissa Schaefer,&nbsp;Oliver Bludau,&nbsp;Andjela Sekulic,&nbsp;Sena Altunok,&nbsp;Stefan Mergler,&nbsp;Christine von Toerne,&nbsp;Stefanie M. Hauck,&nbsp;Antje Grosche,&nbsp;Olaf Strauß,&nbsp;Nadine Reichhart","doi":"10.1002/glia.70170","DOIUrl":"10.1002/glia.70170","url":null,"abstract":"<div>\u0000 \u0000 <p>Previous functional data showed the presence of Cl⁻ channels in Müller cells, among them Ca²⁺-dependent Cl⁻ channels (CaCC). An important step to understanding the role of CaCC in Müller cell function is the clarification of their molecular identity. Here, we found protein expression of the CaCC anoctamin-1 (Ano1, formerly TMEM16A) in Müller cells in retinal sagittal sections of mouse and rat using immunohistochemistry and proteomic analysis, as well as in the Müller cell lines ImM10 (murine) and MIO-M1 (human), accompanied by Western blot. Patch-clamp analysis of both cell lines under K⁺-free conditions showed the activation of membrane currents through an increase in intracellular free Ca²⁺ using either ionomycin, ATP, or adenosine. These currents were sensitive to several blockers: the broad anoctamin blocker niflumic acid, the CaCC blocker CaCCinh-A01, and the Ano1 blocker T16Ainh-A01. To further explore the function of Ano1 in Müller cells, we investigated the adenosine-dependent volume regulation in mouse Müller cells in freshly isolated sagittal sections under hypoosmotic challenge by blockage of K⁺ channels. T16Ainh-A01 partially reversed the beneficial effect of adenosine on Müller cell volume regulation. We conclude that Ano1 is one of the first functionally validated Cl⁻ channels in Müller cells. Ano1 seems to contribute to the adenosine-driven regulation of ion flow across the Müller cell membrane, which is crucial for clearing extracellular fluid from the retina.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 8","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148222220","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":"Organization of Astrocytic GLT-1 at Cortical Inhibitory Synapses","authors":"Marcello Melone,&nbsp;Michael Di Palma,&nbsp;Annalisa Scimemi,&nbsp;Fiorenzo Conti","doi":"10.1002/glia.70180","DOIUrl":"10.1002/glia.70180","url":null,"abstract":"<p>Glutamate spillover from excitatory synapses modulates neighboring inhibitory synapses, yet the ultrastructural organization of the major glutamate transporter GLT-1 at these sites remains poorly defined. Using quantitative pre-embedding electron microscopy in rat and human cortex, we found that GLT-1-positive astrocytic leaflets (ALs) were frequently juxtaposed to morphologically identified symmetric synapses, with similar prevalence across axo-somatic, proximal axo-dendritic, and distal axo-dendritic subtypes. Because inhibitory synapses are embedded in a dense excitatory neuropil, we applied distance-based phenotyping relative to the nearest asymmetric synapse to define symmetric-associated GLT-1+ ALs. Within this population, distal axo-dendritic symmetric synapses showed shorter AL-to-synaptic-edge distances and were embedded in a tighter local excitatory microenvironment. Post-embedding immunogold further showed that GLT-1 was enriched at the plasma membranes of ALs and localized extrasynaptically relative to symmetric synapses. Consistently, symmetric-associated membrane GLT-1 and closely spaced GLT-1/α2 couples (with an interdistance ≤ 50 nm) were preferentially localized within 1000 nm of distal symmetric synapses compared to proximal. Similar organizational features of membrane GLT-1/α2 couples were observed in human cortex. These findings identify a subtype-dependent extrasynaptic astrocytic GLT-1 organization at cortical inhibitory synapses and provide a morphological framework for glutamate-dependent modulation of inhibitory signaling.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 8","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70180","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148196437","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}