Glia最新文献

{"title":"Persisting Region-Specific Microglia Activation and Synaptic Imbalance During Remission in a DSS-Induced Colitis Model","authors":"Lorena Morton,&nbsp;Luis E. Villafuerte,&nbsp;Alejandra P. Garza,&nbsp;Nina Lindemann,&nbsp;Elisa Wider-Eberspächer,&nbsp;Dunja Bruder,&nbsp;Ildiko R. Dunay","doi":"10.1002/glia.70208","DOIUrl":"10.1002/glia.70208","url":null,"abstract":"<p>Ulcerative colitis (UC) patients experience cycles of active gut inflammation and remission, with neuropsychiatric comorbidities persisting even during clinical remission. While the dextran sulfate sodium (DSS) mouse model was previously applied to study gut-brain interactions, those studies focused on acute protocols missing the chronic, relapsing–remitting nature of human UC, when patients continue to experience central nervous system symptoms. Thus, we employed a chronic DSS treatment regimen comprising three cycles of active intestinal inflammation followed by remission phases to investigate region-specific microglial dynamics and their functional consequences on neuronal synapses. Transient blood–brain barrier alteration was detected during active chronic inflammation that was resolved during remission. Cortical microglia exhibited sustained iNOS-enriched activation state during remission, which coincided with synaptic imbalance: VGLUT1+ glutamatergic synaptosomes increased significantly in remission, while VGAT+ GABAergic vesicles declined, alongside suppressed neuronal c-fos expression. Hippocampal microglia adopted an ARG1-dominant phenotype with enriched TREM2, P2Y12R, and F4/80 expression during remission, indicating a phagocytic, reparative state. Hippocampal synaptosome analysis revealed selective excitatory enhancement with preserved inhibitory markers. Morphological analysis confirmed region-specific remodeling: cortical microglia displayed delayed process elaboration during remission, while hippocampal responses varied from transient (CA1) to persistent (CA3) somatic hypertrophy. These findings establish that remission from peripheral inflammation does not fully restore brain immune homeostasis. Persistent, region-specific microglial reactivity with cortical pro-inflammatory states associated with synaptic dysfunction and hippocampal adaptive responses preserving circuit integrity provides a mechanistic understanding for neuropsychiatric comorbidities in UC and suggests that brain-targeted therapies may be required to address the full disease burden.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 11","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13535888/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872407","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":"LILRB4 Attenuates Ischemic Brain Injury by Inhibiting Microglial Necroptosis via a RIPK3-Dependent Mechanism","authors":"Jinglong Hu,&nbsp;Meijuan Zhang,&nbsp;Pinyi Liu,&nbsp;Yanting Chen,&nbsp;Hailan Meng,&nbsp;Shengnan Xia,&nbsp;Xinyu Bao,&nbsp;Yun Xu,&nbsp;Yan Chen","doi":"10.1002/glia.70215","DOIUrl":"10.1002/glia.70215","url":null,"abstract":"<div>\u0000 \u0000 <p>Microglia are central mediators of neuroinflammation following ischemic stroke. Our previous multi-omics data revealed significant upregulation of leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4) in microglia after transient middle cerebral artery occlusion (tMCAO), but its functional role remains unclear. This study demonstrates that LILRB4 expression peaks at 3 days post-tMCAO and is predominantly localized to microglia. Microglia-specific <i>Lilrb4</i> knockout (<i>Lilrb4</i>-cKO) displayed worse neurological functions, larger infarct volumes, and more significant microglial activation. Transcriptomic analysis in vitro and functional experiments further revealed that microglial LILRB4 knockdown promoted the release of proinflammatory factors and enhanced necroptosis. Mechanistically, deletion of LILRB4 mainly drives receptor-interacting protein 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) expression and phosphorylation, without affecting receptor-interacting protein 1 (RIPK1). Pharmacologic inhibition of RIPK3 can relieve the brain damage caused by LILRB4 knockout after stroke. Additional analysis showed that LILRB4 negatively regulates the stimulator of interferon genes (STING)/RIPK3 axis to limit microglial necroptosis. STING suppression blocked the hyperactivation of RIPK3 induced by LILRB4 deficiency. In conclusion, LILRB4 attenuates ischemic brain injury by suppressing STING/RIPK3-mediated microglial necroptosis and neuroinflammation, emphasizing its significance as a potential neuroprotective therapy.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 11","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862914","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":"Pathogenic Variants in HEPACAM Alter Protein Localization and Interactome in Astrocytes of the Developing Mouse Cortex","authors":"Robert W. Lewis,&nbsp;Breana C. Dogan,&nbsp;Amy L. Stanek,&nbsp;Elliot B. Evans,&nbsp;Madelyn G. Coble,&nbsp;Hayli E. Spence-Osorio,&nbsp;Karen L. G. Farizatto,&nbsp;Angie L. Mordant,&nbsp;C. Allie Mills,&nbsp;Laura E. Herring,&nbsp;Katherine T. Baldwin","doi":"10.1002/glia.70218","DOIUrl":"https://doi.org/10.1002/glia.70218","url":null,"abstract":"<p>Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare leukodystrophy characterized by early-onset macrocephaly, white matter edema, seizures, and motor and cognitive decline. Approximately 25% of MLC patients carry <i>HEPACAM</i> pathogenic variants, many of which are dominant missense variants causing remitting MLC Type 2b. <i>HEPACAM</i> encodes hepatic and glial cell adhesion molecule (hepaCAM), also known as GlialCAM, an astrocyte-enriched transmembrane protein with important roles in astrocyte territory establishment, gap junction coupling, branching organization, synaptic function, and development of the gliovascular unit. The molecular mechanisms through which pathogenic variants in <i>HEPACAM</i> alter hepaCAM protein function in vivo and facilitate MLC pathogenesis during brain development remain largely unknown. Here, we used new viral tools and proximity-based proteomics to examine how three different dominant pathogenic variants alter hepaCAM subcellular localization and protein interactome in astrocytes of the developing mouse cortex. We found dramatic changes in hepaCAM distribution throughout the astrocyte, which were common to all mutants tested. We also observed significant changes in protein interactome between wild type and mutant hepaCAM, including decreased association with previously described hepaCAM-interacting proteins Connexin 43 and CLC-2. Moreover, we identified the epilepsy-associate potassium channel KCNQ2 as a novel hepaCAM interaction partner and found reduced association between KCNQ2 and pathogenic variants. Collectively, our data provide new insights into hepaCAM protein function in astrocytes during brain development, reveal altered protein dynamics of pathogenic variants, and provide a new resource to explore the molecular underpinnings of MLC pathogenesis.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 11","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70218","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148816447","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":"Crosstalk Between Oligodendrocyte Lineage Cells and CNS-Resident and Peripheral Immune Cells Governs Demyelination and Remyelination in Multiple Sclerosis","authors":"Joohyun Park,&nbsp;So Yeong Cheon,&nbsp;Fuzheng Guo","doi":"10.1002/glia.70211","DOIUrl":"https://doi.org/10.1002/glia.70211","url":null,"abstract":"<div>\u0000 \u0000 <p>Multiple sclerosis (MS) is an autoimmune neurodegenerative disease characterized by immune-mediated attacks on myelin produced by oligodendrocytes (OLs). Oligodendrocyte precursor cells (OPCs) and mature OLs are CNS cell types essential for generating myelin sheath, which supports saltatory conduction and neuronal metabolic support. Although the roles of CNS resident cells (neurons, microglia, astrocytes) and peripheral immune cells in MS pathogenesis are well established, our understanding of how oligodendrocyte lineage cells (OLCs)—comprising OPCs and mature OLs—bidirectionally interact with these cell types to influence disease progression remains incomplete. Emerging evidence emphasizes the critical role of disease-associated OLCs in neuroimmune responses and their underlying signaling mechanisms. Therefore, elucidating how pathological environments shaped by CNS and peripheral cells influence OLC function may identify critical therapeutic targets for promoting remyelination and recovery in MS. This review synthesizes current knowledge of OLC biology in health and disease, with emphasis on complex intercellular interactions that determine demyelination, remyelination, and axonal integrity in MS.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 10","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148785158","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":"Cell Type-Specific Extracellular Vesicles in Mouse Brain: Proteomic Signatures Highlight Astrocytic GlialCAM Network and GPCR Enrichment","authors":"Alba M. Lucart-Sanchez,&nbsp;Edward Sellés-Climent,&nbsp;Jorge Navarro-Calvo,&nbsp;Guillem Pont-Espinós,&nbsp;Jose A. Gomez-Sanchez,&nbsp;Raúl Estévez,&nbsp;Luis M. Valor,&nbsp;Rocío Pérez-González","doi":"10.1002/glia.70212","DOIUrl":"https://doi.org/10.1002/glia.70212","url":null,"abstract":"<p>Extracellular vesicles (EVs) mediate intercellular communication in the central nervous system (CNS) and are emerging as biomarkers of brain health and disease. However, the molecular composition of cell type-specific brain EVs, particularly astrocyte-derived EVs (ADEVs), remains poorly defined. We performed comparative proteomic analysis of neuronal (NDEVs), microglial (MDEVs), and ADEVs from mouse brain using magnetic immunocapture and LC–MS/MS proteomic profiling. Each EV subtype displayed distinct molecular fingerprints. NDEVs were enriched in synaptic and neurogenesis-related proteins (e.g., APP, SNAP25, GPR158, and BDNF), whereas MDEVs contained immune and phagocytic markers (e.g., TMEM119, CX3CR1, CD11b). Strikingly, the ADEV proteome closely mirrored the recently characterized GlialCAM interactome from leukodystrophy research, encompassing GlialCAM/MLC1 and associated partners involved in ion and water homeostasis (EAAT1/2, AQP4, GJA1), together with GPCRs such as GPRC5B. This overlap suggests that ADEVs encapsulate a molecular scaffold characteristic of astrocytic endfeet, potentially extending their signaling functions to the extracellular space. In conclusion, our study provides a detailed comparative proteomic characterization of brain cell type-specific EVs, revealing that ADEVs contain the GlialCAM/MLC1 network and GPCRs. These findings identify candidate molecular signatures that support the future investigation of ADEVs for biomarker development and provide a proteomic framework for exploring their relationship with astrocytic endfoot biology, blood–brain barrier (BBB)-associated pathways, and neurodegenerative disorders.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 10","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70212","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784837","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":"Crosstalk Between Oligodendrocyte Lineage Cells and CNS-Resident and Peripheral Immune Cells Governs Demyelination and Remyelination in Multiple Sclerosis","authors":"Joohyun Park,&nbsp;So Yeong Cheon,&nbsp;Fuzheng Guo","doi":"10.1002/glia.70211","DOIUrl":"https://doi.org/10.1002/glia.70211","url":null,"abstract":"<div>\u0000 \u0000 <p>Multiple sclerosis (MS) is an autoimmune neurodegenerative disease characterized by immune-mediated attacks on myelin produced by oligodendrocytes (OLs). Oligodendrocyte precursor cells (OPCs) and mature OLs are CNS cell types essential for generating myelin sheath, which supports saltatory conduction and neuronal metabolic support. Although the roles of CNS resident cells (neurons, microglia, astrocytes) and peripheral immune cells in MS pathogenesis are well established, our understanding of how oligodendrocyte lineage cells (OLCs)—comprising OPCs and mature OLs—bidirectionally interact with these cell types to influence disease progression remains incomplete. Emerging evidence emphasizes the critical role of disease-associated OLCs in neuroimmune responses and their underlying signaling mechanisms. Therefore, elucidating how pathological environments shaped by CNS and peripheral cells influence OLC function may identify critical therapeutic targets for promoting remyelination and recovery in MS. This review synthesizes current knowledge of OLC biology in health and disease, with emphasis on complex intercellular interactions that determine demyelination, remyelination, and axonal integrity in MS.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 10","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784838","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":"Cell Type-Specific Extracellular Vesicles in Mouse Brain: Proteomic Signatures Highlight Astrocytic GlialCAM Network and GPCR Enrichment","authors":"Alba M. Lucart-Sanchez,&nbsp;Edward Sellés-Climent,&nbsp;Jorge Navarro-Calvo,&nbsp;Guillem Pont-Espinós,&nbsp;Jose A. Gomez-Sanchez,&nbsp;Raúl Estévez,&nbsp;Luis M. Valor,&nbsp;Rocío Pérez-González","doi":"10.1002/glia.70212","DOIUrl":"https://doi.org/10.1002/glia.70212","url":null,"abstract":"<p>Extracellular vesicles (EVs) mediate intercellular communication in the central nervous system (CNS) and are emerging as biomarkers of brain health and disease. However, the molecular composition of cell type-specific brain EVs, particularly astrocyte-derived EVs (ADEVs), remains poorly defined. We performed comparative proteomic analysis of neuronal (NDEVs), microglial (MDEVs), and ADEVs from mouse brain using magnetic immunocapture and LC–MS/MS proteomic profiling. Each EV subtype displayed distinct molecular fingerprints. NDEVs were enriched in synaptic and neurogenesis-related proteins (e.g., APP, SNAP25, GPR158, and BDNF), whereas MDEVs contained immune and phagocytic markers (e.g., TMEM119, CX3CR1, CD11b). Strikingly, the ADEV proteome closely mirrored the recently characterized GlialCAM interactome from leukodystrophy research, encompassing GlialCAM/MLC1 and associated partners involved in ion and water homeostasis (EAAT1/2, AQP4, GJA1), together with GPCRs such as GPRC5B. This overlap suggests that ADEVs encapsulate a molecular scaffold characteristic of astrocytic endfeet, potentially extending their signaling functions to the extracellular space. In conclusion, our study provides a detailed comparative proteomic characterization of brain cell type-specific EVs, revealing that ADEVs contain the GlialCAM/MLC1 network and GPCRs. These findings identify candidate molecular signatures that support the future investigation of ADEVs for biomarker development and provide a proteomic framework for exploring their relationship with astrocytic endfoot biology, blood–brain barrier (BBB)-associated pathways, and neurodegenerative disorders.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 10","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70212","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148785157","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":"Frozen in Place: Proximity Labeling Maps Glial Interactomes Across Cell States","authors":"João Baltar,&nbsp;Rebecca Abati,&nbsp;Luísa Florido,&nbsp;Matthew G. Holt","doi":"10.1002/glia.70216","DOIUrl":"https://doi.org/10.1002/glia.70216","url":null,"abstract":"<p>Glial cells, including radial glia, oligodendrocyte precursor cells (OPCs), oligodendrocytes, astrocytes, and microglia, are active and dynamic regulators of central nervous system (CNS) development, homeostasis, and disease. Through extensive interactions with neurons, other glial populations, and the vasculature, they form highly specialized communication networks that are essential for normal brain function. While transcriptomic approaches have revealed extensive glial heterogeneity and enabled the prediction of putative signaling networks, a critical challenge remains in validating and translating these findings at the level of distinct protein complexes existing both within and between the various glial cell types. This is largely due to the fact that traditional proteomic technologies lack spatial resolution and/or fail to capture protein interaction networks. Proximity labeling (PL) has emerged as a powerful strategy to overcome these limitations by enabling cell-type-specific mapping of protein networks and subcellular proteomes, with spatial and temporal precision. Emerging studies have applied PL enzymes, such as BioID, TurboID, and HRP, across diverse glial populations, starting to uncover protein networks supporting their interactions with neurons and vascular elements, allowing metabolic support, maintenance of microenvironment homeostasis and cell–cell communication (including synaptic modulation). In this review, we summarize the main PL enzymes, discuss key studies across different glial cell types, and examine the technical challenges and future perspectives of applying PL to investigate glial biology. By complementing transcriptomic data with spatially resolved proteomic insights, PL provides a unique opportunity to deepen our understanding of glial cell biology in health and disease.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 10","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70216","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784233","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":"Frozen in Place: Proximity Labeling Maps Glial Interactomes Across Cell States","authors":"João Baltar,&nbsp;Rebecca Abati,&nbsp;Luísa Florido,&nbsp;Matthew G. Holt","doi":"10.1002/glia.70216","DOIUrl":"https://doi.org/10.1002/glia.70216","url":null,"abstract":"<p>Glial cells, including radial glia, oligodendrocyte precursor cells (OPCs), oligodendrocytes, astrocytes, and microglia, are active and dynamic regulators of central nervous system (CNS) development, homeostasis, and disease. Through extensive interactions with neurons, other glial populations, and the vasculature, they form highly specialized communication networks that are essential for normal brain function. While transcriptomic approaches have revealed extensive glial heterogeneity and enabled the prediction of putative signaling networks, a critical challenge remains in validating and translating these findings at the level of distinct protein complexes existing both within and between the various glial cell types. This is largely due to the fact that traditional proteomic technologies lack spatial resolution and/or fail to capture protein interaction networks. Proximity labeling (PL) has emerged as a powerful strategy to overcome these limitations by enabling cell-type-specific mapping of protein networks and subcellular proteomes, with spatial and temporal precision. Emerging studies have applied PL enzymes, such as BioID, TurboID, and HRP, across diverse glial populations, starting to uncover protein networks supporting their interactions with neurons and vascular elements, allowing metabolic support, maintenance of microenvironment homeostasis and cell–cell communication (including synaptic modulation). In this review, we summarize the main PL enzymes, discuss key studies across different glial cell types, and examine the technical challenges and future perspectives of applying PL to investigate glial biology. By complementing transcriptomic data with spatially resolved proteomic insights, PL provides a unique opportunity to deepen our understanding of glial cell biology in health and disease.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 10","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70216","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784017","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 Astrocyte Clock Controls Circadian Perineuronal Net Remodeling, Synapse Strength and Learning Behavior","authors":"Philip C. Smith,&nbsp;Elsa I. Quillin,&nbsp;Katheryn B. Lefton,&nbsp;Celia A. McKee,&nbsp;Brendan Dang,&nbsp;Thomas Papouin,&nbsp;Erik S. Musiek","doi":"10.1002/glia.70213","DOIUrl":"10.1002/glia.70213","url":null,"abstract":"<p>The circadian clock controls a vast array of cellular and organismal functions, from the molecular scale to behavior. While each cell is regimented by a cell-autonomous clock, few studies in the brain have dissected the circuit and behavioral contributions of cell-specific clocks. Relatedly, astrocytes are now known to play key roles in regulating synaptic function, circuit activity and behavior, but whether these functions are guided by astrocyte-autonomous clocks is unknown. Here, we report that post-natal deletion of the critical circadian clock gene <i>Bmal1</i> in astrocytes, which abrogates core clock function in a cell type specific manner, induced expression of genes related to extracellular matrix (ECM) production, maintenance, and remodeling. Circadian variations have been shown in a specific ECM structure, perineuronal nets (PNNs), which are implicated in synaptic function and plasticity. In astrocyte-specific <i>Bmal1</i> knockouts, hippocampal PNN abundance was decreased, and the circadian rhythm of these structures was also abolished. In line with evidence implicating PNNs, and the ECM in general, in synaptic function and plasticity, we found that astrocyte-specific <i>Bmal1</i> KO mice had increased synaptic strength but blunted long term potentiation (LTP), as well as impaired learning and memory performance in a novel object recognition task. Taken together, these findings suggest that the astrocyte circadian clock regulates circadian rhythms in perineuronal net abundance as well as synaptic plasticity and behavioral learning and memory.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 10","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70213","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148759614","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}