Glia最新文献

{"title":"Mutations in GFAP Alter Early Lineage Commitment of Organoids","authors":"Werner Dykstra,&nbsp;Zuzana Matusova,&nbsp;Rachel A. Battaglia,&nbsp;Pavel Abaffy,&nbsp;Nuria Goya-Iglesias,&nbsp;Dolores Pérez-Sala,&nbsp;Henrik Ahlenius,&nbsp;Mikael Kubista,&nbsp;R. Jeroen Pasterkamp,&nbsp;Li Li,&nbsp;Jianfei Chao,&nbsp;Yanhong Shi,&nbsp;Lukas Valihrach,&nbsp;Milos Pekny,&nbsp;Elly M. Hol","doi":"10.1002/glia.70049","DOIUrl":"10.1002/glia.70049","url":null,"abstract":"<p>Glial fibrillary acidic protein (GFAP) is a type-3 intermediate filament protein mainly expressed in astrocytes in the central nervous system. Mutations in <i>GFAP</i> cause Alexander disease (AxD), a rare and fatal neurological disorder. How exactly mutant GFAP eventually leads to white and gray matter deterioration in AxD remains unknown. GFAP is known to be expressed also in neural precursor cells in the developing brain. Here, we used AxD patient-derived induced pluripotent stem cells (iPSCs) to explore the impact of mutant GFAP during neurodifferentiation. Our results show that GFAP is already expressed in iPSCs. Moreover, we have found that mutations in GFAP can severely affect neural organoid development through altering lineage commitment in embryoid bodies. Together, these results support the notion that GFAP plays a role as an early modulator of neurodevelopment.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 11","pages":"2167-2188"},"PeriodicalIF":5.1,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12436998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740687","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":"Acid-Sensing PAC Channel Promotes Astrocyte Acidosis in Ischemic Stroke","authors":"Yifei Liu,&nbsp;Yun Zhang,&nbsp;Meng Sun,&nbsp;Huiqing Dong,&nbsp;Xinyuan Hu,&nbsp;Tianyi Shen,&nbsp;Liqin Zhou,&nbsp;Lei Zhang,&nbsp;Ting Wang,&nbsp;Zhaobing Gao,&nbsp;Yi Chang,&nbsp;Jing Feng","doi":"10.1002/glia.70073","DOIUrl":"10.1002/glia.70073","url":null,"abstract":"<div>\u0000 \u0000 <p>Astrocyte is critically involved in the central nervous system homeostasis and initiates tissue pathology in response to insults to the central nervous system. However, whether and how astrocytes sense micro-environmental changes, such as ischemic stroke-associated acidification, remains largely unknown. Here we show that the proton-activated chloride (PAC) channel is widely expressed in glial cells in the brain and functionally mediates acid-induced chloride influx. Moreover, conditional knockout of the PAC channel in astrocytes, but not in microglia, reduced infarct volume in a mouse model of ischemic stroke induced by middle cerebral artery occlusion/reperfusion (MCAO/R). Rather than the classic role of chloride channels in cell volume dysregulation-related cell death, activation of the PAC channel contributes to cell apoptosis via the Akt/Bax/Caspase 3 pathway in astrocytes and promotes inflammatory mediator release from astrocytes in response to pH oscillation and oxidative stress. Collectively, our results uncover a role of the PAC channel in astrocyte acidosis, providing a potential therapeutic target for neuroprotection in ischemic stroke.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 12","pages":"2353-2368"},"PeriodicalIF":5.1,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726241","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":"The Influence of Schwann Cell Metabolism and Dysfunction on Axon Maintenance","authors":"Rose Follis,&nbsp;Vishwanath V. Prabhu,&nbsp;Bruce D. Carter","doi":"10.1002/glia.70071","DOIUrl":"10.1002/glia.70071","url":null,"abstract":"<p>Schwann cells are the glial cells in the peripheral nervous system responsible for the production of myelin, which is essential for rapid, saltatory conduction in nerves. However, it has become increasingly recognized that Schwann cells are also key regulators of neuron viability and function, especially for sensory neurons. Neurons and Schwann cells form a tightknit, interdependent couple with complex mechanisms of communication that are only beginning to be understood. There is growing evidence that Schwann cell metabolism profoundly influences axons through the release of a variety of metabolites. These glial cells serve as energy depots for axon function, supplying lactate and/or pyruvate during repeated firing and after injury. Lipid metabolism in Schwann cells, which is critical for myelin production, also affects axon viability, such that disruptions in the production or breakdown of lipids can lead to axon dysfunction and subsequent degeneration. Here, we discuss emerging concepts on the mechanisms by which Schwann cell metabolites influence neuron activity and survival, with particular focus on how dysfunction of lipid metabolism can lead to axon degeneration and the development of peripheral neuropathy.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 12","pages":"2338-2352"},"PeriodicalIF":5.1,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70071","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144705843","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":"Functional Diversity of Two Novel Embryonic Microglial Subpopulations and Their Developmental Trajectories in Developing Mouse Brains","authors":"Siao Muk Cheng,&nbsp;Chi-Lin Ho,&nbsp;Shiou-Lan Chen,&nbsp;Yi-Te Huang,&nbsp;Pin-Cheng Mao,&nbsp;Tzu-Chia Lin,&nbsp;Jia-Shing Chen,&nbsp;H. Sunny Sun,&nbsp;Daw-Yang Hwang,&nbsp;Chun-Hsien Chu","doi":"10.1002/glia.70064","DOIUrl":"10.1002/glia.70064","url":null,"abstract":"<div>\u0000 \u0000 <p>As the primary brain-resident macrophages, embryonic microglia (EM) display functional diversity and significant heterogeneity, which are essential for normal brain development and growth. However, the heterogeneous nature of EM and their developmental trajectory remain contentious. This study isolated individual cells from the brains of embryonic day 14 (E14) mice without using a microglial cell sorting method and subsequently performed single-cell RNA sequencing (scRNA-seq) analysis. Unsupervised subclustering of the microglial population based on gene expression profiles revealed two novel EM subclusters: approximately 60% EM1 (CD68-negative and Iba-1-positive) and about 40% EM2 (CD68- and Iba-1-double-positive). Additionally, bioinformatics analyses indicated that the EM1 cluster represents relatively early and immature microglia with high proliferative capacity. In contrast, the EM2 cluster exhibits a higher expression of genes involved in the stepwise program of microglial development, synaptic phagocytosis, regulation of neuron differentiation and projection, and interaction with other brain cells. To further confirm these findings, double or triple immunofluorescence staining of Iba-1, CD68, or the presynaptic marker synaptophysin demonstrated the presence of the EM1 and EM2 clusters in E14 mouse brains, as well as increased synaptic phagocytosis in the EM2 cluster. Moreover, by monitoring their proportional changes in the brains on postnatal days 1, 14, and 90, our data disclosed the developmental trajectory of the EMs as they transition from CD68-negative to CD68-positive after the postnatal period stages. Overall, this study opens new avenues for exploring the functional diversity and developmental trajectory of EMs during embryonic brain development and growth.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 11","pages":"2236-2252"},"PeriodicalIF":5.1,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717104","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":"Astrocyte-Targeted connexin43 Hemichannel Inhibition Prevents Radiation-Induced Energy Transporter Decrease in Neurons and Astrocytic proBDNF Transport to Synapses","authors":"Steffi Schumacher,&nbsp;Sara Neyt,&nbsp;Christian Vanhove,&nbsp;Lien De Schaepmeester,&nbsp;Robrecht Raedt,&nbsp;Katja Witschas,&nbsp;Luc Leybaert","doi":"10.1002/glia.70063","DOIUrl":"10.1002/glia.70063","url":null,"abstract":"<div>\u0000 \u0000 <p>Radiation therapy is widely used for treating brain tumors but also comes with off-target effects, including vascular blood–brain barrier (BBB) leakage occurring as an early event 24 h postirradiation. Here we investigated brain X-irradiation (20 Gy) effects on the astrocyte-neuronal axis starting from BBB endothelium and ending at synapses. Making use of immune-characterization of brain slices isolated 24 h after irradiation of rodents, we found significantly decreased neuronal expression of GLUT3 glucose transporters and MCT2 monocarboxylate transporters in M1/S1 cortical areas, with no changes in astrocytic GLUT1 transporters. Pre-irradiation animal treatment with the Cx43 hemichannel blocker TATGap19 targeting astrocytes completely prevented these neuronal alterations. Brain uptake of ¹⁸F-deoxy-glucose was decreased in the pre- and infra-limbic cortex 24 h postirradiation, not in other cortical areas, and was prevented by TATGap19 treatment. Electro-encephalographic recordings showed decreased power in delta, theta, beta, and gamma bands, most clearly in S1 cortex 24 h postirradiation. ProBDNF, a precursor of brain-derived neurotrophic factor associated with negative neural effects, was significantly elevated 24 h postirradiation and accompanied by strong activation of its vesicular transport in astrocytes. In particular, proBDNF uptake in astrocytic endfeet at capillary endothelial cells and its VAMP3-associated release at astrocytic extensions to tripartite synapses were both strongly increased and prevented by animal pretreatment with TATGap19. The present data show that astrocytes are a major target for radiotherapeutic intervention whereby Gap19 inhibition of the Cx43 hemichannel membrane leakage pathway prevents radiation-induced alterations in brain glucose handling and activation of vesicular proBDNF transport to tripartite synapses that disturb neural functioning.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 11","pages":"2221-2235"},"PeriodicalIF":5.1,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697153","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":"Suppression of TRPV5 Regulates Microglia-Mediated Neuroinflammation Following Status Epilepticus","authors":"Soojin Park,&nbsp;Se Hoon Kim,&nbsp;Chul Hoon Kim,&nbsp;Kyoung Hoon Jeong,&nbsp;Won-Joo Kim","doi":"10.1002/glia.70068","DOIUrl":"10.1002/glia.70068","url":null,"abstract":"<p>Neuroinflammation, predominantly associated with glial activation and the release of various inflammatory mediators, is a vital hallmark of the pathophysiology of epilepsy. Numerous studies have indicated that identifying novel factors that diminish neuroinflammatory processes may be important for developing effective therapeutic strategies to prevent neuropathological processes and epileptogenic progression. Transient receptor potential vanilloid 5 (TRPV5) is a highly selective calcium ion channel belonging to the TRPV family. TRPV5 expression has been identified in diverse regions of the brain; however, it remains unknown how TRPV5 is implicated in the pathophysiological features of neurological diseases, including epilepsy. Herein, we show that TRPV5 expression is upregulated in the hippocampus of a pilocarpine-induced status epilepticus (PCSE) model, predominantly in activated microglia. Pharmacological inhibition of TRPV5 using econazole attenuated microglial activation, as indicated by the shift of LPS-stimulated primary hippocampal microglia to a resting state. This inhibition suppressed AKT/NF-κB signaling, reduced NLRP3 inflammasome activity, and decreased proinflammatory cytokine production. Additionally, TRPV5 inhibition reduced hippocampal microglial activation and neuroinflammation following PCSE. These findings suggest that TRPV5 contributes to the regulation of microglial activation, resulting in the suppression of microglia-derived neuroinflammation during the sub-acute phase of epilepsy. In conclusion, the present study suggests that targeting TRPV5 may offer a novel therapeutic approach to managing the neuroinflammatory processes during epileptogenic progression.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 11","pages":"2289-2304"},"PeriodicalIF":5.1,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12436994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144705842","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":"Hypothalamic Astrocytes Exhibit Glycolytic Features Making Them Prone for Glucose Sensing","authors":"Sarah Geller,&nbsp;Nadège Zanou,&nbsp;Sylviane Lagarrigue,&nbsp;Tamara Zehnder,&nbsp;Cathy Gouelle,&nbsp;Tania Santoro,&nbsp;Cendrine Repond,&nbsp;Paola Bezzi,&nbsp;Francesca Amati,&nbsp;Anne-Karine Bouzier-Sore,&nbsp;Ariane Sharif,&nbsp;Luc Pellerin","doi":"10.1002/glia.70066","DOIUrl":"10.1002/glia.70066","url":null,"abstract":"<p>In the hypothalamus, detection of energy substrates such as glucose is essential to regulate food intake and peripheral energy homeostasis. Metabolic interactions between astrocytes and neurons via lactate exchange have been proposed as a hypothalamic glucose-sensing mechanism, but the molecular basis remains uncertain. Mouse hypothalamic astrocytes in vitro were found to exhibit a stronger glycolytic phenotype in basal conditions than cortical astrocytes. It was associated with higher protein expression levels of the Pyruvate Kinase Isoform M2 (Pkm2) and its more prominent nuclear localization. In parallel, hypothalamic astrocytes also expressed higher levels of the monocarboxylate transporter <i>Slc16a3</i> (Mct4), which were dependent on Pkm2 expression. The stronger Mct4 expression in hypothalamic versus cortical astrocytes is an intrinsic characteristic, as it was also present after their direct isolation from adult mouse tissue. The high lactate release capacity of hypothalamic astrocytes was demonstrated to depend on the expression of Mct4, but not Mct1. Unlike cortical astrocytes, hypothalamic astrocytes in culture do not respond to glutamate with enhanced glycolysis, but instead, they modulate their lactate production according to glucose concentrations in an AMPK-dependent manner, an effect observed in both mouse and human hypothalamic astrocytes in vitro. Our study shows that hypothalamic and cortical astrocytes are geared to have distinct glycolytic responses to glucose and glutamate, respectively. These results reveal a metabolic specialization of astrocytes in order to fulfill distinct area-specific functions: glucose-sensing in the hypothalamus versus activity-dependent neuronal energetic supply in cortical regions.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 11","pages":"2253-2272"},"PeriodicalIF":5.1,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12436996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144705841","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":"Building Immunocompetent Cerebral Organoids From a Developmental Perspective","authors":"Xabier Cuesta-Puente,&nbsp;Marco Gonzalez-Dominguez,&nbsp;Marta Pereira-Iglesias,&nbsp;Nerea Perez-Arriazu,&nbsp;Patricia Villegas-Zafra,&nbsp;Paula Ramos-Gonzalez,&nbsp;Fabio Cavaliere,&nbsp;Nora Bengoa-Vergniory,&nbsp;Amanda Sierra","doi":"10.1002/glia.70062","DOIUrl":"10.1002/glia.70062","url":null,"abstract":"<p>Cerebral organoids derived from human induced pluripotent stem cells (iPSCs) are increasingly becoming essential tools to study the human brain, from understanding pathological mechanisms in neurodevelopmental, neurodegenerative, and infectious diseases to identifying genetic risks and biomarkers. To resemble the brain environment, cerebral organoids must contain microglia, the resident macrophages of the brain parenchyma that are essential for its homeostasis. As microglia derive from the yolk sac, they are not present in conventional brain organoids, which are generated by reprogramming iPSCs towards the neuroectodermal lineage and must be exogenously incorporated through a variety of strategies. Once in the organoid parenchyma, microglia must recapitulate their developmental milestones to achieve full immunocompetence, reaching a mature transcriptional profile and morphology, a tessellated distribution, efficient phagocytosis, and controlled inflammatory responses. In this review, we will summarize recent protocols that have been developed to generate human microglial-containing cerebral organoids (MCCOs), focusing on the methods used to assess the level of microglial maturation compared to their in vivo counterparts. We provide a series of recommendations to assess microglial immunocompetence using stringent quantitative approaches that will promote developing standardized protocols to culture MCCOs.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 11","pages":"2154-2166"},"PeriodicalIF":5.1,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12436987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697154","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":"Endoplasmic Reticulum Stress Amplifies Cytokine Responses in Astrocytes via a PERK/eIF2α/JAK1 Signaling Axis","authors":"Anirudhya Lahiri,&nbsp;Savannah G. Sims,&nbsp;Jessica A. Herstine,&nbsp;Alicia Meyer,&nbsp;Micah J. Marshall,&nbsp;Ishrat Jahan,&nbsp;Subhodip Adhicary,&nbsp;Allison M. Bradbury,&nbsp;Gordon P. Meares","doi":"10.1002/glia.70067","DOIUrl":"10.1002/glia.70067","url":null,"abstract":"<p>Aberrant activation of multiple cellular processes and signaling pathways is a hallmark of many neurological disorders. Understanding how these processes interact is crucial for elucidating the neuropathogenesis of these diseases. Among these, endoplasmic reticulum (ER) stress, activation of the unfolded protein response (UPR), and neuroinflammation are frequently implicated. Previously, we demonstrated that ER stress synergizes with tumor necrosis factor (TNF)-α to amplify interleukin (IL)-6 and C-C motif chemokine ligand (CCL)20 production in astrocytes through a Janus kinase 1 (JAK1)-dependent mechanism. Here, we expand on this finding by defining the scope and underlying mechanisms of this phenomenon. We show that ER stress and TNF-α cooperatively enhance inflammatory gene expression in astrocytes via a signaling axis that requires both protein kinase R (PKR)-like ER kinase (PERK) and JAK1. PERK-mediated phosphorylation of eukaryotic translation initiation factor (eIF)2α suppresses protein translation, delaying the expression of negative regulators such as NF-κB inhibitor (IκB)α and suppressor of cytokine signaling (SOCS)3 following TNF-α or oncostatin M (OSM) stimulation, respectively. Pharmacological reversal of p-eIF2α-dependent translational suppression using the small molecule integrated stress response inhibitor (ISRIB) restored IκBα and SOCS3 expression and attenuated the ER stress-induced enhancement of TNF-α- or OSM-driven inflammatory responses. Notably, astrocytes harboring a vanishing white matter-associated <i>EIF2B5</i> mutation revealed that translational attenuation alone is insufficient to amplify cytokine-induced gene expression. Together, these findings identify a PERK/eIF2α/JAK1 signaling axis that sensitizes astrocytes to inflammatory cytokines, providing new mechanistic insights into the interactions between ER stress and neuroinflammation.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 11","pages":"2273-2288"},"PeriodicalIF":5.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12436993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673491","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":"Microglial Bmal1 Contributes to Diurnal Physiology and Retinal Homeostasis","authors":"Charles W. Pfeifer,&nbsp;Andrea Santeford,&nbsp;Rajendra S. Apte","doi":"10.1002/glia.70061","DOIUrl":"10.1002/glia.70061","url":null,"abstract":"<div>\u0000 \u0000 <p>Circadian rhythms govern various physiological processes, including innate and adaptive immune responses. Microglia, the sentinels of the central nervous system (CNS), mediate synaptic remodeling and local immune responses that contribute to tissue homeostasis. Recent studies have uncovered that microglial surveillance behavior and cytokine production exhibit rhythmicity. Furthermore, disruption of clock gene expression in microglia impairs phagocytic capacity, metabolism, and inflammatory responses, suggesting that their dynamic functions are regulated in part by circadian rhythms. Given the growing recognition of circadian dysregulation in disease pathophysiology, elucidating molecular mechanisms of microglial chronobiology may reveal novel therapeutic strategies to resynchronize circadian rhythms with components of the immune system. Homeostatic rhythms and the implications of their disruption have yet to be explored in microglia that reside within the neurosensory retina, a tissue in the back of the eye that initiates visual transduction and relays photic information to the brain. In this study, we demonstrate that retinal microglia express rhythms in clock gene expression, morphology, and inflammatory markers that rely on the clock gene <i>Bmal1.</i> We also find that loss of <i>Bmal1</i> in microglia is associated with a decline in retinal health and behavioral dysfunction in the mouse. Lastly, we demonstrate that <i>Bmal1</i> deficiency also induces a senescent, disease-associated phenotype in microglia and transcriptomic reprogramming in the retinal parenchyma. These findings suggest that diurnal clock rhythms regulate microglia physiology within the retinal niche and contribute to homeostatic maintenance of the local tissue environment.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 11","pages":"2206-2220"},"PeriodicalIF":5.1,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144606946","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}