IF 5.4 2区医学

Glia Pub Date : 2024-11-28 DOI: 10.1002/glia.24645

Poornemaa Natarajan, Christina Koupourtidou, Thibault de Resseguier, Manja Thorwirth, Riccardo Bocchi, Judith Fischer-Sternjak, Sarah Gleiss, Diana Rodrigues, Michael H. Myoga, Jovica Ninkovic, Giacomo Masserdotti, Magdalena Götz

{"title":"Single Cell Deletion of the Transcription Factors Trps1 and Sox9 in Astrocytes Reveals Novel Functions in the Adult Cerebral Cortex","authors":"Poornemaa Natarajan, Christina Koupourtidou, Thibault de Resseguier, Manja Thorwirth, Riccardo Bocchi, Judith Fischer-Sternjak, Sarah Gleiss, Diana Rodrigues, Michael H. Myoga, Jovica Ninkovic, Giacomo Masserdotti, Magdalena Götz","doi":"10.1002/glia.24645","DOIUrl":"10.1002/glia.24645","url":null,"abstract":"Astrocytes play key roles in brain function, but how these are orchestrated by transcription factors (TFs) in the adult brain and aligned with astrocyte heterogeneity is largely unknown. Here we examined the localization and function of the novel astrocyte TF Trps1 (Transcriptional Repressor GATA Binding 1) and the well-known astrocyte TF Sox9 by Cas9-mediated deletion using Mokola-pseudotyped lentiviral delivery into the adult cerebral cortex. Trps1 and Sox9 levels showed heterogeneity among adult cortical astrocytes, which prompted us to explore the effects of deleting either Sox9 or Trps1 alone or simultaneously at the single-cell (by patch-based single-cell transcriptomics) and tissue levels (by spatial transcriptomics). This revealed TF-specific functions in astrocytes, such as synapse maintenance with the strongest effects on synapse number achieved by Trps1 deletion and a common effect on immune response. In addition, spatial transcriptomics showed non-cell-autonomous effects on the surrounding cells, such as oligodendrocytes and other immune cells with TF-specific differences on the type of immune cells: Trps1 deletion affecting monocytes specifically, while Sox9 deletion acting mostly on microglia and deletion of both TF affecting mostly B cells. Taken together, this study reveals novel roles of Trps1 and Sox9 in adult astrocytes and their communication with other glial and immune cells.","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 4","pages":"737-758"},"PeriodicalIF":5.4,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24645","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749531","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}

引用次数: 0

Modulation of OPC Mitochondrial Function by Inhibiting USP30 Promotes Their Differentiation 通过抑制 USP30 调节 OPC 线粒体功能可促进其分化。

IF 5.4 2区医学

Glia Pub Date : 2024-11-27 DOI: 10.1002/glia.24648

Allison L. Soung, Roxanne V. Kyauk, Shristi Pandey, Yun-An A. Shen, Mike Reichelt, Han Lin, Zhiyu Jiang, Praveen Kirshnamoorthy, Oded Foreman, Benjamin E. Lauffer, Tracy J. Yuen

{"title":"Modulation of OPC Mitochondrial Function by Inhibiting USP30 Promotes Their Differentiation","authors":"Allison L. Soung, Roxanne V. Kyauk, Shristi Pandey, Yun-An A. Shen, Mike Reichelt, Han Lin, Zhiyu Jiang, Praveen Kirshnamoorthy, Oded Foreman, Benjamin E. Lauffer, Tracy J. Yuen","doi":"10.1002/glia.24648","DOIUrl":"10.1002/glia.24648","url":null,"abstract":"Multiple lines of evidence indicate that mitochondrial dysfunction occurs in demyelinating diseases, such as multiple sclerosis (MS). Failure of remyelination is thought to be caused in part by a block of oligodendrocyte progenitor cell (OPC) differentiation into oligodendrocytes, which generate myelin sheaths around axons. The process of OPC differentiation requires a substantial amount of energy and high demand for ATP which is supplied through the mitochondria. In this study, we highlight mitochondrial gene expression changes during OPC differentiation in two murine models of remyelination and in human postmortem MS brains. Given these transcriptional alterations, we then investigate whether genetic alteration of USP30, a mitochondrial deubiquitinase, enhances OPC differentiation and myelination. By genetic knockout of USP30, we observe increased OPC differentiation and myelination without affecting OPC proliferation and survival in in vitro and ex vivo assays. We also find that OPC differentiation is accelerated in vivo following focal demyelination in USP30 knockout mice. The promotion of OPC differentiation and myelination observed is associated with increased oxygen consumption rates in USP30 knockout OPCs. Together, these data indicate a role for mitochondrial function and USP30 in OPC differentiation and myelination.","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 4","pages":"773-787"},"PeriodicalIF":5.4,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24648","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724364","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}

引用次数: 0

Unboxing “Omics” in Glial Biology to Understand Neurological Disease 揭开神经胶质生物学的 "Omics "神秘面纱，了解神经系统疾病。

IF 5.4 2区医学

Glia Pub Date : 2024-11-25 DOI: 10.1002/glia.24651

Jonathan R. Weinstein, Suman Jayadev, Shane Liddelow, B. J. L. Eggen

引用次数: 0

Astrocytic GAT-3 Regulates Synaptic Transmission and Memory Formation in the Dentate Gyrus 星形胶质细胞 GAT-3 调节齿状回的突触传递和记忆形成

IF 5.4 2区医学

Glia Pub Date : 2024-11-21 DOI: 10.1002/glia.24649

Weida Shen, Fujian Chen, Yejiao Tang, Wen Zhou, Yulu Zhao, Xinrui Li, Jingyin Dong, Feng Zhu, Shishuo Chen, Ling-Hui Zeng

{"title":"Astrocytic GAT-3 Regulates Synaptic Transmission and Memory Formation in the Dentate Gyrus","authors":"Weida Shen, Fujian Chen, Yejiao Tang, Wen Zhou, Yulu Zhao, Xinrui Li, Jingyin Dong, Feng Zhu, Shishuo Chen, Ling-Hui Zeng","doi":"10.1002/glia.24649","DOIUrl":"10.1002/glia.24649","url":null,"abstract":"<div>\u0000 \u0000 GABAergic network activity plays a crucial role in a wide array of physiological processes and is implicated in various pathological conditions. While extensive research has been conducted on how GABAergic network activity modulates both excitatory and inhibitory synaptic transmission in the CA1 region, the mechanisms by which it influences synaptic transmission in the entorhinal cortex-dentate gyrus (EC-DG) circuits are still largely unexplored. Using a combination of whole-cell patch-clamp recordings, optogenetics, immunohistochemistry, and behavioral assays, we demonstrate that activation of GABA transporter 3 (GAT-3) in astrocytes triggers an increase in intracellular Ca2+ via the reverse Na+/Ca2+ exchanger. Intriguingly, inhibiting GAT-3 impedes the GABA-induced elevation of astrocytic Ca2+ levels, thereby curtailing the subsequent enhancement of synaptic transmission. Additionally, we show that endogenously released GABA from interneurons also modulates synaptic transmission through GAT-3 in the DG. Crucially, by selectively diminishing astrocytic calcium signals, we observed a concomitant decrease in the GABA-induced enhancement of synaptic transmission, underscoring the crucial role of astrocytes in this regulatory pathway. Moreover, we found that the activation of GAT-3 enhances excitatory transmission via presynaptic GluN2B-containing N-methyl-D-aspartate receptors (GluN2B-NMDARs) in the DG. Finally, our in vivo experiments demonstrate that inhibiting GAT-3 adversely affects the formation of contextual fear memory, highlighting its pivotal role in cognitive processing. These findings underscore the significance of astrocytic GAT-3 in cognitive functions and offer valuable insights into potential therapeutic targets for cognitive impairments, opening new avenues for the treatment of related disorders.\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 4","pages":"788-804"},"PeriodicalIF":5.4,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685526","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}

引用次数: 0

Microglia and Astrocytes in Postnatal Neural Circuit Formation 出生后神经回路形成中的小胶质细胞和星形胶质细胞

IF 5.4 2区医学

Glia Pub Date : 2024-11-21 DOI: 10.1002/glia.24650

Abigayle S. Duffy, Ukpong B. Eyo

引用次数: 0

All the single cells: Single-cell transcriptomics/epigenomics experimental design and analysis considerations for glial biologists 所有单细胞神经胶质生物学家的单细胞转录组学/表观组学实验设计和分析注意事项。

IF 5.4 2区医学

Glia Pub Date : 2024-11-19 DOI: 10.1002/glia.24633

Katherine E. Prater, Kevin Z. Lin

{"title":"All the single cells: Single-cell transcriptomics/epigenomics experimental design and analysis considerations for glial biologists","authors":"Katherine E. Prater, Kevin Z. Lin","doi":"10.1002/glia.24633","DOIUrl":"10.1002/glia.24633","url":null,"abstract":"Single-cell transcriptomics, epigenomics, and other ‘omics applied at single-cell resolution can significantly advance hypotheses and understanding of glial biology. Omics technologies are revealing a large and growing number of new glial cell subtypes, defined by their gene expression profile. These subtypes have significant implications for understanding glial cell function, cell–cell communications, and glia-specific changes between homeostasis and conditions such as neurological disease. For many, the training in how to analyze, interpret, and understand these large datasets has been through reading and understanding literature from other fields like biostatistics. Here, we provide a primer for glial biologists on experimental design and analysis of single-cell RNA-seq datasets. Our goal is to further the understanding of why decisions are made about datasets and to enhance biologists’ ability to interpret and critique their work and the work of others. We review the steps involved in single-cell analysis with a focus on decision points and particular notes for glia. The goal of this primer is to ensure that single-cell ‘omics experiments continue to advance glial biology in a rigorous and replicable way.","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 3","pages":"451-473"},"PeriodicalIF":5.4,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666550","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}

引用次数: 0

R-Ras1 and R-Ras2 regulate mature oligodendrocyte subpopulations R-Ras1和R-Ras2调控成熟的少突胶质细胞亚群。

IF 5.4 2区医学

Glia Pub Date : 2024-11-19 DOI: 10.1002/glia.24643

Berta Alcover-Sanchez, Gonzalo Garcia-Martin, Víctor Paleo-García, Ana Quintas, Ana Dopazo, Agnès Gruart, José María Delgado-García, Pedro de la Villa, Francisco Wandosell, Marta P. Pereira, Beatriz Cubelos

{"title":"R-Ras1 and R-Ras2 regulate mature oligodendrocyte subpopulations","authors":"Berta Alcover-Sanchez, Gonzalo Garcia-Martin, Víctor Paleo-García, Ana Quintas, Ana Dopazo, Agnès Gruart, José María Delgado-García, Pedro de la Villa, Francisco Wandosell, Marta P. Pereira, Beatriz Cubelos","doi":"10.1002/glia.24643","DOIUrl":"10.1002/glia.24643","url":null,"abstract":"In the mammalian central nervous system, axonal myelination, executed by mature oligodendrocytes (MOLs), enables rapid neural transmission. Conversely, myelin deficiencies are hallmark features of multiple sclerosis, optic neuromyelitis, and some leukodystrophies. Recent studies have highlighted that MOLs are heterogeneous; however, how MOL subpopulations are specified and balanced in physiological settings is poorly understood. Previous works have demonstrated an essential role of the small GTPases R-Ras1 and R-Ras2 in the survival and myelination of oligodendrocytes. In this study, we aimed to determine how R-Ras1 and R-Ras2 contribute to the heterogeneity of MOL subpopulations. Our results evidence that R-Ras1 and R-Ras2 affect specification into the distinct subpopulations MOL1, MOL2, and MOL5/6, which in turn vary in their dependence of these GTPases. In R-Ras1 and/or R-Ras2 mutant mice, we observed an increase in the MOL1 subpopulation and a decrease in the MOL2 and MOL5/6 subpopulations. We identified R-Ras1 and R-Ras2 as key elements in balancing the heterogeneity of MOLs. Our results contribute to the understanding of the molecular mechanisms underlying the heterogeneity of MOLs and the myelination processes, which is crucial for innovating regenerative therapies for nervous system disorders.","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 4","pages":"701-719"},"PeriodicalIF":5.4,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24643","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666551","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}

引用次数: 0

Astrocytic NHERF-1 Increases Seizure Susceptibility by Inhibiting Surface Expression of TREK-1 星形胶质细胞 NHERF-1 通过抑制 TREK-1 的表面表达增加癫痫易感性

IF 5.4 2区医学

Glia Pub Date : 2024-11-14 DOI: 10.1002/glia.24644

Yeonju Bae, Soomin Lee, Ajung Kim, Shinae Lee, Seong-Seop Kim, Sunyoung Park, Junyeol Noh, Kanghyun Ryoo, Gwan-Su Yi, Jae-Yong Park, Eun Mi Hwang

{"title":"Astrocytic NHERF-1 Increases Seizure Susceptibility by Inhibiting Surface Expression of TREK-1","authors":"Yeonju Bae, Soomin Lee, Ajung Kim, Shinae Lee, Seong-Seop Kim, Sunyoung Park, Junyeol Noh, Kanghyun Ryoo, Gwan-Su Yi, Jae-Yong Park, Eun Mi Hwang","doi":"10.1002/glia.24644","DOIUrl":"10.1002/glia.24644","url":null,"abstract":"Mature hippocampal astrocytes exhibit a linear current-to-voltage (I-V) K+ membrane conductance called passive conductance. It is estimated to enable astrocytes to keep potassium homeostasis in the brain. We previously reported that the TWIK-1/TREK-1 heterodimeric channels are crucial for astrocytic passive conductance. However, the regulatory mechanism of these channels by other binding proteins remains elusive. Here, we identified Na+/H+ exchange regulator-1 (NHERF-1), a protein highly expressed in astrocytes, as a novel interaction partner for these channels. NHERF-1 endogenously bound to TWIK-1/TREK-1 in hippocampal cultured astrocytes. When NHERF-1 is overexpressed or silenced, surface expression and activity of TWIK-1/TREK-1 heterodimeric channels are inhibited or enhanced, respectively. Furthermore, we confirmed that reduced astrocytic passive conductance by NHERF-1 overexpressing in the hippocampus increases kainic acid (KA)-induced seizure sensitivity. Taken together, these results suggest that NHERF-1 is a key regulator of TWIK-1/TREK-1 heterodimeric channels in astrocytes and suppression of TREK-1 surface expression by NHERF-1 increases KA-induced seizure susceptibility via reduction of astrocytic passive conductance.","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 4","pages":"720-736"},"PeriodicalIF":5.4,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24644","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613216","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}

引用次数: 0

Aquaporin-4 activation facilitates glymphatic system function and hematoma clearance post-intracerebral hemorrhage 激活Aquaporin-4有助于脑出血后的肾上腺系统功能和血肿清除。

IF 5.4 2区医学

Glia Pub Date : 2024-11-12 DOI: 10.1002/glia.24639

Wenchao Chen, Chuntian Liang, Shasha Peng, Shuangjin Bao, Fang Xue, Xia Lian, Yinghong Liu, Gaiqing Wang

{"title":"Aquaporin-4 activation facilitates glymphatic system function and hematoma clearance post-intracerebral hemorrhage","authors":"Wenchao Chen, Chuntian Liang, Shasha Peng, Shuangjin Bao, Fang Xue, Xia Lian, Yinghong Liu, Gaiqing Wang","doi":"10.1002/glia.24639","DOIUrl":"10.1002/glia.24639","url":null,"abstract":"Efficient clearance of hematomas is crucial for improving clinical outcomes in patients with intracerebral hemorrhage (ICH). The glymphatic system, facilitated by aquaporin-4 (AQP4), plays a crucial role in cerebrospinal fluid (CSF) entry and metabolic waste clearance. This study examined the role of the glymphatic system in ICH pathology, with a focus on AQP4. Collagenase-induced ICH models were established, with AQP4 expression regulated through mifepristone as an agonist, TGN-020 as an inhibitor, and Aqp4 gene knockout. Fluorescence tracing and multimodal magnetic resonance imaging (MRI) were employed to observe glymphatic system functionality, hematoma, and edema volumes. Neurological deficit scoring was performed using the modified Garcia Scale. AQP4 expression was quantified using RT-qPCR and Western blotting, and cellular localization was explored using immunofluorescence. The brain tissue sections were examined for neuronal morphology, degenerative changes, and iron deposition. Three days post-ICH, the AQP4 agonist group showed increased AQP4 protein expression and perivascular polarization, decreased hemoglobin levels, and reduced iron deposition. Conversely, the inhibition group exhibited contrasting trends. AQP4 activation improved glymphatic system function, leading to a wider distribution, improved neurological function, and reduced hematoma. Pharmacological inhibition and genetic knockout of AQP4 have opposing effects. The glymphatic system, facilitated by AQP4, plays a crucial role in hematoma clearance following cerebral hemorrhage. Upregulation of AQP4 improves glymphatic system function, facilitates hematoma clearance, and promotes brain tissue recovery.","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 2","pages":"368-380"},"PeriodicalIF":5.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613212","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}

引用次数: 0

The E3 ubiquitin ligase Nedd4 fosters developmental myelination in the mouse central and peripheral nervous system E3泛素连接酶Nedd4促进了小鼠中枢神经系统和周围神经系统的髓鞘发育。

IF 5.4 2区医学

Glia Pub Date : 2024-11-07 DOI: 10.1002/glia.24642

Cristina Fimiani, Jorge A. Pereira, Joanne Gerber, Ingrid Berg, Jonathan DeGeer, Sven Bachofner, Jonas S. Fischer, Manuel Kauffmann, Ueli Suter

{"title":"The E3 ubiquitin ligase Nedd4 fosters developmental myelination in the mouse central and peripheral nervous system","authors":"Cristina Fimiani, Jorge A. Pereira, Joanne Gerber, Ingrid Berg, Jonathan DeGeer, Sven Bachofner, Jonas S. Fischer, Manuel Kauffmann, Ueli Suter","doi":"10.1002/glia.24642","DOIUrl":"10.1002/glia.24642","url":null,"abstract":"Ubiquitination is a major post-translational regulatory mechanism that tunes numerous aspects of ubiquitinated target proteins, including localization, stability, and function. During differentiation and myelination, Oligodendrocytes (OLs) in the central nervous system and Schwann cells (SCs) in the peripheral nervous system undergo major cellular changes, including the tightly controlled production of large and accurate amounts of proteins and lipids. Such processes have been implied to depend on regulatory aspects of ubiquitination, with E3 ubiquitin ligases being generally involved in the selection of specific ubiquitination substrates by ligating ubiquitin to targets and granting target selectivity. In this study, we have used multiple transgenic mouse lines to investigate the functional impact of the E3 ubiquitin ligase Nedd4 in the OL- and SC-lineages. Our findings in the developing spinal cord indicate that Nedd4 is required for the correct accumulation of differentiated OLs and ensures proper myelination, supporting and further expanding previously suggested conceptual models. In sciatic nerves, we found that Nedd4 is required for timely radial sorting of axons by SCs as a pre-requirement for correct onset of myelination. Moreover, Nedd4 ensures correct myelin thickness in both SCs and spinal cord OLs.","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 2","pages":"422-444"},"PeriodicalIF":5.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602454","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}

引用次数: 0

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