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Axonal Selectivity of Myelination by Single Oligodendrocytes Established During Development in Mouse Cerebellar White Matter. 小鼠小脑白质发育过程中形成的单个少突胶质细胞髓鞘化的轴突选择性
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-17 DOI: 10.1002/glia.24660
Batpurev Battulga, Yasuyuki Osanai, Reiji Yamazaki, Yoshiaki Shinohara, Nobuhiko Ohno

Myelin formation by oligodendrocytes regulates the conduction velocity and functional integrity of neuronal axons. While individual oligodendrocytes form myelin sheaths around multiple axons and control the functions of neural circuits where the axons are involved, it remains unclear if oligodendrocytes selectively form myelin sheaths around specific subtypes of axons. Using the combination of rabies virus-mediated single oligodendrocyte labeling and immunostaining with tissue clearing, we revealed that approximately half of the oligodendrocytes preferentially myelinate axons originating from Purkinje cells in the white matter of adult mouse cerebella. The preference for Purkinje cell axons was more pronounced during development when the process of myelination within cerebellar white matter was initiated; over 90% of oligodendrocytes preferentially myelinated Purkinje cell axons. Preferential myelination of Purkinje cell axons was further confirmed by immuno-electron microscopy and transgenic mice that label early-born oligodendrocytes. Transgenic mice that label oligodendrocytes differentiated at the early development showed that early-born oligodendrocytes preferentially myelinate Purkinje cell axons in the matured cerebellar white matter. In contrast, transgenic mice that label oligodendrocytes differentiated after the peak of cerebellar myelination showed that the later-differentiated oligodendrocytes dominantly myelinated non-Purkinje cell axons. These results demonstrate that a significant proportion of oligodendrocytes preferentially myelinate functionally distinct axons in the cerebellar white matter, and the axonal preference of myelination by individual oligodendrocytes is established depending on the timing of their differentiation during development. Our data provide the evidence that there is a critical time window of myelination that a specific subtype of axons are dominantly myelinated by the oligodendrocytes.

少突胶质细胞髓磷脂的形成调节神经轴突的传导速度和功能完整性。虽然单个少突胶质细胞在多个轴突周围形成髓鞘并控制涉及轴突的神经回路的功能,但尚不清楚少突胶质细胞是否选择性地在特定亚型轴突周围形成髓鞘。利用狂犬病毒介导的单个少突胶质细胞标记和组织清除免疫染色相结合的方法,我们发现大约一半的少突胶质细胞优先于髓鞘化成年小鼠小脑白质中源自浦肯野细胞的轴突。在发育过程中,当小脑白质髓鞘形成过程开始时,浦肯野细胞轴突的偏好更为明显;超过90%的少突胶质细胞优先有髓鞘的浦肯野细胞轴突。免疫电镜和标记早期出生的少突胶质细胞的转基因小鼠进一步证实了浦肯野细胞轴突的优先髓鞘形成。标记在发育早期分化的少突胶质细胞的转基因小鼠表明,早期出生的少突胶质细胞优先在成熟的小脑白质中形成浦肯野细胞轴突。相比之下,标记少突胶质细胞的转基因小鼠在小脑髓鞘形成高峰后分化,发现后期分化的少突胶质细胞主要有髓鞘形成非浦肯野细胞轴突。这些结果表明,在小脑白质中,有相当比例的少突胶质细胞优先向功能不同的轴突形成髓鞘,并且单个少突胶质细胞对轴突形成髓鞘的偏好取决于它们在发育过程中分化的时间。我们的数据提供的证据表明,有一个关键的时间窗口的髓鞘形成,一个特定亚型的轴突主要是由少突细胞髓鞘形成。
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引用次数: 0
Lipids: Emerging Players of Microglial Biology 脂质:小胶质细胞生物学的新角色
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-17 DOI: 10.1002/glia.24654
Priya Prakash, Caitlin E. Randolph, Katherine A. Walker, Gaurav Chopra

Lipids are small molecule immunomodulators that play critical roles in maintaining cellular health and function. Microglia, the resident immune cells of the central nervous system, regulate lipid metabolism both in the extracellular environment and within intracellular compartments through various mechanisms. For instance, glycerophospholipids and fatty acids interact with protein receptors on the microglial surface, such as the Triggering Receptor Expressed on Myeloid Cells 2, influencing cellular functions like phagocytosis and migration. Moreover, cholesterol is essential not only for microglial survival but, along with other lipids such as fatty acids, is crucial for the formation, function, and accumulation of lipid droplets, which modulate microglial activity in inflammatory diseases. Other lipids, including acylcarnitines and ceramides, participate in various signaling pathways within microglia. Despite the complexity of the microglial lipidome, only a few studies have investigated the effects of specific lipid classes on microglial biology. In this review, we focus on major lipid classes and their roles in modulating microglial function. We also discuss novel analytical techniques for characterizing the microglial lipidome and highlight gaps in current knowledge, suggesting new directions for future research on microglial lipid biology.

脂质是一种小分子免疫调节剂,在维持细胞健康和功能方面发挥着至关重要的作用。小胶质细胞是中枢神经系统的常驻免疫细胞,它们通过各种机制调节细胞外环境和细胞内区室的脂质代谢。例如,甘油磷脂和脂肪酸与小胶质细胞表面的蛋白受体(如髓样细胞上表达的触发受体 2)相互作用,影响吞噬和迁移等细胞功能。此外,胆固醇不仅对小胶质细胞的存活至关重要,而且与脂肪酸等其他脂质一起,对脂滴的形成、功能和积聚也至关重要,而脂滴会在炎症性疾病中调节小胶质细胞的活动。包括酰基肉碱和神经酰胺在内的其他脂质参与了小胶质细胞内的各种信号通路。尽管小胶质细胞脂质体非常复杂,但只有少数研究调查了特定脂质类别对小胶质细胞生物学的影响。在本综述中,我们将重点讨论主要脂质类别及其在调节小胶质细胞功能方面的作用。我们还讨论了表征小胶质细胞脂质体的新型分析技术,并强调了当前知识中的空白,为未来小胶质细胞脂质生物学研究提出了新的方向。
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引用次数: 0
Alzheimer's Disease Risk Gene SORL1 Promotes Receptiveness of Human Microglia to Pro-Inflammatory Stimuli. 阿尔茨海默病风险基因SORL1促进人类小胶质细胞对促炎刺激的接受性
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-17 DOI: 10.1002/glia.24659
Peter Lund Ovesen, Kristian Juul-Madsen, Narasimha S Telugu, Vanessa Schmidt, Silke Frahm, Helena Radbruch, Emma Louise Louth, Anders Rosendal Korshøj, Frank L Heppner, Sebastian Diecke, Helmut Kettenmann, Thomas E Willnow

Sorting protein-related receptor containing class A repeats (SORLA) is an intracellular trafficking receptor encoded by the Alzheimer's disease (AD) gene SORL1 (sortilin-related receptor 1). Recent findings argue that altered expression in microglia may underlie the genome-wide risk of AD seen with some SORL1 gene variants, however, the functional significance of the receptor in microglia remains poorly explained. Using unbiased omics and targeted functional analyses in iPSC-based human microglia, we identified a crucial role for SORLA in sensitizing microglia to pro-inflammatory stimuli. We show that SORLA acts as a sorting factor for the pattern recognition receptor CD14, directing CD14 exposure on the cell surface and priming microglia to stimulation by pro-inflammatory factors. Loss of SORLA in gene-targeted microglia impairs proper CD14 sorting and blunts pro-inflammatory responses. Our studies indicate an important role for SORLA in shaping the inflammatory brain milieu, a biological process important to local immune responses in AD.

含有A类重复序列的分选蛋白相关受体(SORLA)是一种由阿尔茨海默病(AD)基因SORL1 (sortilin相关受体1)编码的细胞内转运受体。最近的研究结果认为,小胶质细胞中表达改变可能是一些SORL1基因变异导致AD全基因组风险的基础,然而,该受体在小胶质细胞中的功能意义仍未得到充分解释。通过对基于ipsc的人类小胶质细胞进行无偏组学和靶向功能分析,我们确定了SORLA在使小胶质细胞对促炎刺激敏感方面的关键作用。我们发现SORLA作为模式识别受体CD14的分选因子,引导CD14暴露在细胞表面,并启动促炎因子对小胶质细胞的刺激。SORLA在基因靶向小胶质细胞中的缺失会损害CD14的正确分选并减弱促炎反应。我们的研究表明SORLA在形成炎症性脑环境中发挥重要作用,这是一个对AD局部免疫反应很重要的生物学过程。
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引用次数: 0
Multi Layered Omics Approaches Reveal Glia Specific Alterations in Alzheimer's Disease: A Systematic Review and Future Prospects 多层组学方法揭示阿尔茨海默病中胶质细胞特异性改变:系统回顾和未来展望。
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-09 DOI: 10.1002/glia.24652
Özkan İş, Yuhao Min, Xue Wang, Stephanie R. Oatman, Ann Abraham Daniel, Nilüfer Ertekin-Taner

Alzheimer's disease (AD) is the most common neurodegenerative dementia with multi-layered complexity in its molecular etiology. Multiple omics-based approaches, such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, and lipidomics are enabling researchers to dissect this molecular complexity, and to uncover a plethora of alterations yielding insights into the pathophysiology of this disease. These approaches reveal multi-omics alterations essentially in all cell types of the brain, including glia. In this systematic review, we screen the literature for human studies implementing any omics approach within the last 10 years, to discover AD-associated molecular perturbations in brain glial cells. The findings from over 200 AD-related studies are reviewed under four different glial cell categories: microglia, oligodendrocytes, astrocytes and brain vascular cells. Under each category, we summarize the shared and unique molecular alterations identified in glial cells through complementary omics approaches. We discuss the implications of these findings for the development, progression and ultimately treatment of this complex disease as well as directions for future omics studies in glia cells.

阿尔茨海默病(AD)是最常见的神经退行性痴呆,其分子病因具有多层复杂性。多种基于组学的方法,如基因组学、表观基因组学、转录组学、蛋白质组学、代谢组学和脂质组学,使研究人员能够剖析这种分子复杂性,并揭示大量的改变,从而深入了解这种疾病的病理生理学。这些方法揭示了大脑所有细胞类型的多组学改变,包括神经胶质细胞。在这篇系统综述中,我们筛选了近10年来实施任何组学方法的人类研究文献,以发现ad在脑胶质细胞中的相关分子扰动。本文从小胶质细胞、少突胶质细胞、星形胶质细胞和脑血管细胞四种不同的胶质细胞类别中综述了200多项与ad相关的研究结果。在每个类别下,我们总结了通过互补组学方法在胶质细胞中发现的共享和独特的分子改变。我们讨论了这些发现对这种复杂疾病的发展、进展和最终治疗的意义,以及未来神经胶质细胞组学研究的方向。
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引用次数: 0
Potassium Release From the Habenular Astrocytes Induces Depressive-Like Behaviors in Mice. 小鼠缰状星形胶质细胞释放钾诱导抑郁样行为。
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-29 DOI: 10.1002/glia.24647
Hidenori Aizawa, Miho Matsumata, Laura Ayaka Noguera Oishi, Fumie Nishimura, Deepa Kamath Kasaragod, Xintong Yao, Wanqin Tan, Tomomi Aida, Kohichi Tanaka

The habenula has been implicated in psychiatric disorders such as depression, primarily because of its role in the modulation of the dopaminergic and serotonergic systems, which play a role in the pathophysiology of these disorders. Despite growing evidence supporting the role of the habenula in behavioral regulation, the process by which neural cells develop in the habenula remains elusive. Since the habenular anlage is found in the prosomere 2 domain expressing transcription factor Dbx1 in mouse embryos, we hypothesized that the Dbx1-expressing prosomere domain is a source of astrocytes that modulate neuronal activity in the habenula. To address this, we examined the cell lineage generated from Dbx1-expressing cells in male mice using tamoxifen-inducible Cre recombinase under the control of the Dbx1 promoter. Perinatal induction of Cre activity labeled cells migrating radially from the ventricular zone to the pial side of the habenular anlage, and eventually showed astrocyte-like morphology with expression of the marker protein, S100β, for mature astrocytes in the habenula of the adult mouse. Photostimulation of astrocytes expressing ChR2 released potassium ions into the extracellular space, which in turn excited the neurons with an increased firing rate in the lateral habenula. Finally, photostimulation of habenular astrocytes exacerbated depression-like phenotypes with reduced locomotor activity, exaggerated despair behavior and impaired sucrose preference in open-field, tail suspension and sucrose preference tests, respectively. These results indicated that the Dbx1-expressing perinatal domain generated astrocytes that modulated neuronal activity via the regulation of extracellular potassium levels.

habenula与抑郁症等精神疾病有关,主要是因为它在多巴胺能和血清素能系统的调节中起作用,而多巴胺能和血清素能系统在这些疾病的病理生理学中起作用。尽管越来越多的证据支持缰带在行为调节中的作用,但缰带中神经细胞发育的过程仍然难以捉摸。由于在小鼠胚胎中,在表达转录因子Dbx1的prosomer 2结构域中发现了habenular样本,因此我们假设表达Dbx1的prosomer结构域是调节habenula神经元活动的星形胶质细胞的来源。为了解决这个问题,我们在Dbx1启动子的控制下,使用他莫昔芬诱导的Cre重组酶检测了表达Dbx1的雄性小鼠细胞的细胞系。围产期感应Cre活动标记细胞的迁移从心室区径向的软膜的一侧habenular原基,并最终显示astrocyte-like形态学标记蛋白的表达,S100β,成熟的星形胶质细胞在成年小鼠的系带。光刺激表达ChR2的星形胶质细胞将钾离子释放到细胞外空间,进而刺激神经元,增加外侧缰核的放电率。最后,光刺激缰状星形胶质细胞加重了抑郁样表型,在野外、悬尾和蔗糖偏好试验中分别表现为运动活动减少、绝望行为加剧和蔗糖偏好受损。这些结果表明,表达dbx1的围产期结构域产生的星形胶质细胞通过调节细胞外钾水平来调节神经元活动。
{"title":"Potassium Release From the Habenular Astrocytes Induces Depressive-Like Behaviors in Mice.","authors":"Hidenori Aizawa, Miho Matsumata, Laura Ayaka Noguera Oishi, Fumie Nishimura, Deepa Kamath Kasaragod, Xintong Yao, Wanqin Tan, Tomomi Aida, Kohichi Tanaka","doi":"10.1002/glia.24647","DOIUrl":"https://doi.org/10.1002/glia.24647","url":null,"abstract":"<p><p>The habenula has been implicated in psychiatric disorders such as depression, primarily because of its role in the modulation of the dopaminergic and serotonergic systems, which play a role in the pathophysiology of these disorders. Despite growing evidence supporting the role of the habenula in behavioral regulation, the process by which neural cells develop in the habenula remains elusive. Since the habenular anlage is found in the prosomere 2 domain expressing transcription factor Dbx1 in mouse embryos, we hypothesized that the Dbx1-expressing prosomere domain is a source of astrocytes that modulate neuronal activity in the habenula. To address this, we examined the cell lineage generated from Dbx1-expressing cells in male mice using tamoxifen-inducible Cre recombinase under the control of the Dbx1 promoter. Perinatal induction of Cre activity labeled cells migrating radially from the ventricular zone to the pial side of the habenular anlage, and eventually showed astrocyte-like morphology with expression of the marker protein, S100β, for mature astrocytes in the habenula of the adult mouse. Photostimulation of astrocytes expressing ChR2 released potassium ions into the extracellular space, which in turn excited the neurons with an increased firing rate in the lateral habenula. Finally, photostimulation of habenular astrocytes exacerbated depression-like phenotypes with reduced locomotor activity, exaggerated despair behavior and impaired sucrose preference in open-field, tail suspension and sucrose preference tests, respectively. These results indicated that the Dbx1-expressing perinatal domain generated astrocytes that modulated neuronal activity via the regulation of extracellular potassium levels.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749528","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
Therapeutic Potential of Growth Hormone in Peripheral Nerve Injury: Enhancing Schwann Cell Proliferation and Migration Through IGF-1R-AKT and ERK Signaling Pathways. 生长激素在周围神经损伤中的治疗潜力:通过IGF-1R-AKT和ERK信号通路促进雪旺细胞增殖和迁移。
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-28 DOI: 10.1002/glia.24653
Jiaqian Chen, Tingcheng Zhang, Chaohu Wang, Peirong Niu, Liehao Huang, Rongrong Guo, Chengdong Wu, Huarong Zhang, Zhiyong Wu, Songtao Qi, Yi Liu

Peripheral nerve injury (PNI) represents a prevalent condition characterized by the demyelination of affected nerves. The challenge of remyelinating these nerves and achieving satisfactory functional recovery has long been a persistent issue. The specific contributions of growth hormone (GH) in the aftermath of PNI have remained ambiguous. Our investigations have demonstrated that GH not only enhances neurological function scores but also promotes remyelination within a three-week period. Further in vivo studies corroborated that GH facilitates nerve function improvement by mitigating neuronal apoptosis. In vitro, the ideal concentration of GH for exerting effects on Schwann cells (SCs) has been identified as 80 ng/mL. Subsequent research uncovered GH's profound impact on SCs proliferation, cell cycle progression, and migration. Through RNA sequencing and additional experiments, it was discovered that GH treatment elevates the phosphorylation levels of IGF-1R, AKT, and ERK. Moreover, the GH-induced proliferation and migration of SCs were significantly diminished by the inhibition of the IGF-1R pathway, achieved through pre-treatment with Linsitinib. The outcomes of this investigation suggest that GH can significantly enhance the proliferation and migration of SCs, presenting it as a viable option for PNI repair.

周围神经损伤(PNI)是一种以受影响神经脱髓鞘为特征的普遍疾病。长期以来,对这些神经的髓鞘再生和实现令人满意的功能恢复的挑战一直是一个持久的问题。生长激素(GH)在PNI后的具体贡献仍然不明确。我们的研究表明生长激素不仅能提高神经功能评分,还能在三周内促进髓鞘再生。进一步的体内研究证实生长激素通过减轻神经元凋亡促进神经功能改善。体外,生长激素对雪旺细胞(SCs)发挥作用的理想浓度已被确定为80 ng/mL。随后的研究揭示了生长激素对SCs增殖、细胞周期进展和迁移的深远影响。通过RNA测序和其他实验,发现生长激素治疗可提高IGF-1R、AKT和ERK的磷酸化水平。此外,通过Linsitinib预处理,通过抑制IGF-1R通路,gh诱导的SCs增殖和迁移显著减少。本研究结果表明,生长激素可以显著增强SCs的增殖和迁移,这表明它是修复PNI的可行选择。
{"title":"Therapeutic Potential of Growth Hormone in Peripheral Nerve Injury: Enhancing Schwann Cell Proliferation and Migration Through IGF-1R-AKT and ERK Signaling Pathways.","authors":"Jiaqian Chen, Tingcheng Zhang, Chaohu Wang, Peirong Niu, Liehao Huang, Rongrong Guo, Chengdong Wu, Huarong Zhang, Zhiyong Wu, Songtao Qi, Yi Liu","doi":"10.1002/glia.24653","DOIUrl":"https://doi.org/10.1002/glia.24653","url":null,"abstract":"<p><p>Peripheral nerve injury (PNI) represents a prevalent condition characterized by the demyelination of affected nerves. The challenge of remyelinating these nerves and achieving satisfactory functional recovery has long been a persistent issue. The specific contributions of growth hormone (GH) in the aftermath of PNI have remained ambiguous. Our investigations have demonstrated that GH not only enhances neurological function scores but also promotes remyelination within a three-week period. Further in vivo studies corroborated that GH facilitates nerve function improvement by mitigating neuronal apoptosis. In vitro, the ideal concentration of GH for exerting effects on Schwann cells (SCs) has been identified as 80 ng/mL. Subsequent research uncovered GH's profound impact on SCs proliferation, cell cycle progression, and migration. Through RNA sequencing and additional experiments, it was discovered that GH treatment elevates the phosphorylation levels of IGF-1R, AKT, and ERK. Moreover, the GH-induced proliferation and migration of SCs were significantly diminished by the inhibition of the IGF-1R pathway, achieved through pre-treatment with Linsitinib. The outcomes of this investigation suggest that GH can significantly enhance the proliferation and migration of SCs, presenting it as a viable option for PNI repair.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749535","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
Single Cell Deletion of the Transcription Factors Trps1 and Sox9 in Astrocytes Reveals Novel Functions in the Adult Cerebral Cortex. 星形胶质细胞中转录因子Trps1和Sox9的单细胞缺失揭示了成人大脑皮层的新功能。
IF 5.4 2区 医学 Q1 NEUROSCIENCES 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

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.

星形胶质细胞在脑功能中发挥着关键作用,但这些作用是如何由成人大脑中的转录因子(tf)协调的,以及星形胶质细胞的异质性是如何一致的,这在很大程度上是未知的。在这里,我们通过mokola -伪慢病毒传递到成人大脑皮层,通过cas9介导的缺失,研究了新型星形胶质细胞TF Trps1(转录抑制因子GATA结合1)和著名的星形胶质细胞TF Sox9的定位和功能。Trps1和Sox9水平在成人皮质星形胶质细胞中表现出异质性,这促使我们探索单独或同时删除Sox9或Trps1在单细胞(通过基于斑块的单细胞转录组学)和组织水平(通过空间转录组学)上的影响。这揭示了tf在星形胶质细胞中的特异性功能,如突触维持,其中Trps1缺失对突触数量的影响最大,对免疫反应的影响也很普遍。此外,空间转录组学对周围细胞,如少突胶质细胞和其他在免疫细胞类型上具有TF特异性差异的免疫细胞显示非细胞自主作用:Trps1缺失特异性影响单核细胞,而Sox9缺失主要作用于小胶质细胞,TF的缺失主要影响B细胞。综上所述,本研究揭示了Trps1和Sox9在成人星形胶质细胞及其与其他胶质细胞和免疫细胞的通讯中的新作用。
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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 Q1 NEUROSCIENCES 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

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.

多种证据表明,多发性硬化症(MS)等脱髓鞘疾病会导致线粒体功能障碍。髓鞘再形成失败的部分原因被认为是少突胶质细胞祖细胞(OPC)向少突胶质细胞分化受阻,而少突胶质细胞可在轴突周围生成髓鞘。OPC 分化过程需要大量能量,对 ATP 的需求很高,而 ATP 是通过线粒体提供的。在本研究中,我们重点研究了两种小鼠再髓鞘化模型和人类死后多发性硬化症大脑中 OPC 分化过程中线粒体基因表达的变化。鉴于这些转录改变,我们随后研究了线粒体去泛素化酶 USP30 的基因改变是否会增强 OPC 分化和髓鞘化。通过基因敲除 USP30,我们观察到 OPC 分化和髓鞘化增强,而不影响体外和体内试验中 OPC 的增殖和存活。我们还发现,USP30基因敲除小鼠在体内发生局灶性脱髓鞘后,OPC分化会加速。观察到的 OPC 分化和髓鞘化的促进与 USP30 基因敲除 OPC 的耗氧量增加有关。这些数据共同表明了线粒体功能和 USP30 在 OPC 分化和髓鞘化过程中的作用。
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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 Q1 NEUROSCIENCES Pub Date : 2024-11-25 DOI: 10.1002/glia.24651
Jonathan R. Weinstein, Suman Jayadev, Shane Liddelow, B. J. L. Eggen
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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 Q1 NEUROSCIENCES 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

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.

GABA 能网络活动在一系列生理过程中起着至关重要的作用,并与各种病理状况有关。虽然关于 GABA 能网络活动如何调节 CA1 区兴奋性和抑制性突触传递的研究已经非常广泛,但它影响内侧皮层-齿状回(EC-DG)回路突触传递的机制在很大程度上仍未得到探索。利用全细胞膜片钳记录、光遗传学、免疫组织化学和行为测定等方法,我们证明了激活星形胶质细胞中的 GABA 转运体 3(GAT-3)会通过反向 Na+/Ca2+ 交换器引发细胞内 Ca2+ 的增加。耐人寻味的是,抑制 GAT-3 会阻碍 GABA 诱导的星形胶质细胞 Ca2+ 水平的升高,从而抑制随后的突触传递增强。此外,我们还发现,神经元间内源性释放的 GABA 也会通过 GAT-3 调节 DG 中的突触传递。最重要的是,通过选择性地减少星形胶质细胞的钙信号,我们观察到 GABA 诱导的突触传递增强也随之减少,这强调了星形胶质细胞在这一调节途径中的关键作用。此外,我们还发现,GAT-3 的激活会增强突触前 GluN2B 含 N-甲基-D-天冬氨酸受体(GluN2B-NMDARs)在 DG 中的兴奋传递。最后,我们的体内实验证明,抑制 GAT-3 会对情境恐惧记忆的形成产生不利影响,从而突出了它在认知处理过程中的关键作用。这些发现强调了星形胶质细胞 GAT-3 在认知功能中的重要作用,并为认知障碍的潜在治疗靶点提供了宝贵的见解,为相关疾病的治疗开辟了新的途径。
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引用次数: 0
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