Journal articles on the topic 'Astrocyte'
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1
Domingos, Cátia, Franziska E. Müller, Stefan Passlick, Dagmar Wachten, Evgeni Ponimaskin, Martin K. Schwarz, Susanne Schoch, André Zeug, and Christian Henneberger. "Induced Remodelling of Astrocytes In Vitro and In Vivo by Manipulation of Astrocytic RhoA Activity." Cells 12, no. 2 (January 15, 2023): 331. http://dx.doi.org/10.3390/cells12020331.
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Structural changes of astrocytes and their perisynaptic processes occur in response to various physiological and pathophysiological stimuli. They are thought to profoundly affect synaptic signalling and neuron-astrocyte communication. Understanding the causal relationship between astrocyte morphology changes and their functional consequences requires experimental tools to selectively manipulate astrocyte morphology. Previous studies indicate that RhoA-related signalling can play a major role in controlling astrocyte morphology, but the direct effect of increased RhoA activity has not been documented in vitro and in vivo. Therefore, we established a viral approach to manipulate astrocytic RhoA activity. We tested if and how overexpression of wild-type RhoA, of a constitutively active RhoA mutant (RhoA-CA), and of a dominant-negative RhoA variant changes the morphology of cultured astrocytes. We found that astrocytic expression of RhoA-CA induced robust cytoskeletal changes and a withdrawal of processes in cultured astrocytes. In contrast, overexpression of other RhoA variants led to more variable changes of astrocyte morphology. These induced morphology changes were reproduced in astrocytes of the hippocampus in vivo. Importantly, astrocytic overexpression of RhoA-CA did not alter the branching pattern of larger GFAP-positive processes of astrocytes. This indicates that a prolonged increase of astrocytic RhoA activity leads to a distinct morphological phenotype in vitro and in vivo, which is characterized by an isolated reduction of fine peripheral astrocyte processes in vivo. At the same time, we identified a promising experimental approach for investigating the functional consequences of astrocyte morphology changes.
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Amuti, T., I. Ouko, S. Mukonjia, I. Cheruiyot, J. Munguti, P. Mwachaka, and A. Malek. "Role of heterogeneous astrocyte receptor expression in determining astrocytic response to neuronal disorders." Anatomy Journal of Africa 7, no. 1 (April 11, 2018): 1169–74. http://dx.doi.org/10.4314/aja.v7i1.169490.
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Following neuronal disorders, astrocytes carry out either neuroprotection or neurodegeneration. Previous authors suggest that favoring of neurodegeneration or neuroprotection by astrocytes can be due to many factors such as the influence of cytokines following their binding on their receptors on astrocytes. These receptors have however been shown to be region specific and heterogeneous. Further, research exploiting their role and influence in determining astrocytic response remains partly elucidated. A review of previous and ongoing research on these receptors would be helpful in the disclosure of astrocytic responses to neuronal disorders.Keywords: Astrogliosis, Heterogenous astrocyte expression, Antagonistic astrocyte reaction, Nervous injury, Astrocyte mediated neurodegeneration
3
Huang, Mi, Yixing Du, Conrad Kiyoshi, Xiao Wu, Candice Askwith, Dana McTigue, and Min Zhou. "Syncytial Isopotentiality: An Electrical Feature of Spinal Cord Astrocyte Networks." Neuroglia 1, no. 1 (August 24, 2018): 271–79. http://dx.doi.org/10.3390/neuroglia1010018.
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Due to strong electrical coupling, syncytial isopotentiality emerges as a physiological mechanism that coordinates astrocytes into a highly efficient system in brain homeostasis. Although this electrophysiological phenomenon has now been observed in astrocyte networks established by different astrocyte subtypes, the spinal cord remains a brain region that is still unexplored. In ALDH1L1-eGFP transgenic mice, astrocytes can be visualized by confocal microscopy and the spinal cord astrocytes in grey matter are organized in a distinctive pattern. Namely, each astrocyte resides with more directly coupled neighbors at shorter interastrocytic distances compared to protoplasmic astrocytes in the hippocampal CA1 region. In whole-cell patch clamp recording, the spinal cord grey matter astrocytes exhibit passive K+ conductance and a highly hyperpolarized membrane potential of −80 mV. To answer whether syncytial isopotentiality is a shared feature of astrocyte networks in the spinal cord, the K+ content in a physiological recording solution was substituted by equimolar Na+ for whole-cell recording in spinal cord slices. In uncoupled single astrocytes, this substitution of endogenous K+ with Na+ is known to depolarize astrocytes to around 0 mV as predicted by Goldman–Hodgkin–Katz (GHK) equation. In contrast, the existence of syncytial isopotentiality is indicated by a disobedience of the GHK predication as the recorded astrocyte’s membrane potential remains at a quasi-physiological level that is comparable to its neighbors due to strong electrical coupling. We showed that the strength of syncytial isopotentiality in spinal cord grey matter is significantly stronger than that of astrocyte network in the hippocampal CA1 region. Thus, this study corroborates the notion that syncytial isopotentiality most likely represents a system-wide electrical feature of astrocytic networks throughout the brain.
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Wolfes, Anne C., Saheeb Ahmed, Ankit Awasthi, Markus A. Stahlberg, Ashish Rajput, Daniel S. Magruder, Stefan Bonn, and Camin Dean. "A novel method for culturing stellate astrocytes reveals spatially distinct Ca2+ signaling and vesicle recycling in astrocytic processes." Journal of General Physiology 149, no. 1 (December 1, 2016): 149–70. http://dx.doi.org/10.1085/jgp.201611607.
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Interactions between astrocytes and neurons rely on the release and uptake of glial and neuronal molecules. But whether astrocytic vesicles exist and exocytose in a regulated or constitutive fashion is under debate. The majority of studies have relied on indirect methods or on astrocyte cultures that do not resemble stellate astrocytes found in vivo. Here, to investigate vesicle-associated proteins and exocytosis in stellate astrocytes specifically, we developed a simple, fast, and economical method for growing stellate astrocyte monocultures. This method is superior to other monocultures in terms of astrocyte morphology, mRNA expression profile, protein expression of cell maturity markers, and Ca2+ fluctuations: In astrocytes transduced with GFAP promoter–driven Lck-GCaMP3, spontaneous Ca2+ events in distinct domains (somata, branchlets, and microdomains) are similar to those in astrocytes co-cultured with other glia and neurons but unlike Ca2+ events in astrocytes prepared using the McCarthy and de Vellis (MD) method and immunopanned (IP) astrocytes. We identify two distinct populations of constitutively recycling vesicles (harboring either VAMP2 or SYT7) specifically in branchlets of cultured stellate astrocytes. SYT7 is developmentally regulated in these astrocytes, and we observe significantly fewer synapses in wild-type mouse neurons grown on Syt7−/− astrocytes. SYT7 may thus be involved in trafficking or releasing synaptogenic factors. In summary, our novel method yields stellate astrocyte monocultures that can be used to study Ca2+ signaling and vesicle recycling and dynamics in astrocytic processes.
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Rosa, Juao-Guilherme, Katherine Hamel, Carrie Sheeler, Ella Borgenheimer, Stephen Gilliat, Alyssa Soles, Ferris J. Ghannoum, et al. "Spatial and Temporal Diversity of Astrocyte Phenotypes in Spinocerebellar Ataxia Type 1 Mice." Cells 11, no. 20 (October 21, 2022): 3323. http://dx.doi.org/10.3390/cells11203323.
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While astrocyte heterogeneity is an important feature of the healthy brain, less is understood about spatiotemporal heterogeneity of astrocytes in brain disease. Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by a CAG repeat expansion in the gene Ataxin1 (ATXN1). We characterized astrocytes across disease progression in the four clinically relevant brain regions, cerebellum, brainstem, hippocampus, and motor cortex, of Atxn1154Q/2Q mice, a knock-in mouse model of SCA1. We found brain region-specific changes in astrocyte density and GFAP expression and area, early in the disease and prior to neuronal loss. Expression of astrocytic core homeostatic genes was also altered in a brain region-specific manner and correlated with neuronal activity, indicating that astrocytes may compensate or exacerbate neuronal dysfunction. Late in disease, expression of astrocytic homeostatic genes was reduced in all four brain regions, indicating loss of astrocyte functions. We observed no obvious correlation between spatiotemporal changes in microglia and spatiotemporal astrocyte alterations, indicating a complex orchestration of glial phenotypes in disease. These results support spatiotemporal diversity of glial phenotypes as an important feature of the brain disease that may contribute to SCA1 pathogenesis in a brain region and disease stage-specific manner.
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Birck, Cindy, Aurélien Ginolhac, Maria Angeliki S. Pavlou, Alessandro Michelucci, Paul Heuschling, and Luc Grandbarbe. "NF-κB and TNF Affect the Astrocytic Differentiation from Neural Stem Cells." Cells 10, no. 4 (April 8, 2021): 840. http://dx.doi.org/10.3390/cells10040840.
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The NF-κB signaling pathway is crucial during development and inflammatory processes. We have previously shown that NF-κB activation induces dedifferentiation of astrocytes into neural progenitor cells (NPCs). Here, we provide evidence that the NF-κB pathway plays also a fundamental role during the differentiation of NPCs into astrocytes. First, we show that the NF-κB pathway is essential to initiate astrocytic differentiation as its early inhibition induces NPC apoptosis and impedes their differentiation. Second, we demonstrate that persistent NF-κB activation affects NPC-derived astrocyte differentiation. Tumor necrosis factor (TNF)-treated NPCs show NF-κB activation, maintain their multipotential and proliferation properties, display persistent expression of immature markers and inhibit astrocyte markers. Third, we analyze the effect of NF-κB activation on the main known astrocytic differentiation pathways, such as NOTCH and JAK-STAT. Our findings suggest that the NF-κB pathway plays a dual fundamental role during NPC differentiation into astrocytes: it promotes astrocyte specification, but its persistent activation impedes their differentiation.
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Peteri, Ulla-Kaisa, Juho Pitkonen, Kagistia Hana Utami, Jere Paavola, Laurent Roybon, Mahmoud A. Pouladi, and Maija L. Castrén. "Generation of the Human Pluripotent Stem-Cell-Derived Astrocyte Model with Forebrain Identity." Brain Sciences 11, no. 2 (February 9, 2021): 209. http://dx.doi.org/10.3390/brainsci11020209.
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Astrocytes form functionally and morphologically distinct populations of cells with brain-region-specific properties. Human pluripotent stem cells (hPSCs) offer possibilities to generate astroglia for studies investigating mechanisms governing the emergence of astrocytic diversity. We established a method to generate human astrocytes from hPSCs with forebrain patterning and final specification with ciliary neurotrophic factor (CNTF). Transcriptome profiling and gene enrichment analysis monitored the sequential expression of genes determining astrocyte differentiation and confirmed activation of forebrain differentiation pathways at Day 30 (D30) and D60 of differentiation in vitro. More than 90% of astrocytes aged D95 in vitro co-expressed the astrocytic markers glial fibrillary acidic protein (GFAP) and S100β. Intracellular calcium responses to ATP indicated differentiation of the functional astrocyte population with constitutive monocyte chemoattractant protein-1 (MCP-1/CCL2) and tissue inhibitor of metalloproteinases-2 (TIMP-2) expression. The method was reproducible across several hPSC lines, and the data demonstrated the usefulness of forebrain astrocyte modeling in research investigating forebrain pathology.
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Sulimai, Nurul, Jason Brown, and David Lominadze. "Fibrinogen Interaction with Astrocyte ICAM-1 and PrPC Results in the Generation of ROS and Neuronal Death." International Journal of Molecular Sciences 22, no. 5 (February 27, 2021): 2391. http://dx.doi.org/10.3390/ijms22052391.
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Many neuroinflammatory diseases, like traumatic brain injury (TBI), are associated with an elevated level of fibrinogen and short-term memory (STM) impairment. We found that during TBI, extravasated fibrinogen deposited in vasculo-astrocyte interfaces, which was associated with neurodegeneration and STM reduction. The mechanisms of this fibrinogen-astrocyte interaction and its functional role in neurodegeneration are still unclear. Cultured mouse brain astrocytes were treated with fibrinogen in the presence or absence of function-blocking antibody or peptide against its astrocyte receptors intercellular adhesion molecule-1 (ICAM-1) or cellular prion protein (PrPC), respectively. Fibrinogen interactions with astrocytic ICAM-1 and PrPC were characterized. The expression of pro-inflammatory markers, generations of reactive oxygen species (ROS) and nitric oxide (NO) in astrocytes, and neuronal death caused by astrocyte-conditioned medium were assessed. Data showed a strong association between fibrinogen and astrocytic ICAM-1 or PrPC, overexpression of pro-inflammatory cytokines and overproduction of ROS and NO, resulting in neuronal apoptosis and death. These effects were reduced by blocking the function of astrocytic ICAM-1 and PrPC, suggesting that fibrinogen association with its astrocytic receptors induce the release of pro-inflammatory cytokines, resulting in oxidative stress, and ultimately neuronal death. This can be a mechanism of neurodegeneration and the resultant STM reduction seen during TBI.
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Haydon, Philip G., and Giorgio Carmignoto. "Astrocyte Control of Synaptic Transmission and Neurovascular Coupling." Physiological Reviews 86, no. 3 (July 2006): 1009–31. http://dx.doi.org/10.1152/physrev.00049.2005.
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From a structural perspective, the predominant glial cell of the central nervous system, the astrocyte, is positioned to regulate synaptic transmission and neurovascular coupling: the processes of one astrocyte contact tens of thousands of synapses, while other processes of the same cell form endfeet on capillaries and arterioles. The application of subcellular imaging of Ca2+ signaling to astrocytes now provides functional data to support this structural notion. Astrocytes express receptors for many neurotransmitters, and their activation leads to oscillations in internal Ca2+. These oscillations induce the accumulation of arachidonic acid and the release of the chemical transmitters glutamate, d-serine, and ATP. Ca2+ oscillations in astrocytic endfeet can control cerebral microcirculation through the arachidonic acid metabolites prostaglandin E2 and epoxyeicosatrienoic acids that induce arteriole dilation, and 20-HETE that induces arteriole constriction. In addition to actions on the vasculature, the release of chemical transmitters from astrocytes regulates neuronal function. Astrocyte-derived glutamate, which preferentially acts on extrasynaptic receptors, can promote neuronal synchrony, enhance neuronal excitability, and modulate synaptic transmission. Astrocyte-derived d-serine, by acting on the glycine-binding site of the N-methyl-d-aspartate receptor, can modulate synaptic plasticity. Astrocyte-derived ATP, which is hydrolyzed to adenosine in the extracellular space, has inhibitory actions and mediates synaptic cross-talk underlying heterosynaptic depression. Now that we appreciate this range of actions of astrocytic signaling, some of the immediate challenges are to determine how the astrocyte regulates neuronal integration and how both excitatory (glutamate) and inhibitory signals (adenosine) provided by the same glial cell act in concert to regulate neuronal function.
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Tedeschi, B., J. N. Barrett, and R. W. Keane. "Astrocytes produce interferon that enhances the expression of H-2 antigens on a subpopulation of brain cells." Journal of Cell Biology 102, no. 6 (June 1, 1986): 2244–53. http://dx.doi.org/10.1083/jcb.102.6.2244.
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Using primary culture methods, we show that purified astrocytes from embryonic mouse or rat central nervous system (CNS) can be induced to produce interferon (IFN) activity when pretreated with a standard IFN-superinducing regimen of polyribonucleotide, cycloheximide, and actinomycin D, whereas IFN activity was not inducible in neuronal cultures derived from mouse CNS. Astrocyte IFN displays inductive, kinetic, physicochemical, and antigenic properties similar to those of IFN-alpha/beta, but is dissimilar to lymphocyte IFN (IFN-gamma). Treatment of pure astrocytic cultures or astrocytes cultured with neurons with astrocyte IFN or IFN-alpha/beta induced a dramatic increase in the expression of H-2 antigens on a subpopulation of astrocytes. Neither neurons nor oligodendroglia expressed detectable levels of H-2 antigens when exposed to astrocyte IFN, IFN-alpha/beta, or to IFN-beta. Injection of astrocyte IFN or IFN-alpha/beta directly into brains of newborn mice indicated that H-2 antigens were also induced in vivo. None of the IFNs (astrocyte, alpha/beta, or beta) tested induced Ia antigens on CNS cells in vitro or in vivo. Since H-2 antigens have a critical role in immune responses, astrocyte IFN may initiate and participate in immune reactions that contribute to immunoprotective and immunopathological responses in the CNS.
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Devaraju, Prakash, Min-Yu Sun, Timothy L. Myers, Kelli Lauderdale, and Todd A. Fiacco. "Astrocytic group I mGluR-dependent potentiation of astrocytic glutamate and potassium uptake." Journal of Neurophysiology 109, no. 9 (May 1, 2013): 2404–14. http://dx.doi.org/10.1152/jn.00517.2012.
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One of the most important functions of astrocytes is removal of glutamate released during synaptic transmission. Surprisingly, the mechanisms by which astrocyte glutamate uptake is acutely modulated remain to be clarified. Astrocytes express metabotropic glutamate receptors (mGluRs) and other G protein-coupled receptors (GPCRs), which are activated during neuronal activity. Here, we test the hypothesis that astrocytic group I mGluRs acutely regulate glutamate uptake by astrocytes in situ. This hypothesis was tested in acute mouse hippocampal slices. Activation of astrocytic mGluRs, using a tetanic high-frequency stimulus (HFS) applied to Schaffer collaterals, led to potentiation of the amplitude of the synaptically evoked glutamate transporter currents (STCs) and associated charge transfer without changes in kinetics. Similar potentiation of STCs was not observed in the presence of group I mGluR antagonists or the PKC inhibitor, PKC 19–36, suggesting that HFS-induced potentiation of astrocyte glutamate uptake is astrocytic group I mGluR and PKC dependent. Pharmacological stimulation of a transgenic GPCR (MrgA1R), expressed exclusively in astrocytes, also potentiated STC amplitude and charge transfer, albeit quicker and shorter lasting compared with HFS-induced potentiation. The amplitude of the slow, inward astrocytic current due to potassium (K+) influx was also enhanced following activation of the endogenous mGluRs or the astrocyte-specific MrgA1 Gq GPCRs. Taken together, these findings suggest that astrocytic group I mGluR activation has a synergistic, modulatory effect on the uptake of glutamate and K+.
12
Nassar, Ajmal, Triveni Kodi, Sairaj Satarker, Prasada Chowdari Gurram, Dinesh Upadhya, Fayaz SM, Jayesh Mudgal, and Madhavan Nampoothiri. "Astrocytic MicroRNAs and Transcription Factors in Alzheimer’s Disease and Therapeutic Interventions." Cells 11, no. 24 (December 17, 2022): 4111. http://dx.doi.org/10.3390/cells11244111.
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Astrocytes are important for maintaining cholesterol metabolism, glutamate uptake, and neurotransmission. Indeed, inflammatory processes and neurodegeneration contribute to the altered morphology, gene expression, and function of astrocytes. Astrocytes, in collaboration with numerous microRNAs, regulate brain cholesterol levels as well as glutamatergic and inflammatory signaling, all of which contribute to general brain homeostasis. Neural electrical activity, synaptic plasticity processes, learning, and memory are dependent on the astrocyte–neuron crosstalk. Here, we review the involvement of astrocytic microRNAs that potentially regulate cholesterol metabolism, glutamate uptake, and inflammation in Alzheimer’s disease (AD). The interaction between astrocytic microRNAs and long non-coding RNA and transcription factors specific to astrocytes also contributes to the pathogenesis of AD. Thus, astrocytic microRNAs arise as a promising target, as AD conditions are a worldwide public health problem. This review examines novel therapeutic strategies to target astrocyte dysfunction in AD, such as lipid nanodiscs, engineered G protein-coupled receptors, extracellular vesicles, and nanoparticles.
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Myers, Abigail J., Ayat Brahimi, Imani J. Jenkins, and Andrew O. Koob. "The Synucleins and the Astrocyte." Biology 12, no. 2 (January 19, 2023): 155. http://dx.doi.org/10.3390/biology12020155.
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Synucleins consist of three proteins exclusively expressed in vertebrates. α-Synuclein (αS) has been identified as the main proteinaceous aggregate in Lewy bodies, a pathological hallmark of many neurodegenerative diseases. Less is understood about β-synuclein (βS) and γ-synuclein (γS), although it is known βS can interact with αS in vivo to inhibit aggregation. Likewise, both γS and βS can inhibit αS’s propensity to aggregate in vitro. In the central nervous system, βS and αS, and to a lesser extent γS, are highly expressed in the neural presynaptic terminal, although they are not strictly located there, and emerging data have shown a more complex expression profile. Synapse loss and astrocyte atrophy are early aspects of degenerative diseases of the brain and correlate with disease progression. Synucleins appear to be involved in synaptic transmission, and astrocytes coordinate and organize synaptic function, with excess αS degraded by astrocytes and microglia adjacent to the synapse. βS and γS have also been observed in the astrocyte and may provide beneficial roles. The astrocytic responsibility for degradation of αS as well as emerging evidence on possible astrocytic functions of βS and γS, warrant closer inspection on astrocyte–synuclein interactions at the synapse.
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Melzer, Linda, Thomas M. Freiman, and Amin Derouiche. "Rab6A as a Pan-Astrocytic Marker in Mouse and Human Brain, and Comparison with Other Glial Markers (GFAP, GS, Aldh1L1, SOX9)." Cells 10, no. 1 (January 5, 2021): 72. http://dx.doi.org/10.3390/cells10010072.
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Astrocytes contribute to many higher brain functions. A key mechanism in glia-to-neuron signalling is vesicular exocytosis; however, the identity of exocytosis organelles remains a matter of debate. Since vesicles derived from the trans-Golgi network (TGN) are not considered in this context, we studied the astrocyte TGN by immunocytochemistry applying anti-Rab6A. In mouse brain, Rab6A immunostaining is found to be unexpectedly massive, diffuse in all regions, and is detected preferentially and abundantly in the peripheral astrocyte processes, which is hardly evident without glial fibrillary acid protein (GFAP) co-staining. All cells positive for the astrocytic markers glutamine synthetase (GS), GFAP, aldehyde dehydrogenase 1 family member L1 (Aldh1L1), or SRY (sex determining region Y)-box 9 (SOX9) were Rab6A+. Rab6A is excluded from microglia, oligodendrocytes, and NG2 cells using cell type-specific markers. In human cortex, Rab6A labelling is very similar and associated with GFAP+ astrocytes. The mouse data also confirm the specific astrocytic labelling by Aldh1L1 or SOX9; the astrocyte-specific labelling by GS sometimes debated is replicated again. In mouse and human brain, individual astrocytes display high variability in Rab6A+ structures, suggesting dynamic regulation of the glial TGN. In summary, Rab6A expression is an additional, global descriptor of astrocyte identity. Rab6A might constitute an organelle system with a potential role of Rab6A in neuropathological and physiological processes.
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Shinozaki, Youichi, Kenji Kashiwagi, and Schuichi Koizumi. "Astrocyte Immune Functions and Glaucoma." International Journal of Molecular Sciences 24, no. 3 (February 1, 2023): 2747. http://dx.doi.org/10.3390/ijms24032747.
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Astrocytes, a non-neuronal glial cell type in the nervous system, are essential for regulating physiological functions of the central nervous system. In various injuries and diseases of the central nervous system, astrocytes often change their phenotypes into neurotoxic ones that participate in pro-inflammatory responses (hereafter referred to as “immune functions”). Such astrocytic immune functions are not only limited to brain diseases but are also found in ocular neurodegenerative diseases such as glaucoma, a retinal neurodegenerative disease that is the leading cause of blindness worldwide. The eye has two astrocyte-lineage cells: astrocytes and Müller cells. They maintain the physiological environment of the retina and optic nerve, thereby controlling visual function. Dysfunction of astrocyte-lineage cells may be involved in the onset and progression of glaucoma. These cells become reactive in glaucoma patients, and animal studies have suggested that their immune responses may be linked to glaucoma-related events: tissue remodeling, neuronal death, and infiltration of peripheral immune cells. In this review, we discuss the role of the immune functions of astrocyte-lineage cells in the pathogenesis of glaucoma.
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Shih, Evelyn K., and Michael B. Robinson. "Role of Astrocytic Mitochondria in Limiting Ischemic Brain Injury?" Physiology 33, no. 2 (March 1, 2018): 99–112. http://dx.doi.org/10.1152/physiol.00038.2017.
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Until recently, astrocyte processes were thought to be too small to contain mitochondria. However, it is now clear that mitochondria are found throughout fine astrocyte processes and are mobile with neuronal activity resulting in positioning near synapses. In this review, we discuss evidence that astrocytic mitochondria confer selective resiliency to astrocytes during ischemic insults and the functional significance of these mitochondria for normal brain function.
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Romanos, Jennifer, Dietmar Benke, Daniela Pietrobon, Hanns Ulrich Zeilhofer, and Mirko Santello. "Astrocyte dysfunction increases cortical dendritic excitability and promotes cranial pain in familial migraine." Science Advances 6, no. 23 (June 2020): eaaz1584. http://dx.doi.org/10.1126/sciadv.aaz1584.
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Astrocytes are essential contributors to neuronal function. As a consequence, disturbed astrocyte-neuron interactions are involved in the pathophysiology of several neurological disorders, with a strong impact on brain circuits and behavior. Here, we describe altered cortical physiology in a genetic mouse model of familial hemiplegic migraine type 2 (FHM2), with reduced expression of astrocytic Na+,K+-ATPases. We used whole-cell electrophysiology, two-photon microscopy, and astrocyte gene rescue to demonstrate that an impairment in astrocytic glutamate uptake promotes NMDA spike generation in dendrites of cingulate cortex pyramidal neurons and enhances output firing of these neurons. Astrocyte compensation of the defective ATPase in the cingulate cortex rescued glutamate uptake, prevented abnormal NMDA spikes, and reduced sensitivity to cranial pain triggers. Together, our results demonstrate that impaired astrocyte function alters neuronal activity in the cingulate cortex and facilitates migraine-like cranial pain states in a mouse model of migraine.
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Koyama, Yutaka. "Endothelin ETB Receptor-Mediated Astrocytic Activation: Pathological Roles in Brain Disorders." International Journal of Molecular Sciences 22, no. 9 (April 21, 2021): 4333. http://dx.doi.org/10.3390/ijms22094333.
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In brain disorders, reactive astrocytes, which are characterized by hypertrophy of the cell body and proliferative properties, are commonly observed. As reactive astrocytes are involved in the pathogenesis of several brain disorders, the control of astrocytic function has been proposed as a therapeutic strategy, and target molecules to effectively control astrocytic functions have been investigated. The production of brain endothelin-1 (ET-1), which increases in brain disorders, is involved in the pathophysiological response of the nervous system. Endothelin B (ETB) receptors are highly expressed in reactive astrocytes and are upregulated by brain injury. Activation of astrocyte ETB receptors promotes the induction of reactive astrocytes. In addition, the production of various astrocyte-derived factors, including neurotrophic factors and vascular permeability regulators, is regulated by ETB receptors. In animal models of Alzheimer’s disease, brain ischemia, neuropathic pain, and traumatic brain injury, ETB-receptor-mediated regulation of astrocytic activation has been reported to improve brain disorders. Therefore, the astrocytic ETB receptor is expected to be a promising drug target to improve several brain disorders. This article reviews the roles of ETB receptors in astrocytic activation and discusses its possible applications in the treatment of brain disorders.
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Maysinger, Dusica, Mélanie Lalancette-Hébert, Jeff Ji, Katherine Jabbour, Jens Dernedde, Kim Silberreis, Rainer Haag, and Jasna Kriz. "Dendritic polyglycerols are modulators of microglia-astrocyte crosstalk." Future Neurology 14, no. 4 (November 2019): FNL31. http://dx.doi.org/10.2217/fnl-2019-0008.
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Aim: To determine the ability of sulfated dendritic polyglycerols (dPGS) to modulate neuroglia activation challenged with lipopolysaccharide (LPS). Materials & methods: Microglia/astrocyte activation in vivo was determined in transgenic animals expressing TLR2-/GFAP-luciferase reporter. Mechanisms implicated in microglia-astrocyte crosstalk were studied in primary mouse brain cultures. Results & discussion: dPGS significantly reduced microglia activation in vivo, and decreased astrocytic LCN2 production. Activated microglia are necessary for astrocyte stimulation and increase in LCN2 abundance. LCN2 production in astrocytes involves signaling via toll-like receptor 4, activation of NF-κB, IL6 and enhancement of reactive oxygen species. Conclusion: dPGS are powerful modulators of microglia-astrocyte crosstalk and LCN2 abundance; dPGS are promising anti-inflammatory dendritic nanostructures.
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Skowrońska, Katarzyna, Marta Obara-Michlewska, Magdalena Zielińska, and Jan Albrecht. "NMDA Receptors in Astrocytes: In Search for Roles in Neurotransmission and Astrocytic Homeostasis." International Journal of Molecular Sciences 20, no. 2 (January 14, 2019): 309. http://dx.doi.org/10.3390/ijms20020309.
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Studies of the last two decades have demonstrated the presence in astrocytic cell membranes of N-methyl-d-aspartate (NMDA) receptors (NMDARs), albeit their apparently low abundance makes demonstration of their presence and function more difficult than of other glutamate (Glu) receptor classes residing in astrocytes. Activation of astrocytic NMDARs directly in brain slices and in acutely isolated or cultured astrocytes evokes intracellular calcium increase, by mutually unexclusive ionotropic and metabotropic mechanisms. However, other than one report on the contribution of astrocyte-located NMDARs to astrocyte-dependent modulation of presynaptic strength in the hippocampus, there is no sound evidence for the significant role of astrocytic NMDARs in astrocytic-neuronal interaction in neurotransmission, as yet. Durable exposure of astrocytic and neuronal co-cultures to NMDA has been reported to upregulate astrocytic synthesis of glutathione, and in this way to increase the antioxidative capacity of neurons. On the other hand, overexposure to NMDA decreases, by an as yet unknown mechanism, the ability of cultured astrocytes to express glutamine synthetase (GS), aquaporin-4 (AQP4), and the inward rectifying potassium channel Kir4.1, the three astroglia-specific proteins critical for homeostatic function of astrocytes. The beneficial or detrimental effects of astrocytic NMDAR stimulation revealed in the in vitro studies remain to be proven in the in vivo setting.
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Rouach, Nathalie, Jacques Glowinski, and Christian Giaume. "Activity-Dependent Neuronal Control of Gap-Junctional Communication in Astrocytes." Journal of Cell Biology 149, no. 7 (June 26, 2000): 1513–26. http://dx.doi.org/10.1083/jcb.149.7.1513.
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A typical feature of astrocytes is their high degree of intercellular communication through gap junction channels. Using different models of astrocyte cultures and astrocyte/neuron cocultures, we have demonstrated that neurons upregulate gap-junctional communication and the expression of connexin 43 (Cx43) in astrocytes. The propagation of intercellular calcium waves triggered in astrocytes by mechanical stimulation was also increased in cocultures. This facilitation depends on the age and number of neurons, indicating that the state of neuronal differentiation and neuron density constitute two crucial factors of this interaction. The effects of neurons on astrocytic communication and Cx43 expression were reversed completely after neurotoxic treatments. Moreover, the neuronal facilitation of glial coupling was suppressed, without change in Cx43 expression, after prolonged pharmacological treatments that prevented spontaneous synaptic activity. Altogether, these results demonstrate that neurons exert multiple and differential controls on astrocytic gap-junctional communication. Since astrocytes have been shown to facilitate synaptic efficacy, our findings suggest that neuronal and astrocytic networks interact actively through mutual setting of their respective modes of communication.
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Palabas, Tugba, Andre Longtin, Dibakar Ghosh, and Muhammet Uzuntarla. "Controlling the spontaneous firing behavior of a neuron with astrocyte." Chaos: An Interdisciplinary Journal of Nonlinear Science 32, no. 5 (May 2022): 051101. http://dx.doi.org/10.1063/5.0093234.
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Mounting evidence in recent years suggests that astrocytes, a sub-type of glial cells, not only serve metabolic and structural support for neurons and synapses but also play critical roles in the regulation of proper functioning of the nervous system. In this work, we investigate the effect of astrocytes on the spontaneous firing activity of a neuron through a combined model that includes a neuron–astrocyte pair. First, we show that an astrocyte may provide a kind of multistability in neuron dynamics by inducing different firing modes such as random and bursty spiking. Then, we identify the underlying mechanism of this behavior and search for the astrocytic factors that may have regulatory roles in different firing regimes. More specifically, we explore how an astrocyte can participate in the occurrence and control of spontaneous irregular spiking activity of a neuron in random spiking mode. Additionally, we systematically investigate the bursty firing regime dynamics of the neuron under the variation of biophysical facts related to the intracellular environment of the astrocyte. It is found that an astrocyte coupled to a neuron can provide a control mechanism for both spontaneous firing irregularity and burst firing statistics, i.e., burst regularity and size.
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Hayashi, Mariko Kato, Kaoru Sato, and Yuko Sekino. "Neurons Induce Tiled Astrocytes with Branches That Avoid Each Other." International Journal of Molecular Sciences 23, no. 8 (April 9, 2022): 4161. http://dx.doi.org/10.3390/ijms23084161.
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Neurons induce astrocyte branches that approach synapses. Each astrocyte tiles by expanding branches in an exclusive territory, with limited entries for the neighboring astrocyte branches. However, how astrocytes form exclusive territories is not known. For example, the extensive branching of astrocytes may sterically interfere with the penetration of other astrocyte branches. Alternatively, astrocyte branches may actively avoid each other or remove overlapped branches to establish a territory. Here, we show time-lapse imaging of the multi-order branching process of GFP-labeled astrocytes. Astrocyte branches grow in the direction where other astrocyte branches do not exist. Neurons that had just started to grow dendrites were able to induce astrocyte branching and tiling. Upon neuronal loss by glutamate excitotoxicity, astrocytes’ terminal processes retracted and more branches went over other branches. Our results indicate that neurons induce astrocyte branches and make them avoid each other.
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Inyushin, M. Y., A. Huertas, Y. V. Kucheryavykh, L. Y. Kucheryavykh, V. Tsydzik, P. Sanabria, M. J. Eaton, S. N. Skatchkov, L. V. Rojas, and W. D. Wessinger. "L-DOPA Uptake in Astrocytic Endfeet Enwrapping Blood Vessels in Rat Brain." Parkinson's Disease 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/321406.
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Astrocyte endfeet surround brain blood vessels and can play a role in the delivery of therapeutic drugs for Parkinson’s disease. However, there is no previous evidence of the presence of LAT transporter forL-DOPA in brain astrocytes except in culture. Using systemicL-DOPA administration and a combination of patch clamp, histochemistry and confocal microscopy we found thatL-DOPA is accumulated mainly in astrocyte cell bodies, astrocytic endfeet surrounding blood vessels, and pericytes. In brain slices: (1) astrocytes were exposed to ASP+, a fluorescent monoamine analog of MPP+; (2) ASP+taken up by astrocytes was colocalized withL-DOPA fluorescence in (3) glial somata and in the endfeet attached to blood vessels; (4) these astrocytes have an electrogenic transporter current elicited by ASP+, but intriguingly not byL-DOPA, suggesting a different pathway for monoamines andL-DOPA via astrocytic membrane. (5) The pattern of monoamine oxidase (MAO type B) allocation in pericytes and astrocytic endfeet was similar to that ofL-DOPA accumulation. We conclude that astrocytes controlL-DOPA uptake and metabolism and, therefore, may play a key role in regulating brain dopamine level during dopamine-associated diseases. These data also suggest that different transporter mechanisms may exist for monoamines andL-DOPA.
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Zuidema, Jonathan M., Ryan J. Gilbert, and Manoj K. Gottipati. "Biomaterial Approaches to Modulate Reactive Astroglial Response." Cells Tissues Organs 205, no. 5-6 (2018): 372–95. http://dx.doi.org/10.1159/000494667.
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Over several decades, biomaterial scientists have developed materials to spur axonal regeneration and limit secondary injury and tested these materials within preclinical animal models. Rarely, though, are astrocytes examined comprehensively when biomaterials are placed into the injury site. Astrocytes support neuronal function in the central nervous system. Following an injury, astrocytes undergo reactive gliosis and create a glial scar. The astrocytic glial scar forms a dense barrier which restricts the extension of regenerating axons through the injury site. However, there are several beneficial effects of the glial scar, including helping to reform the blood-brain barrier, limiting the extent of secondary injury, and supporting the health of regenerating axons near the injury site. This review provides a brief introduction to the role of astrocytes in the spinal cord, discusses astrocyte phenotypic changes that occur following injury, and highlights studies that explored astrocyte changes in response to biomaterials tested within in vitro or in vivo environments. Overall, we suggest that in order to improve biomaterial designs for spinal cord injury applications, investigators should more thoroughly consider the astrocyte response to such designs.
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Ahmadpour, Noushin, Meher Kantroo, and Jillian L. Stobart. "Extracellular Calcium Influx Pathways in Astrocyte Calcium Microdomain Physiology." Biomolecules 11, no. 10 (October 6, 2021): 1467. http://dx.doi.org/10.3390/biom11101467.
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Astrocytes are complex glial cells that play many essential roles in the brain, including the fine-tuning of synaptic activity and blood flow. These roles are linked to fluctuations in intracellular Ca2+ within astrocytes. Recent advances in imaging techniques have identified localized Ca2+ transients within the fine processes of the astrocytic structure, which we term microdomain Ca2+ events. These Ca2+ transients are very diverse and occur under different conditions, including in the presence or absence of surrounding circuit activity. This complexity suggests that different signalling mechanisms mediate microdomain events which may then encode specific astrocyte functions from the modulation of synapses up to brain circuits and behaviour. Several recent studies have shown that a subset of astrocyte microdomain Ca2+ events occur rapidly following local neuronal circuit activity. In this review, we consider the physiological relevance of microdomain astrocyte Ca2+ signalling within brain circuits and outline possible pathways of extracellular Ca2+ influx through ionotropic receptors and other Ca2+ ion channels, which may contribute to astrocyte microdomain events with potentially fast dynamics.
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Michinaga, Shotaro, and Yutaka Koyama. "Pathophysiological Responses and Roles of Astrocytes in Traumatic Brain Injury." International Journal of Molecular Sciences 22, no. 12 (June 15, 2021): 6418. http://dx.doi.org/10.3390/ijms22126418.
Full textAbstract:
Traumatic brain injury (TBI) is immediate damage caused by a blow to the head resulting from traffic accidents, falls, and sporting activity, which causes death or serious disabilities in survivors. TBI induces multiple secondary injuries, including neuroinflammation, disruption of the blood–brain barrier (BBB), and brain edema. Despite these emergent conditions, current therapies for TBI are limited or insufficient in some cases. Although several candidate drugs exerted beneficial effects in TBI animal models, most of them failed to show significant effects in clinical trials. Multiple studies have suggested that astrocytes play a key role in the pathogenesis of TBI. Increased reactive astrocytes and astrocyte-derived factors are commonly observed in both TBI patients and experimental animal models. Astrocytes have beneficial and detrimental effects on TBI, including promotion and restriction of neurogenesis and synaptogenesis, acceleration and suppression of neuroinflammation, and disruption and repair of the BBB via multiple bioactive factors. Additionally, astrocytic aquaporin-4 is involved in the formation of cytotoxic edema. Thus, astrocytes are attractive targets for novel therapeutic drugs for TBI, although astrocyte-targeting drugs have not yet been developed. This article reviews recent observations of the roles of astrocytes and expected astrocyte-targeting drugs in TBI.
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Rogers, Richard C., David H. McDougal, Sue Ritter, Emily Qualls-Creekmore, and Gerlinda E. Hermann. "Response of catecholaminergic neurons in the mouse hindbrain to glucoprivic stimuli is astrocyte dependent." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 315, no. 1 (July 1, 2018): R153—R164. http://dx.doi.org/10.1152/ajpregu.00368.2017.
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Hindbrain catecholaminergic (CA) neurons are required for critical autonomic, endocrine, and behavioral counterregulatory responses (CRRs) to hypoglycemia. Recent studies suggest that CRR initiation depends on hindbrain astrocyte glucose sensors (McDougal DH, Hermann GE, Rogers RC. Front Neurosci 7: 249, 2013; Rogers RC, Ritter S, Hermann GE. Am J Physiol Regul Integr Comp Physiol 310: R1102–R1108, 2016). To test the proposition that hindbrain CA responses to glucoprivation are astrocyte dependent, we utilized transgenic mice in which the calcium reporter construct (GCaMP5) was expressed selectively in tyrosine hydroxylase neurons (TH-GCaMP5). We conducted live cell calcium-imaging studies on tissue slices containing the nucleus of the solitary tract (NST) or the ventrolateral medulla, critical CRR initiation sites. Results show that TH-GCaMP5 neurons are robustly activated by a glucoprivic challenge and that this response is dependent on functional astrocytes. Pretreatment of hindbrain slices with fluorocitrate (an astrocytic metabolic suppressor) abolished TH-GCaMP5 neuronal responses to glucoprivation, but not to glutamate. Pharmacologic results suggest that the astrocytic connection with hindbrain CA neurons is purinergic via P2 receptors. Parallel imaging studies on hindbrain slices of NST from wild-type C57BL/6J mice, in which astrocytes and neurons were prelabeled with a calcium reporter dye and an astrocytic vital dye, show that both cell types are activated by glucoprivation but astrocytes responded significantly sooner than neurons. Pretreatment of these hindbrain slices with P2 antagonists abolished neuronal responses to glucoprivation without interruption of astrocyte responses; pretreatment with fluorocitrate eliminated both astrocytic and neuronal responses. These results support earlier work suggesting that the primary detection of glucoprivic signals by the hindbrain is mediated by astrocytes.
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Nett, Wolfgang J., Scott H. Oloff, and Ken D. McCarthy. "Hippocampal Astrocytes In Situ Exhibit Calcium Oscillations That Occur Independent of Neuronal Activity." Journal of Neurophysiology 87, no. 1 (January 1, 2002): 528–37. http://dx.doi.org/10.1152/jn.00268.2001.
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Results presented in this study indicate that a large subpopulation (∼65%) of hippocampal astrocytes in situ exhibit calcium oscillations in the absence of neuronal activity. Further, the spontaneous oscillations observed within individual hippocampal astrocytes generally developed asynchronously throughout the astrocyte's fine processes and occasionally spread through a portion of that astrocyte as a calcium wave but do not appear to spread among astrocytes as an intercellular calcium wave. Bath application of cyclopiazonic acid and injection of individual astrocytes with heparin blocked astrocytic calcium oscillations. Application of tetrodotoxin or incubation of slices with bafilomycin A1 had no effect on astrocytic calcium oscillations but did block evoked and spontaneous postsynaptic currents measured in CA1 pyramidal neurons. Application of a cocktail of antagonists for metabotropic glutamate receptors and purinergic receptors had no effect on the astrocytic calcium oscillations but blocked the ability of purinergic and metabotropic glutamatergic agonists to increase astrocytic calcium levels. These results indicate that the spontaneous calcium oscillations observed in hippocampal astrocytes in situ are mediated by IP3 receptor activation, are not dependent on neuronal activity, and do not depend on activation of metabotropic glutamate receptors or purinergic receptors. To our knowledge, this is the first demonstration that astrocytes in situ exhibit intrinsic signaling. This finding supports the hypothesis that astrocytes, independent of neuronal input, may act as pacemakers to modulate neuronal activity in situ.
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Cho, Sukhee, Allie K. Muthukumar, Tobias Stork, Jaeda C. Coutinho-Budd, and Marc R. Freeman. "Focal adhesion molecules regulate astrocyte morphology and glutamate transporters to suppress seizure-like behavior." Proceedings of the National Academy of Sciences 115, no. 44 (October 16, 2018): 11316–21. http://dx.doi.org/10.1073/pnas.1800830115.
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Astrocytes are important regulators of neural circuit function and behavior in the healthy and diseased nervous system. We screened for molecules in Drosophila astrocytes that modulate neuronal hyperexcitability and identified multiple components of focal adhesion complexes (FAs). Depletion of astrocytic Tensin, β-integrin, Talin, focal adhesion kinase (FAK), or matrix metalloproteinase 1 (Mmp1), resulted in enhanced behavioral recovery from genetic or pharmacologically induced seizure. Overexpression of Mmp1, predicted to activate FA signaling, led to a reciprocal enhancement of seizure severity. Blockade of FA-signaling molecules in astrocytes at basal levels of CNS excitability resulted in reduced astrocytic coverage of the synaptic neuropil and expression of the excitatory amino acid transporter EAAT1. However, induction of hyperexcitability after depletion of FA-signaling components resulted in enhanced astrocyte coverage and an approximately twofold increase in EAAT1 levels. Our work identifies FA-signaling molecules as important regulators of astrocyte outgrowth and EAAT1 expression under normal physiological conditions. Paradoxically, in the context of hyperexcitability, this pathway negatively regulates astrocytic process outgrowth and EAAT1 expression, and their blockade leading to enhanced recovery from seizure.
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SUL, JAI-YOON, GEORGE OROSZ, RICHARD S. GIVENS, and PHILIP G. HAYDON. "Astrocytic Connectivity in the Hippocampus." Neuron Glia Biology 1, no. 1 (February 2004): 3–11. http://dx.doi.org/10.1017/s1740925x04000031.
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Little is known about the functional connectivity between astrocytes in the CNS. To explore this issue we photo-released glutamate onto a single astrocyte in murine hippocampal slices and imaged calcium responses. Photo-release of glutamate causes a metabotropic glutamate receptor (mGluR)-dependent increase in internal calcium in the stimulated astrocyte and delayed calcium elevations in neighboring cells. The delayed elevation in calcium was not caused by either neuronal activity following synaptic transmission or by glutamate released from astrocytes. However, it was reduced by flufenamic acid (FFA), which is consistent with a role for adenosine triphosphate (ATP) release from astrocytes as an intercellular messenger. Exogenous ligands such as ATP (1 µM) increased the number of astrocytes that were recruited into coupled astrocytic networks, indicating that extracellular accumulation of neurotransmitters modulates neuronal excitability, synaptic transmission and functional coupling between astrocytes.
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Wang, Yu-Feng, and Kathryn A. Hamilton. "Chronic vs. Acute Interactions between Supraoptic Oxytocin Neurons and Astrocytes during Lactation: Role of Glial Fibrillary Acidic Protein Plasticity." Scientific World JOURNAL 9 (2009): 1308–20. http://dx.doi.org/10.1100/tsw.2009.148.
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In this article, we review studies of astrocytic-neuronal interactions and their effects on the activity of oxytocin (OXT) neurons within the magnocellular hypothalamo-neurohypophysial system. Previous work over several decades has shown that withdrawal of astrocyte processes increases OXT neuron excitability in the hypothalamic supraoptic nucleus (SON) during lactation. However, chronically disabling astrocyte withdrawal does not significantly affect the functioning of OXT neurons during suckling. Nevertheless, acute changes in a cytoskeletal element of astrocytes, glial fibrillary acidic protein (GFAP), occur in concert with changes in OXT neuronal activity during suckling. Here, we compare these changes in GFAP and related proteins with chronic changes that persist throughout lactation. During lactation, a decrease in GFAP levels accompanies retraction of astrocyte processes surrounding OXT neurons in the SON, resulting from high extracellular levels of OXT. During the initial stage of suckling, acute increases in OXT levels further strengthen this GFAP reduction and facilitate the retraction of astrocyte processes. This change, in turn, facilitates burst discharges of OXT neurons and leads to a transient increase in excitatory neurochemicals. This transient neurochemical surge acts to reverse GFAP expression and results in postburst inhibition of OXT neurons. The acute changes in astrocyte GFAP levels seen during suckling likely recur periodically, accompanied by rhythmic changes in glutamate metabolism, water transport, gliotransmitter release, and spatial relationships between astrocytes and OXT neurons. In the neurohypophysis, astrocyte retraction and reversal with accompanying GFAP plasticity also likely occur during lactation and suckling, which facilitates OXT release coordinated with its action in the SON. These studies of the dynamic interactions that occur between astrocytes and OXT neurons mediated by GFAP extend our understanding of astrocyte functions within the central nervous system.
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Padmashri, Ragunathan, Anand Suresh, Michael D. Boska, and Anna Dunaevsky. "Motor-Skill Learning Is Dependent on Astrocytic Activity." Neural Plasticity 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/938023.
Full textAbstract:
Motor-skill learning induces changes in synaptic structure and function in the primary motor cortex through the involvement of a long-term potentiation- (LTP-) like mechanism. Although there is evidence that calcium-dependent release of gliotransmitters by astrocytes plays an important role in synaptic transmission and plasticity, the role of astrocytes in motor-skill learning is not known. To test the hypothesis that astrocytic activity is necessary for motor-skill learning, we perturbed astrocytic function using pharmacological and genetic approaches. We find that perturbation of astrocytes either by selectively attenuating IP3R2 mediated astrocyte Ca2+signaling or using an astrocyte specific metabolic inhibitor fluorocitrate (FC) results in impaired motor-skill learning of a forelimb reaching-task in mice. Moreover, the learning impairment caused by blocking astrocytic activity using FC was rescued by administration of the gliotransmitter D-serine. The learning impairments are likely caused by impaired LTP as FC blocked LTP in slices and prevented motor-skill training-induced increases in synaptic AMPA-type glutamate receptorin vivo. These results support the conclusion that normal astrocytic Ca2+signaling during a reaching task is necessary for motor-skill learning.
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Tatomir, Alexandru, Dallas Boodhoo, Vinh Nguyen, Cornelia Cudrici, Tudor Constantin Badea, Violeta Rus, and Horea Rus. "RGC-32 regulates astrocyte differentiation during experimental autoimmune encephalomyelitis." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 64.9. http://dx.doi.org/10.4049/jimmunol.204.supp.64.9.
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Abstract Astrocytes are increasingly recognized as critical contributors to multiple sclerosis pathogenesis. We have previously shown that lack of response gene to complement 32 (RGC-32) alters astrocyte morphology in spinal cords during experimental autoimmune encephalomyelitis (EAE), suggesting a role for RGC-32 in astrocyte differentiation. In addition, we found that RGC-32 regulates TGF-β-induced extracellular matrix production and growth factors expression. We investigated if the lack of RGC-32 alters the expression of the glial fibrillary acidic protein (GFAP) and of astrocytes progenitor markers vimentin and fatty acid binding protein 7 (FABP7) during EAE. Immunohistochemical analysis of spinal cords during the acute phase of EAE (day 14 post EAE induction) showed that the elongated, radial glial cell-like astrocytes from RGC-32 knock-out (KO) mice expressed higher levels of vimentin and FABP7 as compared to wild type (WT) mice, confirming their immature phenotype. In addition, we found that the density of white matter GFAP+ astrocytes was higher in WT as compared to KO mice (p=0.02). Using double staining immunohistochemistry for GFAP and connective tissue growth factor (CTGF), known to be involved in astrocyte differentiation, we found a lower number of CTGF+ astrocytes during EAE in spinal cords of RGC-32 KO when compared with WT mice (p=0.002). We next purified neonatal astrocytes from WT and RGC-32 KO mice, and we found significantly lower levels of GFAP and CTGF mRNA and protein and higher levels of vimentin in RGC-32 KO astrocytes when compared with WT astrocytes. The expression pattern of astrocytic progenitor markers and that of CTGF suggests that RGC-32 is an important regulator of astrocyte differentiation during EAE.
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Michinaga, Shotaro, Shigeru Hishinuma, and Yutaka Koyama. "Roles of Astrocytic Endothelin ETB Receptor in Traumatic Brain Injury." Cells 12, no. 5 (February 24, 2023): 719. http://dx.doi.org/10.3390/cells12050719.
Full textAbstract:
Traumatic brain injury (TBI) is an intracranial injury caused by accidents, falls, or sports. The production of endothelins (ETs) is increased in the injured brain. ET receptors are classified into distinct types, including ETA receptor (ETA-R) and ETB receptor (ETB-R). ETB-R is highly expressed in reactive astrocytes and upregulated by TBI. Activation of astrocytic ETB-R promotes conversion to reactive astrocytes and the production of astrocyte-derived bioactive factors, including vascular permeability regulators and cytokines, which cause blood–brain barrier (BBB) disruption, brain edema, and neuroinflammation in the acute phase of TBI. ETB-R antagonists alleviate BBB disruption and brain edema in animal models of TBI. The activation of astrocytic ETB receptors also enhances the production of various neurotrophic factors. These astrocyte-derived neurotrophic factors promote the repair of the damaged nervous system in the recovery phase of patients with TBI. Thus, astrocytic ETB-R is expected to be a promising drug target for TBI in both the acute and recovery phases. This article reviews recent observations on the role of astrocytic ETB receptors in TBI.
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Hastings, Nataly, Wei-Li Kuan, Andrew Osborne, and Mark R. N. Kotter. "Therapeutic Potential of Astrocyte Transplantation." Cell Transplantation 31 (January 2022): 096368972211054. http://dx.doi.org/10.1177/09636897221105499.
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Cell transplantation is an attractive treatment strategy for a variety of brain disorders, as it promises to replenish lost functions and rejuvenate the brain. In particular, transplantation of astrocytes has come into light recently as a therapy for amyotrophic lateral sclerosis (ALS); moreover, grafting of astrocytes also showed positive results in models of other conditions ranging from neurodegenerative diseases of older age to traumatic injury and stroke. Despite clear differences in etiology, disorders such as ALS, Parkinson’s, Alzheimer’s, and Huntington’s diseases, as well as traumatic injury and stroke, converge on a number of underlying astrocytic abnormalities, which include inflammatory changes, mitochondrial damage, calcium signaling disturbance, hemichannel opening, and loss of glutamate transporters. In this review, we examine these convergent pathways leading to astrocyte dysfunction, and explore the existing evidence for a therapeutic potential of transplantation of healthy astrocytes in various models. Existing literature presents a wide variety of methods to generate astrocytes, or relevant precursor cells, for subsequent transplantation, while described outcomes of this type of treatment also differ between studies. We take technical differences between methodologies into account to understand the variability of therapeutic benefits, or lack thereof, at a deeper level. We conclude by discussing some key requirements of an astrocyte graft that would be most suitable for clinical applications.
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Zhang, Xiaolu, Alyssa Wolfinger, Xiaojun Wu, Rawan Alnafisah, Ali Imami, Abdul-rizaq Hamoud, Anna Lundh, et al. "Gene Enrichment Analysis of Astrocyte Subtypes in Psychiatric Disorders and Psychotropic Medication Datasets." Cells 11, no. 20 (October 21, 2022): 3315. http://dx.doi.org/10.3390/cells11203315.
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Astrocytes have many important functions in the brain, but their roles in psychiatric disorders and their responses to psychotropic medications are still being elucidated. Here, we used gene enrichment analysis to assess the relationships between different astrocyte subtypes, psychiatric diseases, and psychotropic medications (antipsychotics, antidepressants and mood stabilizers). We also carried out qPCR analyses and “look-up” studies to assess the chronic effects of these drugs on astrocyte marker gene expression. Our bioinformatic analysis identified gene enrichment of different astrocyte subtypes in psychiatric disorders. The highest level of enrichment was found in schizophrenia, supporting a role for astrocytes in this disorder. We also found differential enrichment of astrocyte subtypes associated with specific biological processes, highlighting the complex responses of astrocytes under pathological conditions. Enrichment of protein phosphorylation in astrocytes and disease was confirmed by biochemical analysis. Analysis of LINCS chemical perturbagen gene signatures also found that kinase inhibitors were highly discordant with astrocyte-SCZ associated gene signatures. However, we found that common gene enrichment of different psychotropic medications and astrocyte subtypes was limited. These results were confirmed by “look-up” studies and qPCR analysis, which also reported little effect of psychotropic medications on common astrocyte marker gene expression, suggesting that astrocytes are not a primary target of these medications. Conversely, antipsychotic medication does affect astrocyte gene marker expression in postmortem schizophrenia brain tissue, supporting specific astrocyte responses in different pathological conditions. Overall, this study provides a unique view of astrocyte subtypes and the effect of medications on astrocytes in disease, which will contribute to our understanding of their role in psychiatric disorders and offers insights into targeting astrocytes therapeutically.
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Filippova, Svetlana Yu, Aleksandr K. Logvinov, and Evgeniya Yu Kirichenko. "Uneven Distribution of Astrocyte Membranes over the Layers of the Rat Primary Somatosensory Cortex." Journal of Medical and Biological Research, no. 4 (November 15, 2020): 409–18. http://dx.doi.org/10.37482/2687-1491-z034.
Full textAbstract:
Astrocytes are the main glial cells maintaining water-electrolyte and energy balance in the brain. Today, astroglia is also believed to take a direct part in the regulation of synaptic transmission and in enabling synchronous operation of neurons at large distances. Astrocytes fulfil their functions through numerous processes that penetrate the entire neuropil. The authors believe that changes in the astrocyte membrane surface area per unit volume of neuropil directly reflect changes in the intensity of the astrocyte–neuron interaction. Strengthening or weakening of astrocyte regulation, undoubtedly, affect the functioning of neural circuits. Nevertheless, in spite of the growing popularity of research into the glia–neuron relations, this aspect remains insufficiently studied when it comes to the cerebral cortex. The purpose of this study was to layer-by-layer determine the astrocyte membrane surface per unit volume in the neuropil of the rat primary somatosensory cortex. The research was conducted on samples of the primary somatosensory cortex obtained from 5 white male rats (P60–80). After immune labeling against astrocytic marker S100B using the pre-embedding method, the samples were prepared for transmission electron microscopy according to the standard technique. In total, 250 electron micrographs were obtained for each layer of the primary somatosensory cortex, which were then used to determine the astrocyte membrane surface area per unit volume in the neuropil by means of the random secant method. The research found that this indicator is the minimum in the first and maximum in the fifth layers of the cortical column. In addition, the article discusses the possible functional consequences of uneven distribution of astrocytic membranes in the neocortex.
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Brunet, JF, I. Allaman, PJ Magistretti, and L. Pellerin. "Glycogen Metabolism as a Marker of Astrocyte Differentiation." Journal of Cerebral Blood Flow & Metabolism 30, no. 1 (October 7, 2009): 51–55. http://dx.doi.org/10.1038/jcbfm.2009.207.
Full textAbstract:
Glycogen is a hallmark of mature astrocytes, but its emergence during astrocytic differentiation is unclear. Differentiation of E14 mouse neurospheres into astrocytes was induced with fetal bovine serum (FBS), Leukemia Inhibitory Factor (LIF), or Ciliary Neurotrophic Factor (CNTF). Cytochemical and enzymatic analyses showed that glycogen is present in FBS- or LIF- but not in CNTF-differentiated astrocytes. Glycogenolysis was induced in FBS- and LIF-differentiated astrocytes but glycogen resynthesis was observed only with FBS. Protein targeting to glycogen mRNA expression appeared with glial fibrillary acidic protein and S100β in FBS and LIF conditions but not with CNTF. These results show that glycogen metabolism constitutes a useful marker of astrocyte differentiation.
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Perelroizen, R., B. Philosof, N. Budick-Harmelin, T. Chernobylsky, K. Rotem, A. Ron, D. Shimon, et al. "P12.15.B Astrocyte immunometabolic regulation of the glioblastoma microenvironment drives tumor pathogenicity." Neuro-Oncology 24, Supplement_2 (September 1, 2022): ii80. http://dx.doi.org/10.1093/neuonc/noac174.280.
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Abstract Background Malignant brain tumors are the cause of a disproportionate level of morbidity and mortality among cancer patients, an unfortunate statistic that has remained constant for decades. Despite considerable advances in the molecular characterization of these tumors, targeting the cancer cells has yet to produce significant advances in treatment. An alternative strategy is to target cells in the glioblastoma microenvironment, such as tumor associated astrocytes. Astrocytes control multiple processes in health and disease, ranging from maintaining the brain's metabolic homeostasis, to modulating neuroinflammation. However, their role in glioblastoma pathogenicity is not well understood. Material and Methods Immunocompetent mice were implanted with murine glioma cell lines and the role of astrocyte in the tumor pathogenicity was analyzed, and further investigated using in-vitro co-cultures. Results Here we report that depletion of reactive astrocytes regresses glioblastoma and prolongs mouse survival. Analysis of the tumor-associated astrocyte translatome, revealed that astrocytes initiate transcriptional programs that shape the immune and metabolic compartments in the glioma microenvironment. Specifically, their expression of CCL2 and CSF1 governs the recruitment of tumor-associated macrophages and promotes a pro-tumorigenic macrophage phenotype. Concomitantly, we demonstrate that astrocyte-derived cholesterol is key to glioma cell survival, and that targeting astrocytic cholesterol efflux, via ABCA1, halts tumor progression. In summary, astrocytes control glioblastoma pathogenicity by reprogramming the immunological properties of the tumor microenvironment and supporting the non-oncogenic metabolic dependency of glioblastoma on cholesterol. Conclusion These findings suggest that targeting astrocyte immunometabolic signaling may help treat this uniformly lethal brain tumor.
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Zhang, Zengli, Zhi Ma, Wangyuan Zou, Hang Guo, Min Liu, Yulong Ma, and Lixia Zhang. "The Appropriate Marker for Astrocytes: Comparing the Distribution and Expression of Three Astrocytic Markers in Different Mouse Cerebral Regions." BioMed Research International 2019 (June 24, 2019): 1–15. http://dx.doi.org/10.1155/2019/9605265.
Full textAbstract:
Astrocytes possess different morphological characteristics depending on the cerebral region in which they are found. However, none of the current astrocytic markers can label all subpopulations successfully. Thus, identifying the appropriate marker for a specific scientific investigation is critical. Here, we compared the distribution and protein expression of three astrocyte markers: NDRG2, GFAP, and S100β, in the cortex, hippocampus, and thalamus. NDRG2- and S100β-positive astrocytes were distributed more uniformly than GFAP-positive astrocytes throughout the whole cerebrum. NDRG2 and S100βimmunoreactivities were the strongest in the dorsal cortex and thalamus, while GFAP immunoreactivity was the strongest in the hippocampus. Moreover, protein expression levels of NDRG2, GFAP, and S100βin adult mice were the highest in the cortex, hippocampus, and thalamus, respectively. We also detected astrocyte morphology and found that, in the corpus callosum and cerebral peduncle, GFAP-positive astrocytes were found with more numerous and longer processes than NDRG2- and S100β-positive astrocytes. These results demonstrate that NDRG2 and S100βare more suitably used to visualize the overall distribution and changes in the number of astrocytes, as well as label astrocytes in the cortex and thalamus. GFAP, however, is more appropriately used to label astrocytes in the corpus callosum, cerebral peduncle, and the hippocampus. These results help to guide researchers in the choice of appropriate astrocyte marker and suggest differences in immunological qualities of astrocytes based on the tissue in which they are found.
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Luarte, Alejandro, Roberto Henzi, Anllely Fernández, Diego Gaete, Pablo Cisternas, Matias Pizarro, Luis Federico Batiz, et al. "Astrocyte-Derived Small Extracellular Vesicles Regulate Dendritic Complexity through miR-26a-5p Activity." Cells 9, no. 4 (April 10, 2020): 930. http://dx.doi.org/10.3390/cells9040930.
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In the last few decades, it has been established that astrocytes play key roles in the regulation of neuronal morphology. However, the contribution of astrocyte-derived small extracellular vesicles (sEVs) to morphological differentiation of neurons has only recently been addressed. Here, we showed that cultured astrocytes expressing a GFP-tagged version of the stress-regulated astrocytic enzyme Aldolase C (Aldo C-GFP) release small extracellular vesicles (sEVs) that are transferred into cultured hippocampal neurons. Surprisingly, Aldo C-GFP-containing sEVs (Aldo C-GFP sEVs) displayed an exacerbated capacity to reduce the dendritic complexity in developing hippocampal neurons compared to sEVs derived from control (i.e., GFP-expressing) astrocytes. Using bioinformatics and biochemical tools, we found that the total content of overexpressed Aldo C-GFP correlates with an increased content of endogenous miRNA-26a-5p in both total astrocyte homogenates and sEVs. Notably, neurons magnetofected with a nucleotide sequence that mimics endogenous miRNA-26a-5p (mimic 26a-5p) not only decreased the levels of neuronal proteins associated to morphogenesis regulation, but also reproduced morphological changes induced by Aldo-C-GFP sEVs. Furthermore, neurons magnetofected with a sequence targeting miRNA-26a-5p (antago 26a-5p) were largely resistant to Aldo C-GFP sEVs. Our results support a novel and complex level of astrocyte-to-neuron communication mediated by astrocyte-derived sEVs and the activity of their miRNA content.
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Gasque, P., P. Chan, C. Mauger, M. T. Schouft, S. Singhrao, M. P. Dierich, B. P. Morgan, and M. Fontaine. "Identification and characterization of complement C3 receptors on human astrocytes." Journal of Immunology 156, no. 6 (March 15, 1996): 2247–55. http://dx.doi.org/10.4049/jimmunol.156.6.2247.
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Abstract Astrocytes express C components and have been implicated as a major source of intrathecal C. To ascertain the effects of C activation on these cells, we have evaluated the expression of CR1, CR2, and CR3 (CD35, CD21, and CD11b/CD18) in primary fetal astrocytes and astrocyte cell lines. None of the astrocyte cells tested expressed CR3, whereas primary astrocytes and one of four astrocyte cell lines expressed CR1 (220 kDa), as assessed at the protein and mRNA level. Primary fetal astrocytes and all four astrocyte cell lines expressed CR2 (155 kDa). Expression of CR2 by astrocytes was confirmed at mRNA level by reverse-transcriptase PCR, using different combinations of seven specific CR2 oligonucleotides, and by partial sequencing of the astrocyte CR2 cDNA. Astrocyte CR2 cDNA presented 100% homology with the lymphocyte CR2 cDNA between the position 181 bp to 600 bp and position 1017 bp to 1347 bp. An alternative splicing pattern of exon 11, reported previously in B cells, was observed in astrocyte CR2 cDNA. Astrocyte CR2 was functional, in that it specifically bound C3d and the EBV surface protein gp340, and the binding was blocked specifically with polyclonal anti-CR2. Scatchard analysis of membrane expression of CR2 on astrocytes revealed 2000 functional sites per cell with a Kd (3 x 10(-7) M) identical with that of CR2 on B cell (Raji).
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Gao, Qi, Mark Katakowski, Xiaoguang Chen, Yi Li, and Michael Chopp. "Human Marrow Stromal Cells Enhance Connexin43 Gap Junction Intercellular Communication in Cultured Astrocytes." Cell Transplantation 14, no. 2-3 (February 2005): 109–17. http://dx.doi.org/10.3727/000000005783983205.
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Human marrow stromal cells (hMSCs) provide functional benefit in rats subjected to stroke. Astrocytes are coupled into a cellular network via gap junction channels, predominantly composed of connexin-43 (Cx43) proteins. Astrocytes are believed to play a vital role in neuroprotection by providing energy substrates to neurons and by regulating the concentrations of K+ and neurotransmitters via gap junctions. We therefore investigated the effect of factors secreted by hMSCs on gap junction intercellular communication (GJIC), expression of Cx43, and phosphorylation of Cx43 in an astrocyte cell culture system. Exposing rat cortical astrocytes to various concentrations of hMSC conditioned medium, we demonstrate that hMSCs produce soluble factors that significantly increase astrocytic GJIC, measured by the scrape-loading dye transfer method. Immunohistochemistry and Western blot showed increased Cx43 expression concomitant with altered GJIC. As the PI3K/Akt signaling pathway has been demonstrated to alter gap junction expression and GJIC, we selectively blocked phosphoinositide 3-kinase (PI3K). Addition of the PI3K inhibitor LY294002 decreased GJIC and Cx43 expression in astrocytes. These inhibitory effects of LY294002 were countered by the addition of hMSC conditioned media. Furthermore, coculturing hMSCs with rat astrocytes increased astrocyte GJIC in a manner dependent upon the hMSC/astrocyte ratio. These findings demonstrate that hMSCs secrete soluble factors that increase GJIC of astrocytes through upregulation of Cx43, and indicate a mechanistic role for PI3K.
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King, Andrew, Boglarka Szekely, Eda Calapkulu, Hanan Ali, Francesca Rios, Shalmai Jones, and Claire Troakes. "The Increased Densities, But Different Distributions, of Both C3 and S100A10 Immunopositive Astrocyte-Like Cells in Alzheimer’s Disease Brains Suggest Possible Roles for Both A1 and A2 Astrocytes in the Disease Pathogenesis." Brain Sciences 10, no. 8 (July 31, 2020): 503. http://dx.doi.org/10.3390/brainsci10080503.
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There is increasing evidence of astrocyte dysfunction in the pathogenesis of Alzheimer’s disease (AD). Animal studies supported by human post-mortem work have demonstrated two main astrocyte types: the C3 immunopositive neurotoxic A1 astrocytes and the S100A10 immunopositive neuroprotective A2 astrocytes. A1 astrocytes predominate in AD, but the number of cases has been relatively small. We examined post-mortem brains from a larger cohort of AD cases and controls employing C3 and S100 immunohistochemistry to identify the astrocytic subtypes. There were a number of C3 immunopositive astrocyte-like cells (ASLCs) in the control cases, especially in the lower cerebral cortex and white matter. In AD this cell density appeared to be increased in the upper cerebral cortex but was similar to controls in other regions. The S100A10 showed minimal immunopositivity in the control cases in the cortex and white matter, but there was increased ASLC density in upper/lower cortex and white matter in AD compared to controls. In AD and control cases the numbers of C3 immunopositive ASLCs were greater than those for S100A10 ASLCs in all areas studied. It would appear that the relationship between A1 and A2 astrocytes and their possible role in the pathogenesis of AD is complex and requires more research.
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Arimoto, Jason M., Angela Wong, Irina Rozovsky, Sharon W. Lin, Todd E. Morgan, and Caleb E. Finch. "Age Increase of Estrogen Receptor-α (ERα) in Cortical Astrocytes Impairs Neurotrophic Support in Male and Female Rats." Endocrinology 154, no. 6 (March 20, 2013): 2101–13. http://dx.doi.org/10.1210/en.2012-2046.
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Abstract Rodent models show decreased neuronal responses to estradiol (E2) during aging (E2-desensitization) in association with reduced neuronal estrogen receptor (ER)-α, but little is known about age changes of E2-dependent astrocytic neurotrophic support. Because elevated expression of astrocyte glial fibrillary acidic protein (GFAP) is associated with impaired neurotrophic activity and because the GFAP promoter responds to ERα, we investigated the role of astrocytic ERα and ERβ in impaired astrocyte neurotrophic activity during aging. In vivo and in vitro, ERα was increased greater than 50% with age in astrocytes from the cerebral cortex of male rats (24 vs 3 months), whereas ERβ did not change. In astrocytes from 3-month-old males, experimentally increasing the ERα to ERβ ratio induced the aging phenotype of elevated GFAP and impaired E2-dependent neurite outgrowth. In 24-month-old male astrocytes, lowering ERα reversed the age elevation of GFAP and partially restored E2-dependent neurite outgrowth. Mixed glia (astrocytes to microglia, 3:1) of both sexes also showed these age changes. In a model of perimenopause, mixed glia from 9- to 15-month rats showed E2 desensitization: 9-month regular cyclers retained young-like ERα to ERβ ratios and neurotrophic activity, whereas 9-month noncyclers had elevated ERα and GFAP but low E2-dependent neurotrophic activity. In vivo, ERα levels in cortical astrocytes were also elevated. The persisting effects of ovarian acyclicity in vitro are hypothesized to arise from steroidal perturbations during ovarian senescence. These findings suggest that increased astrocyte ERα expression during aging contributes to the E2 desensitization of the neuronal responses in both sexes.
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Qian, Changhui, Dandan Tan, Xianghai Wang, Lixia Li, Jinkun Wen, Mengjie Pan, Yuanyuan Li, Wutian Wu, and Jiasong Guo. "Peripheral Nerve Injury-Induced Astrocyte Activation in Spinal Ventral Horn Contributes to Nerve Regeneration." Neural Plasticity 2018 (2018): 1–8. http://dx.doi.org/10.1155/2018/8561704.
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Accumulating evidences suggest that peripheral nerve injury (PNI) may initiate astrocytic responses in the central nervous system (CNS). However, the response of astrocytes in the spinal ventral horn and its potential role in nerve regeneration after PNI remain unclear. Herein, we firstly illustrated that astrocytes in the spinal ventral horn were dramatically activated in the early stage following sciatic nerve injury, and these profiles were eliminated in the chronic stage. Additionally, we found that the expression of neurotrophins, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3), also accompanied with astrocyte activation. In comparison with the irreversible transected subjects, astrocyte activation and the neurotrophic upregulation in the early stage were more drastic in case the transected nerve was rebridged immediately after injury. Furthermore, administering fluorocitrate to inhibit astrocyte activation resulted in decreased neurotrophin expression in the spinal ventral horn and delayed axonal regeneration in the nerve as well as motor function recovery. Overall, the present study indicates that peripheral nerve injury can initiate astrocyte activation accompanied with neurotrophin upregulation in the spinal ventral horn. The above responses mainly occur in the early stage of PNI and may contribute to nerve regeneration and motor function recovery.
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Saas, Philippe, José Boucraut, Anne-Lise Quiquerez, Valérie Schnuriger, Gaelle Perrin, Sophie Desplat-Jego, Dominique Bernard, Paul R. Walker, and Pierre-Yves Dietrich. "CD95 (Fas/Apo-1) as a Receptor Governing Astrocyte Apoptotic or Inflammatory Responses: A Key Role in Brain Inflammation?" Journal of Immunology 162, no. 4 (February 15, 1999): 2326–33. http://dx.doi.org/10.4049/jimmunol.162.4.2326.
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Abstract Astrocytes are a major cellular component of the brain that are capable of intense proliferation and metabolic activity during diverse inflammatory brain diseases (such as multiple sclerosis, Alzheimer’s dementia, tumor, HIV encephalitis, or prion disease). In this biological process, called reactive gliosis, astrocyte apoptosis is frequently observed and could be an important mechanism of regulation. However, the factors responsible for apoptosis in human astrocytes are poorly defined. Here, we report that short term cultured astrocytes derived from different brain regions express significant levels of CD95 at their surface. Only late passage astrocytes are sensitive to CD95 ligation using either CD95 mAb or recombinant CD95 ligand. Blocking experiments using caspase inhibitors with different specificities (DEVD-CHO, z-VAD-fmk, and YVAD-cmk), an enzymatic activity assay, and immunoblotting show that CPP32/caspase-3 play a prominent role in CD95-induced astrocyte death. In contrast, early passage astrocytes are totally resistant to death, but a significant increase in astrocytic IL-8 secretion (p < 0.001, by Wilcoxon’s test for paired samples) is observed after CD95 triggering. Production of IL-8 contributes to the resistance of astrocytes to CD95 ligation. Furthermore, in the presence of IFN-γ, resistant astrocytes became sensitive to CD95-mediated death. These data suggest that microenvironmental factors can influence the consequences of CD95 ligation on astrocytes. Therefore, we propose that CD95 expressed by human astrocytes plays a pivotal role in the regulation of astrocyte life and death and may be a key factor in inflammatory processes in the brain, such as reactive gliosis.
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Kim, Minsu, Sunhong Moon, Hui Su Jeon, Sueun Kim, Seong-Ho Koh, Mi-Sook Chang, Young-Myeong Kim, and Yoon Kyung Choi. "Dual Effects of Korean Red Ginseng on Astrocytes and Neural Stem Cells in Traumatic Brain Injury: The HO-1–Tom20 Axis as a Putative Target for Mitochondrial Function." Cells 11, no. 5 (March 4, 2022): 892. http://dx.doi.org/10.3390/cells11050892.
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Astrocytes display regenerative potential in pathophysiologic conditions. In our previous study, heme oxygenase-1 (HO-1) promoted astrocytic mitochondrial functions in mice via the peroxisome-proliferator-activating receptor-γ coactivator-1α (PGC-1α) pathway on administering Korean red ginseng extract (KRGE) after traumatic brain injury (TBI). In this study, KRGE promoted astrocytic mitochondrial functions, assessed with oxygen consumption and adenosine triphosphate (ATP) production, which could be regulated by the translocase of the outer membrane of mitochondria 20 (Tom20) pathway with a PGC-1α-independent pathway. The HO-1–Tom20 axis induced an increase in mitochondrial functions, detected with cytochrome c oxidase subunit 2 and cytochrome c. HO-1 crosstalk with nicotinamide phosphoribosyltransferase was concomitant with the upregulated nicotinamide adenine dinucleotide (NAD)/NADH ratio, thereby upregulating NAD-dependent class I sirtuins. In adult neural stem cells (NSCs), KRGE-treated, astrocyte-conditioned media increased oxygen consumption and Tom20 levels through astrocyte-derived HO-1. HO inactivation by Sn(IV) protoporphyrin IX dichloride in TBI mice administered KRGE decreased neuronal markers, together with Tom20. Thus, astrocytic HO-1 induced astrocytic mitochondrial functions. HO-1-related, astrocyte-derived factors may also induce neuronal differentiation and mitochondrial functions of adult NSCs after TBI. KRGE-mediated astrocytic HO-1 induction may have a key role in repairing neurovascular function post-TBI in peri-injured regions by boosting astrocytic and NSC mitochondrial functions.
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ALEXANDER, JOHN K., BABETTE FUSS, and RAYMOND J. COLELLO. "Electric field-induced astrocyte alignment directs neurite outgrowth." Neuron Glia Biology 2, no. 2 (January 23, 2006): 93–103. http://dx.doi.org/10.1017/s1740925x0600010x.
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The extension and directionality of neurite outgrowth are key to achieving successful target connections during both CNS development and during the re-establishment of connections lost after neural trauma. The degree of axonal elongation depends, in large part, on the spatial arrangement of astrocytic processes rich in growth-promoting proteins. Because astrocytes in culture align their processes on exposure to an electrical field of physiological strength, we sought to determine the extent to which aligned astrocytes affect neurite outgrowth. To this end, dorsal root ganglia cells were seeded onto cultured rat astrocytes that were pre-aligned by exposure to an electric field of physiological strength (500 mV mm−1). Using confocal microscopy and digital image analysis, we found that neurite outgrowth at 24 hours and at 48 hours is enhanced significantly and directed consistently along the aligned astrocyte processes. Moreover, this directed neurite outgrowth is maintained when grown on fixed, aligned astrocytes. Collectively, these results indicate that endogenous electric fields present within the developing CNS might act to align astrocyte processes, which can promote and direct neurite growth. Furthermore, these results demonstrate a simple method to produce an aligned cellular substrate, which might be used to direct regenerating neurites.