Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury

Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Göteborg University, SE-405 30 Göteborg, Sweden.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/2006; 103(46):17513-8. DOI: 10.1073/pnas.0602841103
Source: PubMed


Reactive astrocytes in neurotrauma, stroke, or neurodegeneration are thought to undergo cellular hypertrophy, based on their morphological appearance revealed by immunohistochemical detection of glial fibrillary acidic protein, vimentin, or nestin, all of them forming intermediate filaments, a part of the cytoskeleton. Here, we used a recently established dye-filling method to reveal the full three-dimensional shape of astrocytes assessing the morphology of reactive astrocytes in two neurotrauma models. Both in the denervated hippocampal region and the lesioned cerebral cortex, reactive astrocytes increased the thickness of their main cellular processes but did not extend to occupy a greater volume of tissue than nonreactive astrocytes. Despite this hypertrophy of glial fibrillary acidic protein-containing cellular processes, interdigitation between adjacent hippocampal astrocytes remained minimal. This work helps to redefine the century-old concept of hypertrophy of reactive astrocytes.

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    • "Reactive astrocytes display an enlarged cell body and processes (Wilhelmsson et al., 2006). In addition, astrocyte arborization is reorganized with reactivity: the number of primary processes changes (Wilhelmsson et al., 2006) or they polarize toward the site of injury (Bardehle et al., 2013) or toward amyloid plaques in AD (see below). Less is known about the thin distal processes in astrocytes called perisynaptic processes (PAP), which contact synapses. "
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    ABSTRACT: Astrocytes play crucial roles in the brain and are involved in the neuroinflammatory response. They become reactive in response to virtually all pathological situations in the brain such as axotomy, ischemia, infection, and neurodegenerative diseases (ND). Astrocyte reactivity was originally characterized by morphological changes (hypertrophy, remodeling of processes) and the overexpression of the intermediate filament glial fibrillary acidic protein (GFAP). However, it is unclear how the normal supportive functions of astrocytes are altered by their reactive state. In ND, in which neuronal dysfunction and astrocyte reactivity take place over several years or decades, the issue is even more complex and highly debated, with several conflicting reports published recently. In this review, we discuss studies addressing the contribution of reactive astrocytes to ND. We describe the molecular triggers leading to astrocyte reactivity during ND, examine how some key astrocyte functions may be enhanced or altered during the disease process, and discuss how astrocyte reactivity may globally affect ND progression. Finally we will consider the anticipated developments in this important field. With this review, we aim to show that the detailed study of reactive astrocytes may open new perspectives for ND.
    Frontiers in Cellular Neuroscience 08/2015; 9:278. DOI:10.3389/fncel.2015.00278 · 4.29 Impact Factor
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    • "Reactive astrogliosis is characterized by hypertrophy of primary processes, a dramatic increase in the expression of intermediate filament proteins such as glial fibrillary acidic protein (GFAP), a decrease in expression of glutamine synthetase [8] [9] [10] and, in some cases, a disruption in domain organization [11]. In addition, we have demonstrated that in the hippocampus (HC), a brain region known to be involved in seizure generation in TLE, there is a dramatic increase in gap junction coupling in reactive astrocytes, glutamate transport becomes more efficient, potassium buffering remains intact [7], and a number of specific subunits of ionotropic kainate receptors (KAR) are found to be expressed in reactive astrocytes soon after kainic acid (KA)-induced SE [12]. "
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    ABSTRACT: Temporal lobe epilepsy (TLE) is a devastating seizure disorder that is often caused by status epilepticus (SE). Temporal lobe epilepsy can be very difficult to control with currently available antiseizure drugs, and there are currently no disease-modifying therapies that can prevent the development of TLE in those patients who are at risk. While the functional changes that occur in neurons following SE and leading to TLE have been well studied, only recently has research attention turned to the role in epileptogenesis of astrocytes, the other major cell type of the brain. Given that epilepsy is a neural circuit disorder, innovative ways to evaluate the contributions that both neurons and astrocytes make to aberrant circuit activity will be critical for the understanding of the emergent network properties that result in seizures. Recently described approaches using genetically encoded calcium-indicating proteins can be used to image dynamic calcium transients, a marker of activity in both neurons and glial cells. It is anticipated that this work will lead to novel insights into the process of epileptogenesis at the network level and may identify disease-modifying therapeutic targets that have been missed because of a largely neurocentric view of seizure generation following SE. This article is part of a Special Issue entitled "Status Epilepticus". Copyright © 2015. Published by Elsevier Inc.
    Epilepsy & Behavior 07/2015; 49. DOI:10.1016/j.yebeh.2015.05.002 · 2.26 Impact Factor
    • "All experiments were approved by the Ethics committee of the University of Gothenburg. Unilateral entorhinal cortex lesion (ECL) was performed as previously described (Wilhelmsson et al. 2006; Pekny et al. 2013). For details, see the Appendix S1. "
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    ABSTRACT: Astrocytes have multiple roles in the CNS including control of adult neurogenesis. We recently showed that astrocyte inhibition of neurogenesis through Notch signaling depends on the intermediate filament proteins GFAP and vimentin. Here, we used real-time quantitative PCR to analyze gene expression in individual mouse astrocytes in primary cultures and in GFAP(POS) or Aldh1L1(POS) astrocytes freshly isolated from uninjured, contralesional and lesioned hippocampus 4 days after entorhinal cortex lesion. To determine the Notch signaling competence of individual astrocytes, we measured the mRNA levels of Notch ligands and Notch1 receptor. We found that whereas most cultured and freshly isolated astrocytes were competent to receive Notch signals, only a minority of astrocytes were competent to send Notch signals. Injury increased the fraction of astrocyte subpopulation unable to send and receive Notch signals, thus resembling primary astrocytes in vitro. Astrocytes deficient of GFAP and vimentin showed decreased Notch signal-sending competence and altered expression of Notch signaling pathway-related genes Dlk2, Notch1 and Sox2. Further, we identified astrocyte subpopulations based on their mRNA and protein expression of nestin and HB-EGF. This study improves our understanding of astrocyte heterogeneity, and points to astrocyte cytoplasmic intermediate filaments as targets for neural cell replacement strategies. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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