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Contents lists available at ScienceDirect
Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Mini-review
The dual role of astrocyte activation and reactive gliosis Milos Pekny a,b,∗ , Ulrika Wilhelmsson a , Marcela Pekna a,b a Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg SE-405 30, Sweden b Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
h i g h l i g h t s • • • • •
Astrocyte activation (AA) and reactive gliosis (RG) accompany many CNS pathologies. AA and RG alter the expression of many genes and astrocyte function. RG benefits include lesion sequestering, neuroprotection, and counteracting acute stress. If not resolved on time, AA and RG inhibit neuroplasticity and CNS regeneration. AA and RG is an important therapeutic target.
a r t i c l e
i n f o
Article history: Received 2 December 2013 Received in revised form 21 December 2013 Accepted 29 December 2013 Keywords: Astrogliosis Intermediate filaments (nanofilaments) GFAP CNS injury Ischemic stroke Alzheimer’s disease Neural plasticity and regeneration
a b s t r a c t Astrocyte activation and reactive gliosis accompany most of the pathologies in the brain, spinal cord, and retina. Reactive gliosis has been described as constitutive, graded, multi-stage, and evolutionary conserved defensive astroglial reaction [Verkhratsky and Butt (2013) In: Glial Physiology and Pathophysiology]. A well- known feature of astrocyte activation and reactive gliosis are the increased production of intermediate filament proteins (also known as nanofilament proteins) and remodeling of the intermediate filament system of astrocytes. Activation of astrocytes is associated with changes in the expression of many genes and characteristic morphological hallmarks, and has important functional consequences in situations such as stroke, trauma, epilepsy, Alzheimer’s disease (AD), and other neurodegenerative diseases. The impact of astrocyte activation and reactive gliosis on the pathogenesis of different neurological disorders is not yet fully understood but the available experimental evidence points to many beneficial aspects of astrocyte activation and reactive gliosis that range from isolation and sequestration of the affected region of the central nervous system (CNS) from the neighboring tissue that limits the lesion size to active neuroprotection and regulation of the CNS homeostasis in times of acute ischemic, osmotic, or other kinds of stress. The available experimental data from selected CNS pathologies suggest that if not resolved in time, reactive gliosis can exert inhibitory effects on several aspects of neuroplasticity and CNS regeneration and thus might become a target for future therapeutic interventions. © 2014 Published by Elsevier Ireland Ltd.
Contents 1. 2. 3. 4. 5. 6. 7.
Experimental models to understand injury- or ischemia-triggered astrocyte activation and reactive gliosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Experimental modulation of astrocyte activation and reactive gliosis in chronic neurodegeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reactive astrocytes and activated microglia–an important crosstalk in neurodegeneration? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Does gender matter? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Astrocytes and synapse elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Are there any downsides of astrocyte activation and reactive gliosis? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Astrocytes and reactive astrocytes as a therapeutic target . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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∗ Corresponding author at: Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Box 440, Gothenburg SE-405 30, Sweden. Tel.: +46 31 7863581. E-mail address:
[email protected] (M. Pekny). 0304-3940/$ – see front matter © 2014 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.neulet.2013.12.071
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In mammalian brain, spinal cord, and retina, astrocytes have multitude of functions. Astrocytes induce the formation of neuronal synapses and are involved in their control [1–4] as well as in the control of the energy supply to neurons and the turnover of neurotransmitters [5–9]. Through their endfeet, which throughout the CNS cover and interact with endothelial cells of blood capillaries, astrocytes help to control the blood-brain barrier [10,11] and regulate the flow of blood within the CNS tissue [12–14]. An astrocentric view of the CNS is that of a system consisting of individual astrocytes and their interconnected domains that, to a large extent, control all the other cellular elements that are physically present within domains of individual astrocytes [15–19]. In the human cortex, a single astrocyte domain can contain as many as 2,000,000 neuronal synapses [20]. The complexity of interaction opportunities between astrocytes and the cellular elements within their action radius is truly enormous and is further increased by the existence of gap junctional coupling between astrocytes which turns each astrocyte unit into an element within the astrocyte network. It is highly probable that astrocytes are as heterogenous a cell population as neurons [21,22]. Attempts to define astrocytes in molecular terms are being made [22–26], and this will allow functional classification of astrocytes and a better understanding of their roles in disease pathogenesis. In vivo, a number of molecules, such as transforming growth factor (TGF) -alpha, cilliary neurotrophic factor (CNTF), interleukin (IL) -6, leukeamia inhibitory factor (LIF), and oncostatin M induce astrocyte activation [27–31]. The levels of IL-6, LIF, and oncostatin M mRNA, all ligands of the gp-130/activator of transcription 3 (STAT3) signaling pathway, were elevated prior to phosphorylation and nuclear translocation of STAT3 in astrocytes and induction of astrogliosis [30]. However it is also conceivable that at least some of the cytokines exert their effects on astrocyte activation through other cell types such as microglia, neurons, or endothelial cells. Some molecular and morphological features of reactive astrocytes have long been considered by histopathologists and experimental researchers as hallmarks of astrocyte activation in conditions such as brain or spinal cord infections, injuries to the brain, spinal cord and retina, epilepsy, stroke, some brain tumors, and neurodegenerative diseases, e.g., AD, amyotrophic lateral sclerosis (ALS), or multiple sclerosis [32–38]. The most prominent of these hallmarks are hypertrophy of astrocyte cellular processes and upregulation of intermediate filament (nanofilament) proteins, in particular the upregulation of glial fibrillary acidic protein (GFAP), which is the main constituent of the intermediate filament system of adult astrocytes [39] (Fig. 1). Reactive gliosis can be graded as mild to very prominent, with the latter being often connected with a glial scar, to the formation of which pericytes also contribute [40]. Reactive astrocytes can be found within the lesion, and they can also constitute a physical barrier between the lesion and the surrounding tissue [41,42]. The latter can be exemplified by reactive astrocytes that surround focal traumatic or focal ischemic lesions.
1. Experimental models to understand injury- or ischemia-triggered astrocyte activation and reactive gliosis Over the past two decades, several animal models have been used in a series of experimental studies to understand the role of astrocyte activation and reactive gliosis in neurological diseases as well as neuroplasticity and regeneration processes. What are the consequences of the elimination of astrocytes, elimination of reactive astrocytes or inhibition/attenuation of astrocyte activation? Elimination of astrocytes in a mammal is lethal [43]. The demarcation of CNS lesion by reactive astrocytes was manipulated in animal experimental models by astrocyte specific ablation of STAT3 and suppressor of cytokine signaling 3
(Socs3) [44,45]. STAT3 was shown to affect reactive gliosis following CNS injury, by being downstream of the action of IL-6, LIF, and CNTF [30,46,47]. Socs3 functions as a negative feedback molecule of STAT3 and an inverse relationship between STAT3 and Socs3 has been reported [48,49]. When STAT3 was specifically ablated in reactive astrocytes, astrocyte migration and the demarcation of the spinal cord traumatic lesion by astrocytes was inhibited, and the infiltration by CD11b positive inflammatory cells was increased. This resulted in the expansion of the lesion area and led to a more pronounced functional impairment [44,45,50]. In the injured spinal cord of mice with conditional ablation of Socs3 in reactive astrocytes, phosphorylation of STAT3 in reactive astrocytes and astrocyte migration increased; contraction of the lesion area was more prominent and the functional recovery improved [45]. These results showed that reactive astrocytes have a key role in the repair of the injured CNS tissue and positively affect the recovery process after spinal cord injury, and that this function of reactive astrocytes depends on STAT3 signaling. Thus, the demarcation of a lesion by reactive astrocytes allows the isolation and protection of the relatively unaffected CNS tissue and might have evolved as the means of sequestering the toxic environment of the lesion [44,45,51,52], albeit at the price of restricted regenerative response at a later stage [53]. The ablation of the dividing fraction of reactive astrocytes in mice aggravates the negative consequences of brain or spinal cord injury [54–57]. This was achieved in a transgenic mouse model with GFAP promoter-driven herpes simplex virus thymidine kinase that allows elimination of proliferating astrocytes after CNS injury [54] with the results suggesting that reactive astrocytes play a positive role in attenuating acute neurodegeneration and repairing the blood-brain barrier [54–56]. Elimination of the astrocyte intermediate filament (nanofilament) system by genetic ablation of intermediate filament proteins GFAP and vimentin in mice results in attenuated reactive gliosis [58,59] and decreased resistance of the CNS tissue to severe mechanical stress [60,61]. The astrocyte intermediate filaments system is both a structural component of the cytoskeleton and an important signaling platform in situations connected with cellular stress [62–64]. Intermediate filaments of reactive astrocytes contain GFAP, vimentin, and nestin, with a subpopulation of reactive astrocytes containing also an intermediate filament protein synemin [25,65,66]. The introduction in mice of null mutations in the gene coding for GFAP (GFAP−/− ) or vimentin (Vim−/− ) still allows formation of intermediate filaments (in GFAP−/− reactive astrocytes composed of vimentin and nestin, and in some of these astrocytes also of synemin, in Vim−/− reactive astrocytes composed of GFAP only) [58,65]. However, simultaneously present null mutations in GFAP and vimentin genes (GFAP−/− Vim−/− ) lead to a complete deficiency of intermediate filaments in reactive astrocytes [59] because in the absence of both GFAP and vimentin, neither nestin [58] nor synemin [65] can form intermediate filaments. After brain injury, astrocytes of GFAP−/− Vim−/− mice show similar abundance and access volumes of brain tissue comparable to those assessed by astrocytes of wild-type mice [67]. However, GFAP−/− Vim−/− astrocytes do not exhibit the reactive phenotype with characteristic processes as do astrocytes in wild-type mice [67–69]. The GFAP−/− Vim−/− astrocytes also display altered levels of some molecules such as plasminogen activator inhibitor I [70,71] under conditions leading to astrocyte activation, exemplified by exposure to fetal calf serum in primary astrocyte cultures in vitro [68], which suggests a less prominent response of GFAP−/− Vim−/− astrocytes to activation. The formation of glial scar is reduced in GFAP−/− Vim−/− mice; posttraumatic healing takes longer time and there is a more prominent loss of neuronal synapses in the acute period following hippocampal de-afferentation induced by entorhinal cortex lesion [59,67]. Experimental ischemic stroke in
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Fig. 1. In response to injury, cellular processes of reactive astrocytes show signs of hypertrophy.A Partial de-afferentation of the hippocampus by enthorhinal cortex lesion leads to astrocyte activation and reactive gliosis. Immunodetection of intermediate filament protein GFAP (green) reveals astrocytes in an unchallenged mouse hippocampus (left) and activated astrocytes in the mouse hippocampus 4 days after enthorhinal cortex lesion, the latter with clear signs of hypetrophy of astrocyte processes (right). Reproduced from [69]. B Schematic rendering of astrocytes responding to injury. The processes of reactive astrocytes become thicker and therefore visible over a longer distance when visualized with antibodies against GFAP, with reactive astrocytes staying within their original tiled domains. Reproduced from [69]. In focal CNS injuries, astrocytes immediately adjacent to the lesion can behave differently: they also exhibit process hypertrophy, but often show prominent extension of their cellular processes towards the lesion, which implies rearrangement of their domains [23,160].
adult mice [68] but not neonatal ischemia [72], leads to the development of larger infarcts in GFAP−/− Vim−/− compared to wild-type mice. This suggests that in the adult, reactive astrocytes are important for the protection of the ischemic penumbra, e.g. by effective elimination of glutamate and reactive oxygen species [68,73] or by effective regulatory volume decrease that in brain ischemia counteracts the development of edema [74]. The mechanisms linking intermediate filaments to the response of reactive astrocytes in situations such as trauma or focal brain ischemia still remain incompletely understood. The intermediate filament system of astrocytes affects viscoelastic properties of astrocytes [75], as well as the intracellular vesicle traffic in astrocytes [76–78], and it was shown to be important for astrocyte response to hypoosmotic stress [74], their spontaneous in vitro motility [79], and possibly also for the interaction of astroglial cells with microglia or blood borne monocytes [80–82]. 2. Experimental modulation of astrocyte activation and reactive gliosis in chronic neurodegeneration Reactive astrocytes are a prominent histopathological feature of many neurodegenerative diseases including AD, where they surround and closely associate with amyloid plaques. In the past, astrocyte activation and reactive gliosis in AD and other neurodegenerative disorders was viewed as part of the neuroinflammatory neurotoxic response [83,84]. On the other hand, adult astrocytes in brain slices from an AD mouse model were shown to migrate and degrade amyloid plaques [85] in an apolipoprotein E-dependent manner [86]. We recently addressed the role of reactive astrocytes in plaque pathogenesis by crossing a mouse AD model with GFAP−/− Vim−/− mice that exhibit attenuated reactive gliosis [80]. The amyloid plaque load was increased with dystrophic neurites
being more numerous even when normalized for amyloid load (Fig. 2A), while the expression and processing of the amyloid precursor protein were unaltered, suggesting that reactive astrocytes influence plaque pathogenesis via direct interaction with amyloid plaques rather than through amyloid protein synthesis or metabolism. As observed before for astrocytes in the lesion area in GFAP−/− Vim−/− mice after brain trauma [67], compared to wild-type, the cellular processes of GFAP−/− Vim−/− astrocytes adjacent to amyloid plaques did not become hypertrophic and the GFAP−/− Vim−/− astrocytes showed only very limited physical interaction with amyloid plaques [80] (Fig. 2B–C). This suggests that in AD, reactive astrocytes inhibit the amyloid plaque formation and growth, and that this process requires physical interaction between such astrocytes and amyloid plaques. Comparison of gene expression between wild-type and GFAP−/− Vim−/− mouse brains, both on the AD background, showed decreased expression of gamma secretase subunit APH-1b (APH-1) and matrix metalloproteinase-9 (MMP-9) mRNA in GFAP−/− Vim−/− mice. The latter finding is compatible with a scenario that MMP-9 released by reactive astrocytes surrounding amyloid plaques [87,88] contributes to plaque degradation. It is also conceivable that increased amyloid plague load and neurite dystrophy observed in AD mice on the GFAP−/− Vim−/− background is at least partly mediated by an altered interaction between astrocytes and the vascular system of the brain. Blood capillaries in the CNS are covered by astrocyte endfeet, the polarization of which is induced by pericytes [89], and the interaction between astrocytes and endothelial cells might become even more critical in a pathological context than it is in a healthy brain [90]. It was proposed that astrocytes play an important role in the transport of amyloid protein out of the brain parenchyma, i.e., across the blood-brain barrier [88]. Although the absence of GFAP and vimentin did not
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Fig. 2. Alzheimer’s disease (AD) mice, when crossed to GFAP−/− Vim−/− mice with attenuated reactive gliosis, show more pronounced amyloid plaque deposits and more prominent microglial infiltration in the vicinity of amyloid plaques. A Amyloid plaques in the cerebral cortex and hippocampus from 4, 8 and 12 months old AD mice and AD mice on the GFAP−/− Vim−/− background were visualized with antibodies against beta-amyloid. B,C Astrocytes (green) in 12 months old mice were visualized by injection of an adenoviral construct driving the expression of green fluorescent protein in GFAP expressing astrocytes, and examined a month later. Amyloid plaques were labeled with X-34 (blue). In AD mice, processes of reactive astrocytes show signs of hypertrophy and astrocytes are in intimate contact with amyloid plaques. In contrast, in AD mice on the GFAP−/− Vim−/− background, no hypertrophy of astrocyte cellular processes is visible and there is very little physical interaction between astrocytes and amyloid plaques. Values represent the mean ±SEM; n = 58–61 plaques in 3 mice/group. ****p < 0.0001. Scale bar, 50 m. D,E The density of microglia, visualized by antibodies against Iba-1 (green), in the vicinity of amyloid plaques (blue) of 8 month old mice, was higher and their infiltration of the amyloid plaques greater in the brains of AD mice compared to AD mice on the GFAP−/− Vim−/− background. Values represent the mean ±SEM; n = 3 mice/group. *p < 0.05, ***p < 0.001. Scale bar, 20 m. The figure mount is modified from [80].
alter brain levels of soluble beta-amyloid, it is possible that the beta-amyloid clearance into the blood compartment [91] is altered in the GFAP−/− Vim−/− AD mice. It remains unclear how activated astrocytes affect the rate of neurite dystrophy in AD. Reactive astrocytes protect neurons by controling the extracellular concentrations of ions and recycling neurotransmitters [90], and this function becomes critical under tissue and cellular stress [64]. Lower density of astrocyte processes surrounding the plaques, their less efficient communication across gap junctions, their reduced glutamate transport [68] or less efficient physical barrier around plaques compared to AD mice with normal astrocytes response [92] might provide an explanation for this phenotype. In order to address the role of astrocyte activation and reactive gliosis in another neurodegenerative disease, namely Batten disease (BD), known also as infantile neuronal ceroid lipofuscinosis [93–95], we took an analogous approach and crossed GFAP−/− Vim−/− mice with a BD mouse model, i.e., mice deficient in palmitoyl protein thioesterase 1 (PPT1) [96]. In BD mice, the upregulation of GFAP is known as the first pathological sign of the disease [97,98]. Compared to BD mice, in BD mice on the GFAP−/− Vim−/− background, the disease onset appeared earlier and the disease progression was accelerated with more prominent neurodegeneration, immune cell infiltration, and decreased survival of mice [81]. Thus, these results show that attenuation of reactive gliosis by genetic ablation of the astrocyte intermediate filament system leads to more pronounced pathologies in both AD and BD
implying that astrocytes and reactive gliosis are beneficial in neurodegenerative diseases. 3. Reactive astrocytes and activated microglia–an important crosstalk in neurodegeneration? Remarkably, there appears to be a bidirectional relationship between the activation of astrocytes and activation/recruitment of microglia and monocytes, at least in the context of neurodegeneration. The ablation of GFAP and vimentin led to attenuated CD11b-positive microglia/monocyte infiltration after retinal detachment, suggesting a key role for reactive retinal glial cells in recruiting microglia/monocytes to the injured areas, conceivably through the production of chemokines such as monocyte chemoattractant protein-1 [82]. In contrast, when astrocyte migration and the demarcation of the spinal cord traumatic lesion by astrocytes was inhibited by STAT3 ablation in reactive astrocytes, the infiltration by CD11b-positive microglia/monocytes was increased and associated with larger lesion area as well as more pronounced functional impairment [44,45,50]. Attenuation of reactive gliosis in a mouse model of AD led to larger abundance of microglial cells in plaque vicinity (Fig. 2D–E) and increased expression of microglia/monocyte markers CD11b and Iba-1 in the cortex [80]. Similarly, attenuation of astrocyte activation in a mouse model of BD was accompanied by an increased number of CD68-positive microglia/monocytes in the brain [81]. Since attenuation of astrocyte activation led to the aggravation of neurodegenerative changes
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in both AD and BD model, it is possible that the more pronounced microglial response is the result of an unsuccessful attempt to compensate for the impaired ability of astrocytes to deal with the underlying insult. Alternatively, activated astrocytes suppress the recruitment and activation of microglia [80]. The exact mechanism, the role of activated astrocytes in the recruitment of blood-borne monocytes as well as the nature of astrocyte-microglia cross-talk, conceivably bidirectional, merit further investigation and may also depend on the underlying cause of the neurodegenerative process. Thus, inflammatory cytokines and chemokines such as tumor necrosis factor (TNF) -alpha and interferon (IFN) -gamma were strongly increased in the BD but not in AD brains with attenuated reactive gliosis [80,81], supporting the notion that the role of various neuroinflammatory processes in neurodegeneration may be specific for the underlying cause. Notably, genomic analysis of reactive astrocytes isolated from the different injury models, namely ischemic stroke and lipopolysaccharide (LPS) -induced neuroinflammation showed that the reactive astrocyte phenotype is dependent on the type of inducing injury [26]. 4. Does gender matter? Given the sex differences in the morphology and function of astrocytes at least in some regions of the developing and adult brain [99,100], it is perhaps not surprising that male and female astrocytes show different sensitivity to hypoxia [101], and may respond differentially to an inflammatory challenge. Despite similar basal expression of IL-6, TNF-alpha, IL-1beta, and the LPS receptor (Toll-like receptor 4), the mRNA levels of IL-6, TNFalpha, and IL-1beta were manifold higher in LPS treated astrocytes derived from males or androgenized females compared to astrocytes derived from control or vehicle-treated females [102]. In contrast, mRNA levels of the chemokine IFN-inducible protein 10 were higher in LPS-treated astrocytes derived from control or vehicle-treated females than in those obtained from males or androgenized females [102]. Furthermore, estrogen and progesterone affect mitochondrial function and viability of astrocytes in a gender-specific manner [103]. These sexually dimorphic responses seem to be predetermined by perinatal exposure to testosterone [102] and might be at least partly causative for the known gender specificity of neurodegenerative processes in the brain [101]. It remains to be determined whether the effects of the attenuation of astrocyte activation on the progression of chronic neurodegeneration or outcome after brain ischemia are genderdependent.
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6. Are there any downsides of astrocyte activation and reactive gliosis? There is a growing body of evidence pointing to negative consequences of reactive gliosis in particular when it does not get resolved within the post-acute and the early chronic stage after injury. Reactive gliosis and glial scarring have inhibitory effects on CNS regeneration as shown in a number of experimental models with the whole range of molecules implicated in this process [110–114]. Post-traumatic axonal regeneration can be improved by inhibition of chondroitin sulphate proteoglycans produced by reactive astrocytes [115–120]. Similarly, genetic ablation or pharmacological inhibition of ephrin A4 resulted in attenuated reactive gliosis, better axonal regeneration, and functional recovery after spinal cord injury in mice [114,121]. Attenuation of reactive gliosis by genetic ablation of GFAP and vimentin when used with concurrent induction of Bcl-2 expression in neurons improved regeneration of the severed optic nerve in postnatal mice [122]. Similarly, regenerative response and functional recovery after spinal cord trauma was improved in GFAP−/− Vim−/− mice [123], which also show increased hippocampal neurogenesis in the adulthood [124] and into the old age [125], as well as after brain injury [124]. GFAP−/− Vim−/− mice also support improved integration of retinal grafts [126] and neuronal and astrocytic differentiation from donor adult hippocampal neural stem/progenitor cells transplanted in their hippocampus [127]. This could be due to attenuated reactive gliosis in the recipient mice, alternatively could have resulted from altered interactions between recipient’s astrocytes and the grafted neural progenitor cells, e.g. decreased Notch signaling from GFAP−/− Vim−/− astrocytes to neural stem cells that normally inhibits neural stem cell differentiation [124]. Thus, the benefits of reactive gliosis at the acute phase of the injury can be balanced against restricted regenerative potential at later stages. These regeneration inhibitory effects can represent the cost for effective handling of the acute stage of an injury that reduces the cellular and tissue stress, and provides effective neuroprotection together with the beneficial isolation of the lesion area from the rest of the CNS [56,128,129]. We can speculate that evolution selected such acute responses that secure survival of the individual through the acute post-traumatic phase, and allow a measure of repair even though this comes at the price of a restricted regenerative capacity and hence limited functional recovery. If so, the right modulatory interventions, when applied within optimal time windows, might be developed into novel therapeutic approaches for a whole range of neurological diseases.
5. Astrocytes and synapse elimination
7. Astrocytes and reactive astrocytes as a therapeutic target
TGF-beta secreted by immature astrocytes in the retina has been recently shown to initiate synaptic elimination in the postnatal thalamus by regulating the expression of C1q in the retinal ganglion cells [104]. C1q is a complement protein that triggers the activation of the classical complement pathway which leads to the tagging of the supernumerary synapses with complementactivation derived C3b fragment and their subsequent elimination by microglia [105,106]. C1q upregulation in microglia is also an early step in glaucoma, one of the most common neurodegenerative diseases, and mice deficient in C1q are protected from glaucoma [107]. It is tempting to speculate that reactive astrocytes regulate also the expression of C1q in microglia and are thus causally linked to neurodegeneration; however, the mechanisms leading to microglial C1q expression in neurodegenerative disorders or normal aging brain [108] remain elusive although both neurodegeneration and aging are associated with increased expression of GFAP, a hallmark of astrocyte activation [109].
Importantly, the available data make it paramount to recognize both the beneficial and detrimental side of reactive gliosis asking for high caution, not least when it comes to the timing of its therapeutic modulation. For example, attenuation of reactive gliosis after partial hippocampal de-afferentation induced by entorhinal cortex lesions [130,131] in GFAP−/− Vim−/− mice resulted in better regeneration of neuronal synapses in the post-acute phase; however, the synaptic loss and signs of neurodegeneration at the acute stage were more prominent than in wild-type controls [67]. One might also have to reach multiple targets, e.g., only a combination of a simultaneous neuronal overexpression of Bcl-2 and attenuation of reactive gliosis by genetic ablation of GFAP and vimentin extended the window for long distance axonal regeneration and reinnervation of the brain targets by severed optic nerve fibers up to 2 weeks postnatally. This indicates that an early postnatal downregulation of Bcl-2 [132] and post-traumatic reactive gliosis are two independent brakes on axonal regeneration in the CNS [122,133].
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It can be safely predicted that astrocytes will become the target for new therapeutic strategies for disorders such as neurotrauma and neurodegenerative diseases [10,90,134,135]. The question is ‘when’ rather than ‘if’. A number of laboratories use high throughput screening strategies and identify potential molecular targets in the context of the whole proteome or transcriptome [24,136,137]. Cell culture systems that allow to assess responses of astrocytes in vitro are used e.g. in current screening systems. However, the traditional 2-dimensional culture systems suffer from number of limitations, such as prominent signs of cellular stress, undesired baseline activation, or the loss of many in vivo morphological and physiological features of astrocytes. Some of these problems have been overcome by the development of new methods for astrocyte preparation [138] and 3-dimensional culture systems for astrocytes and neurons [139,140]. These 3-dimensional culture systems are already proving their usefulness for assessing (patho) physiological and pharmacological responses of astrocytes [140,141]; they may prove useful in the identification of clinically more relevant targets in astrocytes and the compounds that act on these targets. Reactive astrocytes have already emerged as an attractive target for improved recovery after stroke. Neuroplasticity in the periinfarct zone plays an important role in rehabilitation and functional recovery by allowing remapping of sensorimotor functions from the damage areas [142,143]. An example of recently identified target for improving functional recovery after stroke is ephrin-A5, which is expressed in reactive astrocytes in the peri-infarct region and inhibits axonal sprouting. Blockage of ephrin-A5 signaling induced new and widespread axonal projections in the ischemic hemisphere and improved recovery after stroke, and this effect was further enhanced when the blockage was combined with forced use of the affected limb (by the immobilization of the healthy limb) [144]. Astrocytes affect neuroplasticity and functional recovery also by other mechanisms that have shown a promising therapeutic potential. The impaired function of astrocyte GABA (␥-aminobutyric acid) transporter (GAT-3/GAT-4) leads to excess of GABA and tonic neuronal inhibition mediated by extrasynaptic GABAA receptors [145]. Chronic treatment with L-655,708, a cognition enhancing drug that acts as benzodiazepine inverse agonist specific for the alpha5 subunit of GABA receptors [146], that started 3 days after stroke resulted in an early and sustained recovery of function in mice. In contrast, when mice were treated with L-655,708 from stroke onset, infarct volume was increased [145]. Thus, astrocytemediated tonic inhibition in the acute phase is neuroprotective, and the timing of treatment that counteracts tonic inhibition is critical for the treatment outcome [145]. It is also possible that some of the drugs that we already use in clinical practice modulate function of astrocytes as their main effect. For example, reactive astrocytes within the epileptic brain exhibit disorganized cellular domains and a prominent increase in the extent of overlap between neighboring astrocytes [147] in contrast to only a limited overlap between domains of adjacent reactive astrocytes in brain injury [69]. Valproate, a well-known antiepileptic drug, both suppresses the seizures and, what has not been known until recently, reduces the overlap between adjacent astrocyte domains [147]. We currently do not know whether the loss of astrocyte domain organization might be an upstream event preceding the development of clinical epilepsy. But even if this is not the case, reactive gliosis associated with epileptic foci [148] and often present during the early stages of the disease [149–153] might contribute to regional synaptic perturbations [154] and thus amplify the disease symptomatology. Screening of drugs specifically targeting astrocytes in pathological context reveals interesting candidate drugs for a number of diseases ranging from Alexander disease [155,156] to ALS [157]. We anticipate that future therapeutic strategies will likely aim at gentle adjustments of multiple equilibria
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