The original version of this Article contained an error in Fig. 1, in which a number of incorrect fluorescence images were inadvertently incorporated into the panel. This has been corrected in both ...the PDF and HTML versions of the Article.
Astrocytes are the most abundant cell type in the central nervous system (CNS), performing complex functions in health and disease. It is now clear that multiple astrocyte subsets or activation ...states (plastic phenotypes driven by intrinsic and extrinsic cues) can be identified, associated to specific genomic programs and functions. The characterization of these subsets and the mechanisms that control them may provide unique insights into the pathogenesis of neurologic diseases, and identify potential targets for therapeutic intervention. In this article, we provide an overview of the role of astrocytes in CNS inflammation, highlighting recent discoveries on astrocyte subsets and the mechanisms that control them.
Astrocytes display functional and phenotypic heterogeneity across and within CNS regions under homeostatic conditions.CNS insults (trauma, infection, autoimmune inflammation, protein aggregates) induce a broad array of astrocyte activation states, poorly defined in terms of phenotype, function, and role in human pathology.Astrocyte activation during acute microbial infection is essential for pathogen clearance but can contribute to long-term neurological impairments.The plasticity of astrocytes and their ability to adopt either a proinflammatory or an anti-inflammatory phenotype could be targeted for therapeutic intervention.
Chronic pain is a critical clinical problem with an increasing prevalence. However, there are limited effective prevention measures and treatments for chronic pain. Astrocytes are the most abundant ...glial cells in the central nervous system and play important roles in both physiological and pathological conditions. Over the past few decades, a growing body of evidence indicates that astrocytes are involved in the regulation of chronic pain. Recently, reactive astrocytes were further classified into A1 astrocytes and A2 astrocytes according to their functions. After nerve injury, A1 astrocytes can secrete neurotoxins that induce rapid death of neurons and oligodendrocytes, whereas A2 astrocytes promote neuronal survival and tissue repair. These findings can well explain the dual effects of reactive astrocytes in central nervous injury and diseases. In this review, we will summarise the (1) changes in the morphology and function of astrocytes after noxious stimulation and nerve injury, (2) molecular regulators and signalling mechanisms involved in the activation of astrocytes and chronic pain, (3) the role of spinal and cortical astrocyte activation in chronic pain, and (4) the roles of different subtypes of reactive astrocytes (A1 and A2 phenotypes) in nerve injury that is associated with chronic pain. This review provides updated information on the role of astrocytes in the regulation of chronic pain. In particular, we discuss recent findings about A1 and A2 subtypes of reactive astrocytes and make several suggestions for potential therapeutic targets for chronic pain.
Astrocytes participate in numerous aspects of central nervous system (CNS) physiology ranging from ion balance to metabolism, and disruption of their physiological roles can therefore be a ...contributor to CNS dysfunction and pathology. Cellular senescence, one of the mechanisms of aging, has been proposed as a central component of the age dependency of neurodegenerative disorders. Cumulative evidence supports an integral role of astrocytes in the initiation and progression of neurodegenerative disease and cognitive decline with aging. The loss of astrocyte function or the gain of neuroinflammatory function as a result of cellular senescence could have profound implications for the aging brain and neurodegenerative disorders, and we propose the term “astrosenescence” to describe this phenotype. This review summarizes the current evidence pertaining to astrocyte senescence from early evidence, in vitro characterization and relationship to age‐related neurodegenerative disease. We discuss the significance of targeting senescent astrocytes as a novel approach toward therapies for age‐associated neurodegenerative disease.
Network activity in the brain is associated with a transient increase in extracellular K super(+) concentration. The excess K super(+) is removed from the extracellular space by mechanisms proposed ...to involve Kir4.1-mediated spatial buffering, the Na super(+)/K super(+)/2Cl super(-) cotransporter 1 (NKCC1), and/or Na super(+)/K super(+)-ATPase activity. Their individual contribution to K super(+) sub(o) management has been of extended controversy. This study aimed, by several complementary approaches, to delineate the transport characteristics of Kir4.1, NKCC1, and Na super(+)/K super(+)-ATPase and to resolve their involvement in clearance of extracellular K super(+) transients. Primary cultures of rat astrocytes displayed robust NKCC1 activity with K super(+) sub(o) increases above basal levels. Increased K super(+) sub(o) produced NKCC1-mediated swelling of cultured astrocytes and NKCC1 could thereby potentially act as a mechanism of K super(+) clearance while concomitantly mediate the associated shrinkage of the extracellular space. In rat hippocampal slices, inhibition of NKCC1 failed to affect the rate of K super(+) removal from the extracellular space while Kir4.1 enacted its spatial buffering only during a local K super(+) sub(o) increase. In contrast, inhibition of the different isoforms of Na super(+)/K super(+)-ATPase reduced post-stimulus clearance of K super(+) transients. The astrocyte-characteristic alpha2beta2 subunit composition of Na super(+)/K super(+)-ATPase , when expressed in Xenopus oocytes, displayed a K super(+) affinity and voltage-sensitivity that would render this subunit composition specifically geared for controlling K super(+) sub(o) during neuronal activity. In rat hippocampal slices, simultaneous measurements of the extracellular space volume revealed that neither Kir4.1, NKCC1, nor Na super(+)/K super(+)-ATPase accounted for the stimulus-induced shrinkage of the extracellular space. Thus, NKCC1 plays no role in activity-induced extracellular K super(+) recovery in native hippocampal tissue while Kir4.1 and Na super(+)/K super(+)-ATPase serve temporally distinct roles. GLIA 2014; 62:608-622 Main Points * Kir4.1 and Na super(+)/K super(+)-ATPase serve distinct roles in recovery of activity-induced K super(+) sub(o) in hippocampus. * The alpha2beta2 Na super(+)/K super(+)-ATPase is specifically geared for controlling K super(+) sub(o). * NKCC1 is not involved in stimulus-induced shrinkage of the extracellular space.
ApoE4, a strong genetic risk factor for Alzheimer disease, has been associated with increased risk for severe COVID-19. However, it is unclear whether ApoE4 alters COVID-19 susceptibility or ...severity, and the role of direct viral infection in brain cells remains obscure. We tested the neurotropism of SARS-CoV2 in human-induced pluripotent stem cell (hiPSC) models and observed low-grade infection of neurons and astrocytes that is boosted in neuron-astrocyte co-cultures and organoids. We then generated isogenic ApoE3/3 and ApoE4/4 hiPSCs and found an increased rate of SARS-CoV-2 infection in ApoE4/4 neurons and astrocytes. ApoE4 astrocytes exhibited enlarged size and elevated nuclear fragmentation upon SARS-CoV-2 infection. Finally, we show that remdesivir treatment inhibits SARS-CoV2 infection of hiPSC neurons and astrocytes. These findings suggest that ApoE4 may play a causal role in COVID-19 severity. Understanding how risk factors impact COVID-19 susceptibility and severity will help us understand the potential long-term effects in different patient populations.
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•SARS-CoV-2 infects hiPSC-derived neurons, astrocytes, and brain organoids•ApoE4 neurons and astrocytes are more susceptible to SARS-CoV-2 infection•APOE4 astrocytes exhibit a more severe response to SARS-CoV-2 infection•RDV inhibits SARS-CoV-2 infection in neurons and astrocytes
Shi and colleagues used hiPSC-derived neurons, astrocytes, and brain organoids to model SARS-CoV-2 neurotropism. They found that ApoE4/4 genotype led to an increased rate of SARS-CoV-2 infection in both neurons and astrocytes, and ApoE4 astrocytes exhibited a more severe response. Moreover, remdesivir could inhibit SARS-CoV-2 infection in neurons and astrocytes.
Summary
Astrocytes are the most abundant glial cells in the central nervous system (CNS) and participate in synaptic, circuit, and behavioral functions. The well‐developed protoplasmic astrocytes ...contain numerous processes forming well‐delineated bushy territories that overlap by as little as 5% at their boundaries. This highly complex morphology, with up to approximately 80% of the cell's membrane constituted by fine processes with dimensions on the tens of nanometer scale and high surface area to volume ratios, comes in contact with synapses, blood vessels, and other glial cells. Recent progress is challenging the conventional view that astrocytes are morphologically homogeneous throughout the brain; instead, they display circuit‐ and region‐specific morphological diversity that may contribute to the heterogeneous astrocyte‐neuron spatiotemporal interplay in different brain areas. Further, the fine structure of astrocytes is found to be highly plastic and activity‐dependent. We are beginning to understand how astrocyte structural plasticity contributes to brain functions. The change/loss of astrocyte morphology, traditionally known as a hallmark for reactive astrogliosis, is a common pathological feature in many neurological disorders. However, recent data suggest the fine structural deficits preceding reactive astrogliosis may drive disease progression. This review summarizes recent advances in astrocyte morphological diversity, plasticity, and disease‐related deficits.
Microglia-astrocyte crosstalk has recently been at the forefront of glial research. Emerging evidence illustrates that microglia- and astrocyte-derived signals are the functional determinants for the ...fates of astrocytes and microglia, respectively. By releasing diverse signaling molecules, both microglia and astrocytes establish autocrine feedback and their bidirectional conversation for a tight reciprocal modulation during central nervous system (CNS) insult or injury. Microglia, the constant sensors of changes in the CNS microenvironment and restorers of tissue homeostasis, not only serve as the primary immune cells of the CNS but also regulate the innate immune functions of astrocytes. Similarly, microglia determine the functions of reactive astrocytes, ranging from neuroprotective to neurotoxic. Conversely, astrocytes through their secreted molecules regulate microglial phenotypes and functions ranging from motility to phagocytosis. Altogether, the microglia-astrocyte crosstalk is fundamental to neuronal functions and dysfunctions. This review discusses the current understanding of the intimate molecular conversation between microglia and astrocytes and outlines its potential implications in CNS health and disease.
Experience-dependent plasticity of synaptic transmission, which represents the cellular basis of learning, is accompanied by morphological changes in dendritic spines. Astrocytic processes are ...intimately associated with synapses, structurally enwrapping and functionally interacting with dendritic spines and synaptic terminals by responding to neurotransmitters and by releasing gliotransmitters that regulate synaptic function. While studies on structural synaptic plasticity have focused on neuronal elements, the structural-functional plasticity of astrocyte-neuron relationships remains poorly known. Here we show that stimuli inducing hippocampal synaptic LTP enhance the motility of synapse-associated astrocytic processes. This motility increase is relatively rapid, starting <5 min after the stimulus, and reaching a maximum in 20-30 min (t(1/2) = 10.7 min). It depends on presynaptic activity and requires G-protein-mediated Ca(2+) elevations in astrocytes. The structural remodeling is accompanied by changes in the ability of astrocytes to regulate synaptic transmission. Sensory stimuli that increase astrocyte Ca(2+) also induce similar plasticity in mouse somatosensory cortex in vivo. Therefore, structural relationships between astrocytic processes and dendritic spines undergo activity-dependent changes with metaplasticity consequences on synaptic regulation. These results reveal novel forms of synaptic plasticity based on structural-functional changes of astrocyte-neuron interactions.
The destruction of calcium homeostasis is an important factor leading to neurological diseases. Store-operated Ca super(2+) (SOC) channels are essential for Ca super(2+) homeostasis in many cell ...types. However, whether SOC channels are involved in astrocyte activation induced by lipopolysaccharide (LPS) still remains unknown. In this study, we used LPS as an exogenous stimulation to investigate the role of SOC channels in astrocyte activation. Using calcium imaging technology, we first found that SOC channels blockers, 1-h-3-(4-methoxyphenyl)propoxy-4-methoxyphenethyl-1H-imidazole (SKF-96365) and 2-aminoethyldiphenyl borate (2-APB), inhibited LPS induced Ca super(2+) sub(i) increase, which prompted us to speculate that SOC channels may be involved in LPS induced astrocyte activation. Further experiments confirmed our speculation shown as SOC channels blockers inhibited LPS induced astrocyte activation characterized as cell proliferation by MTS and BrdU assay, raise in glial fibrillary acidic protein expression by immunofluorescence and Western Blot and secretion of interleukin 6 (IL-6) and interleukin 1 beta (IL-1 beta ) by ELISA. So, our studies showed that SOC channels are involved in LPS-induced astrocyte activation.
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