Astrocytes are morphologically complex, ubiquitous cells that are viewed as a homogeneous population tiling the entire central nervous system (CNS). However, this view has been challenged in the last ...few years with the availability of RNA sequencing, immunohistochemistry, electron microscopy, morphological reconstruction, and imaging data. These studies suggest that astrocytes represent a diverse population of cells and that they display brain area- and disease-specific properties and functions. In this review, we summarize these observations, emphasize areas where clear conclusions can be made, and discuss potential unifying themes. We also identify knowledge gaps that need to be addressed in order to exploit astrocyte diversity as a biological phenomenon of physiological relevance in the CNS. We thus provide a summary and a perspective on astrocyte diversity in the vertebrate CNS.
Extracellular adenosine 5′ triphosphate (ATP) is a widespread cell-to-cell signaling molecule in the brain, where it activates cell surface P2X and P2Y receptors. P2X receptors define a protein ...family unlike other neurotransmitter-gated ion channels in terms of sequence, subunit topology, assembly, and architecture. Within milliseconds of binding ATP, they catalyze the opening of a cation-selective pore. However, recent data show that P2X receptors often underlie neuromodulatory responses on slower time scales of seconds or longer. Herein, we review these findings at molecular, cellular and systems levels. We propose that, while P2X receptors are fast ligand-gated cation channels, they are most adept at mediating slow neuromodulatory functions that are more widespread and more physiologically utilized than fast ATP synaptic transmission in the CNS.
Khakh and North discuss the latest breakthroughs on P2X receptors in the CNS. Their review covers ATP signaling from molecules to systems, highlighting the critical roles of P2X receptors in the modulation of neuronal, glial, and circuit function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Astrocytes tile the entire CNS. They are vital for neural circuit function, but have traditionally been viewed as simple, homogenous cells that serve the same essential supportive roles everywhere. ...Here, we summarize breakthroughs that instead indicate that astrocytes represent a population of complex and functionally diverse cells. Physiological diversity of astrocytes is apparent between different brain circuits and microcircuits, and individual astrocytes display diverse signaling in subcellular compartments. With respect to injury and disease, astrocytes undergo diverse phenotypic changes that may be protective or causative with regard to pathology in a context-dependent manner. These new insights herald the concept that astrocytes represent a diverse population of genetically tractable cells that mediate neural circuit-specific roles in health and disease.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
The physiological functions of astrocytes within neural circuits remain incompletely understood. There has been progress in this regard from recent work on striatal astrocytes, where detailed studies ...are emerging. In this review, findings on striatal astrocyte identity, form, and function, are summarized with a focus on how astrocytes regulate striatal neurons, circuits, and behavior. Specific features of striatal astrocytes are highlighted to illustrate how they may be specialized to regulate medium spiny neurons (MSNs) by responding to, and altering, excitation and inhibition. Further experiments should reveal additional mechanisms for astrocyte–neuron interactions in the striatum and potentially reveal insights into the functions of astrocytes in neural circuits more generally.
The striatum has been leveraged for studying astrocytes systematically in a defined circuitry, and for examining how their interactions with neurons relate to specific behaviors.Morphologically complex ‘bushy’ astrocytes are integral to neural circuits and evenly tile the entire striatum, the largest nucleus of the basal ganglia.Striatal astrocytes have several specific molecular features, such as high μ-crystallin expression, low GFAP expression, and striatal astrocyte-specific gene expression.Striatal astrocytes make extensive contacts with striatal medium spiny neuron somata and additional finger-like connections with most excitatory synapses.Striatal astrocytes modulate medium spiny neuron synapses to alter circuit function and mouse behavior, such as causing OCD-like excessive self-grooming, via slow homeostatic functions involving ambient GABA, K+, and synaptogenic cues.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Astrocytes are abundant glial cells that tile the entire central nervous system and mediate well-established functions for neurons, blood vessels, and other glia. These ubiquitous cells display ...intracellular Ca2+ signals, which have been intensely studied for 25 years. Recently, the use of improved methods has unearthed the panoply of astrocyte Ca2+ signals and a variable landscape of basal Ca2+ levels. In vivo studies have started to reveal the settings under which astrocytes display behaviorally relevant Ca2+ signaling. Studies in mice have emphasized how astrocyte Ca2+ signaling is altered in distinct neurodegenerative diseases. Progress in the past few years, fueled by methodological advances, has thus reignited interest in astrocyte Ca2+ signaling for brain function and dysfunction.
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Improved tools to study astrocytes Yu, Xinzhu; Nagai, Jun; Khakh, Baljit S
Nature reviews. Neuroscience,
03/2020, Volume:
21, Issue:
3
Journal Article
Peer reviewed
Astrocytes are a type of glial cell that tile the CNS. They interact with multiple cell types, including neurons, glial cells and blood vessels, and are involved or implicated in brain disorders. ...Progress has been made in understanding astrocytes, but the field lacks detailed information concerning how they perform their multifarious functions, and how and when they influence the operations of the neural circuits with which they interact. One recognized bottleneck to progress has been the paucity of reliable tools with which to explore astrocytes within the adult vertebrate CNS in vivo. However, improved tools for molecular, genetic, morphological and physiological assessments have been developed recently or have been adapted from their original purposes to study neurons and are now being used to systematically document and interrogate astrocyte biology in vivo. These tools, their uses and limitations, and the insights that they afford are summarized in this Review.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We provide an overview of recent progress on the study of astrocyte intracellular Ca(2+) signaling. We consider the methods that have been used to monitor astrocyte Ca(2+) signals, the various types ...of Ca(2+) signals that have been discovered (waves, microdomains, and intrinsic fluctuations), the approaches used to broadly trigger and block Ca(2+) signals, and, where possible, the proposed and demonstrated physiological roles for astrocyte Ca(2+) signals within neuronal microcircuits. Although important progress has been made, we suggest that further detailed work is needed to explore the biophysics and molecular mechanisms of Ca(2+) signaling within entire astrocytes, including their fine distal extensions, such as processes that interact spatially with neurons and blood vessels. Improved methods are also needed to mimic and block molecularly defined types of Ca(2+) signals within genetically specified populations of astrocytes. Moreover, it will be essential to study astrocyte Ca(2+) activity in vivo to distinguish between pharmacological and physiological activity, and to study Ca(2+) activity in situ to rigorously explore mechanisms. Once methods to reliably measure, mimic, and block specific astrocyte Ca(2+) signals with high temporal and spatial precision are available, researchers will be able to carefully explore the correlative and causative roles that Ca(2+) signals may play in the functions of astrocytes, blood vessels, neurons, and microcircuits in the healthy and diseased brain.
Astrocytes tile the entire CNS, but their functions within neural circuits in health and disease remain incompletely understood. We used genetically encoded Ca(2+)and glutamate indicators to explore ...the rules for astrocyte engagement in the corticostriatal circuit of adult wild-type (WT) and Huntington's disease (HD) model mice at ages not accompanied by overt astrogliosis (at approximately postnatal days 70-80). WT striatal astrocytes displayed extensive spontaneous Ca(2+)signals, but did not respond to cortical stimulation, implying that astrocytes were largely disengaged from cortical input in healthy tissue. In contrast, in HD model mice, spontaneous Ca(2+)signals were significantly reduced in frequency, duration, and amplitude, but astrocytes responded robustly to cortical stimulation with evoked Ca(2+)signals. These action-potential-dependent astrocyte Ca(2+)signals were mediated by neuronal glutamate release during cortical stimulation, accompanied by prolonged extracellular glutamate levels near astrocytes and tightly gated by Glt1 glutamate transporters. Moreover, dysfunctional Ca(2+)and glutamate signaling that was observed in HD model mice was largely, but not completely, rescued by astrocyte specific restoration of Kir4.1, emphasizing the important contributions of K(+)homeostatic mechanisms that are known to be reduced in HD model mice. Overall, our data show that astrocyte engagement in the corticostriatal circuit is markedly altered in HD. Such prodromal astrocyte dysfunctions may represent novel therapeutic targets in HD and other brain disorders.
We report how early-onset astrocyte dysfunction without detectable astrogliosis drives disease-related processes in a mouse model of Huntington's disease (HD). The cellular mechanisms involve astrocyte homeostasis and signaling mediated by Kir4.1, Glt1, and Ca(2+) The data show that the rules for astrocyte engagement in a neuronal circuit are fundamentally altered in a brain disease caused by a known molecular defect and that fixing early homeostasis dysfunction remedies additional cellular deficits. Overall, our data suggest that key aspects of altered striatal function associated with HD may be triggered, at least in part, by dysfunctional astrocytes, thereby providing details of an emerging striatal microcircuit mechanism in HD. Such prodromal changes in astrocytes may represent novel therapeutic targets.
Astrocytes, a type of glia, are abundant and morphologically complex cells. Here, we report astrocyte molecular profiles, diversity, and morphology across the mouse central nervous system (CNS). We ...identified shared and region-specific astrocytic genes and functions and explored the cellular origins of their regional diversity. We identified gene networks correlated with astrocyte morphology, several of which unexpectedly contained Alzheimer's disease (AD) risk genes. CRISPR/Cas9-mediated reduction of candidate genes reduced astrocyte morphological complexity and resulted in cognitive deficits. The same genes were down-regulated in human AD, in an AD mouse model that displayed reduced astrocyte morphology, and in other human brain disorders. We thus provide comprehensive molecular data on astrocyte diversity and mechanisms across the CNS and on the molecular basis of astrocyte morphology in health and disease.
The spatiotemporal activities of astrocyte Ca2+ signaling in mature neuronal circuits remain unclear. We used genetically encoded Ca2+ and glutamate indicators as well as pharmacogenetic and ...electrical control of neurotransmitter release to explore astrocyte activity in the hippocampal mossy fiber pathway. Our data revealed numerous localized, spontaneous Ca2+ signals in astrocyte branches and territories, but these were not driven by neuronal activity or glutamate. Moreover, evoked astrocyte Ca2+ signaling changed linearly with the number of mossy fiber action potentials. Under these settings, astrocyte responses were global, suppressed by neurotransmitter clearance, and mediated by glutamate and GABA. Thus, astrocyte engagement in the fully developed mossy fiber pathway was slow and territorial, contrary to that frequently proposed for astrocytes within microcircuits. We show that astrocyte Ca2+ signaling functionally segregates large volumes of neuropil and that these transients are not suited for responding to, or regulating, single synapses in the mossy fiber pathway.
•Astrocyte branches/territories were studied using optical and pharmacogenetic tools•Spontaneous astrocyte Ca2+ signals were not due to action potentials or glutamate•Evoked astrocyte Ca2+ signals were slow, territorial and triggered by spike trains•Astrocyte Ca2+ signaling was tightly gated by neurotransmitter clearance
Haustein et al. use optical and genetic methods to explore the rules under which astrocytes are engaged in a model neuronal circuit. The findings show that astrocytes listen to synapses during bursts of action potentials in mossy fiber axons.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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