Functional Roles of Astrocyte Calcium Elevations: From Synapses to Behavior

Guerra‐Gomes, Sónia; Sousa, Nuno; Pinto, Luísa; Oliveira, João Filipe

doi:10.3389/fncel.2017.00427

Cited by 159 publications

(131 citation statements)

References 67 publications

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“…The correlations between [Ca 2+ ] i elevations (even mediated by activation of G i ‐coupled receptors) in astrocytes and neuronal activity have been reported in numerous studies over the past decade (Agulhon et al, ; Guerra‐Gomes, Sousa, Pinto, & Oliveira, ). We show that ammonium‐induced [Ca 2+ ] i oscillations in neurons remained after UK 14,304 application in the presence of bicuculline, U73122, and gallein.…”

Section: Discussionmentioning

confidence: 82%

Activation of alpha‐2 adrenergic receptors stimulates GABA release by astrocytes

Gaidin

Зинченко

Сергеев

et al. 2019

Glia

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Norepinephrine is one of the key neurotransmitters in the hippocampus, but its role in the functioning of the neuroglial networks remains unclear. Here we show that norepinephrine suppresses NH4Cl‐induced oscillations of the intracellular Ca2+ concentration ([Ca2+]i) in hippocampal neurons. We found that the inhibitory effect of norepinephrine against ammonium‐induced [Ca2+]i oscillations is mediated by activation of alpha‐2 adrenergic receptors. Furthermore, UK 14,304, an agonist of alpha‐2 adrenergic receptors, evokes a biphasic [Ca2+]i elevation in a minor population of astrocytes. This elevation consists of an initial fast, peak‐shaped [Ca2+]i rise, mediated by Giβγ subunit and subsequent PLC‐induced mobilization of Ca2+ from internal stores, and a plateau phase, mediated by a Ca2+ influx from the extracellular medium through store‐operated and TRPC3 channels. We show the correlation between the Ca2+ response in astrocytes and suppression of [Ca2+]i oscillations in neurons. The inhibitory effect of UK 14,304 is abolished in the presence of gallein, an inhibitor of Gβγ‐signaling. In turn, application of the agonist in the presence of the PLC inhibitor decreases the frequency and amplitude of [Ca2+]i oscillations in neurons but does not suppress them. The same effect is observed in the presence of bicuculline, a GABA(A) receptor antagonist. We demonstrate that UK 14,304 application increases the frequency and amplitude of slow outward chloride currents in neurons, indicating the release of GABA by astrocytes. Thus, our findings indicate that the activation of astrocytic alpha‐2 adrenergic receptors stimulates GABA release from astrocytes via Giβγ subunit‐associated signaling pathway, contributing to the suppression of neuronal activity.

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Section: Discussionmentioning

confidence: 82%

Activation of alpha‐2 adrenergic receptors stimulates GABA release by astrocytes

Gaidin

Зинченко

Сергеев

et al. 2019

Glia

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“…Although microglia and astrocytes are master regulators of the central immune system, mounting evidence demonstrates that they influence processes beyond inflammation and immune surveillance. These cells actively regulate synaptic glutamate spillover, activity‐dependent synaptogenesis and elimination, neuronal morphology, neurotransmitter synthesis, synaptic connectivity, and neural circuit function (Scofield & Kalivas, ; Guerra‐Gomes et al ., ; York et al ., ). These functions of glial cells are significantly altered by exposure to abused drugs, and such changes likely contribute to the behavioral outcomes associated with substance abuse (Miguel‐Hidalgo, ; Coller & Hutchinson, ).…”

Section: Introductionmentioning

confidence: 97%

“…These cells actively regulate synaptic glutamate spillover, activitydependent synaptogenesis and elimination, neuronal morphology, neurotransmitter synthesis, synaptic connectivity, and neural circuit function Guerra-Gomes et al, 2017;York et al, 2017). These functions of glial cells are significantly altered by exposure to abused drugs, and such changes likely contribute to the behavioral outcomes associated with substance abuse (Miguel-Hidalgo, 2009;Coller & Hutchinson, 2012).…”

Section: Introductionmentioning

confidence: 99%

Glial mechanisms underlying substance use disorders

Linker

Cross

Leslie

2018

Eur J of Neuroscience

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Addiction is a devastating disorder that produces persistent maladaptive changes to the central nervous system, including glial cells. Although there is an extensive body of literature examining the neuronal mechanisms of substance use disorders, effective therapies remain elusive. Glia, particularly microglia and astrocytes, have an emerging and meaningful role in a variety of processes beyond inflammation and immune surveillance, and may represent a promising therapeutic target. Indeed, glia actively modulate neurotransmission, synaptic connectivity and neural circuit function, and are critically poised to contribute to addictive‐like brain states and behaviors. In this review, we argue that glia influence the cellular, molecular, and synaptic changes that occur in neurons following drug exposure, and that this cellular relationship is critically modified following drug exposure. We discuss direct actions of abused drugs on glial function through immune receptors, such as Toll‐like receptor 4, as well as other mechanisms. We highlight how drugs of abuse affect glia‐neural communication, and the profound effects that glial‐derived factors have on neuronal excitability, structure, and function. Recent research demonstrates that glia have brain region‐specific functions, and glia in different brain regions have distinct contributions to drug‐associated behaviors. We will also evaluate the evidence demonstrating that glial activation is essential for drug reward and drug‐induced dopamine release, and highlight clinical evidence showing that glial mechanisms contribute to drug abuse liability. In this review, we synthesize the extensive evidence that glia have a unique, pivotal, and underappreciated role in the development and maintenance of addiction.

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“…DEG analysis includes increased expression of SLC6A1, SLC6A11, and GABBR2 in VWM, which encode major transmembrane GABA transporter GAT-1, GAT-3, and GABAb receptor subunit 2, respectively. Increased extracellular levels of GABA, released by interneurons for example, lead to astrocytic Ca2 + elevations mediated by GABAb receptor activation (Guerra-Gomes et al, 2017). This may further lead to astrocytic glutamate release, thereby potentiating inhibitory synaptic transmission (Kang et al, 1998), and to astrocytic ATP/adenosine-mediated heterosynaptic suppression affecting excitatory transmission (Boddum et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Human and mouse iPSC-derived astrocyte subtypes reveal vulnerability in Vanishing White Matter

Leferink

Dooves

Hillen

et al. 2019

Preprint

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Astrocytes gained attention as important players in neurological disease, including a number of leukodystrophies. Several studies explored the generation of induced pluripotent stem cell-derived astrocytes for drug screening and regenerative studies. Developing robust models of patient induced pluripotent stem cells is challenged by high variability due to diverse genetic backgrounds and long-term culture procedures. While human models are of special interest, mouse-based models have the advantage that for them these issues are less pronounced. Here we present astrocyte differentiation protocols for both human and mouse induced pluripotent stem cells to specifically induce grey and white matter astrocytes. Both subtypes expressed astrocyte-associated markers, had typical astrocyte morphologies, and gave a reactive response to stress. Importantly, the grey and white matter-like astrocytes differed in size, complexity of processes, and expression profile, conform primary grey and white matter astrocytes. The newly presented mouse and human stem cell-based models for the leukodystrophy Vanishing White Matter replicated earlier findings, such as increased proliferation, decreased OPC maturation and modulation by hyaluronidase. We studied intrinsic astrocyte subtype vulnerability in Vanishing White Matter in both human and mouse cells. Oligodendrocyte maturation was specifically inhibited in cultures with Vanishing WhiteMatter white matter-like astrocytes. By performing RNA sequencing, we found more differentially regulated genes in the white than in the grey matter-like astrocytes. Human and mouse astrocytes showed the same affected pathways, although human white matter-like astrocytes presented human-specific disease mechanisms involved in Vanishing White Matter. Using both human and mouse induced pluripotent stem cells, our study presents protocols to generate white and grey matter-like astrocytes, and shows astrocyte subtypespecific defects in Vanishing White Matter. While mouse induced pluripotent stem cell-based cultures may be less suitable to mimic human astrocyte subtype-or patient-specific changes, they might more robustly represent disease mutation-related cellular phenotypes as the cells are derived from inbred mice and the protocols are faster. The presented models give new tools to generate astrocyte subtypes for in vitro disease modeling and in vivo regenerative applications.

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Functional Roles of Astrocyte Calcium Elevations: From Synapses to Behavior

Cited by 159 publications

References 67 publications

Activation of alpha‐2 adrenergic receptors stimulates GABA release by astrocytes

Activation of alpha‐2 adrenergic receptors stimulates GABA release by astrocytes

Glial mechanisms underlying substance use disorders

Human and mouse iPSC-derived astrocyte subtypes reveal vulnerability in Vanishing White Matter

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