Spatial separation of two different pathways accounting for the generation of calcium signals in astrocytes

Oschmann, Franziska; Mergenthaler, Konstantin; Jungnickel, Evelyn; Obermayer, Klaus

doi:10.1371/journal.pcbi.1005377

Cited by 28 publications

(38 citation statements)

References 38 publications

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“…One third of the single astrocyte models took into account neurotransmitters in a simplistic way just as a stimulus, having either the neurotransmitter as a constant, step function, or something similar (see e.g., Larter and Craig, 2005 ; Gibson et al, 2007 ; Bennett et al, 2008b ; De Pittà et al, 2009a ; Dupont et al, 2011 ; Toivari et al, 2011 ; Witthoft and Karniadakis, 2012 ; Hadfield et al, 2013 ; Witthoft et al, 2013 ; Kenny et al, 2018 ). Only two models (Chander and Chakravarthy, 2012 ; Oschmann et al, 2017 ) actually modeled the amount of neurotransmitter with a differential equation. The stimulus to the astrocyte model by Oschmann et al ( 2017 ) was taken from the model by Tsodyks and Markram ( 1997 ).…”

Section: Resultsmentioning

confidence: 99%

“…However, it has been shown that the concentration of certain chemical species, such as Ca 2+ , can vary drastically in different parts of the cell (see e.g., Thul, 2014 ; Dupont et al, 2016 ), and several models took into account the spatiality by modeling diffusion of at least some of the chemical species in astrocytes using partial differential equations (PDEs, see e.g., Roth et al, 1995 ; Höfer et al, 2002 ; Bennett et al, 2008a ; Gibson et al, 2008 ; Allegrini et al, 2009 ; Kang and Othmer, 2009 ; Edwards and Gibson, 2010 ; Wei and Shuai, 2011 ; Li et al, 2012 ; López-Caamal et al, 2014 ; Mesiti et al, 2015a ; Yao et al, 2018 ). Some models took a simpler approach to spatiality by modeling ODEs combined with fluxes between different astrocytic compartments, such as cytosol and ER (see e.g., Larter and Craig, 2005 ; Di Garbo et al, 2007 ; Postnov et al, 2007 ; Lavrentovich and Hemkin, 2008 ; Di Garbo, 2009 ; Zeng et al, 2009 ; Amiri et al, 2011a ; DiNuzzo et al, 2011 ; Farr and David, 2011 ; Oschmann et al, 2017 ; Kenny et al, 2018 ). In addition of modeling Ca 2+ fluxes between ER and cytosol, Silchenko and Tass ( 2008 ) modeled free diffusion of extracellular glutamate as a flux.…”

Section: Methodsmentioning

confidence: 99%

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Computational Models for Calcium-Mediated Astrocyte Functions

Manninen

Havela

Linne

2018

Front. Comput. Neurosci.

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The computational neuroscience field has heavily concentrated on the modeling of neuronal functions, largely ignoring other brain cells, including one type of glial cell, the astrocytes. Despite the short history of modeling astrocytic functions, we were delighted about the hundreds of models developed so far to study the role of astrocytes, most often in calcium dynamics, synchronization, information transfer, and plasticity in vitro, but also in vascular events, hyperexcitability, and homeostasis. Our goal here is to present the state-of-the-art in computational modeling of astrocytes in order to facilitate better understanding of the functions and dynamics of astrocytes in the brain. Due to the large number of models, we concentrated on a hundred models that include biophysical descriptions for calcium signaling and dynamics in astrocytes. We categorized the models into four groups: single astrocyte models, astrocyte network models, neuron-astrocyte synapse models, and neuron-astrocyte network models to ease their use in future modeling projects. We characterized the models based on which earlier models were used for building the models and which type of biological entities were described in the astrocyte models. Features of the models were compared and contrasted so that similarities and differences were more readily apparent. We discovered that most of the models were basically generated from a small set of previously published models with small variations. However, neither citations to all the previous models with similar core structure nor explanations of what was built on top of the previous models were provided, which made it possible, in some cases, to have the same models published several times without an explicit intention to make new predictions about the roles of astrocytes in brain functions. Furthermore, only a few of the models are available online which makes it difficult to reproduce the simulation results and further develop the models. Thus, we would like to emphasize that only via reproducible research are we able to build better computational models for astrocytes, which truly advance science. Our study is the first to characterize in detail the biophysical and biochemical mechanisms that have been modeled for astrocytes.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Computational Models for Calcium-Mediated Astrocyte Functions

Manninen

Havela

Linne

2018

Front. Comput. Neurosci.

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“…The computation of the NCX strength was based on the obtained experimental data obtained here and according to an earlier study (Oschmann et al, 2017) (Table 1).…”

Section: Methodsmentioning

confidence: 99%

“…8A). These were fed into an equation describing the current strength of the NCX as described previously (Oschmann et al, 2017). Figure 8B shows that, in this model, NCX current is inward under baseline conditions (i.e., in the sodium import/calcium extrusion mode).…”

Section: Nmda-induced Ion Signaling and Ncx Activitymentioning

confidence: 99%

Heterogeneity of Activity-Induced Sodium Transients between Astrocytes of the Mouse Hippocampus and Neocortex: Mechanisms and Consequences

et al. 2019

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Activity-related sodium transients induced by glutamate uptake represent a special form of astrocyte excitability. Astrocytes of the neocortex, as opposed to the hippocampus proper, also express ionotropic glutamate receptors, which might provide additional sodium influx. We compared glutamate-related sodium transients in astrocytes and neurons in slices of the neocortex and hippocampus of juvenile mice of both sexes, using widefield and multiphoton imaging. Stimulation of glutamatergic afferents or glutamate application induced sodium transients that were twice as large in neocortical as in hippocampal astrocytes, despite similar neuronal responses. Astrocyte sodium transients were reduced by ϳ50% upon blocking NMDA receptors in the neocortex, but not hippocampus. Neocortical, but not hippocampal, astrocytes exhibited marked sodium increases in response to NMDA. These key differences in sodium signaling were also observed in neonates and in adults. NMDA application evoked local calcium transients in processes of neocortical astrocytes, which were dampened upon blocking sodium/calcium exchange (NCX) with KB-R7943 or SEA0400. Mathematical computation based on our data predict that NMDA-induced sodium increases drive the NCX into reverse mode, resulting in calcium influx. Together, our study reveals a considerable regional heterogeneity in astrocyte sodium transients, which persists throughout postnatal development. Neocortical astrocytes respond with much larger sodium elevations to glutamatergic activity than hippocampal astrocytes. Moreover, neocortical astrocytes experience NMDA-receptor-mediated sodium influx, which hippocampal astrocytes lack, and which drives calcium import through reverse NCX. This pathway thereby links sodium to calcium signaling and represents a new mechanism for the generation of local calcium influx in neocortical astrocytes.Astrocyte calcium signals play a central role in neuron-glia interaction. Moreover, activity-related sodium transients may represent a new form of astrocyte excitability. Here we show that activation of NMDA receptors results in prominent sodium transients in neocortical, but not hippocampal, astrocytes in the mouse brain. NMDA receptor activation is accompanied by local calcium signaling in processes of neocortical astrocytes, which is augmented by sodium-driven reversal of the sodium/calcium exchanger. Our data demonstrate a significant regional heterogeneity in the magnitude and mechanisms of astrocyte sodium transients. They also suggest a close interrelation between NMDA-receptor-mediated sodium influx and calcium signaling through the reversal of sodium/ calcium exchanger, thereby establishing a new pathway for the generation of local calcium signaling in astrocyte processes.

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“…However, the Ca 2+ entry through the VGCCs may still need to be amplified by CICR (Carmignoto, Pasti, & Pozzan, 1998). Na + /Ca 2+ exchanger (NCX) can transport Ca 2+ into the astrocytes upon increase in intracellular Na + concentration which occurs during glutamate uptake (Brazhe, Verisokin, Verveyko, & Postnov, 2018;Oschmann, Mergenthaler, Jungnickel, & Obermayer, 2017;Rojas et al, 2007). Other sources of the Ca 2+ entry in astrocytes include store-operated channels ORAI1 and transient receptor potential type A channels (TRPAs) (Bazargani & Attwell, 2016;Shigetomi, Jackson-Weaver, Huckstepp, O'Dell, & Khakh, 2013).…”

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confidence: 99%

Morphological profile determines the frequency of spontaneous calcium events in astrocytic processes

Gordleeva²,

Tang

et al. 2018

Glia

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Astrocytes express a complex repertoire of intracellular Ca2+ transients (events) that represent a major form of signaling within individual cells and in astrocytic syncytium. These events have different spatiotemporal profiles, which are modulated by neuronal activity. Spontaneous Ca2+ events appear more frequently in distal astrocytic processes and independently from each other. However, little is known about the mechanisms underlying such subcellular distribution of the Ca2+ events. Here, we identify the initiation points of the Ca2+ events within the territory of single astrocytes expressing genetically encoded Ca2+ indicator GCaMP2 in culture or in hippocampal slices. We found that most of the Ca2+ events start in an optimal range of thin distal processes. Our mathematical model demonstrated that a high surface‐to‐volume of the thin processes leads to increased amplitude of baseline Ca2+ fluctuations caused by a stochastic opening of Ca2+ channels in the plasma membrane. Suprathreshold fluctuations trigger Ca2+‐induced Ca2+ release from the Ca2+ stores by activating inositol 1,4,5‐trisphosphate (IP3) receptors. In agreement with the model prediction, the spontaneous Ca2+ events frequency depended on the extracellular Ca2+ concentration. Astrocytic depolarization by high extracellular K+ increased the frequency of the Ca2+ events through activation of voltage‐gated Ca2+ channels in cultured astrocytes. Our results suggest that the morphological profile of the astrocytic processes is responsible for tuning of the Ca2+ events frequency. Therefore, structural plasticity of astrocytic processes can be directly translated into changes in astrocytic Ca2+ signaling. This may be important for both physiological and pathological astrocyte remodeling.

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Spatial separation of two different pathways accounting for the generation of calcium signals in astrocytes

Cited by 28 publications

References 38 publications

Computational Models for Calcium-Mediated Astrocyte Functions

Computational Models for Calcium-Mediated Astrocyte Functions

Heterogeneity of Activity-Induced Sodium Transients between Astrocytes of the Mouse Hippocampus and Neocortex: Mechanisms and Consequences

Morphological profile determines the frequency of spontaneous calcium events in astrocytic processes

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