Macro scale modelling of cortical spreading depression and the role of astrocytic gap junctions

Kenny, Allanah; Plank, Michael J.; Todem, David

doi:10.1016/j.jtbi.2018.09.006

Cited by 9 publications

(5 citation statements)

References 58 publications

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“…The characteristic time for the activation variable for the NaP channel is defined as τ = ±10% in either θ 62 or θ 63 can either reduce or increase the extracellular K + by approximately 15%. We should note that these results do not take into account the spatial buffering carried out by the astrocytic syncytium which may have a significantly greater effect on the extracellular K + [4,21].…”

Section: Average Ecs Potassiummentioning

confidence: 86%

“…However, we recognise that a decrease in radius upon stimulation does not necessarily mean an incorrect result. Indeed these cases are of particular importance (due to the possibility of the existence of cortical spreading depression [21]) and a topic of future research. This processing yields 660 samples for analysis when the rectangular pulse stimulus is applied and 438 samples when the experimental pulse stimulus is applied.…”

Section: Sobol' Indicesmentioning

confidence: 99%

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Global Sensitivity Analysis of High-Dimensional Neuroscience Models: An Example of Neurovascular Coupling

2019

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The complexity and size of state-of-the-art cell models have significantly increased in part due to the requirement that these models possess complex cellular functions which are thought-but not necessarily proven-to be important. Modern cell models often involve hundreds of parameters; the values of these parameters come, more often than not, from animal experiments whose relationship to the human physiology is weak with very little information on the errors in these measurements. The concomitant uncertainties in parameter values result in uncertainties in the model outputs or Quantities of Interest (QoIs). Global Sensitivity Analysis (GSA) aims at apportioning to individual parameters (or sets of parameters) their relative contribution to output uncertainty thereby introducing a measure of influence or importance of said parameters. New GSA approaches are required to deal with increased model size and complexity; a three stage methodology consisting of screening (dimension reduction), surrogate modeling, and computing Sobol' indices, is presented. The methodology is used to analyze a physiologically validated numerical model of neurovascular coupling which possess 160 uncertain parameters. The sensitivity analysis investigates three quantities of interest (QoIs), the average value of K + in the extracellular space, the average volumetric flow rate through the perfusing vessel, and the minimum value of the J.actin/myosin complex in the smooth muscle cell. GSA provides a measure of the influence of each parameter, for each of the three QoIs, giving insight into areas of possible physiological dysfunction and areas of further investigation.

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Section: Average Ecs Potassiummentioning

confidence: 86%

Section: Sobol' Indicesmentioning

confidence: 99%

Global Sensitivity Analysis of High-Dimensional Neuroscience Models: An Example of Neurovascular Coupling

2019

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“…The model builds on the work in Kenny et al ( 2018a , b ), and is updated by including NCX, glutamate transporters, NMDA and AMPA receptors. Equations for NCX and glutamate transporters are taken from Oschmann ( 2018 ).…”

Section: Methodsmentioning

confidence: 99%

“…It should be noted that our simulations are not based on geometric model and assumes the astrocyte to be a point cell. However, following the approach in Kenny et al ( 2018a , b ), we assume the Ca 2+ buffering capacity to be heterogeneous across the cell such that channels/receptors in different compartments contribute differently to the average free cytosolic Ca 2+ concentration.…”

Section: Methodsmentioning

confidence: 99%

Modeling the heterogeneity of sodium and calcium homeostasis between cortical and hippocampal astrocytes and its impact on bioenergetics

Thapaliya

Pape

Rose

et al. 2023

Front. Cell. Neurosci.

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Emerging evidence indicates that neuronal activity-evoked changes in sodium concentration in astrocytes Naa represent a special form of excitability, which is tightly linked to all other major ions in the astrocyte and extracellular space, as well as to bioenergetics, neurotransmitter uptake, and neurovascular coupling. Recently, one of us reported that Naa transients in the neocortex have a significantly higher amplitude than those in the hippocampus. Based on the extensive data from that study, here we develop a detailed biophysical model to further understand the origin of this heterogeneity and how it affects bioenergetics in the astrocytes. In addition to closely fitting the observed experimental Naa changes under different conditions, our model shows that the heterogeneity in Naa signaling leads to substantial differences in the dynamics of astrocytic Ca2+ signals in the two brain regions, and leaves cortical astrocytes more susceptible to Na+ and Ca2+ overload under metabolic stress. The model also predicts that activity-evoked Naa transients result in significantly larger ATP consumption in cortical astrocytes than in the hippocampus. The difference in ATP consumption is mainly due to the different expression levels of NMDA receptors in the two regions. We confirm predictions from our model experimentally by fluorescence-based measurement of glutamate-induced changes in ATP levels in neocortical and hippocampal astrocytes in the absence and presence of the NMDA receptor's antagonist (2R)-amino-5-phosphonovaleric acid.

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“…We build on our previous work, where we modeled dynamic changes in astrocytic Na + , K + , Cl − , and Ca 2+ concentrations [45,46] by incorporating the main pathways regulating intra-and extracellular pH (pH i and pH o , respectively). The equations for intra-and extracellular Na + concentrations ([Na + ] i and [Na + ] o , respectively) are modified accordingly.…”

Section: Modeling Nbce1 Activitymentioning

confidence: 99%

Inward Operation of Sodium-Bicarbonate Cotransporter 1 Promotes Astrocytic Na+ Loading and Loss of ATP in Mouse Neocortex during Brief Chemical Ischemia

Everaerts,

Thapaliya,

Pape

et al. 2023

Cells

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Ischemic conditions cause an increase in the sodium concentration of astrocytes, driving the breakdown of ionic homeostasis and exacerbating cellular damage. Astrocytes express high levels of the electrogenic sodium-bicarbonate cotransporter1 (NBCe1), which couples intracellular Na+ homeostasis to regulation of pH and operates close to its reversal potential under physiological conditions. Here, we analyzed its mode of operation during transient energy deprivation via imaging astrocytic pH, Na+, and ATP in organotypic slice cultures of the mouse neocortex, complemented with patch-clamp and ion-selective microelectrode recordings and computational modeling. We found that a 2 min period of metabolic failure resulted in a transient acidosis accompanied by a Na+ increase in astrocytes. Inhibition of NBCe1 increased the acidosis while decreasing the Na+ load. Similar results were obtained when comparing ion changes in wild-type and Nbce1-deficient mice. Mathematical modeling replicated these findings and further predicted that NBCe1 activation contributes to the loss of cellular ATP under ischemic conditions, a result confirmed experimentally using FRET-based imaging of ATP. Altogether, our data demonstrate that transient energy failure stimulates the inward operation of NBCe1 in astrocytes. This causes a significant amelioration of ischemia-induced astrocytic acidification, albeit at the expense of increased Na+ influx and a decline in cellular ATP.

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Macro scale modelling of cortical spreading depression and the role of astrocytic gap junctions

Cited by 9 publications

References 58 publications

Global Sensitivity Analysis of High-Dimensional Neuroscience Models: An Example of Neurovascular Coupling

Global Sensitivity Analysis of High-Dimensional Neuroscience Models: An Example of Neurovascular Coupling

Modeling the heterogeneity of sodium and calcium homeostasis between cortical and hippocampal astrocytes and its impact on bioenergetics

Inward Operation of Sodium-Bicarbonate Cotransporter 1 Promotes Astrocytic Na+ Loading and Loss of ATP in Mouse Neocortex during Brief Chemical Ischemia

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