| Autor: |
Moshkforoush, Arash, Balachandar, Lakshmini, Moncion, Carolina, Montejo, Karla A., Riera, Jorge |
| Předmět: |
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| Zdroj: |
PLoS Computational Biology; 2/10/2021, Vol. 17 Issue 2, p1-24, 24p, 1 Color Photograph, 3 Charts, 4 Graphs |
| Abstrakt: |
Optogenetic targeting of astrocytes provides a robust experimental model to differentially induce Ca2+ signals in astrocytes in vivo. However, a systematic study quantifying the response of optogenetically modified astrocytes to light is yet to be performed. Here, we propose a novel stochastic model of Ca2+ dynamics in astrocytes that incorporates a light sensitive component—channelrhodopsin 2 (ChR2). Utilizing this model, we investigated the effect of different light stimulation paradigms on cells expressing select variants of ChR2 (wild type, ChETA, and ChRET/TC). Results predict that depending on paradigm specification, astrocytes might undergo drastic changes in their basal Ca2+ level and spiking probability. Furthermore, we performed a global sensitivity analysis to assess the effect of variation in parameters pertinent to the shape of the ChR2 photocurrent on astrocytic Ca2+ dynamics. Results suggest that directing variants towards the first open state of the ChR2 photocycle (o1) enhances spiking activity in astrocytes during optical stimulation. Evaluation of the effect of Ca2+ buffering and coupling coefficient in a network of ChR2-expressing astrocytes demonstrated basal level elevations in the stimulated region and propagation of calcium activity to unstimulated cells. Buffering reduced the diffusion range of Ca2+ within the network, thereby limiting propagation and influencing the activity of astrocytes. Collectively, the framework presented in this study provides valuable information for the selection of light stimulation paradigms that elicit desired astrocytic activity using existing ChR2 constructs, as well as aids in the engineering of future application-oriented optogenetic variants. Author summary: Optogenetics is a novel technique involving the targeted delivery of light-sensitive ion channels like Channelrhodopsin-2 (ChR2) to cells. Recently, this technique has been expanded to non-neuronal cell types, e.g., astrocytes. Optogenetic control of astrocytes in vivo can aid in further understanding the intricacies of their debated roles in the brain. Here, using a mathematical model, we evaluate the effect of short and long-term light stimulation of ChR2-expressing astrocytes on their Ca2+ spiking activity and basal level. We further investigate how ChR2 gating dynamics, buffering, and coupling coefficient of Ca2+ influence astrocytic activity in a single cell and a network. Results of our study can serve as a tool for experimental design and engineering of new application-oriented optogenetic constructs targeting astrocytes. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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