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Sunday, July 19 • 7:00pm - 8:00pm
P41: Reaction-diffusion simulations of astrocytic Ca2+ signals in realistic geometries

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Audrey Denizot, Corrado Calì, Weiliang Chen, Iain Hepburn, Hugues Berry, Erik De Schutter

 Here is the link to the virtual room of the presentation:  https://oist.zoom.us/j/97032096119?pwd=ZnRoeWkvNnZGaER6M3dqMzlJZmVBdz09   Password: 429623

 2-minute teaser: https://youtu.be/KawxI1RiMrM

Astrocytes, glial cells of the central nervous system, display a striking diversity of Ca2+ signals in response to neuronal activity. 80% of those signals take place in cellular ramifications that are too fine to be resolved by conventional light microscopy [1], often in apposition to synapses (perisynaptic astrocytic processes, PAPs). Understanding Ca2+ signaling in PAPs, where astrocytes potentially regulate neuronal information processing [2], is crucial. At this spatial scale, Ca2+ signals are not distributed uniformly, being preferentially located in so-called Ca2+ hotspots [3], suggesting the existence of subcellular spatial domains. However, because of the spatial scale at stake, little is currently known about the mechanisms that regulate Ca2+ signaling in fine processes. Here, we investigate the geometry of the endosplamic reticulum (ER), the predominant astrocytic Ca2+ store, using electron microscopy. Contrary to previous reports [4], we detect ER in PAPs, which can be as close as ~60nm to the closest postsynaptic density. We use computational modeling to investigate the impact of the observed cellular and ER geometries on Ca2+ signaling. Simulations using the stochastic voxel-based model from Denizot et al [5], both in simplified and in realistic 3D geometries, reproduce spontaneous astrocytic microdomain Ca2+ transients measured experimentally. In our simulations, the effect of the clustering of IP3R channels observed in 2 spatial dimensions [5] is still valid in a simple cylinder geometry but no longer holds in complex realistic geometries. We propose that those discrepancies might result from the geometry of the ER and that, in 3 spatial dimensions, the effects of molecular distributions (such as e.g IP3R clustering) are particularly enhanced at ER- plasma membrane contact sites. Our results suggest that the predictions from simulations in 1D, 2D or simplified 3D geometries should be cautiously interpreted. Overall, this work provides a better understanding of IP3R-dependent Ca2+ signals in fine astrocytic processes and more generally in subcellular compartments, a prerequisite for understanding the dynamics of Ca2+ hotspots, which are deemed essential for local intercellular communication.

References
[1] Bindocci, E., Savtchouk, I., Liaudet, N., et al. “Three-dimensional Ca2+ imaging advances understanding of astrocyte biology,” Science, May 2017, vol. 356, no. 6339, p. eaai8185. [2] Savtchouk, I., Volterra, A. “Gliotransmission: Beyond Black-and-White,” J. Neurosci., Jan. 2018, vol. 38, no. 1, pp. 14–25.
[3] Thillaiappan, N. B., Chavda, A., Tovey, S., et al. “Ca2+ signals initiate at immobile IP3 receptors adjacent to ER-plasma membrane junctions,” Nat. Commun., Dec. 2017 , vol. 8.
[4] Patrushev, I., Gavrilov, N., Turlapov, V., et al. “Subcellular location of astrocytic calcium stores favors extrasynaptic neuron-astrocyte communication,” Cell Calcium, Nov. 2013, vol. 54, no. 5, pp. 343–349.
[5] Denizot, A., Arizono, M., Nägerl, U. V., et al. “Simulation of calcium signaling in fine astrocytic processes: Effect of spatial properties on spontaneous activity,” PLOS Comput. Biol., Aug. 2019, vol. 15, no. 8, p. e1006795.


Speakers
avatar for Audrey Denizot

Audrey Denizot

Postdoctoral Scholar, Computational Neuroscience Unit, Okinawa Institute of Science and Technology
I am currently a postdoctoral scholar in Erik De Schutter's unit in the Okinawa Institute of Science and Technology, Japan. My research aims at better understanding Ca2+ signals in astrocytes, notably the formation of local microdomain signals. I am a biologist by training (ENS Lyon... Read More →



Sunday July 19, 2020 7:00pm - 8:00pm CEST
Slot 09