Structural Basis of Astrocytic Ca &lt;sup&gt;2 &lt;/sup&gt; Signals at Tripartite Synapses

Arizono, Misa; Panatier, Aude; Inavalli, V. V. G. Krishna; Pfeiffer, Thomas; Angibaud, Julie; Stobart, Jillian; Bellocchio, Luigi; Marsicano, Giovanni; Mikoshiba, Katsuhiko; Oliet, Stéphane H. R.; Weber, Bruno; Nägerl, U. Valentin

doi:10.2139/ssrn.3287791

“…Notice that these experimental traces correspond to spontaneous signals to the extent that they were measured in the absence of any neuronal or astrocytic stimulation. In particular, TTX application in this preparation did not alter peak frequency [69].…”

Section: Resultsmentioning

confidence: 99%

“…[92] and [93]). In our preparation, bath-application of bafilomycin strongly decreased peak frequency and amplitude [69]. As bafilomycin has a wide range of effects on calcium signaling that is independent of its effect on the refill of presynaptic neurotransmitter vesicles [94, 95], we cannot conclude whether those signals are triggered by EPSCs and further investigation is needed to decipher whether the “spontaneous” calcium signals reported in astrocyte processes are due to spontaneous release of presynaptic vesicles or rely on a synapse-independent mechanism inherent to the CICR system.…”

Section: Discussionmentioning

confidence: 99%

Simulation of calcium signaling in fine astrocytic processes: Effect of spatial properties on spontaneous activity

Denizot

¹

,

Arizono

²

,

Nägerl

³

et al. 2019

Self Cite

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Astrocytes, a glial cell type of the central nervous system, have emerged as detectors and regulators of neuronal information processing. Astrocyte excitability resides in transient variations of free cytosolic calcium concentration over a range of temporal and spatial scales, from sub-microdomains to waves propagating throughout the cell. Despite extensive experimental approaches, it is not clear how these signals are transmitted to and integrated within an astrocyte. The localization of the main molecular actors and the geometry of the system, including the spatial organization of calcium channels IP 3 R , are deemed essential. However, as most calcium signals occur in astrocytic ramifications that are too fine to be resolved by conventional light microscopy, most of those spatial data are unknown and computational modeling remains the only methodology to study this issue. Here, we propose an IP 3 R -mediated calcium signaling model for dynamics in such small sub-cellular volumes. To account for the expected stochasticity and low copy numbers, our model is both spatially explicit and particle-based. Extensive simulations show that spontaneous calcium signals arise in the model via the interplay between excitability and stochasticity. The model reproduces the main forms of calcium signals and indicates that their frequency crucially depends on the spatial organization of the IP 3 R channels. Importantly, we show that two processes expressing exactly the same calcium channels can display different types of calcium signals depending on the spatial organization of the channels. Our model with realistic process volume and calcium concentrations successfully reproduces spontaneous calcium signals that we measured in calcium micro-domains with confocal microscopy and predicts that local variations of calcium indicators might contribute to the diversity of calcium signals observed in astrocytes. To our knowledge, this model is the first model suited to investigate calcium dynamics in fine astrocytic processes and to propose plausible mechanisms responsible for their variability.

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“…[105] and [106]). In our preparation, bath-application of bafilomycin strongly 633 decreased peak frequency and amplitude [80]. As bafilomycin has a wide range of effects 634 on calcium signaling that is independent of its effect on the refill of presynaptic 635 neurotransmitter vesicles [107,108], we cannot conclude whether those signals are 636 triggered by EPSCs and further investigation is needed to decipher whether the 637 "spontaneous" calcium signals reported in astrocyte processes are due to spontaneous 638 release of presynaptic vesicles or rely on a synapse-independent mechanism inherent to 639 the CICR system.…”

mentioning

confidence: 60%

“…Notice that these experimental traces correspond to spontaneous 535 signals to the extent that they were measured in the absence of any neuronal nor 536 astrocytic stimulation. In particular, TTX application in this preparation did not alter 537 peak frequency [80].…”

mentioning

confidence: 66%

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Simulation of calcium signaling in fine astrocytic processes: effect of spatial properties on spontaneous activity

Denizot

¹

,

Arizono

²

,

Valentin

³

et al. 2019

Preprint

0

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Astrocytes, a glial cell type of the central nervous system, have emerged as detectors and regulators of neuronal information processing. Astrocyte excitability resides in transient variations of free cytosolic calcium concentration over a range of temporal and spatial scales, from sub-microdomains to waves propagating throughout the cell. Despite extensive experimental approaches, it is not clear how these signals are transmitted to and integrated within an astrocyte. The localization of the main molecular actors and the geometry of the system, including calcium channels IP3R spatial organization, are deemed essential. However, as most calcium signals occur in astrocytic ramifications that are too fine to be resolved by conventional light microscopy, most of those spatial data are unknown and computational modeling remains the only methodology to study this issue. Here, we propose an IP3R-mediated calcium signaling model for dynamics in such small sub-cellular volumes. To account for the expected stochasticity and low copy numbers, our model is both spatially explicit and particle-based. Extensive simulations show that spontaneous calcium signals arise in the model via the interplay between excitability and stochasticity. The model reproduces the main forms of calcium signals and indicates that their frequency crucially depends on the spatial organization of the IP3R channels. Importantly, we show that two processes expressing exactly the same calcium channels can display different types of calcium signals depending on channels spatial organization. Our model with realistic process volume and calcium concentrations successfully reproduces spontaneous calcium signals that we measured in calcium micro-domains with confocal microscopy. To our knowledge, this model is the first model suited to investigate calcium dynamics in fine astrocytic processes and to propose plausible mechanisms responsible for their variability. Introduction 1 Astrocytes were first characterized as non-excitable cells of the central nervous 2 system since, although they express voltage-gated channels [1], they do not exhibit 3 electrical excitability [2]. Astrocytes excitability instead results from variations of 4 cytosolic calcium concentration [3]. At the cellular level, those calcium signals emerge in 5 astrocytes in response to synaptic activity and may cause the release of molecules called 6 1 gliotransmitters such as glutamate, ATP, tumor necrosis factor-α, or D-serine, which 7can modulate synaptic transmission [4][5][6][7] and vasoconstriction/vasodilatation [8][9][10][11]. 8 This close association of astrocytes to pre-and post-synaptic elements, both 9 structurally and functionally, is referred to as tripartite synapse (see e.g. [12][13][14][15] for 10 reviews on tripartite synapses and the associated controversies). On a larger scale, 11 astrocytic calcium signals can modulate neuronal synchronization and firing 12 pattern [16][17][18] and have been observed in vivo in response to external stimuli [19,20]. 13 Altogether, those obse...

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Axon growth and synaptic function: A balancing act for axonal regeneration and neuronal circuit formation in CNS trauma and disease

Kiyoshi

¹

,

Tedeschi

²

2020

Developmental Neurobiology

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Axon regeneration failure following central nervous system (CNS) trauma and disease often leads to permanent functional disability. Promoting axon sprouting and regeneration of spared and injured axons as well as refinement of existing or de novo formation of neuronal circuits can attain neurological recovery (Hutson & Di Giovanni, 2019; Maier & Schwab, 2006). The development of neuronal circuits in the mammalian CNS is a dynamic process that requires coordinated epigenetic regulation of gene expression (Henikoff, 2008; Jaenisch & Bird, 2003). Genome-wide remodeling of the epigenetic landscape allows axon elongation, membrane expansion and navigation toward target areas as well as axon branching, synapse formation, and refinement to be spatially and temporally ordered (Kolodkin & Tessier

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Structural Basis of Astrocytic Ca <sup>2 </sup> Signals at Tripartite Synapses

Cited by 17 publications

References 42 publications

Simulation of calcium signaling in fine astrocytic processes: Effect of spatial properties on spontaneous activity

Simulation of calcium signaling in fine astrocytic processes: Effect of spatial properties on spontaneous activity

Simulation of calcium signaling in fine astrocytic processes: effect of spatial properties on spontaneous activity

Axon growth and synaptic function: A balancing act for axonal regeneration and neuronal circuit formation in CNS trauma and disease

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