Control of Ca<sup>2+</sup> signals by astrocyte nanoscale morphology at tripartite synapses

Denizot, Audrey; Arizono, Misa; Nägerl, U. Valentin; Berry, Hugues; Schutter, Erik De

doi:10.1002/glia.24258

Cited by 17 publications

(7 citation statements)

References 79 publications

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“…In our previous studies, we have systematically categorized computational astrocyte models based on the mechanisms modeled (Manninen et al., 2018b , 2019 ). The most recently published single astrocyte models mostly consider the Ca 2+ mechanisms of the ER and cell membrane (Taheri et al., 2017 ; Cresswell-Clay et al., 2018 ; Savtchenko et al., 2018 ; Denizot et al., 2019 , 2022 ; Wu et al., 2019 ), but there are studies in which mechanisms related to, for example, mitochondria have been modeled (Diekman et al., 2013 ; Komin et al., 2015 ). Many of these recent single astrocyte models are multicompartmental representing the whole-cell morphology either as a simple (Cresswell-Clay et al., 2018 ) or detailed (Savtchenko et al., 2018 ) way or representing a part of the cell, such as a branchlet (Denizot et al., 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Analysis of Network Models with Neuron-Astrocyte Interactions

2023

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Neural networks, composed of many neurons and governed by complex interactions between them, are a widely accepted formalism for modeling and exploring global dynamics and emergent properties in brain systems. In the past decades, experimental evidence of computationally relevant neuron-astrocyte interactions, as well as the astrocytic modulation of global neural dynamics, have accumulated. These findings motivated advances in computational glioscience and inspired several models integrating mechanisms of neuron-astrocyte interactions into the standard neural network formalism. These models were developed to study, for example, synchronization, information transfer, synaptic plasticity, and hyperexcitability, as well as classification tasks and hardware implementations. We here focus on network models of at least two neurons interacting bidirectionally with at least two astrocytes that include explicitly modeled astrocytic calcium dynamics. In this study, we analyze the evolution of these models and the biophysical, biochemical, cellular, and network mechanisms used to construct them. Based on our analysis, we propose how to systematically describe and categorize interaction schemes between cells in neuron-astrocyte networks. We additionally study the models in view of the existing experimental data and present future perspectives. Our analysis is an important first step towards understanding astrocytic contribution to brain functions. However, more advances are needed to collect comprehensive data about astrocyte morphology and physiology in vivo and to better integrate them in data-driven computational models. Broadening the discussion about theoretical approaches and expanding the computational tools is necessary to better understand astrocytes’ roles in brain functions.

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Section: Discussionmentioning

confidence: 99%

Analysis of Network Models with Neuron-Astrocyte Interactions

2023

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“…Actually, Denizot et al have proposed a model with realistic 3D geometries of fine processes after their super-resolution investigation (Arizono et al, 2020;Denizot et al, 2022). They designed an isolated section of fine process with five identical nodes connected by four identical shafts.…”

Section: Discussionmentioning

confidence: 99%

“…We directly simulated this stochastic dynamics by a two-state Markov process, adapted from Li-Rinzel (Shuai and Jung, 2002). [Figure 1A adapted from (Arizono et al, 2020) and (Denizot et al, 2022)].…”

Section: Ca 2+ Dynamics In Nodesmentioning

confidence: 99%

“…Denizot et al used a stochastic spatially explicit individual-based strategy and proposed an IP 3 R-mediated Ca 2+ signaling model for dynamics in fine processes (Denizot et al, 2019). Subsequently, they modelled node-shaft geometries of the gliapil by designing an isolated fine process containing five identical nodes and four identical shafts based on their super-resolution study (Denizot et al, 2022). Verisokin et al flattened astrocyte images used as spatial templates to reduce the 3D of realistic astrocytes to 2D allowing for smaller computational costs than Savtchenko et al (2018), Verisokin et al (2021).…”

Section: Introductionmentioning

confidence: 99%

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Probing microdomain Ca2+ activity and synaptic transmission with a node-based tripartite synapse model

Liu

Gao

et al. 2023

Front. Netw. Physiol.

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Astrocytic fine processes are the most minor structures of astrocytes but host much of the Ca2+ activity. These localized Ca2+ signals spatially restricted to microdomains are crucial for information processing and synaptic transmission. However, the mechanistic link between astrocytic nanoscale processes and microdomain Ca2+ activity remains hazily understood because of the technical difficulties in accessing this structurally unresolved region. In this study, we used computational models to disentangle the intricate relations of morphology and local Ca2+ dynamics involved in astrocytic fine processes. We aimed to answer: 1) how nano-morphology affects local Ca2+ activity and synaptic transmission, 2) and how fine processes affect Ca2+ activity of large process they connect. To address these issues, we undertook the following two computational modeling: 1) we integrated the in vivo astrocyte morphological data from a recent study performed with super-resolution microscopy that discriminates sub-compartments of various shapes, referred to as nodes and shafts to a classic IP3R-mediated Ca2+ signaling framework describing the intracellular Ca2+ dynamics, 2) we proposed a node-based tripartite synapse model linking with astrocytic morphology to predict the effect of structural deficits of astrocytes on synaptic transmission. Extensive simulations provided us with several biological insights: 1) the width of nodes and shafts could strongly influence the spatiotemporal variability of Ca2+ signals properties but what indeed determined the Ca2+ activity was the width ratio between nodes and shafts, 2) the connectivity of nodes to larger processes markedly shaped the Ca2+ signal of the parent process rather than nodes morphology itself, 3) the morphological changes of astrocytic part might potentially induce the abnormality of synaptic transmission by affecting the level of glutamate at tripartite synapses. Taken together, this comprehensive model which integrated theoretical computation and in vivo morphological data highlights the role of the nanomorphology of astrocytes in signal transmission and its possible mechanisms related to pathological conditions.

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“…Mouse models lacking this receptor have been studied to tackle the physiological relevance of calcium signaling in astrocytes [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. While astrocytes in the IP 3 R2 knockout (KO) model still display calcium activity in the distal processes and leaflets [28][29][30], they lack entirely spontaneous or evoked somatic calcium activity. In contrast, the neuronal activity remains intact [13,17,28], making it an excellent model for exploring calcium-dependent intracellular signaling.…”

Section: Introductionmentioning

confidence: 99%

Astrocytic Foxo1 regulates hippocampal spinogenesis and synaptic plasticity to enhance fear memory

Viana

Guerra‐Gomes

Abreu

et al. 2023

Preprint

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Astrocytes are active players in brain circuits, sensing and responding to neuronal activity, impacting behavior production. Activation of astrocytes triggers intracellular calcium elevations displaying complex spatiotemporal properties. Intracellular calcium activity is thought to underlie synaptic transmission, metabolism, and brain homeostasis modulation. However, the calcium-dependent signaling pathways involved in these processes are poorly understood, representing a critical knowledge gap in this field. To reveal calcium-dependent signaling pathways involved in circuit structure and function, we performed a multi-level analysis of the inositol 1,4,5-triphosphate receptor type 2 knockout (IP3R2 KO) mouse model which lacks somatic calcium elevations specifically in astrocytes. We focused on the hippocampus, a brain region responsible for cognitive function and emotional behaviors. The transcriptomic analysis of hippocampal tissue revealed that the lack of astrocytic somatic calcium causes the differential expression of hundreds of genes. Among these, 76 genes are regulated by the astrocyte-specific Foxo1 transcription factor. This transcription factor is over-expressed in the hippocampal astrocytes of this mouse model and regulates the expression of genes involved in spinogenesis and synaptic coverage. A detailed morphological analysis of hippocampal pyramidal neurons revealed dendrites with a shift to a more immature spine profile. This spine profile shift may underlie previously described a reduction of long-term depression and performance in fear memory tasks observed in this mouse model. Indeed, we confirmed that these mice lacking astrocytic somatic calcium display an enhancement of long-term fear memory. To verify a causal relationship between these structural, synaptic, and behavioral observations, we used a viral approach to induce the over-expression of Foxo1 in hippocampal astrocytes in naive C57BL/6J mice. This viral-driven over-expression of Foxo1 in astrocytes of the stratum radiatum replicated the shift to an immature spine profile in dendrites of pyramidal neurons crossing the territory of these astrocytes and led to a reduction of long-term depression in the same region. Finally, this manipulation was sufficient to enhance long-term fear memory. The detailed characterization of the mouse model lacking astrocytic somatic calcium revealed that astrocytes modulate hippocampal circuit structure and function through Foxo1 signaling to enhance fear memory.

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Control of Ca²⁺ signals by astrocyte nanoscale morphology at tripartite synapses

Cited by 17 publications

References 79 publications

Analysis of Network Models with Neuron-Astrocyte Interactions

Analysis of Network Models with Neuron-Astrocyte Interactions

Probing microdomain Ca2+ activity and synaptic transmission with a node-based tripartite synapse model

Astrocytic Foxo1 regulates hippocampal spinogenesis and synaptic plasticity to enhance fear memory

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Control of Ca2+ signals by astrocyte nanoscale morphology at tripartite synapses

Cited by 17 publications

References 79 publications

Analysis of Network Models with Neuron-Astrocyte Interactions

Analysis of Network Models with Neuron-Astrocyte Interactions

Probing microdomain Ca2+ activity and synaptic transmission with a node-based tripartite synapse model

Astrocytic Foxo1 regulates hippocampal spinogenesis and synaptic plasticity to enhance fear memory

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Control of Ca²⁺ signals by astrocyte nanoscale morphology at tripartite synapses