A Compartmental Model to Investigate Local and Global Ca2+ Dynamics in Astrocytes

Cresswell-Clay, Evan; Crock, Nathan; Tabak, Joël; Erlebacher, Gordon

doi:10.3389/fncom.2018.00094

Cited by 14 publications

(3 citation statements)

References 62 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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“…The same hold true for studying cellular signalling in astrocytes. In this vein, Cresswell-Clay et al proposed a minimal compartmental model for astrocytes that can qualitatively reproduce essential hierarchical features of spatiotemporal Ca 2+ dynamics in astrocytes (Cresswell-Clay et al, 2018). Savtchenko et al systematically incorporated multi-scale, 3D astroglial architecture into a realistic multi-compartmental cell model (Savtchenko et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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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“…Previous computational models have focused on global Ca 2+ signals in astrocytes [43][44][45] and proposed phenomenological models to capture feedback to neurons via gliotransmission at a tripartite synapse [46][47][48]. Recently, studies have also shed light on the microscale mechanisms at fine astrocytic processes [49][50][51][52]. These models have made several valuable predictions on the contribution of astrocytes to brain function.…”

Section: Introductionmentioning

confidence: 99%

Amyloid pathology disrupts gliotransmitter release in astrocytes

Pillai

Nadkarni

2022

PLoS Comput Biol

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Accumulation of amyloid-beta (Aβ) is associated with synaptic dysfunction and destabilization of astrocytic calcium homeostasis. A growing body of evidence support astrocytes as active modulators of synaptic transmission via calcium-mediated gliotransmission. However, the details of mechanisms linking Aβ signaling, astrocytic calcium dynamics, and gliotransmission are not known. We developed a biophysical model that describes calcium signaling and the ensuing gliotransmitter release from a single astrocytic process when stimulated by glutamate release from hippocampal neurons. The model accurately captures the temporal dynamics of microdomain calcium signaling and glutamate release via both kiss-and-run and full-fusion exocytosis. We investigate the roles of two crucial calcium regulating machineries affected by Aβ: plasma-membrane calcium pumps (PMCA) and metabotropic glutamate receptors (mGluRs). When we implemented these Aβ-affected molecular changes in our astrocyte model, it led to an increase in the rate and synchrony of calcium events. Our model also reproduces several previous findings of Aβ associated aberrant calcium activity, such as increased intracellular calcium level and increased spontaneous calcium activity, and synchronous calcium events. The study establishes a causal link between previous observations of hyperactive astrocytes in Alzheimer’s disease (AD) and Aβ-induced modifications in mGluR and PMCA functions. Analogous to neurotransmitter release, gliotransmitter exocytosis closely tracks calcium changes in astrocyte processes, thereby guaranteeing tight control of synaptic signaling by astrocytes. However, the downstream effects of AD-related calcium changes in astrocytes on gliotransmitter release are not known. Our results show that enhanced rate of exocytosis resulting from modified calcium signaling in astrocytes leads to a rapid depletion of docked vesicles that disrupts the crucial temporal correspondence between a calcium event and vesicular release. We propose that the loss of temporal correspondence between calcium events and gliotransmission in astrocytes pathologically alters astrocytic modulation of synaptic transmission in the presence of Aβ accumulation.

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A Compartmental Model to Investigate Local and Global Ca2+ Dynamics in Astrocytes

Cited by 14 publications

References 62 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

Amyloid pathology disrupts gliotransmitter release in astrocytes

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