Abstract
Neuronal firing and neuron-to-neuron synaptic wiring are currently widely described as orchestrated by astrocytes—elaborately ramified glial cells tiling the cortical and hippocampal space into non-overlapping domains, each covering hundreds of individual dendrites and hundreds thousands synapses. A key component to astrocytic signaling is the dynamics of cytosolic Ca2+ which displays multiscale spatiotemporal patterns from short confined elemental Ca2+ events (puffs) to Ca2+ waves expanding through many cells. Here, we synthesize the current understanding of astrocyte morphology, coupling local synaptic activity to astrocytic Ca2+ in perisynaptic astrocytic processes and morphology-defined mechanisms of Ca2+ regulation in a distributed model. To this end, we build simplified realistic data-driven spatial network templates and compile model equations as defined by local cell morphology. The input to the model is spatially uncorrelated stochastic synaptic activity. The proposed modeling approach is validated by statistics of simulated Ca2+ transients at a single cell level. In multicellular templates we observe regular sequences of cell entrainment in Ca2+ waves, as a result of interplay between stochastic input and morphology variability between individual astrocytes. Our approach adds spatial dimension to the existing astrocyte models by employment of realistic morphology while retaining enough flexibility and scalability to be embedded in multiscale heterocellular models of neural tissue. We conclude that the proposed approach provides a useful description of neuron-driven Ca2+-activity in the astrocyte syncytium.
Highlights
Astrocytes of the cortical and hippocampal gray matter are important actors in a number of information processing processes, including synaptic plasticity, long-term potentiation, and synchronization of neuronal firing (Haydon, 2001; Lee et al, 2014; De Pitta et al, 2016; Poskanzer and Yuste, 2016) as well as in coupling neuronal activity to blood flow changes (Otsu et al, 2015)
To test for agreement between model behavior and the experimentally observed dynamics, first, we looked at the effect of the level of mean neuronal firing rate on spatio-temporal dynamics of astrocytic calcium, and second, we tested whether the artificial spatial templates could provide for realistic intercellular calcium waves or other collective variants of astrocytic calcium dynamics
We proposed a spatially detailed model of astrocytic calcium activity, which reflects current understanding of the two distinct mechanisms of Ca2+ dynamics: excitable IP3-mediated exchange with ER in astrocyte soma and branches and plasma membrane exchange in the fine astrocytic processes and leaflets, sensitive to external conditions
Summary
Astrocytes of the cortical and hippocampal gray matter are important actors in a number of information processing processes, including synaptic plasticity, long-term potentiation, and synchronization of neuronal firing (Haydon, 2001; Lee et al, 2014; De Pitta et al, 2016; Poskanzer and Yuste, 2016) as well as in coupling neuronal activity to blood flow changes (Otsu et al, 2015). It is important to note that many of the mentioned astrocyte functions are not directly related to neural activity, but are governed by their own regulatory pathways (O’Donnell et al, 2015). Some of these functions are tightly linked to dynamic regulation of astrocyte morphology and volume and depend, for example, on the circadian rhythm of aquaporin expression (Hablitz et al, 2020). This frames a new mindset for understanding the function of astrocytes and at the same time poses a challenge for modeling studies. This problem breaks down into three specific tasks: (i) to provide tractable, but still biologically reasonable mathematical account for contribution of subcellular morphological features to intracellular calcium dynamics; (ii) to further develop approaches to modeling of Ca2+ dynamics on data-driven irregular structures, both for an individual cell and for a network; (iii) to reveal how realistic morphological features are manifested in the spatiotemporal patterns of the calcium dynamics
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