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

Abstract

Ca2+ signals in astrocytes can trigger the modulation of neuronal activity. Recent developments in Ca2+ imaging and super-resolution microscopy have allowed to characterize the complex morphology of astrocyte branchlets that communicate with neurons and the associated Ca2+ microdomains. Here, we use computational tools to investigate the causal relationship between branchlet morphology and spatio-temporal profile of Ca2+ signals. 3D reticular branchlet geometries were designed, alternating between large (nodes) and thinner cellular compartments (shafts). Simulations confirm experimental observations that a decreased shaft width is associated with a decreased diffusion flux from nodes, enhancing local Ca2+ activity. Upon successive neuronal stimuli, a decreased shaft width facilitates signal propagation in astrocyte branchlets. We further identify parameters that decrease local Ca2+ activity, such as a discontinuous ER geometry and an increased Ca2+ buffering. Overall, this study proposes key parameters that regulate Ca2+ activity locally, potentially favoring neuron-astrocyte communication at tripartite synapses.

The endoplasmic reticulum in perisynaptic astrocytic processes: shape, distribution and effect on calcium activity

“…Importantly, our results nuance the effect of the clustering of Ca 2+ channels, which is stronger in 2D or simple 3D shapes than in more realistic 3D meshes. This is crucial as, until now, modeling studies on PAPs were conducted in 1D, 2D or in simple 3D shapes, notably cylinders [47, 24, 13, 20, 22, 32]. The 3D meshes provided by this study, together with our realistic 3D PAP mesh generator, pave the way for future modeling studies in realistic 3D meshes to investigate the mechanisms governing neuron-astrocyte communication at tripartite synapses.…”

Reinforcing Interdisciplinary Collaborations to Unravel the Astrocyte “Calcium Code”

“…Lastly, computational models are useful to go beyond correlational observations and to propose mechanistic principles that explain experimentally observed data. For example, models have shown the effect of cellular morphology on the compartmentalization of calcium signals in dendritic spines (Bell et al 2019;Biess et al 2011;Santamaria et al 2011;Yasuda 2017) as well as in astrocyte processes (Denizot et al 2022).…”

Experimental and computational analysis of calcium dynamics in 22q11.2 deletion model astrocytes

“…Calcium signaling in astrocytes has been linked to regulation of synaptic transmission (e.g., Arizono et al, 2020;Denizot et al, 2021;Ishibashi et al, 2019), neurodegeneration (Lattke et al, 2017;Li et al, 2018), neuroimmunological response (Ouali Alami et al, 2018), inflammation (Robb et al, 2020), and brain energy metabolism (Jha and Morrison, 2018;Maly et al, 2021;Takahashi, 2020). The contribution of astrocytes to the maintenance of adaptive levels of brain metabolism, in particular, breaks down in a number of major psychiatric disorders.…”