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

Abstract

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.

Keywords: astrocyte; computational model; fine processes; microdomain Ca2+ activity; tripartite synapse.