Gq—GPCR stimulated increases in astrocytic calcium, and their role in neurovascular coupling

Abstract

Astrocytes are a type of glial cell in the central nervous system. Astrocytes primarily interface with neurons, through long, thin, branching projections called processes. A large proportion of astrocytes also ensheath blood vessels, through special processes called endfeet. It has been long hypothesised that astrocytes communicate neuronal activation to proximal blood vessels, which respond by increasing blood flow. However, with many experiments presenting vastly different conclusions, the role of astrocytes, in this process, is still under question. Existing mathematical astrocyte models usually model an astrocyte as being spatially homogenous, by describing the concentrations of solutes within a single cytosolic mass. This thesis examines experimental calcium imaging results, and proposes a model which seperate an astrocyte into distinct chambers, to represent morphological and functional characteristics. In doing so, a model is presented to explain the relationship between intracellular calcium and changes in cerebral blood flow. The first model has three chambers: a Process chamber, a Soma chamber, and an Endfoot chamber. Within the three chambers, concentrations of IP3 and arachidonic acid diffuse freely. The concentration of IP3 affects calcium release from IP3 receptors. In the Endfoot chamber, arachidonic acid is metabolised into EETs and 20-HETE. Increases in EETs results in an extracellular calcium influx, and an increase in 20-HETE decreases the outflux of potassium. The second model examines the effect of separating the processes component into multiple smaller chambers. This is to examine the effect of non-synchronised increases of IP3, in the semi-independent mains process branches. This model also examines partial activation of an astrocyte, by activation of a subset of the processes chambers. The change in arachidonic acid metabolites is examined in relation to the concentration of perivascular potassium.