Diversity of Evoked Astrocyte Ca²⁺ Dynamics Quantified through Experimental Measurements and Mathematical Modeling

Astrocytes are a major cell type in the mammalian brain. They are not electrically excitable, but generate prominent Ca²⁺ signals related to a wide variety of critical functions. The mechanisms driving these Ca²⁺ events remain incompletely understood. In this study, we integrate Ca²⁺ imaging, quantitative data analysis, and mechanistic computational modeling to study the spatial and temporal heterogeneity of cortical astrocyte Ca²⁺ transients evoked by focal application of ATP in mouse brain slices. Based on experimental results, we tune a single-compartment mathematical model of IP₃-dependent Ca²⁺ responses in astrocytes and use that model to study response heterogeneity. Using information from the experimental data and the underlying bifurcation structure of our mathematical model, we categorize all astrocyte Ca²⁺ responses into four general types based on their temporal characteristics: Single-Peak, Multi-Peak, Plateau, and Long-Lasting responses. We find that the distribution of experimentally-recorded response types depends on the location within an astrocyte, with somatic responses dominated by Single-Peak (SP) responses and large and small processes generating more Multi-Peak responses. On the other hand, response kinetics differ more between cells and trials than with location within a given astrocyte. We use the computational model to elucidate possible sources of Ca²⁺ response variability: (1) temporal dynamics of IP₃, and (2) relative flux rates through Ca²⁺ channels and pumps. Our model also predicts the effects of blocking Ca²⁺ channels/pumps; for example, blocking store-operated Ca²⁺ (SOC) channels in the model eliminates Plateau and Long-Lasting responses (consistent with previous experimental observations). Finally, we propose that observed differences in response type distributions between astrocyte somas and processes can be attributed to systematic differences in IP₃ rise durations and Ca²⁺ flux rates.