Abstract
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.