Calcium Buffering in Astrocytes and Its Relevance for Experimental Data Interpretation and Computational Modeling

ABSTRACT Astrocytic Ca 2+ signaling is essential for maintaining physiological brain function, including the modulation of synaptic transmission, neurovascular coupling, and ion homeostasis. However, the spatiotemporal dynamics of astrocytic Ca 2+ activity are highly sensitive to Ca 2+ buffering, which shapes the amplitude, duration, and spread of cytosolic and organellar signals. These buffers include endogenous components such as cytosolic Ca 2+ binding proteins, as well as organelles like the endoplasmic reticulum acting as Ca 2+ stores. Additionally, exogenous buffers are introduced in experiments, including chelators, synthetic dyes, and genetically encoded Ca 2+ indicators. Both types of buffers can profoundly alter experimental observations, making it challenging to accurately interpret Ca 2+ dynamics. Computational modeling offers a powerful approach to separate these effects, enabling systematic exploration of how the buffering capacity of specific system components influences astrocytic intracellular and intercellular signaling. By incorporating experimental data with realistic biophysical buffering parameters, models can make predictions that are difficult to achieve empirically and help identify key parameters that shape astrocytic Ca 2+ physiology. In this review, we discuss how buffering components influence astrocyte Ca 2+ activity and their integration into modeling predictions. Future advances in computational modeling, combined with extensive experimental data, will be crucial for enhancing our understanding of astrocytic Ca 2+ regulation and elucidating its role in health and disease. image