Modeling predicts a biochemical feedback mechanism underlying astrocyte calcium refractory periods

SUMMARY Astrocytes exhibit intracellular calcium fluctuations in response to neuronal activity. Repeated receptor stimulation can induce a transient suppression of calcium signaling—a refractory period—yet the underlying mechanisms and timescales of this phenomenon during behavior remain poorly understood. Here, we present a biophysically grounded computational model of astrocytic calcium signaling that incorporates a novel feedback mechanism mediated by conventional protein kinase C (cPKC) and predicts the refractory phenomenon. Unlike previous models developed in vitro, our model is directly validated using in vivo two-photon calcium imaging data from behaving mice. It closely recapitulates astrocytic calcium dynamics across both time and frequency domains, including the emergence of refractory periods and their negative correlation with inter-stimulus intervals. Simulations further predict the timing of recovery from refractory states, consistent with experimental observations. This work provides a mechanistic explanation for astrocytic refractory behavior and establishes a framework for integrating computational modeling with in vivo functional imaging.