A Bayesian approach to modelling heterogeneous calcium responses in cell populations

Calcium responses have been observed as spikes of the whole-cell calcium concentration in numerous cell types and are essential for translating extracellular stimuli into cellular responses. While there are several suggestions for how this encoding is achieved, we still lack a comprehensive theory. To achieve this goal it is necessary to reliably predict the temporal evolution of calcium spike sequences for a given stimulus. Here, we propose a modelling framework that allows us to quantitatively describe the timing of calcium spikes. Using a Bayesian approach, we show that Gaussian processes model calcium spike rates with high fidelity and perform better than standard tools such as peri-stimulus time histograms and kernel smoothing. We employ our modelling concept to analyse calcium spike sequences from dynamically-stimulated HEK293T cells. Under these conditions, different cells often experience diverse stimulus time courses, which is a situation likely to occur in vivo. This single cell variability and the concomitant small number of calcium spikes per cell pose a significant modelling challenge, but we demonstrate that Gaussian processes can successfully describe calcium spike rates in these circumstances. Our results therefore pave the way towards a statistical description of heterogeneous calcium oscillations in a dynamic environment.Author summary: Upon stimulation a large number of cell types respond with transient increases of the intracellular calcium concentration, which often take the form of repetitive spikes. It is therefore believed that calcium spikes play a central role in cellular signal transduction. A critical feature of these calcium spikes is that they occur randomly, which raises the question of how we can predict the timing of calcium spikes. We here show that by using Bayesian ideas and concepts from stochastic processes, we can quantitatively compute the calcium spike rate for a given stimulus. Our analysis also demonstrates that traditional methods for spike rate estimation perform less favourably compared to a Bayesian approach when small numbers of cells are investigated. To test our methodology under conditions that closely mimic those experienced in vivo we challenged cells with agonist concentrations that vary both in space and time. We find that cells that experience similar stimulus profiles are described by similar calcium spike rates. This suggests that calcium spike rates may constitute a quantitative description of whole-cell calcium spiking that reflects both the randomness and the spatiotemporal organisation of the calcium signalling machinery.