Synchrony and causality in stimulated communicating cell populations*

Cells routinely respond to both input stimuli and communication from neighbors, and it is still poorly understood how these two types of signals are integrated at the population level. In the case of temporal stimuli, the presence of cell-cell communication raises several possibilities: non-communicating cells may exhibit asynchronous responses to the stimulus due to cell-to-cell heterogeneity, whereas strongly communicating cells may exhibit highly synchronized responses to the stimulus. However, at intermediate communication strength it is unclear what temporal patterns may emerge, e.g., due to particularly responsive cells triggering subsequent responses in their neighbors. Here we investigate the relationships between cell-cell communication, synchrony, and causality using a simple excitable-response model to describe experiments performed in monolayers of kisspeptin neurons stimulated by time-varying ATP concentrations. Surprisingly, the model predicts that as cell-cell communication strength is increased, the cell responses first desynchronize before ultimately becoming fully synchronous. This prediction is confirmed by perturbing the degree of communication in the experiments. Our work elucidates the complex interplay between cell-cell communication and synchrony in interacting multicellular systems responding to time-varying signals.