Nonlinear Gap Junctions Enable Long-Distance Propagation of Pulsating Calcium Waves in Astrocyte Networks

A new paradigm has recently emerged in brain science whereby communications between glial cells and neuron-glia interactions should be considered together with neurons and their networks to understand higher brain functions. In particular, astrocytes, the main type of glial cells in the cortex, have been shown to communicate with neurons and with each other. They are thought to form a gap-junction-coupled syncytium supporting cell-cell communication via propagating Ca2+ waves. An identified mode of propagation is based on cytoplasm-to-cytoplasm transport of inositol trisphosphate (IP3) through gap junctions that locally trigger Ca2+ pulses via IP3-dependent Ca2+-induced Ca2+ release. It is, however, currently unknown whether this intracellular route is able to support the propagation of long-distance regenerative Ca2+ waves or is restricted to short-distance signaling. Furthermore, the influence of the intracellular signaling dynamics on intercellular propagation remains to be understood. In this work, we propose a model of the gap-junctional route for intercellular Ca2+ wave propagation in astrocytes. Our model yields two major predictions. First, we show that long-distance regenerative signaling requires nonlinear coupling in the gap junctions. Second, we show that even with nonlinear gap junctions, long-distance regenerative signaling is favored when the internal Ca2+ dynamics implements frequency modulation-encoding oscillations with pulsating dynamics, while amplitude modulation-encoding dynamics tends to restrict the propagation range. As a result, spatially heterogeneous molecular properties and/or weak couplings are shown to give rise to rich spatiotemporal dynamics that support complex propagation behaviors. These results shed new light on the mechanisms implicated in the propagation of Ca2+ waves across astrocytes and the precise conditions under which glial cells may participate in information processing in the brain.Author Summary: In recent years, the focus of Cellular Neuroscience has progressively stopped only being on neurons but started to include glial cells as well. Indeed, astrocytes, the main type of glial cells in the cortex, dynamically modulate neuron excitability and control the flow of information across synapses. Moreover, astrocytes have been shown to communicate with each other over long distances using calcium waves. These waves spread from cell to cell via molecular gates called gap junctions, which connect neighboring astrocytes. In this work, we used a computer model to question what biophysical mechanisms could support long-distance propagation of Ca2+ wave signaling. The model shows that the coupling function of the gap junction must be non-linear and include a threshold. This prediction is largely unexpected, as gap junctions are classically considered to implement linear functions. Recent experimental observations, however, suggest their operation could actually be more complex, in agreement with our prediction. The model also shows that the distance traveled by waves depends on characteristics of the internal astrocyte dynamics. In particular, long-distance propagation is facilitated when internal calcium oscillations are in their frequency-modulation encoding mode and are pulsating. Hence, this work provides testable experimental predictions to decipher long-distance communication between astrocytes.