Microdomain [Ca²⁺] Fluctuations Alter Temporal Dynamics in Models of Ca²⁺-Dependent Signaling Cascades and Synaptic Vesicle Release

Ca²⁺-dependent signaling is often localized in spatially restricted microdomains and may involve only 1 to 100 Ca²⁺ ions. Fluctuations in the microdomain Ca²⁺ concentration (Ca²⁺) can arise from a wide range of elementary processes, including diffusion, Ca²⁺ influx, and association/dissociation with Ca²⁺ binding proteins or buffers. However, it is unclear to what extent these fluctuations alter Ca²⁺-dependent signaling. We construct Markov models of a general Ca²⁺-dependent signaling cascade and Ca²⁺-triggered synaptic vesicle release. We compare the hitting (release) time distribution and statistics for models that account for [Ca²⁺] fluctuations with the corresponding models that neglect these fluctuations. In general, when Ca²⁺ fluctuations are much faster than the characteristic time for the signaling event, the hitting time distributions and statistics for the models with and without Ca²⁺ fluctuation are similar. However, when the timescale of Ca²⁺ fluctuations is on the same order as the signaling cascade or slower, the hitting time mean and variability are typically increased, in particular when the average number of microdomain Ca²⁺ ions is small, a consequence of a long-tailed hitting time distribution. In a model of Ca²⁺-triggered synaptic vesicle release, we demonstrate the conditions for which [Ca²⁺] fluctuations do and do not alter the distribution, mean, and variability of release timing. We find that both the release time mean and variability can be increased, demonstrating that Ca²⁺ fluctuations are an important aspect of microdomain Ca²⁺ signaling and further suggesting that Ca²⁺ fluctuations in the presynaptic terminal may contribute to variability in synaptic vesicle release and thus variability in neuronal spiking.