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Abstract

Chemical synaptic transmission enables information flow in the brain between neurons. This process critically depends on neurotransmitter release, which is governed by calcium-regulated exocytosis. The speed, efficacy, and reliability of synaptic transmission are critically affected by the spatiotemporal calcium dynamics and the distance that Ca2+ ions travel to reach the vesicular sensor. We hypothesize that variations in the nanoscale organization of VGCCs and synaptic vesicles contribute to the diversity of synaptic function. However, direct experimental observation of this fundamental second messenger system is not currently possible due to its submillisecond timescale and submicron spatial scale. Therefore, we have taken a computational approach to study the spatiotemporal dynamics of Ca2+ -triggered vesicle fusion. In the course of this work, we have adapted classical point process methods and generative models to interpret differences in channel-vesicle topographies in the weak and strong cerebellar synapses. The function impact of inferred arrangements was further explored using Monte Carlo (MC) simulations of calcium dynamics and vesicular fusion, with experimentally constrained parameters. We found that small VGCC clusters with tight coupling distance between calcium channels and vesicle can account for the functional characterises of the strong synapses, while the arrangement where VGCCs are loosely coupled and excluded from the vicinity of the vesicle can reproduce the behaviour of weak synapses. Thus suggesting that nanoscale distribution of VGCCs and synaptic vesicles differs among synapses and is a key factor underlying functional synaptic diversity. Along the way, we have delineated critical factors and parameters for simulations of vesicle release time course and probability. We found that among the critical factors are the stochastic opening of the calcium channels, affinity of fixed endogenous buffer and vesicles sensor, as well as duration of calcium entry. Month-long particle-based simulations motivated our efforts to explore novel analytical methods inspired from mean-field first-passage methods. We have established a probability distribution of a single calcium ion being bound to the sensor. The model was validated using particle based Monte Carlo simulations. Because of the nature of the analytical method we were able to simulate the binding of Ca2+ ions to a sensor between nanoseconds to 100’s milliseconds of diffusion-reaction time. The rapid calculations using the analytical method were much more amenable to parameter searching and understanding how on and off-rate constants of the sensor and competing buffers interacted. These simulations, for example, showed clearly that the off-rate constant of the buffer critically influenced the time course of the sensor occupancy on the microsecond and millisecond time scale for experimental-like parameters, and in turn also define the time course of vesicle fusion. Once we surpass some of the initial hurdles, this novel approach will represent the first analytical-based approach that predicts spatial-temporal profile Ca2+ dynamics and how it drives vesicle fusion. We aspire to use this approach as a building block for a new, efficient diffusion reaction simulator of vesicle release, enhancing precision and accuracy while significantly reducing computational time.

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