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Sunday, July 19 • 7:00pm - 8:00pm
P37: A Realistic Spatial Model of the Complete Synaptic Vesicle Cycle

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Andrew Gallimore, Iain Hepburn, Erik De Schutter

The release of neurotransmitters from synaptic vesicles is the fundamental mechanism of information transmission between neurons in the brain. The entire synaptic vesicle cycle involves a highly complex interplay of proteins that direct vesicle docking at the active zone, the detection of intracellular calcium levels, fusion with the presynaptic membrane, and the subsequent retrieval of the vesicle protein material for recycling[1]. Despite its central importance in many aspects of neuronal function, and even though computational models of subcellular neuronal processes are becoming increasingly important in neuroscience research, realistic models of the synaptic vesicular cycle are almost non-existent. This is largely because the modeling tools for detailed spatial modeling of vesicles are not available.

Extending the STEPS simulator[2], we have pioneered spherical ‘vesicle’ objects that occupy a unique excluded volume and sweep a path through the tetrahedral mesh as they diffuse through the cytosol. Our vesicles incorporate endo- and exocytosis, fusion with and budding from intracellular membranes, neurotransmitter packing, as well as interactions between vesicular proteins and cytosolic and plasma membrane proteins. This allows us to model all key aspects of the synaptic vesicle cycle, including docking, priming, calcium detection and vesicle fusion, as well as dynamin-mediated vesicle retrieval and recycling.

Using quantitative measurements of protein copy numbers[3], membrane and cytosolic diffusion rates, protein-protein interactions, and an EM-derived spatial model of a hippocampal pyramidal neuron, we used this technology to construct the complete synaptic vesicle cycle at the Schaffer Collateral–CA1 synapse at an unprecedented level of spatially-realistic and biochemical detail (Fig. 1). We envisage that this new modeling technology will open up pioneering research into all aspects of neural function in which synaptic transmission plays a role.

1\. Sudhof TC. The molecular machinery of neurotransmitter release (Nobel lecture). Angew. Chem. Int. Ed. 2014, 53, 12696-12717 ****

2\. Hepburn I, Chen W, Wils S, De Schutter E. STEPS: efficient simulation of stochastic reaction-diffusion models in realistic morphologies. BMC Syst. Biol. 2012, 6, 36

3\. Wilhelm BG, Mandad S, Truckenbrodt S, et al. Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins. Science. 2014, 344(6187), 1023-1028

Speakers
AG

Andrew Gallimore

Computational Neuroscience Unit, Okinawa Institute of Science and Technology


Sunday July 19, 2020 7:00pm - 8:00pm CEST
Slot 03