Time-coded neurotransmitter release at excitatory and inhibitory synapses

Significance Neurotransmitter exocytosis and short-term synaptic plasticity (STSP) regulate large-scale brain electrical activity. This study is the first, to our knowledge, proposing a multiple-time-scale model that bridges between the microscopic and mesoscopic scales. It is parsimonious, yet with enough descriptive power to express, on the one hand, the interactions between the SNARE and Sec1/Munc18 (SM) protein complexes mediating all forms of neurotransmitter release and STSP and, on the other hand, the electrical activity required for neuronal communication. A key finding is the discovery of a mathematical structure, termed activity-induced transcritical canard, which quantifies and explains delayed and irregular exocytosis. This structure also provides a previously unidentified way to understand delayed and irregular processes sensitive to initial conditions across various biology processes. Communication between neurons at chemical synapses is regulated by hundreds of different proteins that control the release of neurotransmitter that is packaged in vesicles, transported to an active zone, and released when an input spike occurs. Neurotransmitter can also be released asynchronously, that is, after a delay following the spike, or spontaneously in the absence of a stimulus. The mechanisms underlying asynchronous and spontaneous neurotransmitter release remain elusive. Here, we describe a model of the exocytotic cycle of vesicles at excitatory and inhibitory synapses that accounts for all modes of vesicle release as well as short-term synaptic plasticity (STSP). For asynchronous release, the model predicts a delayed inertial protein unbinding associated with the SNARE complex assembly immediately after vesicle priming. Experiments are proposed to test the model’s molecular predictions for differential exocytosis. The simplicity of the model will also facilitate large-scale simulations of neural circuits.

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