Time-coded neurotransmitter release at excitatory and inhibitory synapses

Abstract

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.SM complex | exocytotic-endocytotic cycle | short-term synaptic plasticity | SNARE complex | asynchronous neurotransmitter release M olecular and electrophysiological data have revealed differences in the regulation of presynaptic exocytotic machinery, giving rise to multiple forms of neurotransmitter release: synchronous release promptly after stimulation, delayed asynchronous release, and spontaneous release. Synchronous release is induced by rapid calcium influx and, subsequently, calcium-mediated membrane fusion (1). Asynchronous release occurs only under certain conditions (1, 2). Finally, spontaneous mini-releases occur in the absence of action potentials (2).Two distinct mechanisms have been proposed to explain the various modes of exocytosis. One view suggests distinct signaling pathways and possibly independent vesicle pools (3, 4). The second and more parsimonious view argues that the three modes of release share key mechanisms for exocytosis, specifically, the canonical fusion machinery that operates by means of the interaction between the SNARE attachment protein receptor proteins and Sec1/Munc18 (SM) proteins (5-10) (Fig. 1). The SNARE proteins syntaxin, 25-kDa synaptosome-associated protein (SNAP-25), and vesicleassociated membrane protein (VAMP2; also called synaptobrevin 2), localized on the plasma membrane and the synaptic vesicle, bind to form a tight protein complex, bridging the membranes to fuse.The canonical building block forms a substrate from which the three release modes differentially specialize with additional regulatory mechanisms and specific Ca 2+ sources(s) and sensor(s) that trigger the exocytosis cycle. Calcium sensors for synchronous release have been identified as synaptotagmin (e.g., Syt1, Syt2, Syt9). In contrast, the biomolecular processes generating asynchronous and spontaneous release remain unclear and controversial. However, experiments suggest multiple mechanistically distinct forms of asynchronous release operating at any given synapse, and these forms have...

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