Molecular Regulation of Synaptic Release

Abstract

The Synaptic Vesicle Cycle Governs the Release of Neurotransmitter. Synaptic transmission at chemical synapses is mediated by the release of neurotransmitters from presynaptic axonal specializations that either are interspersed along terminal axonal branches or demarcate the end point of axonal arborization (nerve terminals). At these sites, the axonal lumen is enlarged, and the cytoplasmic space is filled with numerous small membrane vesicles, termed synaptic vesicles, that serve as storage organelles for neurotransmitters. When an action potential arrives, presynaptic calcium channels open. The resulting influx of calcium ions triggers exocytosis of synaptic vesicles that, in many fast synapses, are pre-attached to specialized release sites termed active zones. The neurotransmitter then diffuses across the synaptic cleft and alters the ion permeability of the postsynaptic membrane, by activating either the ligand-gated ion channels or receptors linked to second messenger cascades.

After exocytosis, the membrane of synaptic vesicles is retrieved by endocytosis. Although the details of the endocytotic pathway are still debated (see section “Exo-endocytotic Cycling of Synaptic Vesicles”), endocytosis takes place close to the exocytotic sites, and the endocytosed membrane is used to regenerate fresh synaptic vesicles. Exo- and endocytosis are functionally coupled and allow for maintaining a steady state that is capable of adapting to a large dynamic range of activity. After endocytosis, synaptic vesicles are reloaded with neurotransmitter and become competent for another round of exo-endocytotic cycling. Synaptic vesicles are capable of recycling thousands of times, thus endowing the presynaptic compartment with a robust and versatile trafficking pathway capable of keeping up with even high levels of sustained synaptic activity.