Synaptic vesicle reuse and its implications

Presynaptic nerve terminals are exquisite vesicle trafficking machines. Neurotransmission is sustained by constant recycling of a handful of vesicles. Therefore, the rate and the pathway of vesicle trafficking can critically determine synaptic efficacy during activity. However, it is yet unclear whether synaptic vesicle recycling becomes rate limiting on a rapid time scale during physiologically relevant forms of activity in the brain. Several forms of synaptic plasticity arise from persistent alterations in the dynamics of vesicle trafficking in presynaptic terminals. What makes presynaptic forms of plasticity particularly interesting is that they not only increase or decrease the amplitude of synaptic responses but also cause frequency-dependent changes in neurotransmission. In this manner, plasticity can alter the information coding in neural circuits beyond simple scaling of synaptic responses. However, studying the synaptic vesicle cycle beyond exocytosis and endocytosis has been difficult. In the past decade, several methods have been developed to infer vesicles' trajectory during their cycle in the synapse. Nevertheless, several questions remain. A better understanding of the role of synaptic vesicle trafficking in neurotransmission will require novel approaches that either combine existing methods or the development of new methods to trace vesicles during their cycle. Recent evidence suggests that various presynaptic proteins involved in the synaptic function and homeostasis are either mutated or altered in their expression in several neurological and psychiatric disorders. Therefore, elucidation of the mechanisms that underlie the synaptic vesicle cycle may reveal novel therapeutic targets for brain disorders.