Synaptic vesicles: Turning reluctance into action

Vesicle availability partly determines the efficacy of synaptic communication in the CNS. The authors recently found that some hippocampal glutamate vesicles exhibit reluctance to exocytose during short, high-frequency action potential trains. These same vesicles can be "coaxed" into exocytosis by increased Ca²⁺ entry, by direct depolarization of synaptic terminals, or by challenge with hypertonic sucrose, a tool used to cause fusion of the population of release-ready synaptic vesicles. Interestingly, the authors did not find evidence of reluctance at hippocampal GABA synapses, suggesting that vesicle reluctance might be a negative feedback mechanism to prevent runaway excitation. It is also possible that synapses exhibit reluctance to retain a dormant population of readily accessible vesicles, ready to respond to triggers such as enhanced Ca²⁺ influx or neuromodulators. Recent work from the calyx of Held synapse suggests that reluctance might arise from inactivation of Ca²⁺ channels. The authors review this work, along with several other potential mechanisms of reluctance.