Release of neurotransmitters from synaptic vesicles is a central event in synaptic transmission. Recent evidence suggests that synaptic vesicles fuse with the plasma membrane by multiple routes during exocytosis, but the regulation and physiological implications of this choice are unclear. At hippocampal synapses, two modes of synaptic vesicle exocytosis can be distinguished by virtue of the rate and extent of loss of a fluorescent lipid marker (FM1-43). Here these two modes of exocytosis were investigated with a combination of electrophysiological recording and fluorescence imaging. It is shown that these exocytic modes result in distinct postsynaptic consequences, such that so-called 'kiss-and-run' exocytosis results in negligible activation of AMPA receptors, compared to the robust postsynaptic responses elicited by apparent full fusion. In contrast NMDA receptors are robustly activated by this form of glutamate delivery. Addition of cyclothiazide, which blocks AMPA receptor desensitization, reveals that the relatively slow rate of release of glutamate during kiss-and-run exocytosis shifts the population of AMPA receptors into a desensitized state, rather than simply being insufficient for receptor activation. These findings provide further support for the existence of a fusion pore mediated mode of exocytosis, and demonstrate that these two exocytic modes directly affect the throughput of synaptic transmission.
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