Synaptic vesicle release comes in two sizes: large and small.

Neuroendocrine cells have two modes of exocytosis. In one mode, the vesicle fuses to the target membrane, and in the other—referred to as kiss-and-run—the vesicle touches the membrane and creates a small temporary pore. On page 929, Richards et al. show that the small synaptic vesicles in hippocampal neurons also use both mechanisms. The two modes of exocytosis differ in their kinetics and amplitude of the release, and may generate different postsynaptic responses.

To determine whether neurons have two pathways for exocytosis, the team loaded only a fraction of the synaptic vesicles with a fluorescent dye, a trick that allows them to resolve the activity of individual vesicles. They saw two types of exocytic events occurring: fast large releases of dye and slow small ones. The researchers conclude that the fast release events occur when a vesicle fuses with the plasma membrane, dumping its total dye content at a rate limited only by diffusion. On the other hand, the small release events appear to occur when a vesicle forms only a small pore in the plasma membrane. The speed of dye release in these small events is the same as that which occurs if the researchers use a toxin to poke a 1–2-nm hole in the membrane of a synthetic vesicle.

Richards et al. hypothesize that these different types of synaptic release may have a functional role in neural signaling. For example, it is known that when the vesicles of these hippocampal neurons fuse with the membrane and dump their whole load of neurotransmitter into the synaptic cleft, they excite the postsynaptic neuron. It could be that the dribbling release of neurotransmitter that occurs in the slow small exocytic events instead desensitizes the postsynaptic neuron. The data to confirm this are lacking, but several groups are now trying to figure out how to combine the electrophysiology and fluorescence experiments to find out.