This Week in The Journal

When an action potential enters a synaptic terminal, voltage-gated calcium channels open, allowing calcium ions to enter and promote synaptic vesicle release. How many vesicles are released depends on the number of release sites and the density and location of calcium channels. If channels are close to release sites, incoming ions quickly bind to vesicle-associated calcium sensors, and relatively few channels must open to trigger release. If channels are farther away, calcium ions have to diffuse farther to reach the sensors, and many ions instead bind to other proteins; thus, more channels must open to trigger vesicle release. In either case, the probability of release may increase during spike trains, when calcium accumulates in the synaptic terminal. This phenomenon, called short-term facilitation, causes neurons to exert greater influence during bursts than during single spikes. Prominent short-term facilitation occurs at synapses between dentate granule cells and CA3 pyramidal cells. Previous work by Chamberland et al. (2014 J Neurosci 34: 11032) indicated that both an increase in the number of release sites and an increase in multivesicular release contribute to this facilitation. They now report that when P/Q-type calcium channels were blocked in mouse hippocampal slices, spike trains no longer increased the number of release sites; trains continued to stimulate multivesicular release, however. Conversely, when N-type channels were blocked, spike trains increased the number of release sites, but did not promote multivesicular release. Imaging revealed that blocking P/Q-type channels made spike-evoked calcium elevation less spatially homogeneous within the presynaptic terminal, whereas blocking N-type channels did not. Finally, comparing the effects of channel blockers and a calcium buffer on short-term facilitation suggested that while N-type channels activate release only at nearby sites, P/Q-type channels activate release at both nearby and more distant sites. These results suggest that Nand P/Qtype channels produce different patterns of calcium elevation in mossy fiber terminals andmakedistinctcontributionstoshort-term facilitation. Specifically, N-type channels cause calcium elevation at discrete locations and trigger multivesicular release during spike trains, whereas P/Q-type channels cause more widespread calcium elevation and allow more release sites to be activated during trains. This distinction may allow the two types of facilitation to be independently regulated by selectively modulating Nor P/Q-channel function.