Syt-12 (green) on synaptic vesicles increases spontaneous release of neurotransmitters.

On page 113, Maximov et al. show that a calcium-independent synaptotagmin (syt) enhances the spontaneous release of neurotransmitters. By linking to another syt that does respond to calcium, the calcium-independent syt might also alter evoked neurotransmitter release.

There are many synaptotagmins, but only syt-1 and syt-2 have a well-defined function, which is to trigger the release of neurotransmitters in response to calcium. Syt-12 does not bind to calcium, yet the authors found it is still localized to synaptic vesicles.

To understand its function, the authors expressed syt-12 in cultured neurons, which did not make their own endogenous version. The presence of syt-12 increased the spontaneous release of neurotransmitter in these neurons.

The function of spontaneous release is controversial: some neuroscientists believe these release events are physiologically important for neuronal structure and function, whereas others argue that they are only a meaningless byproduct of a system that is poised to fuse many vesicles so quickly. Future syt-12 studies might address this debate.

Spontaneous release might not be syt-12's only trick, however. In synaptic vesicle fractions, syt-12 interacted with syt-1, the calcium-responsive release trigger. Syt-1 must partner with SNAREs for evoked release, but this interaction was precluded by the syt-12 association.

The authors found that calcium-evoked release worked just fine in cultured neurons in the presence of syt-12, but they note that acute and long-term changes in synaptic strength, known as plasticity, cannot be studied in this system. An animal knockout should be a better model.

Syt-12 is phosphorylated by PKA, which is necessary for plasticity, but PKA's plasticity-related targets have not been identified. Given its location, Syt-12 is a promising candidate. Its late expression in mice, only after birth, also coincides well with the onset of synaptic maturation and plasticity.