CAPS-1 promotes fusion competence of stationary dense-core vesicles in presynaptic terminals of mammalian neurons

Our ability to think and act is due to the remarkable capacity of the brain to process complex information. This involves nerve cells (or neurons) communicating with each other in a rapid and precise manner by releasing synaptic vesicles containing neurotransmitters across the gaps—called synapses—between neurons. In addition to this fast neurotransmitter signalling, neurons can transmit signals by releasing chemical signals called neuropeptides. Neuropeptides are major regulators of human brain function, including mood, anxiety, and social interactions. Neuropeptides and other neuromodulators such as serotonin and dopamine are normally packaged into bubble-like compartments called dense-core vesicles. Compared to synaptic vesicles we know much less about how dense-core vesicles are trafficked and released. Dense-core vesicles are generally mobile and move around the inside of cells to release neuropeptides where and when they are needed. However, some vesicles are stationary and may even be loosely tethered to the cell membrane. Most of the sites where dense-core vesicles can fuse with the cell membrane are at synapses. Previous work has suggested that the protein CAPS-1 is important for moving dense-core vesicles to the correct sites on the cell membrane, and for releasing neuropeptides across the synapses of worms and flies. However, detailed insights into this process in mammalian neurons are lacking. By examining neurons from both normal mice and mice lacking the CAPS-1 protein, Farina et al. have now analyzed the role CAPS-1 plays in releasing neuropeptides. In cells lacking CAPS-1 fewer dense-core vesicles merged with the cell membrane than in cells containing the protein. However, a new technique that tracks the movement of individual vesicles revealed that only stationary dense-core vesicles had difficulties fusing; mobile vesicles continued to fuse with the cell membrane in the normal manner. Introducing CAPS-1 into cells lacking this protein corrected the fusion defect experienced by the stationary vesicles. Farina et al. also showed that CAPS-1 was present at most—but not all—synapses, and synapses that had more CAPS-1 released more neuropeptides. This work shows that CAPS proteins strongly influence the probability of dense-core vesicle release and that neurons can tune this probability at individual synapses by controlling the expression of CAPS. Future work will be aimed at understanding how neurons can achieve this and which protein domains in CAPS are required.