New work from Leal-Ortiz et al. shows how a protein helps neurons fine-tune synapse sensitivity. The protein reduces synapse responsiveness by detaining another protein that holds down neurotransmitter-containing vesicles.

Like paratroopers ready to jump, vesicles line up at a neuron's presynaptic membrane, waiting for an action potential to arrive. Behind this so-called active zone, many more vesicles remain in reserve. Leal-Ortiz et al. wanted to nail down the function of a giant protein called Piccolo, which researchers suspect helps shape the active zone and serves as a scaffold for other proteins.

The team used RNAi to eliminate the protein from cultured neurons. Synapses between the cells formed normally even when Piccolo was absent. But the neurons released neurotransmitter vesicles more readily after stimulation than did cells with Piccolo.

A protein called Synapsin 1a straps reserve vesicles to the cytoskeleton. To move forward to the active zone, the vesicles need to sever their bonds. Piccolo appeared to limit this movement by regulating the mobility of Synapsin 1a. In cells without Piccolo, Synapsin1a was more likely to drift away from the synaptic terminal, allowing the reserve vesicles to break free. How Piccolo keeps Synapsin1a close to the active zone is the next question to be answered, say the authors.

Leal-Ortiz, S., et al.
J. Cell Biol.