How to maintain active zone integrity during high-frequency transmission

In the central nervous system, the frequency at which reliable synaptic transmission can be maintained varies strongly between different types of synapses. Several pre- and postsynaptic processes must interact to enable high-frequency synaptic transmission. One of the mechanistically most challenging issues arises during repetitive neurotransmitter release, when synaptic vesicles fuse in rapid sequence with the presynaptic plasma membrane within the active zone (AZ), potentially interfering with the structural integrity of the AZ itself. Here we summarize potential mechanisms that help to maintain AZ integrity, including arrangement and mobility of release sites, calcium channel mobility, as well as release site clearance via lateral diffusion of vesicular proteins and via endocytotic membrane retrieval. We discuss how different types of synapses use these strategies to maintain high-frequency synaptic transmission.