How to Make an Active Zone: Unexpected Universal Functional Redundancy between RIMs and RIM-BPs

• RIM and RBP active zone proteins exhibit universal redundancy at synapses
• Combined, but not individual, RIM and RBP deletion blocks synaptic vesicle priming
• RIM/RBP-deficient synapses lack tethered vesicles and localized Ca2+ channels
• Presynaptic combined RIM/RBP deletion impairs postsynaptic density organization

SummaryRIMs and RIM-binding proteins (RBPs) are evolutionary conserved multidomain proteins of presynaptic active zones that are known to recruit Ca2+ channels; in addition, RIMs perform well-recognized functions in tethering and priming synaptic vesicles for exocytosis. However, deletions of RIMs or RBPs in mice cause only partial impairments in various active zone functions and have no effect on active zone structure, as visualized by electron micrographs, suggesting that their contribution to active zone functions is limited. Here, we show in synapses of the calyx of Held in vivo and hippocampal neurons in culture that combined, but not individual, deletions of RIMs and RBPs eliminate tethering and priming of synaptic vesicles, deplete presynaptic Ca2+ channels, and ablate active zone complexes, as analyzed by electron microscopy of chemically fixed synapses. Thus, RBPs perform unexpectedly broad roles at the active zone that together with those of RIMs are essential for all active zone functions.