RIM-BPs Mediate Tight Coupling of Action Potentials to Ca2+-Triggered Neurotransmitter Release

Ultrafast neurotransmitter release requires tight colocalization of voltage-gated Ca2+ channels with primed, release-ready synaptic vesicles at the presynaptic active zone. RIM-binding proteins (RIM-BPs) are multidomain active zone proteins that bind to RIMs and to Ca2+ channels. In Drosophila, deletion of RIM-BPs dramatically reduces neurotransmitter release, but little is known about RIM-BP function in mammalian synapses. Here, we generated double conditional knockout mice for RIM-BP1 and RIM-BP2, and analyzed RIM-BP-deficient synapses in cultured hippocampal neurons and the calyx of Held. Surprisingly, we find that in murine synapses, RIM-BPs are not essential for neurotransmitter release as such, but are selectively required for high-fidelity coupling of action potential-induced Ca2+ influx to Ca2+-stimulated synaptic vesicle exocytosis. Deletion of RIM-BPs decelerated action-potential-triggered neurotransmitter release and rendered it unreliable, thereby impairing the fidelity of synaptic transmission. Thus, RIM-BPs ensure optimal organization of the machinery for fast release in mammalian synapses without being a central component of the machinery itself. •RIM-BPs are required for normal mouse survival, but not for synapse structure•RIM-BPs tighten the trial-to-trial variability of evoked neurotransmitter release•RIM-BP deletion increases the sensitivity of release to slow calcium chelators•RIM-BPs regulate the fidelity of synaptic transmission at central synapses Acuna et al. show that active zone proteins called RIM-BPs are not essential for neurotransmitter release as such, but are required for tight coupling of presynaptic Ca2+ channels to the release machinery. As a result, deletion of RIM-BPs impairs the reliability and fidelity of synaptic transmission in response to action potentials.