Redundant functions of RIM1a and RIM2a in Ca2þ-triggered neurotransmitter release

a-RIMs (RIM1a and RIM2a) are multidomain active zone proteins of presynaptic terminals. a-RIMs bind to Rab3 on synaptic vesicles and to Munc13 on the active zone via their N-terminal region, and interact with other synaptic proteins via their central and C-terminal regions. Although RIM1a has been well characterized, nothing is known about the function of RIM2a. We now show that RIM1a and RIM2a are expressed in overlapping but distinct patterns throughout the brain. To examine and compare their functions, we generated knockout mice lacking RIM2a, and crossed them with previously produced RIM1a knockout mice. We found that deletion of either RIM1a or RIM2a is not lethal, but ablation of both a-RIMs causes postnatal death. This lethality is not due to a loss of synapse structure or a developmental change, but to a defect in neurotransmitter release. Synapses without a-RIMs still contain active zones and release neuro-transmitters, but are unable to mediate normal Ca2þ-trig-gered release. Our data thus demonstrate that a-RIMs are not essential for synapse formation or synaptic exocytosis, but are required for normal Ca2þ-triggering of exocytosis