Abstract

At a synapse, presynaptic terminals form a specialized area of the plasma membrane called the active zone that mediates neurotransmitter release. RIM1 alpha is a multidomain protein that constitutes a central component of the active zone by binding to other active zone proteins such as Munc13s, alpha-liprins, and ELKS, and to synaptic vesicle proteins such as Rab3 and synaptotagmin-1. In mice, knockout of RIM1 alpha significantly impairs synaptic vesicle priming and presynaptic long-term plasticity, but is not lethal. We now find that the RIM1 gene encodes a second, previously unknown RIM1 isoform called RIM1 beta that is upregulated in RIM1 alpha knock-out mice. RIM1 beta is identical to RIM1 alpha except for the N terminus where RIM1 beta lacks the N-terminal Rab3-binding sequence of RIM1 alpha. Using newly generated knock-out mice lacking both RIM1 alpha and RIM1 beta, we demonstrate that different from the deletion of only RIM1 alpha, deletion of both RIM1 alpha and RIM1 beta severely impairs mouse survival. Electrophysiological analyses show that the RIM1 alpha beta deletion abolishes long-term presynaptic plasticity, as does RIM1 alpha deletion alone. In contrast, the impairment in synaptic strength and short-term synaptic plasticity that is caused by the RIM1 alpha deletion is aggravated by the deletion of both RIM1 alpha and RIM1 beta. Thus, our data indicate that the RIM1 gene encodes two different isoforms that perform overlapping but distinct functions in neurotransmitter release.