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The Journal of Neuroscience, December 10, 2008, 28(50):13435-13447; doi:10.1523/JNEUROSCI.3235-08.2008

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Cellular/Molecular
RIM1 and RIM1β Are Synthesized from Distinct Promoters of the RIM1 Gene to Mediate Differential But Overlapping Synaptic Functions

Pascal S. Kaeser,^1,3,4 Hyung-Bae Kwon,⁶ Chiayu Q. Chiu,⁶ Lunbin Deng,^1,3,4 Pablo E. Castillo,⁶ and Thomas C. Südhof^1,2,3,4,5

Departments of ¹Neuroscience and ²Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111, ³Institutes of Medicine and ⁴Department of Molecular and Cellular Physiology, Stanford University, Palo Alto, California 94304-5543, ⁵Howard Hughes Medical Institute and ⁶Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461

Correspondence should be addressed to either of the following: Pascal S. Kaeser or Thomas C. Südhof, Institutes of Medicine and Department of Molecular and Cellular Physiology, Stanford University, 1050 Arastradero Road, Palo Alto, CA 94304-5543, Email: pkaeser{at}stanford.edu or Email: tcs1{at}stanford.edu

At a synapse, presynaptic terminals form a specialized area of the plasma membrane called the active zone that mediates neurotransmitter release. RIM1 is a multidomain protein that constitutes a central component of the active zone by binding to other active zone proteins such as Munc13 s, -liprins, and ELKS, and to synaptic vesicle proteins such as Rab3 and synaptotagmin-1. In mice, knockout of RIM1 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 RIM1β that is upregulated in RIM1 knock-out mice. RIM1β is identical to RIM1 except for the N terminus where RIM1β lacks the N-terminal Rab3-binding sequence of RIM1. Using newly generated knock-out mice lacking both RIM1 and RIM1β, we demonstrate that different from the deletion of only RIM1, deletion of both RIM1 and RIM1β severely impairs mouse survival. Electrophysiological analyses show that the RIM1β deletion abolishes long-term presynaptic plasticity, as does RIM1 deletion alone. In contrast, the impairment in synaptic strength and short-term synaptic plasticity that is caused by the RIM1 deletion is aggravated by the deletion of both RIM1 and RIM1β. Thus, our data indicate that the RIM1 gene encodes two different isoforms that perform overlapping but distinct functions in neurotransmitter release.

Key words: RIM; Rab3; Munc13; active zone; synaptic plasticity; neurotransmitter release

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Received July 11, 2008; revised Oct. 15, 2008; accepted Oct. 27, 2008.

Correspondence should be addressed to either of the following: Pascal S. Kaeser or Thomas C. Südhof, Institutes of Medicine and Department of Molecular and Cellular Physiology, Stanford University, 1050 Arastradero Road, Palo Alto, CA 94304-5543, Email: pkaeser{at}stanford.edu or Email: tcs1{at}stanford.edu

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