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RIM1α forms a protein scaffold for regulating neurotransmitter release at the active zone

Nature volume 415, pages 321–326 (2002)Cite this article

Abstract

Neurotransmitters are released by synaptic vesicle fusion at the active zone1,2. The active zone of a synapse mediates Ca2+-triggered neurotransmitter release, and integrates presynaptic signals in regulating this release. Much is known about the structure of active zones and synaptic vesicles, but the functional relation between their components is poorly understood3. Here we show that RIM1α, an active zone protein that was identified as a putative effector for the synaptic vesicle protein Rab3A4,5, interacts with several active zone molecules, including Munc13-1 (ref. 6) and α-liprins7,8, to form a protein scaffold in the presynaptic nerve terminal. Abolishing the expression of RIM1α in mice shows that RIM1α is essential for maintaining normal probability of neurotransmitter release, and for regulating release during short-term synaptic plasticity. These data indicate that RIM1α has a central function in integrating active zone proteins and synaptic vesicles into a molecular scaffold that controls neurotransmitter release.

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Figure 1: Generation and protein analysis of RIM1α knockout mice.
Figure 2: Excitatory and inhibitory synaptic responses to paired-pulse stimulation in mutant mice.
Figure 3: Synaptic plasticity in RIM1α and Rab3A knockout mice.
Figure 4: Synaptic efficacy and release probability at Schaffer collateral/CA1 pyramidal cell synapses in RIM1α and Rab3A knockout mice.
Figure 5: Biochemical definition of RIM1α as a synaptic scaffolding protein.

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Acknowledgements

We thank H. Riedesel for help with the RIM1α knockout mice; R. Jahn and N. Brose for antibodies; and N. Brose, Y. Jin and M. Nonet for discussing results before publication. We are grateful to I. Leznicki, A. Roth and E. Borowicz for technical assistance. This study was supported by a fellowship to S.S. from the Deutscher Akademische Austauschdienst and grants from the NIH (R.C.M).

Author information

Author notes

  1. Martin Geppert

    Present address: Genomics Sciences, Pharmacia Corporation, Kalamazoo, Michigan, 49007, USA

  2. Frank Schmitz

    Present address: Leibniz Institut für Neurobiologie, 39118, Magdeburg, Germany

  3. Susanne Schoch, Pablo E. Castillo, Tobias Jo and Martin Geppert: These authors contributed equally to this work

Authors and Affiliations

  1. The Center for Basic Neuroscience and Department of Molecular Genetics, Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, 75390-9111, Texas, USA

    Susanne Schoch, Konark Mukherjee, Yun Wang, Frank Schmitz & Thomas C. Südhof

  2. Department of Psychiatry and Behavioral Sciences, Nancy Friend Pritzker Laboratory, Stanford University School of Medicine, Stanford, 94304, California, USA

    Pablo E. Castillo & Robert C. Malenka

  3. Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, 10461, New York, USA

    Pablo E. Castillo

  4. Department of Molecular Neurobiology, Max-Planck-Institut für experimentelle Medizin, Göttingen, 37075, Germany

    Tobias Jo & Martin Geppert

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Correspondence to Thomas C. Südhof.

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Schoch, S., Castillo, P., Jo, T. et al. RIM1α forms a protein scaffold for regulating neurotransmitter release at the active zone. Nature 415, 321–326 (2002). https://doi.org/10.1038/415321a

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