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The Journal of Neuroscience, January 1, 2001, 21(1):10-17
The Cerebellum-Specific Munc13 Isoform Munc13-3 Regulates Cerebellar Synaptic Transmission and Motor Learning in Mice
Iris Augustin1, Stefan Korte2, 3, Michael Rickmann4, Hans A. Kretzschmar2, 3, Thomas C. Südhof5, Jochen W. Herms2, 3, and Nils Brose1 1 AG Molekulare Neurobiologie, Max-Planck-Institut für experimentelle Medizin, D-37075 Göttingen, Germany, 2 Institut für Neuropathologie, Georg-August-Universität Göttingen, D-37075 Göttingen, Germany, 3 Institut für Neuropathologie, Ludwig-Maximilians-Universität München, D-81377 München, Germany, 4 Zentrum Anatomie, Abteilung Neuroanatomie, Georg-August-Universität Göttingen, D-37075 Göttingen, Germany, and 5 Center for Basic Neuroscience, Department of Molecular Genetics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75235
Munc13 proteins form a family of three, primarily brain-specific phorbol ester receptors (Munc13-1/2/3) in mammals. Munc13-1 is a component of presynaptic active zones in which it acts as an essential synaptic vesicle priming protein. In contrast to Munc13-1, which is present in most neurons throughout the rat and mouse CNS, Munc13-3 is almost exclusively expressed in the cerebellum. Munc13-3 mRNA is present in granule and Purkinje cells but absent from glia cells. Munc13-3 protein is localized to the synaptic neuropil of the cerebellar molecular layer but is not found in Purkinje cell dendrites, suggesting that Munc13-3, like Munc13-1, is a presynaptic protein at parallel fiber-Purkinje cell synapses. To examine the role of Munc13-3 in cerebellar physiology, we generated Munc13-3-deficient mutant mice. Munc13-3 deletion mutants exhibit increased paired-pulse facilitation at parallel fiber-Purkinje cell synapses. In addition, mutant mice display normal spontaneous motor activity but have an impaired ability to learn complex motor tasks. Our data demonstrate that Munc13-3 regulates synaptic transmission at parallel fiber-Purkinje cell synapses. We propose that Munc13-3 acts at a similar step of the synaptic vesicle cycle as does Munc13-1, albeit with less efficiency. In view of the present data and the well established vesicle priming function of Munc13-1, it is likely that Munc13-3-loss leads to a reduction in release probability at parallel fiber-Purkinje cell synapses by interfering with vesicle priming. This, in turn, would lead to increases in paired-pulse facilitation and could contribute to the observed deficit in motor learning.
Key words: exocytosis; secretion; synaptic vesicle; priming; phorbol ester; unc-13
Copyright © 2001 Society for Neuroscience 0270-6474/01/21110-08$05.00/0
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