title: The cerebellum-specific Munc13 isoform Munc13-3 regulates cerebellar synaptic transmission and motor learning in mice.
abstract: 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.
authors.affiliation: AG Molekulare Neurobiologie, Max-Planck-Institut für experimentelle Medizin, D-37075 Göttingen, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Augustin
authors.forename: S
authors.initials: S
authors.lastname: Korte
authors.forename: M
authors.initials: M
authors.lastname: Rickmann
authors.forename: H A
authors.initials: HA
authors.lastname: Kretzschmar
authors.forename: T C
authors.initials: TC
authors.lastname: Südhof
authors.forename: J W
authors.initials: JW
authors.lastname: Herms
authors.forename: N
authors.initials: N
authors.lastname: Brose
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism*; D004558:Electric Stimulation; D005260:Female; D017353:Gene Deletion; D018390:Gene Targeting; D018698:Glutamic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D007858:Learning / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D018408:Patch-Clamp Techniques; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011597:Psychomotor Performance / Q000502:physiology; D011689:Purkinje Cells / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000235:genetics*
chemical_list: D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D020033:Protein Isoforms; D012333:RNA, Messenger; C485550:Unc13c protein, mouse; D018698:Glutamic Acid