title: Fast cerebellar reflex circuitry requires synaptic vesicle priming by munc13-3.
abstract: Munc13-3 is a member of the Munc13 family of synaptic vesicle priming proteins and mainly expressed in cerebellar neurons. Munc13-3 null mutant (Munc13-3 (-/-)) mice show decreased synaptic release probability at parallel fiber to Purkinje cell, granule cell to Golgi cell, and granule cell to basket cell synapses and exhibit a motor learning deficit at highest rotarod speeds. Since we detected Munc13-3 immunoreactivity in the dentate gyrus, as reported here for the first time, and current studies indicated a crucial role for the cerebellum in hippocampus-dependent spatial memory, we systematically investigated Munc13-3 (-/-) mice versus wild-type littermates of both genders with respect to hippocampus-related cognition and a range of basic behaviors, including tests for anxiety, sensory functions, motor performance and balance, sensorimotor gating, social interaction and competence, and repetitive and compulsive behaviors. Neither basic behavior nor hippocampus-dependent cognitive performance, evaluated by Morris water maze, hole board working and reference memory, IntelliCage-based place learning including multiple reversals, and fear conditioning, showed any difference between genotypes. However, consistent with a disturbed cerebellar reflex circuitry, a reliable reduction in the acoustic startle response in both male and female Munc13-3 (-/-) mice was found. To conclude, complete deletion of Munc13-3 leads to a robust decrease in the acoustic startle response. This readout of a fast cerebellar reflex circuitry obviously requires synaptic vesicle priming by Munc13-3 for full functionality, in contrast to other behavioral or cognitive features, where a nearly perfect compensation of Munc13-3 deficiency by related synaptic proteins has to be assumed.
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Pallavi Rao
authors.initials: PR
authors.lastname: Netrakanti
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Cooper
authors.forename: Ekrem
authors.initials: E
authors.lastname: Dere
authors.forename: Giulia
authors.initials: G
authors.lastname: Poggi
authors.forename: Daniela
authors.initials: D
authors.lastname: Winkler
authors.forename: Nils
authors.initials: N
authors.lastname: Brose
authors.forename: Hannelore
authors.initials: H
authors.lastname: Ehrenreich
mesh_terms: D000818:Animals; D001007:Anxiety / Q000523:psychology; D001522:Behavior, Animal / Q000502:physiology*; D002531:Cerebellum / Q000378:metabolism* / Q000502:physiology; D003071:Cognition / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011597:Psychomotor Performance / Q000502:physiology; D013216:Reflex, Startle / Q000502:physiology*; D012919:Social Behavior; D065852:Spatial Memory / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology; D013572:Synaptic Vesicles / Q000378:metabolism*
chemical_list: D009419:Nerve Tissue Proteins; C485550:Unc13c protein, mouse