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.