The cerebellum-specific Munc13 isoform Munc13-3 regulates cerebellar synaptic transmission and motor learning in mice

Munc13 proteins form a family of three, primarily brain-specific phorbol es ter receptors (Munc13-1/2/3) in mammals. Munc13-1 is a component of presyna ptic active zones in which it acts as an essential synaptic vesicle priming protein. In contrast to Munc13-1, which is present in most neurons through out 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 abse nt from glia cells. Munc13-3 protein is localized to the synaptic neuropil of the cerebellar molecular layer but is not found in Purkinje cell dendrit es, suggesting that Munc13-3, like Munc13-1, is a presynaptic protein at pa rallel fiber-Purkinje cell synapses. To examine the role of Munc13-3 in cer ebellar physiology, we generated Munc13-3-deficient mutant mice. Munc13-3 d eletion mutants exhibit increased paired-pulse facilitation at parallel fib er-Purkinje cell synapses. In addition, mutant mice display normal spontane ous motor activity but have an impaired ability to learn complex motor task s. Our data demonstrate that Munc13-3 regulates synaptic transmission at pa rallel fiber-Purkinje cell synapses. We propose that Munc13-3 acts at a sim ilar 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 pr iming function of Munc13-1, it is likely that Munc13-3-loss leads to a redu ction in release probability at parallel fiber-Purkinje cell synapses by in terfering with vesicle priming. This, in turn, would lead to increases in p aired-pulse facilitation and could contribute to the observed deficit in mo tor learning.