Cerebellar granule cell signaling is indispensable for normal motor performance

Within the cerebellar cortex, mossy fibers (MFs) excite granule cells (GCs) that excite Purkinje cells (PCs), which provide outputs to the deep cerebellar nuclei (DCNs). It is well established that PC disruption produces motor deficits such as ataxia. This could arise from either decreases in ongoing PC-DCN inhibition, increases in the variability of PC firing, or disruption of the flow of MF-evoked signals. Remarkably, it is not known whether GCs are essential for normal motor function. Here we address this issue by selectively eliminating calcium channels that mediate transmission (CaV2.1, CaV2.2, and CaV2.3) in a combinatorial manner. We observe profound motor deficits but only when all CaV2 channels are eliminated. In these mice, the baseline rate and variability of PC firing are unaltered, and locomotion-dependent increases in PC firing are eliminated. We conclude that GCs are indispensable for normal motor performance and that disruption of MF-induced signals impairs motor performance. [Display omitted] •Transgenic and viral disruption of granule cell signaling impairs motor performance•CaV2.1, CaV2.2, and CaV2.3 must all be deleted from GCs to impair motor performance•Disrupting GC signaling does not alter cerebellar ultrastructure or PC firing rates•Locomotion-dependent increases in Purkinje cell firing require GC signaling It is well established that the cerebellum is vital for normal motor performance, but whether granule cells are also essential is not known. Lee et al. show that disrupting granule cell signaling causes profound motor deficits, establishing that granule cells are crucial for normal motor performance.