Motor learning is regulated by GDNF levels in postnatal cerebellar Purkinje cells

Purkinje cells, the sole output neurons of the cerebellar cortex, are crucial for cerebellum-dependent motor learning. Previously we demonstrated that a ubiquitous 2-3-fold increase of endogenous glial cell line-derived neurotrophic factor (GDNF) improves motor learning. However, GDNF impacts many organ systems and cell types throughout the body leaving the underlying mechanism elusive. Here, we utilize an innovative conditional GDNF Hypermorphic mouse model to show that a 2-fold increase in endogenous GDNF specifically in postnatal Purkinje cells (PCs) is sufficient to enhance motor learning in adult animals. We demonstrate that improved motor learning is associated with increased glutamatergic input to PCs and elevated spontaneous firing rate of these cells, opposite to cerebellar ataxia where reduction in motor function and learning associates with decreased spontaneous activity of PCs. Notably, the GDNF expression levels variation range studied in our mouse model’s cerebellum falls within the normal range of variation observed in healthy human cerebellums. Our findings uncover a molecular pathway and a specific cell type that regulate motor learning, potentially explaining some individual differences in human motor skill acquisition.