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

Purkinje cells (PCs), the sole output neurons of the cerebellar cortex, are crucial for cerebellum-dependent motor learning. In cerebellar ataxia, reduction in motor function and learning associates with decreased spontaneous activity of PCs. Thus, understanding what molecules regulate PCs activity is important. Previously, we demonstrated that a ubiquitous 2-fold increase of endogenous glial cell line-derived neurotrophic factor (GDNF) improves motor function in adult mice and motor learning and coordination in aged mice. However, since GDNF impacts many organ systems the underlying mechanism remained elusive. Here we utilize GDNF Hypermorphic, conditional GDNF Hypermorphic and conditional knock-out mouse models to reveal that up to a 2-fold increase in endogenous GDNF, specifically in PCs postnatally, is sufficient to enhance motor learning. We find that improved motor learning associates with increased glutamatergic input to PCs and with elevated spontaneous firing rate of PCs, opposite to cerebellar ataxia where reduction in motor function and learning associates with decreased spontaneous activity of PCs. Analysis of the human cerebellum revealed that normal interindividual variation in GDNF expression levels falls in the same variation range as studied in the mouse models, suggesting that interindividual variation in PC GDNF levels may contribute to interindividual variation in PC function. Collectively, our findings reveal how a relatively small change in postnatal GDNF expression level within the physiological range in one cell type, the PCs, affects motor learning. Thus, drugs enhancing postnatal GDNF expression in PCs or cerebellar GDNF signaling may have potential in treating cerebellar ataxias, making an interesting topic for future studies.