Cerebellar Control of Locomotion in Health and Disease

Abstract

Modern neuroscience is paving the way for new insight into cerebellar functions including the control of cognitive, autonomic and emotional processes. Yet, how the cerebellum contributes to complex motor behaviors, such as locomotion, is still only partially understood. Here, we have investigated the contribution of the cerebellum to locomotion from the perspective of studies performed on mutant mouse lines generated through genetic engineering techniques. Specifically, our observations have allowed us to link particular alterations in various cellular process in the cortical cerebellar network with gait impairments of various degrees of severity. Our findings suggest that cerebellar cortical dysfunction, without causing gross structural changes, leads to gait impairments. In this way, interventions that specifically target the output of the network (Purkinje cells) have more deleterious consequences on locomotion than those that directly target the input (granule cells). It is likely that whereas Purkinje cells are crucial for fine-tuning of basic walking patterns, granule cells play a fundamental role in gait adaptability. Moreover, our results are congruent with the idea that different types of plasticity involving various network components act synergistically to ensure optimal control of locomotion. On the other hand, our observations of several mouse models of human diseases that cause cognitive and/or language problems (fragile X syndrome, developmental verbal dyspraxia) suggest that cognitive and motor functions share common neural pathways, or at least depend on each other. Finally, we have shown that the Erasmus Ladder is a useful, reliable and non-invasive tool that can be used to assess the efficacy of pharmacological therapies in mouse models of human diseases.