Learning deficits in cerebellar diseases

Memory disorders form one of the most common neurological diseases. They have a severe impact on the quality of life and the economic burden they impose on society is enormous. Most forms of procedural learning are controlled by the cerebellum and different cerebellar syndromes such as occurring in paraneoplastic cerebellar ataxia (PCA), fragile X syndrome (fX), and various forms of calcium channelopathies (CC-pathies) show different deficits in procedural memory formation. Investigations of mouse models of these diseases indicate that all deficits in cerebellar motor learning can be associated with aberrations in induction of Long-Term Depression (LTD) of the parallel fiber to Purkinje cell synapse. However, pilot experiments show that LTD can be differently affected in that its induction can be reduced or enhanced and that this induction can either be stable or change at a later stage. In addition, our data suggest that LTD can be reversed by Long-Term Potentiation (LTP) and that this reversal mechanism can be differently affected in different cerebellar diseases. We are therefore putting forward the hypothesis that an optimal balance between LTD and LTP is necessary for appropriate procedural learning and that any specific disruption in this process will cause specific deficits in cerebellar motor learning. To identify the specific abnormalities in both LTD and LTP induction as well as the specific behavioral consequences of the diseases mentioned above, we will test the balance between LTD and LTP in Purkinje cell specific mouse models of PCA, fX, and CC-paties, and correlate these outcomes to the behavioral parameters of motor learning. Moreover, to further verify the hypothesis we will also create and test a Purkinje cell specific inducible mouse mutant in which the LTP-pathway, rather than the LTD-pathway, is affected as the initial target. This experiment should allow us to elucidate for the first time the function of postsynaptic LTP at the parallel fiber to Purkinje cell synapse in cerebellar motor coordination. Still, all the forward genetics experiments described above provide strong indications, but by themselves alone they do not provide the unequivocal evidence about the underlying mechanisms of cerebellar motor learning and its related diseases, because they remain correlational experiments. To demonstrate a causal effect, we will also take the reverse approach in that we will investigate the cellular and molecular changes in Purkinje cells during cerebellar learning by visualizing the endocytosis or insertion of GFP-tagged GluR2 receptors in vivo. Although high risk and technically demanding, this experiment could provide the ultimate complementary evidence. Finally, we want to find out which molecular pathways are disrupted in the Purkinje cells of PCA, CC-paties and fX patients. Therefore, we will subject the Purkinje cells of all mouse models described above in both the trained and untrained state to micro-array analysis and mass spectrometry to find out which RNA's and proteins are up- or downregulated. Once we have established these integrative molecular and cell physiological processes underlying deficits in cerebellar motor learning, we should be able to create an integrated molecular and physiological, computational model and design new therapeutic approaches for the future.