The aim of the studies described in this thesis was to investigate how abnormal CaV2.1 channel function can cause disease, in particular motor coordination dysfunction. The chapters illustrate how... Show moreThe aim of the studies described in this thesis was to investigate how abnormal CaV2.1 channel function can cause disease, in particular motor coordination dysfunction. The chapters illustrate how various neuronal cell types in the periphery (peripheral nervous system) and the central nervous system are affected by mutations in subunits of CaV2.1 channels. Using existing and newly generated mouse models, the consequences of such mutations were investigated at the molecular, cellular, and systems level so as to unravel pathways involved in motor coordination. Show less
The Guillain-Barr_ syndrome (GBS) is an acute, post-infectious neuropathy. Several clinical presentations are known, but general symptoms are symmetric muscle weakness and loss of tendon reflexes.... Show moreThe Guillain-Barr_ syndrome (GBS) is an acute, post-infectious neuropathy. Several clinical presentations are known, but general symptoms are symmetric muscle weakness and loss of tendon reflexes. In more than half of the GBS patients, antibodies against gangliosides can be detected in their serum. Gangliosides are glycosphingolipids, which are located in the outer layer of cell membranes, and play a role in cell-cell recognition and communication. Because gangliosides are highly enriched in the presynaptic nerve membranes, a role in synaptic transmission and the process of neurotransmitter release is assumed. We explored the physiological role of these gangliosides in transmitter release in neuromuscular synapses of mice using electrophysiological techniques. Furthermore, these synapses were also studied for the pathophysiological effects caused by antibodies against the gangliosides. The results show that gangliosides appear not to be fundamental for neuromuscular function, but rather have a modulating role. In addition, blocking of the complement system, using complement-component C5-inhibitors, is an effective method to protect the nerve membrane against the damaging effects of the activated complement system as a result of anti-ganglioside antibody binding. These and other experimental findings of this thesis are discussed in view of the current literature and the pathogenesis and therapeutical aspects of GBS. Show less
