In acquired Ca 2+ channelopathies such as paraneoplastic cerebellar degeneration (PCD) and Lambert-Eaton myasthenic syndrome (LEMS), neuronal dysfunction is presumably initiated by the binding of autoantibodies against PQCC at the plasma membrane. Pathogenesis of PCD may include alteration of channel physiology, down-regulation of channel proteins, or immune-mediated processes following antibody binding. Although it is not clear how dysfunction of a channel leads to the ataxic phenotype, the pathogenesis is likely related to altered synaptic physiology, since PQCC is a key player in the pre- and post-synaptic membranes important in synaptic transmission and plasticity. Because it is impossible to study human cerebellar neurotransmission, this grant application proposes the creation of a cellular model of PCD using anti-PQCC antibodies to knockdown channel function. Well-established techniques including electrophysiological recordings and FM1- 43 experiments will be used to determine the mechanisms of anti-PQCC antibody inhibition and to evaluate its effects on activity-dependent Ca 2+ entry, neurotransmitter release, and synaptic physiology at the parallel fiber-Purkinje cell synapse. In particular, repetitive stimulation of the parallel fibers will be used to see if a LEMS-type facilitation of glutamate release may exist in this model of PCD. In addition to the antibody knockdown model, alternative models of PQCC dysfunction, the alpha1A -/- and omega-Agatoxin-IVA-treated cerebella, will be used. The alpha1A -/- and omega-Agatoxin-IVA models exemplify the ultimate loss of channel function, while the antibody knockdown approach most closely resembles an acquired human channelopathy and can be used to dissect the consequences of loss of channel function in real time. Altered pre- and post-synaptic physiology in the cerebellum will likely have complex impacts on synaptic plasticity, cerebellar circuitry, and motor learning because of their dependence on coincident signals from different pathways. The ataxic phenotype in PCD may be the culmination of a multiplicity of errors in neurotransmitter release and in the translation of coincident signal detection by the post-synaptic neurons. ? ?
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