Doctor of Philosophy, Case Western Reserve University, 2008, Neurosciences

Ca2+ channel β subunits determine the transport and physiological properties of high voltage activated Ca2+ channel complexes, and the poly-glutamination within the C-terminus (CT) of the P/Q-type Ca2+ channel α subunit is linked with Spinocerebellar ataxia type 6 (SCA6). In the first part of this study we analyzed the distribution of the Cavβ subunit family members in hippocampal neurons and correlated their synaptic distribution with their involvement in transmitter release. We found that exogenously expressed Cavβ4b and Cavβ2a subunits distribute in clusters and localize to synapses, while Cavβ1b and Cavβ3 are homogenously distributed. According to their localization Cavβ2a and 4b subunits modulate the synaptic plasticity of autaptic hippocampal neurons, i.e. Cavβ2a induces depression, while Cavβ4b induces paired-pulse facilitation followed by synaptic depression during longer stimuli trains. The induction of paired-pulse facilitation by Cavβ4b is correlated with a reduction in the release probability and cooperativity of the transmitter release. These results suggest that Cavβ subunits determine the gating properties of the presynaptic Ca2+ channels within the presynaptic terminal in a subunit specific manner and may be involved in the organization of the Ca2+ channel relative to the release machinery. We also examined whether the poly-glutamination of P/Q-type channel CT can increase the channel stability and induce a gradual accumulation of a CT degradation product. We demonstrated that the poly-glutaminated CT degradation product distributes in cytoplasmic aggregates in cultured neurons as found in SCA6 patients and has drastic physiological effects on synaptic function and synapse assembly. Our results show that the CTs induce a change in the Ca2+ dependence of transmitter release correlated with a reduced vesicular release probability, which causes synaptic depression during repetitive high frequency stimulations. The CT containing the SCA6 mutation also ca (open full item for complete abstract)

Committee: Stefan Herlitze (Advisor) Subjects: Biology, Neuroscience