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UBC Theses and Dissertations

Global neuroprotection of huntingtin in culture and alterations of cortico-striatal connections in Huntington’s disease culture and mouse models Buren, Caodu


Huntington’s disease (HD) is a genetic neurodegenerative disorder caused by expansion of a CAG repeat in exon 1 of the HTT gene, encoding an elongated poly-glutamine repeat in the N-terminal region of the protein huntingtin (mutant huntingtin; mHtt). The average age of onset is 38, and the disease is characterized by psychiatric disorders and cognitive deficits that, in general, gradually develop over 10 years before the overt onset of the disease phenotype – difficulties in movement control. In the past two decades, many studies have focused on cell death that is obvious in mid to late stage of the disease when the overt disease symptoms become irreversible, despite the fact that altered neuronal/synaptic functions may underlie the mood/cognitive disorders that precede a motor diagnosis. In order to uncover the potentially preventable and/or reversible changes in cortico-striatal (C-S) connections in pre- and early stages of HD, we first studied the C-S coculture platform that represents its in vivo counterparts in order to investigate the role of wild-type huntingtin (wtHtt) protein in cell-death and C-S synaptic malfunctions in HD. I found that coculture with low cortical-to-striatal neuronal plating ratio (1:3 plating ratio) is a closer replica of its in vivo origin with slight differences in membrane properties, but with a significant increase in extrasynaptic NMDA receptor portion and a decrease in cell-survival signaling compared with the control (1:1). On the other hand, we found that wtHtt provides neuroprotective effects to striatal, cortical and hippocampal neurons, in a phospho-CREB-independent way in the case of the latter two neuronal types. Finally, using the C-S coculture and acute brain slice to study C-S synapse development and functions, I found that mHtt impairs the connection not only via suppressing striatal dendritic tree development but also by altering excitatory presynaptic vesicle release and recovery of the glutamate pool. In summary, this work is a further proof of HD as synaptopathy, and is a foundation for future research of drug discovery for HD targeting synaptic malfunctions at the pre-symptomatic stage.

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