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Excitotoxicity and bioenergetics in Huntington's disease transgenic neurons
Carrier, Raeann Lynn

2008, Doctor of Philosophy, Ohio State University, Pharmacy.
Huntington's disease (HD) is a hereditary neurodegenerative disease caused by a polyglutamine expansion (>39 repeats) in the huntingtin protein. HD causes loss of striatal neurons and patients develop progressive chorea, rigidity, and lack of motor coordination. We have cultured forebrain neurons from both the R6/2 transgenic mouse line (expressing an N-terminal fragment of human huntingtin with ~150 glutamines) and the YAC72 line (expressing full-length human huntingtin with 72 glutamines) to study the effect of mutant huntingtin expression on AMPA/kainate receptor-mediated neuronal signaling and cell death. Using a sensitive and selective neuronal cell death assay our lab recently developed, we found that R6/2 neurons, but not YAC72 neurons, are significantly more vulnerable to glutamate and kainate-mediated neuronal death compared to wildtype (WT) control neurons. Since calcium is a key mediator of glutamate receptor-mediated neuronal death, we measured calcium levels in response to kainate. Kainate-induced (30 second) neuronal calcium responses were significantly greater in R6/2 neurons compared to WT neurons; however, this increased sensitivity to kainate was not seen in YAC72 neurons. When we used a low-affinity fluorescent calcium indicator to monitor longer (15 minute) exposures to kainate, we revealed a subset (~20%) of neurons that exhibit very large increases in calcium. However, there were few notable differences between kainate-mediated calcium responses in HD and WT neurons under these recording conditions. Similarly, kainate-induced mitochondrial depolarization and ATP decreases were comparable in HD and WT neurons. Collectively, our results suggest that mutant huntingtin expression in young cultured neurons does not profoundly affect AMPA/kainate receptor mediated signaling. This is in contrast to the reports of robust modulation of NMDA receptor-mediated signaling and death in HD transgenic neurons. While we have focused on the short-term effect (weeks) of mutant huntingtin expression on AMPA/kainate receptor signaling, we do not know the cumulative effect of mutant huntingtin expression on both NMDA and AMPA/kainate receptor-mediated signaling over the decades of disease progression in HD patients. Whether the relatively modest potentiation of AMPA/kainate receptors that we discovered, along with previously reported effects on NMDA receptors, contribute to neuronal dysfunction in HD patients remains to be determined.
Kari Hoyt, PhD (Advisor)
Lane Wallace, PhD (Committee Member)
Lakhu Keshvara, PhD (Committee Member)
Karl Obrietan, PhD (Committee Member)
Peng Wang, PhD (Committee Member)
205 p.

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Carrier, R. (2008). Excitotoxicity and bioenergetics in Huntington's disease transgenic neurons. (Electronic Thesis or Dissertation). Retrieved from https://etd.ohiolink.edu/

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Carrier, Raeann. "Excitotoxicity and bioenergetics in Huntington's disease transgenic neurons." Electronic Thesis or Dissertation. Ohio State University, 2008. OhioLINK Electronic Theses and Dissertations Center. 28 Jul 2015.

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Carrier, Raeann "Excitotoxicity and bioenergetics in Huntington's disease transgenic neurons." Electronic Thesis or Dissertation. Ohio State University, 2008. https://etd.ohiolink.edu/

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